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1.
Biomater Sci ; 2021 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-33459733

RESUMO

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Sorafenib (sfb) is widely used in clinics for advanced HCC therapy. However, the therapeutic efficacy of sfb is suboptimal due to its poor water solubility, low bioavailability, and side effects. Here, we employed a clinically safe polymer poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) to prepare a nanoparticle (NP)-based sfb formulation (NP-sfb) and tested its antitumor effect in multiple HCC models. NP-sfb could achieve effective drug loading and remain stable under physiological conditions. NP-sfb could be taken up by HepG2, Hepa1-6, and H22 cells and could efficiently inhibit cell proliferation and/or promote cell apoptosis. In vivo studies indicated that NP-sfb showed significantly improved therapeutic efficacy compared with free-sfb at the same dose or even higher doses. Mechanistic studies demonstrated that NP-sfb not only inhibited tumor proliferation and angiogenesis but also stimulated the tumor microenvironment by reducing the infiltration of immunosuppressive myeloid cells and increasing the ratio of cytotoxic T cells. This study demonstrates that the NP-based formulation is a promising strategy to improve the clinical application of sfb.

2.
Environ Res ; 194: 110644, 2020 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-33358876

RESUMO

During anaerobic digestion, methanogenic activities and pathways can be affected by intermediates. Here, the effects of intermediates acetate, propionate, and ethanol on methanogenesis were investigated. Four anaerobic sequencing batch reactors were acclimated with propionate (ASBR_P), ethanol/propionate (ASBR_EP), acetate/propionate (ASBR_AP), and ethanol/acetate/propionate (ASBR_EAP). Ethanol was the easiest one to be biodegraded, thereby enhancing the maximum methane production rate and shortening the lag phase, while the longest acclimation time and lowest methane production rate were observed in ASBR_P. Different microbial communities and syntrophic patterns existed in four reactors. Desulfovibrio and Geobacter were the dominant ethanol-oxidizing bacteria in ASBR_EP and ASBR_EAP, respectively. Both Desulfovibrio and Geobacter possessed the potential of extracellular electron transfer, which might be the advantage of ethanol dosage for enhancing methanogenesis through direct interspecies electron transfer. Methanosarcina was enriched in ASBR_P and ASBR_AP, while Methanosaeta in ASBR_EP and ASBR_EAP. Genes responsible for acetoclastic methanogenesis were significantly enriched in ASBR_EAP, possibly resulting in the highest methanogenic activity from acetate. Results from this study will advance the optimization of practical anaerobic systems, which can be achieved by regulating the intermediates with different fermenting pathways.

3.
Aging (Albany NY) ; 122020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33290255

RESUMO

BACKGROUND: Ischemic stroke is a devastating disease that causes long-term disability. However, its pathogenesis is unclear, and treatments for ischemic stroke are limited. Recent studies indicate that oxidative stress is involved in the pathological progression of ischemic stroke and that angiogenesis participates in recovery from ischemic stroke. Furthermore, previous studies have shown that Coicis Semen has antioxidative and anti-inflammatory effects in a variety of diseases. In the present study, we investigated whether Coicis Semen has a protective effect against ischemic stroke and the mechanism of this protective effect. RESULTS: Coicis Semen administration significantly decreased the infarct volume and mortality and alleviated neurological deficits at 3, 7 and 14 days after MCAO. In addition, cerebral edema at 3 days poststroke was ameliorated by Coicis Semen treatment. DHE staining showed that ROS levels in the vehicle group were increased at 3 days after reperfusion and then gradually declined, but Coicis Semen treatment reduced ROS levels. The levels of GSH and SOD in the brain were increased by Coicis Semen treatment, while MDA levels were reduced. Furthermore, Coicis Semen treatment decreased the extravasation of EB dye in MCAO mouse brains and elevated expression of the tight junction proteins ZO-1 and Occludin. Double immunofluorescence staining and western blot analysis showed that the expression of angiogenesis markers and TGFß pathway-related proteins was increased by Coicis Semen administration. Consistent with the in vivo results, cytotoxicity assays showed that Coicis Semen substantially promoted HUVEC survival following OGD/RX in vitro. Additionally, though LY2109761 inhibited the activation of TGFß signaling in OGD/RX model animals, Coicis Semen cotreatment markedly reversed the downregulation of TGFß pathway-related proteins and increased VEGF levels. METHODS: Adult male wild-type C57BL/6J mice were used to develop a middle cerebral artery occlusion (MCAO) stroke model. Infarct size, neurological deficits and behavior were evaluated on days 3, 7 and 14 after staining. In addition, changes in superoxide dismutase (SOD), GSH and malondialdehyde (MDA) levels were detected with a commercial kit. Blood-brain barrier (BBB) permeability was assessed with Evans blue (EB) dye. Western blotting was also performed to measure the levels of tight junction proteins of the BBB. Additionally, ELISA was performed to measure the level of VEGF in the brain. The colocalization of CD31, angiogenesis markers, and Smad1/5 was assessed by double immunofluorescent staining. TGFß pathway-related proteins were measured by western blotting. Furthermore, the cell viability of human umbilical vein endothelial cells (HUVECs) following oxygen-glucose deprivation/reoxygenation (OGD/RX) was measured by Cell Counting Kit (CCK)-8 assay. CONCLUSIONS: Coicis Semen treatment alleviates brain damage induced by ischemic stroke through inhibiting oxidative stress and promoting angiogenesis by activating the TGFß/ALK1 signaling pathway.

4.
Aging (Albany NY) ; 122020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33259334

RESUMO

Mitochondrial calcium uptake 1 (MICU1) is a pivotal molecule in maintaining mitochondrial homeostasis under stress conditions. However, it is unclear whether MICU1 attenuates mitochondrial stress in angiotensin II (Ang-II)-induced cardiac hypertrophy or if it has a role in the function of melatonin. Here, small-interfering RNAs against MICU1 or adenovirus-based plasmids encoding MICU1 were delivered into left ventricles of mice or incubated with neonatal murine ventricular myocytes (NMVMs) for 48 h. MICU1 expression was depressed in hypertrophic myocardia and MICU1 knockdown aggravated Ang-II-induced cardiac hypertrophy in vivo and in vitro. In contrast, MICU1 upregulation decreased cardiomyocyte susceptibility to hypertrophic stress. Ang-II administration, particularly in NMVMs with MICU1 knockdown, led to significantly increased reactive oxygen species (ROS) overload, altered mitochondrial morphology, and suppressed mitochondrial function, all of which were reversed by MICU1 supplementation. Moreover, peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α)/MICU1 expression in hypertrophic myocardia increased with melatonin. Melatonin ameliorated excessive ROS generation, promoted mitochondrial function, and attenuated cardiac hypertrophy in control but not MICU1 knockdown NMVMs or mice. Collectively, our results demonstrate that MICU1 attenuates Ang-II-induced cardiac hypertrophy by inhibiting mitochondria-derived oxidative stress. MICU1 activation may be the mechanism underlying melatonin-induced protection against myocardial hypertrophy.

5.
Int J Endocrinol ; 2020: 1030518, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33204258

RESUMO

Background: Functional pancreatic neuroendocrine neoplasms (PanNENs) are very rare disorders but have complex spectrum, including insulinoma, gastrinoma, glucagonoma, somatostatinoma, and VIPoma. Patients with PanNENs usually present with characteristic symptoms caused by corresponding hormone hypersecretion. It has always been challenging in dealing with such rare but complicated disorders. In this report, we analyzed the clinical characteristics of functional PanNENs in a large cohort of Chinese patients and summarized our clinical experience in diagnosis and treatment. Methods: The retrospective analysis was performed in patients with a definite diagnosis of functional PanNENs hospitalized in Chinese PLA General Hospital between 2000 and 2020. The clinical characteristics, surgical information, and pathological findings were extracted from their medical records and were analyzed. Results: Totally, 286 patients (gender: male 103 and female 183; age: 45.55 ± 15.23 years old) were diagnosed with definite functional PanNENs. The most frequent functional PanNENs were insulinoma (266/286) followed by glucagonoma (10/286), somatostatinoma (3/286), adrenocorticotropic hormone- (ACTH-) producing tumor (3/286), gastrinoma (2/286), and VIPoma (2/286). Nine patients were diagnosed with multiple endocrine neoplasia type 1 (MEN1) in which all the associated functional PanNENs were insulinomas. The duration from symptoms' onset to confirmed diagnosis was 3.67 ± 4.28 years. Two hundred and eighty patients with tumor localized in pancreatic or with limited metastasis underwent surgery. The symptoms associated with hormonal oversecretion were improved significantly after surgery. Five patients with unresectable metastases or tumor recurrence after surgery were administrated with systemic chemotherapy or other targeted therapies. With these various therapies, the symptoms were also partially relieved. According to findings in pathological and immunochemical examination, all the functional PanNENs were categorized into NEN-G1 (41.95%), NEN-G2 (54.90%), NEN-G3 (3.15%), and NEC-G3 (0%). Conclusion: Patients with suspected functional PanNENs should have a systematic endocrine examination at diagnosis. Multidisciplinary collaborations are essential for precise diagnosis and tumor localization. A successful surgery or other targeted therapies can improve the prognosis of patients with such rare but complex disorders.

6.
Ann Transl Med ; 8(18): 1173, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33241022

RESUMO

Background: Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a rare condition with untypical subclinical symptoms of Cushing's syndrome (CS). This study aimed to compare the clinical and pathological features of PBMAH with unilateral cortisol-secreting adrenal adenoma (UAA). Methods: We prospectively included 46 PBMAH patients and 205 UAA patients from January 2000 to February 2014. Cortisol levels and 24 hours urine free cortisol (UFC) were determined at baseline and during dexamethasone suppression test (DST) using the chemiluminescence method. Computed tomography (CT) examination of the adrenal glands was performed in all patients. For patients treated with adrenalectomy, hematoxylin, and eosin, staining was performed for pathological examination. Results: The proportion of patients with autonomous cortisol secretion was significantly higher in PBMAH patients (39.1%) than UAA patients (6.8%). The PBMAH patients showed significantly lower levels of basal cortisol, low dose dexamethasone suppressed cortisol, and high dose dexamethasone suppressed cortisol than the UAA patients (452.6±183.3 vs. 578.7±166.4 nmol/L, P=0.003; 394.5±298.9 vs. 549.2±217.7 nmol/L, P=0.002; 397.3±282.3 vs. 544.3±187.6 nmol/L, P=0.003). Similarly, the PBMAH patients had significantly lower levels of basal 24 hours UFC, low dose dexamethasone suppressed 24 hours UFC, and high dose dexamethasone suppressed 24 hours UFC than the UAA patients (1,144.4±1,048.1 vs. 1,674.9±1,520.4 nmol/24 h, P=0.032; 1,157.3±1,483.5 vs. 1,940.1±1,360.9 nmol/24 h, P=0.003; 1,256.4±1,767.0 vs. 1,969.9±1,361.7 nmol/24 h, P=0.011). Conclusions: PBMAH is often associated with atypical CS symptoms. The clinical and imaging features of PBMAH are useful for the differential diagnosis of this disease.

7.
Clin Interv Aging ; 15: 2227-2230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33244225

RESUMO

Background: Ankylosing spondylitis with Andersson lesions is not rare, but its potential pathogenesis and natural course remain unclear. Case Description: We describe a case of CT image changes in ankylosing spondylitis from fracture to Andersson lesions. A 40-year-old man with a 23-year history of ankylosing spondylitis presented with acute back pain after a slight fall, and the CT showed a T12 fracture; the patient refused surgery for 12 months. The process from fracture to Andersson lesions was characterized by CT, including the subsequent interbody bone graft with internal fixation and successful bone fusion at the last follow-up. Histopathologic analysis showed degenerative fibrocartilage tissue calcification, necrotic intervertebral disc tissue, fibrovascular hyperplasia, and focal accumulation of inflammatory cells. Conclusion: Aseptic inflammation and persistent instability caused by a fracture contributed in the course from fracture to Andersson lesions in ankylosing spondylitis. CT can accurately track the pathological process, and interbody fusion via the posterior pedicle lateral approach can achieve satisfactory effectiveness, good fusion and kyphosis correction.

8.
Sci Total Environ ; : 142724, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33082040

RESUMO

Syntrophic methanogenesis can be improved by the addition of conductive materials. In this study, conductive carbon fibers (CFs) were applied to efficiently enrich syntrophic microorganisms with potential direct interspecies electron transfer (DIET) ability and promote methanogenic activity. With ethanol as the substrate, CFs shortened the acclimation time remarkably. The maximum methane production rate and the ethanol degradation rate of suspended biomass were increased by 40% and 68%, respectively, even when CFs were subsequently removed. However, with acetate and propionate as the mixed substrate, CFs decreased the methanogenic activity. In the reactor fed with ethanol, CFs increased the relative abundance of Geobacter, Desulfovibrio, and methanogens by 57%, 39%, and 63%, respectively. Methanosaeta possessed most methane production genes and might involve in DIET. Furthermore, CFs increased the relative abundance of ethanol-degradation genes assigned to Geobacter, Desulfovibrio and Pelobacter, suggesting the promoted ethanol-degradation. The triggered electron transport system activity and acetoclastic methanogenesis also explained the accelerated effects on ethanol-degradation by long-term acclimation with CFs. Notably, the dominance of Geobacter and Methanosaeta combined with the increased electron transfer constant in the CFs-amended ethanol reactor indicated the potential role of DIET after the removal of CFs, which deserved further clarification.

9.
Small ; 16(46): e2004240, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33107142

RESUMO

Activation of the phagocytosis of macrophages to tumor cells is an attractive strategy for cancer immunotherapy, but the effectiveness is limited by the fact that many tumor cells express an increased level of anti-phagocytic signals (e.g., CD47 molecules) on their surface. To promote phagocytosis of macrophages, a pro-phagocytic nanoparticle (SNPACALR&aCD47 ) that concurrently carries CD47 antibody (aCD47) and a pro-phagocytic molecule calreticulin (CALR) is constructed to simultaneously modulate the phagocytic signals of macrophages. SNPACALR&aCD47 can achieve targeted delivery to tumor cells by specifically binding to the cell-surface CD47 and block the CD47-SIRPα pathway to inhibit the "don't eat me" signal. Tumor cell-targeted delivery increases the exposure of recombinant CALR on the cell surface and stimulates an "eat me" signal. Simultaneous modulation of the two signals enhances the phagocytosis of 4T1 tumor cells by macrophages, which leads to significantly improved anti-tumor efficacy in vivo. The findings demonstrate that the concurrent blockade of anti-phagocytic signals and activation of pro-phagocytic signals can be effective in macrophage-mediated cancer immunotherapy.

10.
Artigo em Inglês | MEDLINE | ID: mdl-33019530

RESUMO

BACKGROUND: In recent years, a three-dimensional ankle exercise has been proposed as a practice for strengthening the intrinsic foot muscles, however this topic still requires further research. This study aimed to compare the activities of the intrinsic muscles in healthy participants during 3D foot-ankle exercises, namely, short foot (SF), and toe spread out (TSO). METHODS: Prior to the experiment, 16 healthy adults were trained on how to perform SF, TSO, and 3D foot-ankle exercises for an hour. Once all participants passed the foot-ankle exercise performance test, we randomly measured the activity of the intrinsic foot muscles using electromyography while the patients were performing foot-ankle exercises. RESULTS: The abductor hallucis (AbH), extensor hallucis longus (EHL), and flexor hallucis brevis (FHB) activities showed significant differences among the exercises for intrinsic foot muscle strengthening (p < 0.01). Additionally, the AbH/AdH (adductor hallucis) ratio showed significant differences among the exercises for strengthening the intrinsic foot muscles (p < 0.01). CONCLUSIONS: Our results showed that the 3D extension exercise is as effective as the therapeutic exercise in terms of the AbH and FHB activities, and the AbH/AdH ratio. On the contrary, the 3D flexion exercise showed superiority in terms of the EHL activity.

11.
Artigo em Inglês | MEDLINE | ID: mdl-33104016

RESUMO

BACKGROUND: Problems related to ankle instability, decreased proprioceptive sensation, altered static and dynamic balance abilities are suggested as major representative factors that contribute to the recurrence of ankle sprains. OBJECTIVE: To assess the effect of a three-week intervention (intervention emphasizing diagonal eccentric contraction (IEDEC) and intervention of general exercise (IGE)) on static and dynamic balance abilities, ankle strength and joint position sense at pre- and post-intervention, and at two- and three-week post-intervention. METHODS: Twenty-five participants with ankle instability, including a history of ankle sprain and recurrent episodes of giving way, were enrolled in the study. They were randomly classified into the IEDEC group (n= 12) and the IGE group (n= 13). Dynamic balance was examined using the Y Balance Test, four-way ankle strength was measured, and the static balance was evaluated using the total displacement of the center of pressure (COP). To identify the joint position error, eversion and inversion of the ankle angle were measured. RESULTS: The results revealed significant increases in ankle dynamic stability and strength at two and three weeks post-intervention (p< 0.05). Similarly, the total displacement of the COP differed significantly over time, with a higher COP during the initial measurement than at two and three weeks intervention (p< 0.05) General balance training with IEDEC can improve position sense during ankle inversion (p< 0.05). CONCLUSION: General balance training with IEDEC improved the position sense of the inversion. Combined therapeutic intervention, such as with the manual technique, could be a beneficial approach to maximize the treatment effects.

12.
Food Chem ; 341(Pt 1): 128222, 2020 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-33065469

RESUMO

The relationship between the fine structure of original starch, leached starch during cooking, and the adhesiveness of noodles prepared by adding starches separated from different wheat cultivars was analyzed. The adhesiveness of noodles was primarily determined by the chain-length distributions of amylopectin rather than amylose. The adhesiveness of cooked noodles was positively correlated with the amount of short amylopectin chains with the degree of polymerization (DP) of 6-12, but negatively correlated with the amount of long chains with 25 < DP ≤ 36. The decrease of the proportion of short amylopectin chains and amylose chains and the increase of the amount of very long amylopectin chains with 37 < DP ≤ 100 in leachate led to decreased adhesiveness of cooked noodles. The reduction of the short-chain content in leached amylopectin caused by the increased proportion of long chains in original amylopectin is proposed to weaken the adhesiveness of cooked noodles.

13.
Abdom Radiol (NY) ; 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32964274

RESUMO

PURPOSE: To determine the utility of diffusion kurtosis imaging (DKI) for assessing bowel fibrosis and to establish a new magnetic resonance imaging (MRI)-based classification based on DKI and conventional MRI parameters for characterizing intestinal strictures in Crohn's disease (CD) using the histological evaluation of resected intestine samples as the reference standard. METHODS: Thirty-one patients with CD undergoing preoperative conventional MRI and diffusion-weighted imaging (DWI) (b values = 0-2000 s/mm2) were consecutively enrolled. We classified the mural T2-weighted signal intensity and arterial-phase enhancement patterns on conventional MRI. We also measured DWI-derived apparent diffusion coefficients (ADCs) and DKI-derived apparent diffusion for non-Gaussian distribution (Dapp) and apparent diffusional kurtosis (Kapp). A new MRI-based classification was established to characterize intestinal strictures in CD. Its performance was validated in nine additional patients with CD. RESULTS: Histological inflammation grades were significantly correlated to T2-weighted signal intensity (r = 0.477; P < 0.001) and ADC (r = - 0.226; P = 0.044). Histological fibrosis grades were moderately correlated to Kapp (r = 0.604, P < 0.001); they were also correlated to Dapp (r = - 0.491; P < 0.001) and ADC (r = - 0.270; P = 0.015). T2-weighted signal intensity could differentiate between no-to-mild and moderate-to-severe bowel inflammation (sensitivity, 0.970; specificity, 0.479). Kapp could differentiate between no-to-mild and moderate-to-severe bowel fibrosis (sensitivity, 0.959; specificity, 0.781). The agreement between the new MRI-based classification and the histological classification was moderate in the test (κ = 0.507; P < 0.001) and validation (κ = 0.530; P < 0.001) sets. CONCLUSIONS: DKI can be used to assess bowel fibrosis. The new MRI-based classification can help to distinguish between fibrotic and inflammatory intestinal strictures in patients with CD.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32760349

RESUMO

The anti-thyroglobulin antibody (TgAb) has been suggested to be more common in patients with papillary thyroid cancer (PTC). Here, we performed a retrospective study investigated the correlation between TgAb level and PTC in Chinese patients between 2011 and 2015. Patients with goiter who underwent thyroidectomy and received a confirmed pathological diagnosis were enrolled into the study. Clinical characteristics and preoperative thyroglobulin antibody (TgAb) level data were collected from all enrolled patients. Based on the preoperative TgAb test results, patients were divided into a TgAb negative (TgAb-) group (<60 IU/mL) and a TgAb positive (TgAb+) group (≧60 IU/mL). Of the 4,046 patients, 671 patients were TgAb+ while 3,375 patients were TgAb-. There were 535 (79.7%) patients with PTC in the TgAb+ group, and 2,154 (63.8%) patients with PTC in the TgAb- group. The prevalance of PTC was significantly higher in TgAb+ patients than in TgAb- patients. TgAb+ patients were stratified into four groups based on the TgAb titer. The prevalence of PTC did not increase with TgAb titer. No significant difference in TgAb level was noted in patients with different clinicopathologies, including TNM stage, lymph node metastasis, and multifocal carcinoma. Regression analysis suggested a higher risk of PTC malignancy among TgAb+ patients. Preoperative TgAb level ≥60 IU/mL might be associated with a higher risk of PTC. However, there was no titer-dependent association between elevated TgAb titer and PTC malignancy.

15.
J Orthop Surg Res ; 15(1): 348, 2020 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-32831125

RESUMO

BACKGROUND: We propose a new classification system for chronic symptomatic osteoporotic thoracolumbar fracture (CSOTF) based on fracture morphology. Research on CSOTF has increased in recent years; however, the lack of a standard classification system has resulted in inconvenient communication, research, and treatment. Previous CSOTF classification studies exhibit different symptoms, with none being widely accepted. METHODS: Imaging data of 368 patients with CSOTF treated at our hospital from January 2010 to June 2017 were systematically analyzed to develop a classification system. Imaging examinations included dynamic radiography, computed tomography scans, and magnetic resonance imaging. Ten investigators methodically studied the classification system grading in 40 cases on two occasions, examined 1 month apart. Kappa coefficients (κ) were calculated to determine intraobserver and interobserver reliability. Based on the radiographic characteristics, the patients were divided into 5 types, and different treatments were suggested for each type. Clinical outcome evaluation included using the visual analog score (VAS), the Oswestry disability index (ODI), and the American Spinal Injury Association (ASIA) impairment scale. RESULTS: The new classification system for CSOTF was divided into types I-V according to whether the CSOTF exhibited dynamic instability, spinal stenosis or kyphosis deformity. Intra- and interobserver reliability were excellent for all types (κ = 0.83 and 0.85, respectively). The VAS score and ODI of each type were significantly improved at the final follow-up compared with those before surgery. In all patients with neurological impairment, the ASIA grading after surgery was significantly improved compared with that before surgery (P < 0.001). CONCLUSIONS: The new classification system for CSOTF demonstrated excellent reliability in this initial assessment. The treatment algorithm based on the classification can result in satisfactory improvement of clinical efficacy for the patients of CSOFT.

16.
J Cell Mol Med ; 24(16): 9176-9188, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32648620

RESUMO

The therapeutic hypothermia is an effective tool for TBI-associated brain impairment, but its side effects limit in clinical routine use. Hypothermia up-regulates RNA-binding motif protein 3 (RBM3), which is verified to protect synaptic plasticity. Here, we found that cognitive and LTP deficits, loss of spines, AD-like tau pathologies are displayed one month after TBI in mice. In contrast, the deficits of LTP and cognitive, loss of spines and tau abnormal phosphorylation at several sites are obviously reversed in TBI mice combined with hypothermia pre-treatment (HT). But, the neuroprotective role of HT disappears in TBI mouse models under condition of blocking RBM3 expression with RBM3 shRNA. In other hand, overexpressing RBM3 by AAV-RBM3 plasmid can mimic HT-like neuroprotection against TBI-induced chronic brain injuries, such as improving LTP and cognitive, loss of spines and tau hyperphosphorylation in TBI mouse models. Taken together, hypothermia pre-treatment reverses TBI-induced chronic AD-like pathology and behaviour deficits in RBM3 expression dependent manner, RBM3 may be a potential target for neurodegeneration diseases including Alzheimer disease.

17.
J Mater Chem B ; 8(31): 6686-6696, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32579660

RESUMO

Engineering nanoparticles (NPs) as delivery systems of anticancer therapeutics has attracted tremendous attention in recent decades, and some nanoscale drug formulations have been approved for clinical use. However, their therapeutic efficacies are still limited by the presence of a series of biological barriers during the delivery process. Among these obstacles, tumor barriers are generally recognized as the bottleneck, because they dominate the NP extravasation from the tumor vasculature and penetration into the tumor parenchyma. Therefore, this review first discussed tumor barriers from two aspects: tumor vascular barriers and tumor stromal barriers. Pathological features of the two sets of barriers as well as their influence on the delivery efficacy were described. Then, we outlined strategies for engineering NPs to overcome these challenges: increasing extravasation through physical property optimization and tumor vascular targeting; and facilitating deep penetration through particle size manipulation, modulation of the tumor extracellular matrix, and some new mechanisms. This review will provide a critical perspective on engineering strategies for more efficient nanomedicine in oncology.

18.
Reprod Sci ; 27(11): 2038-2051, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32542540

RESUMO

Obesity is associated with altered fatty acid profiles, reduced fertility, and assisted reproductive technology (ART) success. The effects of palmitic acid (PA), oleic acid (OA), and their combination on mouse preimplantation development, endoplasmic reticulum (ER) stress pathway gene expression, lipid droplet formation, and mitochondrial reactive oxygen species (ROS) were characterized. Two-cell stage mouse embryos collected from superovulated and mated CD1 females were placed into culture with KSOMaa medium, or PA alone or in combination with OA for 46 h. PA significantly reduced blastocyst development in a concentration-dependent manner, which was prevented by co-treatment with OA. PA and OA levels in mouse reproductive tracts were assessed by liquid chromatography coupled to mass spectrometry (LC-MS). LC-MS indicated higher concentrations of PA in the mouse oviduct than the uterus. Transcript analysis revealed that PA alone groups had increased ER stress pathway (ATF3, CHOP, and XBP1 splicing) mRNAs, which was alleviated by OA co-treatment. OA co-treatment significantly increased lipid droplet accumulation and significantly decreased mitochondrial ROS from PA treatment alone. PA treatment for only 24 h significantly reduced its impact on blastocyst development from the 2-cell stage. Thus, PA affects ER stress pathway gene expression, lipid droplet accumulation, and mitochondrial ROS in treated preimplantation embryos. These mechanisms may serve to offset free fatty acid exposure effects on preimplantation development, but their protective ability may be overwhelmed by elevated PA.

19.
Nano Lett ; 20(7): 4882-4889, 2020 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-32551705

RESUMO

Tumor-infiltrating dendritic cells (TIDCs) are mostly immature and immunosuppressive, usually mediating immune inhibition. The utilization of cytosine-guanine oligodeoxynucleotides (CpG ODNs) to stimulate the activation of TIDCs has been demonstrated to be effective for improving antitumor immunity. However, a series of biological barriers has limited the efficacy of previous nanocarriers for delivering CpG to TIDCs. Herein, we developed a dual-sensitive dendrimer cluster-based nanoadjuvant for delivering CpG ODNs into TIDCs. We show that the tumor acidity triggers the rapid release of CpG conjugated polyamidoamine (PAMAM) dendrimers from the nanoadjuvant, thus facilitating its perfusion deep into tumors and phagocytosis by TIDCs. Thereafter, the reductive condition of the endolysosomes led to the subsequent release of CpG, which promotes the DCs activation and enhances antitumor immunotherapies. Programmable delivery of immune adjuvant efficiently overcomes the barriers for targeted delivery to TIDCs and provides a promising strategy for improving cancer immunotherapy.

20.
Plant Mol Biol ; 103(6): 705-718, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32577984

RESUMO

Fritillariae Bulbus are the most commonly used antitussive and edible herbs in China. Based on UPLC-QTOF-MS and UPLC-QQQ-MS, the validated MRM-based non-targeted quantitative method was applied to determinate the contents of 48 Fritillaria alkaloids (FAs) in three Fritillaria species (F. thunbergii Miq., F. unibracteata and F. ussuriensis). The RNA-Seq results showed that gene transcript levels have different expression patterns in three Fritillaria species. Based on transcriptome data, the full-length cDNA sequences of squalene epoxidase gene were cloned and characterized. Natural evolution of squalene epoxidase genes resulted in four mutations (C236R, M489L, G510A and K517R) in three Fritillaria species. Molecular docking analysis showed that the 236 residue is located inside the pocket and the binding center while other three residues are located on the surface of the protein. Functional verification indicated the mutations of SQE (C236R) could effectively increase the activity of SQE and obtain higher yield of 2,3-oxidosqualene in recombinant yeast. And the mutations of SQE (M489L and G510A), which increased the hydrophobicity of the protein surface, could also enhance the activity of SQE. This study provides major insights into the metabolites differentiation of FAs biosynthesis, and a firm foundation for the quality control and metabolic engineering of Fritillariae bulbus.


Assuntos
Fritillaria/enzimologia , Esqualeno Mono-Oxigenase/metabolismo , Alcaloides/metabolismo , Cromatografia Líquida de Alta Pressão , DNA Complementar/genética , Simulação de Acoplamento Molecular , Mutação/genética , Filogenia , Alinhamento de Sequência , Esqualeno Mono-Oxigenase/genética
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