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1.
Arch Dis Child ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31666243

RESUMO

OBJECTIVES: The 22q11.2 deletion syndrome is considered the most frequent chromosomal microdeletion syndrome in humans and the second leading chromosomal cause of congenital heart disease (CHD). We aimed to identify the prevalence and the detailed genetic characterisation of 22q11.2 region in children with CHD including simple defects and to explore the genotype-phenotype relationship between deletion/amplification type and clinical data. METHODS: Patients with CHD for surgery were screened by multiplex ligation-dependent probe amplification and capillary electrophoresis methods. Universal Probe Library technology was applied for validation. RESULTS: In 354 patients with CHD, 40 (11.3%) carried different levels of deletions/amplifications at the 22q11.2 region with various phenotypes. The affected genes at this region include CDC45 (15 patients), TBX1 (8), USP18 (8), RTDR1 (7), SNAP29 (6), TOP3B (6), ZNF74 (4) and other genes with less frequency. Among those, two patients carried 3 Mb typically deleted region from CLTCL1 to LZTR1 (low copy repeats A-D) or 1.5 Mb deletions from CLTCL1 to MED15 (low copy repeats A-C). Clinical facial manifestations were found in 12 patients. CONCLUSIONS: This study revealed an unexpected high prevalence of chromosome 22q11.2 variations in patients with CHD even in simple defects. The genotype-phenotype relationship analysis suggests that genetic detection of 22q11.2 may become necessary in all patients with CHD and that detection of unique deletions or amplifications may provide useful insight into personalised management in patients with CHD.

2.
Molecules ; 24(21)2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31661774

RESUMO

Acute kidney injury (AKI) is a common, complex, and severe clinical syndrome characterized by rapid decline in renal function, combined with tissue damage. Currently, the prevention and treatment of AKI are focused on symptomatic treatment, rather than treating the underlying causes. Therefore, there is no specific treatment to prevent renal injury except for renal dialysis. In this study, we used cisplatin-induced AKI mouse and human kidney-2 (HK-2) cell models to evaluate the renal protective effect of eleutheroside B, an active compound in traditional Chinese medicines. MTT assay was used to detect the effect of eleutheroside B on proliferation of human HK-2 cells in presence and in absence of cisplatin. Western blot and immunostaining were used to detect the protein level of kidney injury molecule-1 (KIM-1), cleaved caspase-3, receptor-interacting protein kinase (RIPK)-1, and RIPK-3. Real-time PCR was used to detect the mRNA levels of chemokines (like monocyte chemotactic protein 1, MCP-1) and pro-inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor (TNF-α). Flow cytometry assay was used to detect apoptosis of HK-2 cells. In vivo results showed that eleutheroside B reduced the increase in serum creatinine and blood urea nitrogen (BUN) levels in the AKI model. Periodic acid-Schiff staining and Western blot analysis of KIM-1 showed that eleutheroside B alleviated tubular cell injury. Further, eleutheroside B reduced macrophage infiltration and production of inflammatory cytokines, inhibited the activation of nuclear factor (NF)-κB, and inhibited apoptosis and programmed necrosis. The mechanism may be that eleutheroside B can activate the insulin-like growth factor (IGF) pathway and its downstream pathway by downregulating the expression of IGFBP-7, thus promoting cell proliferation. Therefore, our results suggest that eleutheroside B is a potential drug for AKI treatment.

3.
PLoS One ; 14(9): e0222408, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31513652

RESUMO

BACKGROUND: The widespread use of central venous catheters (CVCs) has exposed patients to a high risk of catheter-related infection (CRI), which is linked to substantial morbidity and mortality. Several strategies for preventing CRI, including ethanol lock prophylaxis, have been explored. This study aimed to provide a comprehensive summary of randomized controlled trials (RCTs) assessing the efficacy and safety of ethanol locks for preventing CRI in patients with CVC. METHODS: We searched six electronic databases, earlier relevant meta-analyses and the reference lists of the included studies for RCTs that assessed the effects of ethanol locks on CRI in patients with CVC versus a control group. Two authors independently assessed the methodological quality of the included studies using the Cochrane Risk of Bias tool and extracted relevant information according to a predesigned extraction form. Data were analyzed using the Cochrane Collaboration's RevMan 5.3. RESULTS: Nine studies involving 2451 patients were included. Although limited in power, the results of the meta-analysis indicated a positive effect of ethanol lock prophylaxis on reducing catheter-related bloodstream infection (CRBSI) compared to heparin alone [OR = 0.53, 95% CI 0.34, 0.82, P = 0.004]. The effects on other outcomes, such as exit site infection, catheter dysfunction, catheter removal, thrombosis and mortality, were not statistically significant (P > 0.05). Moreover, although the effect of ethanol on CRBSI was in the expected direction compared to 0.9% NaCl locks, this effect was not statistically significant (P > 0.05). CONCLUSIONS: The present data indicate that ethanol lock prophylaxis is a potential candidate for the prevention of CRBSI in patients with CVC. However, more attention should be paid to the uniform ethanol lock procedure and toxic effects after long-term ethanol lock exposure.

4.
Mol Cell Biol ; 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527078

RESUMO

Accumulating evidence demonstrated that long non-coding RNAs (lncRNAs) exert essential biological functions in modulating the progression of endometrial carcinoma (EC). HOTAIR has been widely recognized as a crucial mediator in various tumors, including EC. However, the specific molecular mechanism of HOTAIR in the development of EC remains to be further explored. In the present study, we demonstrated that HOTAIR was significantly up-regulated in EC tissues, which was negatively correlated with PTEN, while positively correlated with PI3k and Akt. Overexpression of HOTAIR promoted proliferation and inhibited apoptosis of EC cells, which was similar with PTEN knockdown. Additionally, RNA pull-down demonstrated the direct binding relationship between HOTAIR and PTEN. Furthermore, HOTAIR activated PI3k/Akt pathway to promote EC progression by suppressing PTEN in vivo Taken together, we revealed that high expression of HOTAIR promoted cell proliferation and inhibited apoptosis through activating PI3k/Akt pathway via binding to PTEN, which might proved a prognostic marker and therapeutic target of EC.

5.
EBioMedicine ; 47: 470-483, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31474551

RESUMO

BACKGROUND: NACHT and WD repeat domain-containing protein 1 (Nwd1) is a member of the innate immune protein subfamily. Nwd1 contributes to the androgen receptor signaling pathway and is involved in axonal growth. However, the mechanisms that underlie pathophysiological dysfunction in seizures remain unclear. METHODS: Biochemical methods were used to assess Nwd1 expression and localization in a mouse model of kainic acid (KA)-induced acute seizures and temporal lobe epilepsy (TLE) patients. Electrophysiological recordings were used to measure the role of Nwd1 in regulating synaptic transmission and neuronal hyperexcitability in a model of magnesium-free-induced seizure in vitro. Behavioral experiments were performed, and seizure-induced pathological changes were evaluated in a KA-induced seizure model in vivo. GluN2B expression was measured and its correlation with Tyr1472-GluN2B phosphorylation was analyzed in primary hippocampal neurons. FINDINGS: We demonstrated high protein levels of Nwd1 in brain tissues obtained from mice with acute seizures and TLE patients. Silencing Nwd1 in mice using an adeno-associated virus (AAV) profoundly suppressed neuronal hyperexcitability and the occurrence of acute seizures, which may have been caused by reducing GluN2B-containing NMDA receptor-dependent glutamatergic synaptic transmission. Moreover, the decreased activation of Nwd1 reduced GluN2B expression and the phosphorylation of the GluN2B subunit at Tyr1472. INTERPRETATION: Here, we report a previously unrecognized but important role of Nwd1 in seizure models in vitro and in vivo, i.e., modulating the phosphorylation of the GluN2B subunit at Tyr1472 and regulating neuronal hyperexcitability. Meanwhile, our findings may provide a therapeutic strategy for the treatment of epilepsy or other hyperexcitability-related neurological disorders. FUND: The funders have not participated in the study design, data collection, data analysis, interpretation, or writing of the report.

6.
Pharmacol Res ; 148: 104457, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31536782

RESUMO

Dysregulated host immune homeostasis in sepsis is life-threatening even after a successfully treated bacterial infection. Lipopolysaccharide (LPS) is an endotoxin that is a major contributor to the aberrant immune responses and endotoxic shock in gram-negative bacterial sepsis. However, the current knowledge of the role of B cells in endotoxic shock is limited. Here, we report that CD1d expression in B cells and the percentage of CD5+CD1dhi regulatory B (Breg) cells decreased in a mouse model of endotoxic shock. Interestingly, IL-10 but not FasL expression in CD5+CD1dhi Breg cells in response to endotoxin was dramatically reduced in severe septic shock mice, and the regulatory function of CD5+CD1dhi Breg cells in vitro to control the Th1 response was also diminished. Adoptive transfer of CD5+CD1dhi Breg cells from healthy WT mice but not IL-10 deficient mice downregulated the IFN-γ secretion in CD4+ T cells and conferred protection against severe endotoxic shock in vivo. Our findings demonstrate the change and notable therapeutic potential of IL-10-producing Breg cells in endotoxic shock.

7.
J Agric Food Chem ; 67(39): 10984-10993, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31525294

RESUMO

The objective of the present study was to reveal the effects of four types of nitrogen sources (soymeal, yeast extract, KNO3, and ammonium tartrate) on the lipid metabolism of the oleaginous fungus Mortierella alpina using untargeted lipidomics, targeted fatty acid, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis. Our results showed clear differences in the contents and compositions of lipids between four types of nitrogen sources. Soymeal and ammonium tartrate supplementation favored the accumulation of triglycerides with arachidonic acid (ARA) and C16-18 fatty acids, respectively. These results were further validated by our targeted fatty acid analysis. RT-qPCR analysis of related genes in M. alpina between the four nitrogen source conditions found that soymeal supplementation dramatically increased the expression of GPAT, ELOVL, and Δ12/Δ6 desaturase. Our findings provided new insights into the regulation of lipid biosynthesis in M. alpina and potential avenues for genetic manipulation and highlighted the importance of an optimal nitrogen source for ARA-rich oil production.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Lipídeos/biossíntese , Lipídeos/química , Espectrometria de Massas/métodos , Mortierella/metabolismo , Nitrogênio/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos/biossíntese , Ácidos Graxos/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Mortierella/química , Mortierella/enzimologia , Mortierella/genética
8.
Artigo em Inglês | MEDLINE | ID: mdl-31479235

RESUMO

Biomimetic design has been extensively investigated. The only FDA-approved biomimetic albumin-bound paclitaxel may not be beneficial to some treated patients due to rapid dissociation upon intravenous infusion and no substantial improvement in the drug's pharmacokinetics or biodistribution. Herein, we developed an alternative and injectable preformed albumin-bound anticancer drug delivery. We combined HSA, Kolliphor HS 15 (HS15), and pirarubicin (THP) via purely physical forces in a thin-film hydration method to obtain an albumin-bound complex of HSA-THP. The lack of any chemical reactions preserves HSA bioactivity, in contrast to the destroyed secondary structure within AN-THP (albumin nanoparticle of THP) for the harsh manipulation during preparation. In vitro, HSA-THP showed a significantly higher cellular uptake efficiency than THP, and the complex was more cytotoxic. In vivo, HSA-THP showed longer half-life than THP. It also exhibited greater tumor accumulation and tumor penetration via gp60- and SPARC-mediated biomimetic transport than THP and AN-THP. As a result, HSA-THP showed strong antitumor and antimetastasis efficacy, with relatively little toxicity. These results suggest the clinical potential of biomimetic tumor-targeted drug delivery.

9.
Cell Cycle ; 18(19): 2550-2565, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31438762

RESUMO

In recent years, the impact of microRNAs (miRNAs) on coronary heart disease (CHD) has been identified. This study was aimed to investigate the regulative role of microRNA (miR-429) in myocardial injury of rats with CHD. Expression of miR-429 in CHD patients and healthy people was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The CHD rat models were injected with normal saline, mimics negative control (NC), miR-429 mimics, inhibitors NC and miR-429 inhibitors twice a week, for 4 weeks. Levels of inflammatory factors, oxidative stress indices as well as apoptosis of cardiomyocytes were determined by a series of assays. Expression of miR-429 was up-regulated in CHD patients. Reduced miR-429 could decline the expression of oxidative stress-related factors and inflammation-related factors, and inhibit the apoptosis of cardiomyocytes in rats with CHD. Moreover, the down-regulation of miR-429 could promote the expression of CrkL and repress activation of the MEK/ERK signaling pathway. This study reveals that restrained miR-429 could exert a protective impact on myocardial injury of rats with CHD by suppressing oxidative stress, inflammation reaction and apoptosis of cardiomyocytes. The function mechanisms may relate to the up-regulation of CrkL and inhibition of the MEK/ERK signaling pathway.

10.
Artigo em Inglês | MEDLINE | ID: mdl-31420296

RESUMO

BACKGROUND: The gram-negative bacteria secreted endotoxin, Lipopolysaccharide (LPS), plays important roles in the formation and recurrence of hepatolithiasis and chronic biliary inflammation in patients of Southeast Asia. We aimed to elucidate the anti-inflammatory effect and mechanism of local antibiotics irrigation on chronic proliferative cholangitis (CPC) and hepatolithiasis. METHODS: Escherichia coli was injected into rabbit bile ducts to induce CPC. Rabbits were divided into sham operation (SO), povidone-iodine, Metronidazole plus chlorhexidine, ofloxacin, furacillin, Neosporin® G.U., and CPC groups. Local irrigation was performed for 28 days after CPC was established. Residual E. coli and LPS, and the expression of MCP-1, CD14, COX-2, VEGF, IL-6, NF-κB, TNF-α, Fas, TGF-ß1, α-SMA, Collagen-I, ß-glucuronidase, PKC, C-myc, and Mucin 5AC were assessed in bile duct tissues. RESULTS: The residual E. coli and LPS, and expression of MCP-1, CD14, COX-2, IL-6, NF-κB, TNF-α, Fas, TGF-ß1, α-SMA, ß-glucuronidase, PKC, C-myc, and Mucin 5AC in the SO, povidone-iodine, Metronidazole plus chlorhexidine, ofloxacin, and Neosporin® G.U. groups were significantly lower than those in the furacillin and CPC groups (P<0.05). VEGF and Collagen-I levels in the SO, povidone-iodine, metronidazole plus chlorhexidine, and ofloxacin groups were significantly lower than those in the furacillin, Neosporin® G.U., and CPC groups (P<0.05). CONCLUSIONS: LPS affects the pathophysiology of E. coli caused chronic proliferative cholangitis and hepatolithiasis recurrence. Local antibiotics irrigation could prevent chronic proliferative cholangitis and stones formation by decreasing LPS-induced proinflammatory and profibrotic cytokines release. Povidone iodine, metronidazole plus chlorhexidine, and ofloxacin were more effective than Neosporin® G.U. and furacillin.

11.
Acta Pharmacol Sin ; 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431733

RESUMO

In chronic infectious diseases caused by gram-negative bacteria, such as osteomyelitis, septic arthritis, and periodontitis, osteoclastic activity is enhanced with elevated inflammation, which disturbs the bone homeostasis and results in osteolysis. Lipopolysaccharide (LPS), as a bacteria product, plays an important role in this process. Recent evidence shows that an antimalarial drug artesunate attenuates LPS-induced osteolysis independent of RANKL. In this study we evaluated the effects of artesunate on LPS-induced osteoclastogenesis in vitro and femur osteolysis in vivo, and explored the mechanisms underlying the effects of artesunate on LPS-induced osteoclast differentiation independent of RANKL. In preosteoclastic RAW264.7 cells, we found that artesunate (1.56-12.5 µM) dose dependently inhibited LPS-induced osteoclast formation accompanied by suppressing LPS-stimulated osteoclast-related gene expression (Fra-2, TRAP, Cathepsin K, ß3-integrin, DC-STAMP, and Atp6v0d2). We showed that artesunate (3.125-12.5 µM) inhibited LPS-stimulated nuclear factor of activated T cells c1 (NFATc1) but not NF-κB transcriptional activity; artesunate (6.25, 12.5 µM) significantly inhibited LPS-stimulated NFATc1 protein expression. Furthermore, artesunate treatment markedly suppressed LPS-induced Ca2+ influx, and decreased the expression of PP2B-Aα (calcineurin) and pPLCγ1 in the cells. In addition, artesunate treatment significantly decreased the expression of upstream signals TLR4 and TRAF6 during LPS-induced osteoclastogenesis. Administration of artesunate (10 mg/kg, ip) for 8 days effectively inhibited serum TNF-α levels and ameliorated LPS (5 mg/kg, ip)-induced inflammatory bone loss in vivo. Taken together, artesunate attenuates LPS-induced inflammatory osteoclastogenesis by inhibiting the expression of TLR4/TRAF6 and the downstream PLCγ1-Ca2+-NFATc1 signaling pathway. Artesunate is a valuable choice to treat bone loss induced by gram-negative bacteria infection or inflammation in RANKL-independent pathway.

13.
Cancer Chemother Pharmacol ; 84(4): 861-872, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31428819

RESUMO

BACKGROUND: FK506-binding protein 12 (FKBP12) is abundant, ubiquitously expressed cytoplasmic protein with multiple functions in cell signaling transduction. Recently, we reported a novel function for FKBP12 in oncoprotein mouse double minute 2 (MDM2) self-ubiquitination and degradation, which greatly enhanced the sensitivity of cancer cells to chemotherapy. However, the clinical relevance remains unclear. METHODS: An immunohistochemical analysis of FKBP12 expression was performed in a cohort of 524 patients with invasive breast cancer. The correlations of FKBP12 expression with patient survival and chemoresponse were statistically analyzed. MDA-MB-468 cells were transfected with FKBP12 siRNA or Myc-tagged FKBP12, and then, the tumor cells were treated with doxorubicin followed by western blot, cell viability, and apoptosis assay. RESULTS: The expression of FKBP12 was decreased in breast cancer tissues, and there was a significant correlation between FKBP12 loss and MDM2 overexpression. Furthermore, FKBP12 loss was specifically correlated with poor prognosis and increased resistance to anthracycline-based chemotherapy. Kaplan-Meier survival analysis showed that overall survival (OS) and disease-free survival (DFS) were both significantly lower in the low FKBP12 expression group than those in the high FKBP12 expression group. In patients treated with anthracycline-based preoperative chemotherapy, low FKBP12 expression patients had a significant lower rate of pathologic complete response (pCR). Importantly, these results seemed to be driven mainly by MDM2. These observations were especially prominent in the MDM2-positive subgroup. Univariate and multivariate analyses revealed that FKBP12 loss was an independent factor for predicting prognosis and pCR. In in vitro assay, FKBP12 silence led to significant upregulation of MDM2. Accordingly, MDA-MB-468 cells with FKBP12 silence were less responsive to doxorubicin-induced cytotoxic and apoptotic effect. In contrast, in FKBP12-transfected MDA-MB-468 cells, MDM2 was more greatly inhibited by doxorubicin, resulting in greater cytotoxic and apoptotic effect. CONCLUSIONS: We propose that FKBP12 loss, which can be enhanced by MDM2 overexpression, predicts poor prognosis and chemoresistance. Increasing the expression of FKBP12 may be a valuable strategy to add to anthracycline-based chemotherapy, especially in MDM2-overexpressed patients.

14.
Environ Sci Pollut Res Int ; 26(26): 26472-26487, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31290043

RESUMO

Environmental regulations affect employment through productivity output and factor substitution. This paper employs a difference-in-differences (DID) method to investigate the effect of China's Two Control Zones (TCZ) policy on the urban employment in 287 cities from 1994 to 2009. We apply the DID method to two time points: 1998 for policy issuance and 2000 for the policy implementation. From the results of analyses on full-sample cities, the TCZ policy did not contribute to increasing total urban employment. Moreover, a negative impact on employment resulted from sulfur dioxide and acid rain controls in secondary and tertiary industries, respectively. In the acid rain control zone, the TCZ policy increased the average wage of urban workers. Negative effects on employment were observed in larger cities. The policy triggered labor migration from larger to smaller cities, resulting in significant increases in primary and tertiary industry employment in smaller cities, although the effects on mid-size cities were insignificant. This study provides important empirical evidence and insight into the impact of the TCZ policy on urban employment.

15.
J Org Chem ; 84(16): 10371-10379, 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31318545

RESUMO

An enantioselective palladium-catalyzed hydrogenation of ß-fluoroalkyl ß-amino acrylic acid derivatives has been successfully developed, providing the corresponding chiral ß-fluoroalkyl ß-amino acid derivatives in good yields with excellent enantioselectivities. In addition, chiral γ-fluoroalkyl γ-amino alcohol could be synthesized by a simple reduction of the corresponding hydrogenated product. The mechanism of the reaction was explored by deuterium-labeling experiments.

16.
Genome Biol ; 20(1): 136, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300020

RESUMO

BACKGROUND: Bread wheat is one of the most important and broadly studied crops. However, due to the complexity of its genome and incomplete genome collection of wild populations, the bread wheat genome landscape and domestication history remain elusive. RESULTS: By investigating the whole-genome resequencing data of 93 accessions from worldwide populations of bread wheat and its diploid and tetraploid progenitors, together with 90 published exome-capture data, we find that the B subgenome has more variations than A and D subgenomes, including SNPs and deletions. Population genetics analyses support a monophyletic origin of domesticated wheat from wild emmer in northern Levant, with substantial introgressed genomic fragments from southern Levant. Southern Levant contributes more than 676 Mb in AB subgenomes and enriched in the pericentromeric regions. The AB subgenome introgression happens at the early stage of wheat speciation and partially contributes to their greater genetic diversity. Furthermore, we detect massive alien introgressions that originated from distant species through natural and artificial hybridizations, resulting in the reintroduction of ~ 709 Mb and ~ 1577 Mb sequences into bread wheat landraces and varieties, respectively. A large fraction of these intra- and inter-introgression fragments are associated with quantitative trait loci of important traits, and selection events are also identified. CONCLUSION: We reveal the significance of multiple introgressions from distant wild populations and alien species in shaping the genetic components of bread wheat, and provide important resources and new perspectives for future wheat breeding.


Assuntos
Evolução Biológica , Variação Genética , Genoma de Planta , Hibridização Genética , Triticum/genética , Cromossomos de Plantas , Domesticação , Sequenciamento Completo do Genoma
17.
Food Chem ; 301: 125226, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31357003

RESUMO

The glutenin (Glu) and gliadin (Gli) were modified by protein-glutaminase (PG) to obtain soluble glutenin (PG-Glu) and gliadin (PG-Gli), and PG-Glu or PG-Gli was added to potato starch (PS) according to different amounts (0.5%, 1.0%, and 1.5%, based on dry starch weight, w/w) to explore the effect of modified proteins on the retrogradation behavior and digestibility of PS. The results showed that the long-term retrogradation of PS was accelerated by the addition of PG-Glu or PG-Gli. The addition of PG-Glu or PG-Gli led to an increase in hydrogen bonds within starch molecules and induced a significant increase in resistant starch content. The hydrolysis kinetic parameters, C∞ and K, both decreased with the increasing level of modified protein, indicating the deceleration of hydrolysis rate by the addition of PG-Glu or PG-Gli. In summary, the addition of PG-Glu or PG-Gli could promote the retrogradation of PS and mitigate the digestion of starch.


Assuntos
Digestão , Gliadina/química , Glutaminase/metabolismo , Glutens/química , Solanum tuberosum/química , Amido/química , Amido/metabolismo , Gliadina/metabolismo , Glutens/metabolismo , Hidrólise , Solubilidade
18.
Clin Sci (Lond) ; 133(14): 1609-1627, 2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31315969

RESUMO

Acute kidney injury (AKI) is a destructive clinical condition induced by multiple insults including ischemic reperfusion, nephrotoxic drugs and sepsis. It is characterized by a sudden decline in renal function, in addition to excessive inflammation, oxidative stress and programmed cell death of renal tubular epithelial cells. RIPK1-mediated necroptosis plays an important role in AKI. In the present study, we evaluated the treatment effects of Compound-71 (Cpd-71), a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure-activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, in vivo and in vitro Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the up-regulated serum creatinine (Cr) and blood urea nitrogen (BUN) levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type III ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation and phosphor-MLKL membrane translocation by molecular docking, Western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment.

19.
Food Chem ; 297: 124978, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31253262

RESUMO

Rice glutelin (RG) and phosphorylated rice glutelin (PPRG) were treated with heating for different time (15, 30, and 45 min), the effects of phosphorylation modification on the structure, interactions and rheological properties of rice glutelin during heat treatment were investigated. The results showed that the turbidity of PPRG samples were higher than those of RG samples after heating. Particle size distribution showed that the protein aggregates with particle size of 1000-1500 nm were formed after heating for 45 min. Changes in protein structure indicated that the protein unfolded after heating for a short time, and aggregated when heating time extended to 45 min. In addition, the microstructure of PPRG sample became tight when heated for 45 min. Rheological analysis showed that phosphorylation modification and heat treatment improved RG viscoelasticity. These results suggest that phosphorylation modification improves thermal aggregation of RG, which will facilitate the application of RG in food industry.


Assuntos
Glutens/análise , Estrutura Molecular , Oryza/química , Agregados Proteicos , Reologia , Indústria Alimentícia , Calefação , Temperatura Alta , Tamanho da Partícula , Fosforilação , Viscosidade
20.
Artigo em Chinês | MEDLINE | ID: mdl-31245952

RESUMO

OBJECTIVE: To study the effects of Zuogui Jiangtang Jieyu Formula (ZGJTJYF, the Chinese Medicine) on hippocampal neuron apoptosis in diabetes mellitus complicated with depression (DD). METHODS: The primary cultured hippocampal neurons were treated with high glucose (150 mmol/L) and corticosterone (200 micromol/L) to establish the cell model of DD in vitro. The cultured hippocampal neurons were randomly divided into five groups: blank serum group, normal group, Zuogui Jiangtang Jieyu recipe drug-containing serum group, positive drug (metformin + fluoxetine) drug-containing serum group and model group (three compound holes in each group). The model group and the normal group were given the same amount of culture medium, and the other groups were given the corresponding serum with 10% volume fraction for 18 hours. Hoechst staining, high content cell imaging and RT-PCR were used to detect the apoptosis of hippocampal neurons and the expressions of apoptosis-related ETS-like 1 transcription factor(ELK-1), C-Jun N-terminal kinase(JNK) and c-Fos proteins and genes. RESULTS: Compared with the blank group, the apoptotic number of hippocampal neurons in the model group was increased significantly, and the expression levels of ELK-1, JNK and c-Fos were increased significantly (P<0.05). Compared with the model group, the local bright spots of hippocampal neurons in the Zuogui Jiangtang Jieyu recipe-containing serum group and the positive drug-containing serum group were decreased significantly, and the number of apoptotic cells was decreased significantly. The expressions of JNK, c-fos protein and mRNA were down-regulated significantly (P< 0.05), and the neural network and dendritic junction were improved significantly. CONCLUSION: Zuo Gui Jiang Tang Jie Yu Formula can reverse the expressions of ELK-1, JNK and c-Fos signals in hippocampal neurons under DD environment and play an anti-apoptotic effect.


Assuntos
Depressão , Complicações do Diabetes , Diabetes Mellitus , Medicamentos de Ervas Chinesas , Hipocampo , Animais , Apoptose/efeitos dos fármacos , Depressão/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Hipocampo/efeitos dos fármacos , MAP Quinase Quinase 4/efeitos dos fármacos , Neurônios , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Distribuição Aleatória , Ratos , Proteínas Elk-1 do Domínio ets/efeitos dos fármacos
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