Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 353
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-32031326

RESUMO

BACKGROUND: Neoadjuvant chemoradiotherapy (NACRT) and total mesorectal excision (TME) are standard treatments of stage II/III locally advanced rectal cancer (LARC), currently. Here, we evaluated the oncological outcomes in LARC patients treated with NACRT compared to TME alone, and determined whether tumor regression grade (TRG) and pathologic response after NACRT was related to prognosis. METHODS: This is a retrospective comparison of 358 LARC patients treated with either TME alone (non-NACRT group, n = 173) or NACRT plus TME (NACRT group, n = 185) during 2003-2013. Perioperative and oncologic outcomes, like overall survival (OS), disease-free survival (DFS) and recurrence were compared using 1:1 propensity score matching analysis. RESULTS: A total of 133 patients were matched for the analysis. After a median follow-up of 45 months (8-97 months), the 5-year OS (NACRT vs non-NACRT: 75.42% vs 72.76%; P = 0.594) and 5-year DFS (NACRT vs non-NACRT: 74.25% vs 70.13%; P = 0.224) were comparable between NACRT and non-NACRT, whereas the 5-year DFS rate was higher in the NACRT group when only stage IIIb/IIIc patients were considered (NACRT vs. non-NACRT: 74.79% vs. 62.29%; P = 0.056). In the NACRT group of 185 patients, those with pCR/stage I (vs stage II/stage III disease) or TRG3/TRG4 disease (vs TRG0/TRG1/TRG2) had significantly better prognosis. CONCLUSION: NACRT might provide survival benefit in patients with stage IIIb/IIIc locally advanced rectal cancer.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32077155

RESUMO

Chemical architectures with ordered porous backbone and high charge transfer are significant for fiber-shaped supercapacitors (FSCs). However, due to the sluggish ion kinetic diffusion and storage in compacted fibers, achieving high energy density remains a challenge. Here, we propose an innovative magnetothermal microfluidic method to efficiently design hierarchical carbon polyhedrons/holey graphene (CP/HG) core-shell microfibers. Due to highly magnetothermal etching and microfluidic reactions, the CP/HG fibers maintain open inner-linked ionic pathway, large specific surface area and moderate nitrogen active-site, facilitating rapider ionic dynamic transportation and accommodation. The CP/HG FSCs display an ultra-high energy density of 806 µWh cm -2 and large areal capacitance of 2760 mF cm -2 . More importantly, an actually self-powered endurance application with the integration of chip-based FSCs is designed to profoundly drive the durable motions of electric car and walking robot.

3.
Med Sci Monit ; 26: e919150, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32052794

RESUMO

BACKGROUND Myasthenia gravis (MG) is a progressive autoimmune disorder caused by the production of antibodies directed against acetylcholine receptors (AChRs), resulting in muscle weakness and fatigue. This study aimed to explore the effect and mechanism of grilled nux vomica (GNV) in experimental autoimmune myasthenia gravis (EAMG) rats. MATERIAL AND METHODS Rat 97-116 peptides were used to mediate disease in the EAMG model in SPF female Lewis rats. The treatment groups received grilled nux vomica (75 mg/kg, 150 mg/kg, and 225 mg/kg). The autoantibody and inflammatory cytokines levels were measured by enzyme-linked immunosorbent assay (ELISA). RNA profiling was performed on high-dose and model group rats. Profiling results and TLR-4/NF-kappaB signaling were validated by q-PCR and Western blot analysis. RESULTS The results showed that GNV could attenuate the symptoms of EAMG rats. There was a decreased level of AChR-ab, IFN-γ, TNF-alpha, IL-2, IL-4, and IL-17 levels, and an increased level of TGF-ß1. In total, 235 differentially expressed genes (DEGs), consisting of 175 upregulated DEGs and 60 downregulated DEGs, were identified. Functional annotation demonstrated that DEGs were largely associated with leukocyte cell-cell adhesion, NF-kappa B signaling pathway, muscle contraction, and cardiac muscle contraction pathway. Rac2, Itgb2, Lcp2, Myl3, and Tnni1 were considered as hub genes with a higher degree value in the protein-protein interaction (PPI) network. The q-PCR and Western blot results of hub genes were consistent with RNA profiles. GNV treatment also significantly reduced the TLR-4 and NF-kappaB p65 protein expression in EAMG rats. CONCLUSIONS These results indicate that grilled nux vomica ameliorates EAMG by depressing the TLR-4/NF-kappaB signaling pathway, and hub genes may serve as potential targets for MG treatment.

4.
J Cell Physiol ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31950510

RESUMO

Long noncoding RNA (lncRNA) NKILA has been well studied in several types of human tumors as a tumor suppressor, while its involvement in cervical squamous cell carcinoma (CSCC) remains unclear. In our studies, we found that serum NKILA was at lower levels and serum microRNA-21 (miRNA-21) was at higher levels in patients with early stage CSCC than in the healthy female. Altered expression of NKILA and miRNA-21 can effectively separate patients with CSCC at an early stage from healthy controls. Serum levels of NKILA were significantly and negatively correlated with miRNA-21 in patients with CSCC but not in normal controls. Overexpression of NKILA mediated the inhibited expression of miRNA-21 in CSCC cells, but mimic transfection of miRNA-21 did not significantly change the expression level of NKILA. Overexpression of NKILA repressed the proliferation and promoted the apoptosis of CSCC cells, while miRNA-21 showed opposite functions. In addition, miRNA-21 mimic transfection reduced the effects of NKILA on CSCC cells. Collectively, lncRNA NKILA could repress the proliferation and promote the apoptosis of CSCC cells by downregulating miRNA-21.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31975581

RESUMO

In complex environments, there are often toxic and harmful conditions, and so self-powered sensors that use wireless access have a huge advantage. However, there is still a risk of short circuit for self-powered sensors in harsh environments. A single-electrode self-powered sensor was designed, which can be used to monitor body movements such as walking and running, as well as monitoring the motion of some mechanical devices, such as peristaltic pumps, door, and window switches. By using a threshold delay algorithm, this self-powered sensor can be connected to the phone to warn the phone user to check for theft or illegal intrusion when the door and window are opened. Further research shows that the single-electrode configuration can avoid the short-circuit behavior caused by device damage so that the self-powered sensor can still work even if it is pierced. Therefore, the wireless single-electrode self-powered sensor system has better reliability and is more applicable to harsh environments.

6.
Acc Chem Res ; 53(2): 300-310, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-31939278

RESUMO

Electrochemical synthesis of organic compounds has emerged as an attractive and environmentally benign alternative to conventional approaches for oxidation and reduction of organic compounds that utilizes electric current instead of chemical oxidants and reductants. As such, many useful transformations have been developed, including the Kolbe reaction, the Simons fluorination process, the Monsanto adiponitrile process, and the Shono oxidation, to name a few. Electrochemical C-H functionalization represents one of the most promising reaction types among many electrochemical transformations, since this process avoids prefunctionalization of substrates and provides novel retrosynthetic disconnections. However, site-selective anodic oxidation of C-H bonds is still a fundamental challenge due to the high oxidation potentials of C-H bonds compared to organic solvents and common functional groups. To overcome this issue, indirect electrolysis via the action of a mediator (a redox catalyst) is regularly employed, by which the selectivity can be controlled following reaction of said mediator with the substrate. Since the redox potentials of transition metal complexes can be easily tuned by modification of the ligand, the synergistic use of electrochemistry and transition metal catalysis to achieve site-selective C-H functionalization is an attractive strategy. In this Account, we summarize and contextualize our recent efforts toward transition metal-catalyzed electrochemical C-H functionalization proximal to a suitable directing group. We have developed C-H oxygenation, acylation, alkylation, and halogenation reactions in which a Pd(II) species is oxidized to a Pd(III) or Pd(IV) intermediate by anodic oxidation, followed by reductive elimination to form the corresponding C-O, C-C, and C-X bonds. Importantly, improved monofunctionalization selectivity is achieved in the Pd-catalyzed C(sp3)-H oxygenation compared to conventional approaches using PhI(OAc)2 as the chemical oxidant. Physical separators are sometimes used to prevent the electrochemical deposition of Pd black on the cathode resulting from reduction of high valent Pd species. We skirted this issue through the development a Cu-catalyzed electrochemical C(sp2)-H amination using n-Bu4NI as a redox cocatalyst in an undivided cell. In addition, we developed Ir-catalyzed electrochemical vinylic C-H functionalization of acrylic acids with alkynes in an undivided cell, affording various substituted α-pyrones in good to excellent yield. More importantly, chemical oxidants, including Ag2CO3, Cu(OAc)2, and PhI(OAc)2, resulted in much lower yields in the absence of electrical current under otherwise identical conditions. As elaborated below, progress in the area of electrochemical transition metal-catalyzed synthesis provides an effective platform for environmentally friendly and sustainable selective chemical transformations.

7.
Sci Total Environ ; 703: 135493, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31759714

RESUMO

Chemical modification of agricultural waste biomass has proved to be an economy and effective approach to capture phosphate ions, except for that under acidic conditions and highly competitive ion systems. According to this, a new nanocomposite (HFO@St+) was fabricated by incorporating nano-sized hydrous Fe(III) oxides (HFO) within aminated wheat straw in order to overcome the bottleneck. The optimal pH of phosphate uptake by HFO@St+ was greatly broadened and observed over a wide pH range between 2.0 and 7.0. The binary exchange reaction indicated that phosphate was strongly and preferably adsorbed by HFO@St+ with the separation factor K of phosphate over nitrate increasing from 0.23-1 or 0.20-0.26 to 2.5-38 or 2.5-15 for near neutral or acidic pHs, respectively. The sorption selectivity for HFO@St+ followed the order of phosphate > nitrate > chloride under experimental conditions. The presence of inorganic and organic ligands (SO4 and HA) showed no significant effect on phosphate adsorption. XPS and FT-IR analyses were performed to explore the underlying mechanism of adsorption. The exhausted material could be regenerated with NaOH-NaCl solution for at least ten cycles, indicating that HFO@St+ can be used as a sustainable biomass product with excellent adsorption affinity for phosphate removal.

8.
Acta Physiol (Oxf) ; 228(2): e13339, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31278836

RESUMO

AIM: Type 2 diabetes and obesity are diseases related to surplus energy in the body. Abnormal interaction between the hypothalamus and adipose tissues is a key trigger of energy metabolism dysfunction. Extracellular vesicles (EVs) regulate intercellular communication by transporting intracellular cargo to recipient cells thereby altering the function of recipient cells. This study aimed to evaluate whether adipocyte-derived EVs can act on hypothalamic neurons to modulate energy intake and to identify the EV-associated non-coding RNAs. METHODS: Confocal imaging was used to trace the uptake of labelled adipocyte-derived exosomes by hypothalamic anorexigenic POMC neurons. The effects of adipocyte-derived EVs on the mammalian target of rapamycin (mTOR) signalling pathway in POMC neurons were evaluated based on mRNA and protein expression in vitro using quantitative real-time PCR and western blotting. In addition, adipocyte-derived EVs were injected into recipient mice, and changes in mice body weight and daily food intake were monitored. The biological effects of the EV-associated MALAT1 on POMC neurons were explored. RESULTS: Adipocyte-derived EVs were successfully transferred into POMC neurons in vitro. Results showed that adipocytes of obese mice secreted MALAT1-containing EVs, which increased appetite and weight when administered to lean mice. Conversely, adipocyte-derived EVs from lean mice decreased food intake and weight when administered to obese mice. CONCLUSION: Adipocyte-derived EVs play important roles in mediating the interaction between adipocytes and hypothalamic neurons. Adipocyte-derived EVs can regulate POMC expression through the hypothalamic mTOR signalling in vivo and in vitro, thereby affecting body energy intake.

9.
Artif Cells Nanomed Biotechnol ; 48(1): 305-314, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31858836

RESUMO

Combining DNA damage repair inhibitors and chemotherapeutic agents is an emerging strategy in cancer treatment. In this study, we engineered the polycation nanoparticle (NP), which co-encapsulated DNA damage repair inhibitor Dbait and chemotherapeutic drug Docetaxel (Dtxl), using H1 nanopolymer (folate--polyethylenimine600-cyclodextrin), and the size of H1/Dbait/Dtxl was about 117 nm. We demonstrated that H1/Dbait/Dtxl enhanced the efficiency of radio-chemotherapy in prostate cancer cells by CCK-8 assay and colony-forming assay. Importantly, the improvement of radio-chemotherapy of H1/Dbait/Dtxl in prostate cancer was also validated in vivo, and the NP did not have a high toxicity profile. The results of immunohistochemistry and western blot supported that the improved therapeutic efficacy was through inhibiting DNA damage repair signalling pathway. Our study supports further investigations using NP to co-deliver DNA damage repair inhibitors and chemotherapeutics to improve the therapeutic efficacy of cancer.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31793156

RESUMO

A highly regioselective Ni-catalyzed electrochemical reductive relay cross-coupling between an aryl halide and an alkyl halide has been developed in an undivided cell. Various functional groups are tolerated under these mild reaction conditions, which provides an alternative approach for the synthesis of 1,1-diarylalkanes.

11.
Huan Jing Ke Xue ; 40(8): 3509-3518, 2019 Aug 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854756

RESUMO

Eighty-nine soil samples were collected from the Binzhou oil mining area of the Yellow River Delta (including 83 farmland soil samples and 6 soil samples from an oil extraction area). A total of 16 US-EPA priority polycyclic aromatic hydrocarbons (PAHs) were measured by gas chromatography-mass spectrometry (GC-MS). Principal component analysis (PCA) and positive matrix factorization (PMF) were employed to investigate potential source apportionment of PAHs in the farmland soil. The total PAH concentrations ranged from 31.5 µg·kg-1 to 1399.4 µg·kg-1 (dry weight) with an arithmetic mean concentration of 119.4 µg·kg-1. The characteristics of PAHs showed that 4- to 6-ring PAHs were slightly dominant in this study area, and most of the PAHs were significantly correlated (P<0.01), which indicates that the sources of the PAHs had some similarities in this sampling area. Source apportionment results derived from two different models were similar, indicating that the sources of PAHs were coal combustion, biomass combustion, fossil fuel combustion, and diesel combustion. The results of the PMF were more detailed, with the following four factors being identified:gasoline combustion (24.05%), diesel combustion (6.17%), low-temperature pyrolysis processes (60.67%), and coal combustion (9.11%).

12.
Zhongguo Zhong Yao Za Zhi ; 44(19): 4285-4292, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31872711

RESUMO

Artemisinin is a kind of sesquiterpene lactone containing endoperoxide bridge,which is the most effective anti-malarial drug at present. However,low content of artemisinin in Artemisia annua,ranging from 0. 1%-1. 0% of dry weight,as well as the complicated extraction process have resulted in low yield and high cost of artemisinin,making it difficult to meet market demand.Based on the development of high-throughput sequencing and molecular biology,the related enzyme genes and transcription factors involved in the artemisinin metabolic pathway were cloned and identified. Metabolic engineering and synthetic biology methods to modify the original metabolic pathway of A. annua and genetic engineering in heterologous host cells have become one of the hotspots in this field. Therefore,the molecular mechanism of artemisin biosynthesis,different strategies of genetic modifications of A. annua,and the research status and application prospect of artemisinin synthesis in heterologous host cells( Nicotiana benthamiana,Physcomitrella patens) were summarized in our review,hoping to provide molecular basis and theoretical basis for breeding new varieties of A. annua with high artemisinin output.


Assuntos
Antimaláricos , Artemisia annua , Artemisininas , Engenharia Metabólica , Fatores de Transcrição
13.
J Natl Compr Canc Netw ; 17(10): 1174-1183, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31590148

RESUMO

BACKGROUND: Differences between the features of primary cancer and matched metastatic cancer have recently drawn attention in research. This study investigated the concordance in microsatellite instability (MSI) and mismatch repair (MMR) status between primary and corresponding metastatic colorectal cancer (CRC). METHODS: Consecutive patients with metastatic CRC who had both primary and metastatic tumors diagnosed at our institution in January 2008 through December 2016 were identified. Immunohistochemistry was used to test the MMR status of both primary and matched metastatic tumors, and PCR analysis was performed to test MSI in patients with deficient MMR (dMMR) status. RESULTS: A total of 369 patients were included. Of the 46 patients with MSI-high primary tumors, 37 (80.4%) also had MSI-high metastatic tumors, whereas 9 (19.6%) had microsatellite stable (MSS) metastatic tumors. A high concordance was found in patients with liver, lung, or distant lymph node metastases. Interestingly, the discrepancy was more likely to be limited to peritoneal (5/20) or ovarian (4/4) metastasis (chi-square test, P<.001). These organ-specific features were also found in the pooled analysis. Along with the change of MSI-high in primary cancer to MSS in metastatic cancer, lymphocyte infiltration decreased significantly (P=.008). However, the change did not influence survival; the median overall survival of MSI-high and MSS metastatic tumors was 21.3 and 21.6 months, respectively (P=.774). The discrepancy rate was 1.6% for patients with proficient MMR primary tumors. CONCLUSIONS: For patients with dMMR primary tumors, the concordance of MSI and MMR status in primary CRC and corresponding metastatic cancer is potentially organ-specific. High concordance is found in liver, lung, and distant lymph node metastases, whereas discrepancy is more likely to occur in peritoneal or ovarian metastasis. Rebiopsy to evaluate MSI-high/dMMR status might be needed during the course of anti-PD-1 therapy in cases of peritoneal or ovarian metastasis.

14.
Exp Ther Med ; 18(4): 2524-2530, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31572503

RESUMO

Gastric cancer (GC) is a global health problem with poor clinical outcomes. The mechanism of its development and progression remains largely unclear. The present study investigated the role of microRNA-9 (miR-9-5p) in the development and progression of GC. Overexpression of miR-9-5p led to reduced expression of neuropilin-1 (NRP-1) in GC cells. Dual-luciferase reporter assay results indicated that miR-9-5p directly targeted NRP-1. Furthermore, overexpression of miR-9-5p in GC cells increased the expression of mesenchymal markers, N-cadherin and vimentin, and decreased the expression of epithelial markers, E-cadherin and ß-catenin. Overexpression of miR-9-5p inhibited GC cell proliferation, migration and invasion, and increased the sensitivity of GC cells to the anti-cancer drug cisplatin. By contrast, the opposite effects were observed in GC cells following downregulation of miR-9-5p. Taken together, the present findings suggested that miR-9-5p suppressed NRP-1 expression and inhibited GC cell proliferation and invasion. In addition, miR-9-5p overexpression attenuated GC cell resistance to anti-cancer drugs, which highlighted the potential of miR-9-5p as a target for the treatment of GC.

15.
J Int Med Res ; 47(11): 5844-5848, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31552763

RESUMO

Highlights • Dissecting basilar artery aneurysm (DBAA) is relatively rare. • We report the first case of a DBAA manifesting as sudden sensorineural hearing loss. • This case report adds to the symptom spectrum of DBAA.

16.
Cancer Biol Ther ; 20(12): 1409-1415, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31411522

RESUMO

Malignant peritoneal mesothelioma is a very rare tumor originating from the peritoneal serous mesothelium. Meningeal metastasis of malignant peritoneal is even more rare. Here, we reported a case of a 60-year-old female patient with a history of exposure to asbestos for 10 years who presented with massive peritoneal effusion followed by disorder of consciousness and symptoms of cranial nerve injury. The patient was diagnosed as peritoneal mesothelioma with meningeal metastasis through neurological symptoms, cytological finding of cerebrospinal fluid combined with cranial magnetic resonance imaging (MRI). The patient received systemic chemotherapy and total craniospinal irradiation. The follow up visits showed that the survival time of patient after diagnosis of meningeal metastasis from peritoneal mesothelioma was 5 months. To our knowledge, this is the first case of menigeal metastasis of peritoneal mesothelioma. We hope this particular case may be helpful in providing some experience to the treatment of peritoneal mesothelioma with meningeal metastasis.

17.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1033-1039, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418353

RESUMO

]Objective:To investigate the efficacy and safety of induction regimens containing arsenite, allo-transretinoic acid (ATRA) and anthracyclines of different doses as induction chemotherapy for acute promyelocytic leukemia (APL). METHODS: The clinical data of 129 consecutive hospitalized newly diagnosed APL patients from January 2011 to December 2017 were collected and retrospectively analyzed. Sixty-six patients received arsenite, ATRA and anthracyclines of low doses (low dose group), while other 63 patients received arsenite, ATRA and anthracyclines of standard doses (standard dose group), the efficacy and safety were compared and analyzed in 2 groups. RESULTS: There were no statistically significant differences in terms of age, sex, routine blood indexes,LDH level, bone marrow promyelocyte count,prognostic stratification between patients in two groups (P>0.05). During the treatment, WBC count peak and its time point were not significantly different between two groups (P>0.05). Both induction regimens showed good efficacy, the PML-RARα gene conversion rate from positive into negative, the 2-year overall survival rate and disease-free survival rate in the low-dose group were similar to those in the standard dose group(P>0.05). The recovery time of neutrophils and platelets in the low-dose group was 0 d and 11 d, respectively, which were statistically  significantly shorter than those in the standard dose group (3 d,15 d) (both P=0.000). The median value of platelet and erythrocyte transfusion in the low-dose group was 6.9 U and 4.2 U, respectively, which were statistically significantly lower than that in the standard dose group (8.4 U,6.8 U) (P=0.037,0.000). And the inpatient time in the low and the standard dose groups were 30.98 and 30.71 days, respectively (P=0.770). CONCLUSION: For newly diagnosed patients with APL, the efficacy was similar between induction therapy containing arsenite,ATRA and low dose anthracyclines and the induction therapy containing arsenite, ATRA and standard dose anthracyclines, however, the former appears even safer.


Assuntos
Leucemia Promielocítica Aguda , Antraciclinas , Protocolos de Quimioterapia Combinada Antineoplásica , Humanos , Indução de Remissão , Estudos Retrospectivos , Resultado do Tratamento , Tretinoína
18.
Artigo em Inglês | MEDLINE | ID: mdl-31428922

RESUMO

The study aimed to investigate the role of oxidised low-density lipoprotein (oxLDL)/lectin-like-oxLDL receptor-1 (LOX-1) in coronary artery lesions (CALs) in Kawasaki disease (KD) and of plasma oxLDL concentration in the early prediction of CALs in KD. This prospective study included 80 KD patients, 20 febrile and 20 healthy children. oxLDL, LOX-1 and other parameters were analysed in the acute phase. Plasma oxLDL concentration and LOX-1 mRNA expression in peripheral blood mononuclear cells (PBMCs) were significantly increased in KD patients compared with febrile and healthy children (P < 0.001 and P = 0.022, respectively), particularly in the group with CALs (P < 0.001 and P = 0.027, respectively). Coronary Z-score was significantly correlated with plasma oxLDL concentration and LOX-1 mRNA expression (r = 0.739 and 0.637, respectively; P < 0.01). The sensitivity and specificity of predicting CALs were 71.4% and 77.2%, respectively, at plasma oxLDL concentration ≥ 12.38 mU/L. oxLDL/LOX-1 may be involved in CAL development. The plasma oxLDL concentration in the acute phase is a potentially useful biological indicator for predicting CAL in KD patients.

19.
Zhen Ci Yan Jiu ; 44(7): 469-75, 2019 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-31368275

RESUMO

OBJECTIVE: To observe the effect of acupuncture and moxibustion on renal Fas and Fas ligand (FasL) expression in contrast-induced nephropathy (CIN) diabetic rats, so as to explore its protective mechanisms. METHODS: A total of 40 diabetic male SD rats were randomly divided into control, model, acupuncture, moxibustion and combined treatment (acupuncture combined with moxibustion) groups (n=8 rats in each group). The diabetic model was established by i.p. injection of Streptozotocin (60 mg/kg), followed by regular raising for 9 weeks. Then, the manual acupuncture, moxibustion or acupuncture plus moxibustion at "Sanyinjiao"(SP6) "Shenshu"(BL23) and "Pishu"(BL20) was given to the diabetic rats, once daily for 7 days. On the 8th day, these diabetic rats received i.p. injection of compound Meglumine Diatrizoate Injection (10 mL/kg) for establishing CIN model. Then, the venous blood specimens were collected for detecting contents of serum urine nitrogen (BUN, with urease method) and creatinine (Scr, with picric acid method). The kindey tissues were exteriorized for detecting nitricoxide synthase (NOS, with oxidation-reduction method), malondialdehyde (MDA, with thiobarbituric acid method), superoxide dismutase (SOD, with xanthine oxidase technique) and total antioxidant capacity (T-AOC, with colorimetric technique). The expression levels of Fas and FasL in the kidney tissues were detected by quantitative real-time PCR and Western blot separately. The histopathological and ultrastructural changes of the kidney were observed under microscope (after H.E. staining) and transmission electron microscope, respectively. RESULTS: Following modeling and compared with the control group, the BUN, Scr and renal MDA contents, and Fas and FasL mRNA and protein expression levels were significantly increased (P<0.01, P<0.05), and renal NOS, SOD and T-AOC levels considerably decreased in the model group (P<0.05). After the interventions and compared with the model group, serum BUN and Scr contents and renal Fas mRNA and protein expression levels in both acupuncture group and combined treatment group, BUN in the moxibustion group, and renal MDA content and FasL mRNA and protein expression levels in the 3 treatment groups were obviously down-regulated (P<0.05,P<0.01), while renal NOS in the 3 treatment groups, and SOD and T-AOC levels in the combined treatment group were considerably up-regulated (P<0.01,P<0.05). The effects of the combined treatment were significantly superior to those of simple acupuncure and simple moxibustion in down-regulating serum BUN contents, and Fas and FasL mRNA and protein expression levels, and in up-regulating renal NOS, SOD and T-AOC activity (P<0.05). No significant differences were found between the acupuncture and moxibustion groups in down-regulating serum BUN, Scr and renal MDA contents, and Fas and FasL mRNA and protein levels, as well as in up-regulating NOS content (P>0.05). H.E. staining showed lobular changes of glomeruli, many local necrosis and vascular degeneration in the model group, and transmission electron microscope displayed thickened basement membrane of the glomerular blood loop, many vacuoles in the cytoplasm of renal tubular epithelial cells, severely swollen mitochondria with disordered, broken or disappeared cristae, and some apoptotic cells in the model group, which were relatively milder in the combined treatment group. CONCLUSION: Joint application of acupuncture and moxibustion can reduce the oxidative stress and renal injury in CIN diabetic rats, which may be associated with its function in down-regulating the expression of renal Fas and FasL genes and proteins. Acupuncture and moxibustion has a synergistic effect.


Assuntos
Terapia por Acupuntura , Diabetes Mellitus Experimental , Moxibustão , Animais , Proteína Ligante Fas , Rim , Masculino , RNA Mensageiro , Ratos , Ratos Sprague-Dawley
20.
J Med Chem ; 62(17): 7643-7655, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31368705

RESUMO

Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib hold a prominent role in the treatment of B cell malignancies. However, further refinement is needed to this class of agents, particularly in terms of adverse events (potentially driven by kinase promiscuity), which preclude their evaluation in nononcology indications. Here, we report the discovery and preclinical characterization of evobrutinib, a potent, obligate covalent inhibitor with high kinase selectivity. Evobrutinib displayed sufficient preclinical pharmacokinetic and pharmacodynamic characteristics which allowed for in vivo evaluation in efficacy models. Moreover, the high selectivity of evobrutinib for BTK over epidermal growth factor receptor and other Tec family kinases suggested a low potential for off-target related adverse effects. Clinical investigation of evobrutinib is ongoing in several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA