Publications by authors named "Zhuo Ma"

134 Publications

Pericardial Toxicities Associated With Immune Checkpoint Inhibitors: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS) Database.

Front Pharmacol 2021 2;12:663088. Epub 2021 Jul 2.

Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.

Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes for a wide range of cancers but can also lead to serious or fatal immune-related adverse events (irAEs). Although ICI-related pericardial toxicities have been reported, the clinical features are not well characterized in real-world studies. To characterize the main features of ICI-related pericardial toxicities and identify factors associated with death. Data from January 1, 2011 to March 31, 2020 in the FDA Adverse Event Reporting System database were retrieved for disproportionality analysis. We used the reporting odds ratio and the information component (IC) to evaluate the association between ICIs and pericardial adverse events. Clinical characteristics of patients with ICI-associated pericardial toxicities were collected and compared between fatal and non-fatal groups. The time to onset following different ICI regimens was further investigated. We identified a total of 705 ICI-associated pericardial toxicities which appeared to influence more men (53.90%) than women (36.03%), with a median age of 63 (interquartile range [IQR] 54-69) years. Patients with lung cancer accounted for the largest proportion (55.6%). ICI therapies were detected with pharmacovigilance signals of pericardial toxicities, corresponding to IC = 2.11 and ROR 4.87 [4.51-5.25]. Nevertheless, there was a lack of association between anti-CTLA-4 and pericardial toxicities. There was no difference in onset time among all ICI regimens. However, TTO of fatal cases (25 days (interquartile range [IQR] 6-70)) occurred statistically earlier than non-fatal cases (42 days (IQR 12-114), = 0.003). ICI monotherapy (PD-1/PD-L1 therapy) and combination therapy can lead to pericardial toxicities that can result in serious outcomes and tend to occur early. Early recognition and management of ICI-related pericardial disorders should attract clinical attention. The findings require further clinical surveillance for the quantification.
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http://dx.doi.org/10.3389/fphar.2021.663088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283181PMC
July 2021

Thromboembolic events associated with immune checkpoint inhibitors: A real-world study of data from the food and drug administration adverse event reporting system (FAERS) database.

Int Immunopharmacol 2021 Jun 12;98:107818. Epub 2021 Jun 12.

Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing Institute of Respiratory Medicine, Beijing 100020, China. Electronic address:

Background: Although there have been a few studies reporting thromboembolic events (TEEs) in patients treated with immune checkpoint inhibitors (ICIs), the detailed profile of the TEEs and the prothrombotic effects of ICIs remain mostly unknown.

Methods: Data from January 2004 to December 2019 in the FAERS database were retrieved. We investigated the clinical characteristics of the TEEs and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare ICIs with the full database and other anti-cancer agents.

Results: We identified 1855 reports of TEEs associated with ICIs. Affected patients tended to be male (59.68%) and older than 65 (47.12%). The case-fatality rate of the reported TEEs was high (38%). The median time to onset (TTO) of all cases was 42 (interquartile range [IQR] 15-96) days and the median TTO of fatal cases (31 [IQR 13-73] days) was significantly shorter than non-fatal cases (50 [IQR 20-108] days, p = 0.000002). ICIs showed increased risks of VTE (ROR 2.81, 95% CI 2.69-2.95) and ATE (ROR 1.44, 95% CI 1.37-1.52) compared with the full database. Compared with protein kinase inhibitors, ICIs showed an increased risk of VTE (ROR 1.23, 95% CI 1.17-1.29), but only anti-PD-L1 showed an increased risk of cerebral ATE (ROR 1.38, 95% CI 1.08-1.76). Compared with chemotherapy, ICIs showed an increased risk of PE (ROR 1.14, 95% CI 1.07-1.21).

Conclusions: Our study suggested ICIs tend to increase risks of VTE and ATE. The poor clinical outcome and early onset of these events should attract clinical attention.
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http://dx.doi.org/10.1016/j.intimp.2021.107818DOI Listing
June 2021

Resveratrol attenuates manganese-induced oxidative stress and neuroinflammation through SIRT1 signaling in mice.

Food Chem Toxicol 2021 Jul 21;153:112283. Epub 2021 May 21.

Department of Environmental Health, School of Public Health, China Medical University, Address:No.77 Puhe Road, Shenyang North New Area, Shenyang,110122, Liaoning, China. Electronic address:

Exposure to excess levels of manganese (Mn) leads to neurotoxicity. Increasing evidence demonstrates that oxidative stress and neuroinflammation are important pathological causes of neurotoxicity. Resveratrol (Rsv), a sirtuin-1 (SIRT1) activator, plays an important role in neuroprotection. However, the molecular mechanisms of Rsv alleviating Mn-induced oxidative stress and neuroinflammation are not fully understood. To evaluate whether Rsv treatment relieves the oxidative stress and neuroinflammation in the hippocampus after Mn exposure through SIRT1 signaling, C57BL/6 adult mice were exposed to MnCl (200 μmol/kg), Rsv (30 mg/kg), and EX527 (5 mg/kg). Our results showed that administering MnCl for 6 weeks caused behavioral impairment and nerve cell injury in hippocampal tissue, which was related to oxidative stress and neuroinflammation. Activating Mn-induced JNK and inhibiting SIRT1 increased the phosphorylated and acetylated levels of NF-κB and STAT3, respectively. However, Rsv reduced the phosphorylated and acetylated levels of NF-κB and STAT3, and attenuated Mn-induced oxidative stress and inflammatory cytokines by activating SIRT1 signaling. Most importantly, EX527, a potent SIRT1 inhibitor, inactivated SIRT1, which prevented Rsv from exerting its beneficial effects. Taken together, our findings revealed that Rsv alleviated Mn-induced oxidative stress and neuroinflammation in adult mice by activating SIRT1.
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http://dx.doi.org/10.1016/j.fct.2021.112283DOI Listing
July 2021

Risk of pneumonitis in cancer patients treated with PARP inhibitors: A meta-analysis of randomized controlled trials and a pharmacovigilance study of the FAERS database.

Gynecol Oncol 2021 Aug 19;162(2):496-505. Epub 2021 May 19.

Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Chaoyang District, Beijing, China. Electronic address:

Objective/background: We aimed to evaluate the risk of PARP inhibitors (PARPis) causing pneumonitis in randomized controlled trials (RCTs) and in the real-world practice.

Methods: First, a systematic review based on meta-analysis was conducted. RCTs with available data reporting pneumonitis events for PARPis were eligible for analysis. Second, we conducted a disproportionality analysis based on data from the FDA Adverse Event Reporting System (FAERS) database to characterize the main features of PARPi-related pneumonitis.

Results: 16 trials with 5771 patients were included in our meta-analysis. Compared with control arms, PARPis showed a significant increase in the risk of pneumonitis events (Peto OR 2.68 [95% CI 1.31-5.47], p = 0.007) with no heterogeneity (I = 0%, χp = 0.70). The incidence of pneumonitis across treatment arms was 0.79% (28/3551). In the FAERS database, we identified 84 cases of PARPi-pneumonitis with a fatality rate of 16% (13/79). The median time to event onset was 81 (interquartile range [IQR] 27-131) days and 87% of the adverse events occurred within 6 months.

Conclusion: PARPis increased the risk of pneumonitis that can result in serious outcomes and tend to occur early. Early recognition and management of PARPi-pneumonitis is of vital importance in clinical practice. The mechanisms and risk factors should be studied further to improve clinical understanding and innovative treatment strategies for these diseases.
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http://dx.doi.org/10.1016/j.ygyno.2021.05.012DOI Listing
August 2021

A cysteine-selective fluorescent probe for monitoring stress response cysteine fluctuations.

Chem Commun (Camb) 2021 Jun;57(47):5810-5813

CAS Key Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China. and Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China.

Rare studies provided evidence for the real-time monitoring of stress response cysteine fluctuations. Here, we have successfully designed and synthesized a cysteine-selective fluorescent probe 1 to monitor stress response Cys fluctuations, providing visual evidence of Hg2+ regulated cysteine fluctuations for the first time, which may open a new way to help researchers to reveal the mechanism of heavy metal ion poisoning.
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http://dx.doi.org/10.1039/d1cc01110cDOI Listing
June 2021

The overexpression and variant of CYP6G4 associated with propoxur resistance in the housefly, Musca domestica L.

Pest Manag Sci 2021 May 4. Epub 2021 May 4.

Department of Entomology, China Agricultural University, Beijing, China.

Background: The control of the housefly, Musca domestica, heavily relies on the application of insecticides. Propoxur, a carbamate, has been widely used for vector control. The housefly populations with high propoxur resistance display point mutations and overexpression of acetylcholinesterase. However, the roles of cytochrome P450 monoxygenases (P450s), as important detoxification enzymes, remain poorly understand in the housefly resistant to propoxur.

Results: P450s were implied to contribute to propoxur resistance based on the synergism of piperonyl butoxide (PBO) and the increase of P450 enzyme activity in the near-isogenic line propoxur resistant strain (N-PRS). Five P450 genes (CYP6G4, CYP6A25, CYP304A1, CYP6D3, and CYP6A1) by RNA-sequencing comparison were significantly up-regulated in the N-PRS strain with >1035-fold resistance to propoxur. A total of 13 non-synonymous mutations of three P450 genes (CYP6G4, CYP6D3, and CYP6D8) were found in the N-PRS strain. The amino acid substitutions of CYP6D3 and CYP6D8 were probably not resistance-associated single nucleotide polymorphisms (SNPs) because they were also found in the aabys susceptible strain. However, CYP6G4 variant in the N-PRS strain was not found in the aabys strain. The conjoint analysis of mutations and a series of genetic crosses exhibited that the housefly propoxur resistance was strongly associated with the mutations of CYP6G4 gene.

Conclusion: Our results suggested that a combination of up-regulated transcript levels and mutations of CYP6G4 contributed to propoxur resistance in the housefly.
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http://dx.doi.org/10.1002/ps.6461DOI Listing
May 2021

Lenvatinib and osteonecrosis of the jaw: A pharmacovigilance study.

Eur J Cancer 2021 Jun 3;150:211-213. Epub 2021 May 3.

Department of Pharmacy, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China. Electronic address:

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http://dx.doi.org/10.1016/j.ejca.2021.03.046DOI Listing
June 2021

Aim2 and Nlrp3 Are Dispensable for Vaccine-Induced Immunity against Francisella tularensis Live Vaccine Strain.

Infect Immun 2021 Jun 16;89(7):e0013421. Epub 2021 Jun 16.

Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, New York, USA.

Francisella tularensis is a facultative, intracellular, Gram-negative bacterium that causes a fatal disease known as tularemia. Due to its extremely high virulence, ease of spread by aerosolization, and potential to be used as a bioterror agent, F. tularensis is classified by the CDC as a tier 1 category A select agent. Previous studies have demonstrated the roles of the inflammasome sensors absent in melanoma 2 (AIM2) and NLRP3 in the generation of innate immune responses to F. tularensis infection. However, contributions of both the AIM2 and NLRP3 to the development of vaccine-induced adaptive immune responses against F. tularensis are not known. This study determined the contributions of Aim2 and Nlrp3 inflammasome sensors to vaccine-induced immune responses in a mouse model of respiratory tularemia. We developed a model to vaccinate Aim2- and Nlrp3-deficient ( and ) mice using the mutant of the F. tularensis live vaccine strain (LVS). The results demonstrate that the innate immune responses in and mice vaccinated with the mutant differ from those of their wild-type counterparts. However, despite these differences in the innate immune responses, both and mice are fully protected against an intranasal lethal challenge dose of F. tularensis LVS. Moreover, the lack of both Aim2 and Nlrp3 inflammasome sensors does not affect the production of vaccination-induced antibody and cell-mediated responses. Overall, this study reports a novel finding that both Aim2 and Nlrp3 are dispensable for vaccination-induced immunity against respiratory tularemia caused by F. tularensis.
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http://dx.doi.org/10.1128/IAI.00134-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208512PMC
June 2021

Manganese-induced alpha-synuclein overexpression aggravates mitochondrial damage by repressing PINK1/Parkin-mediated mitophagy.

Food Chem Toxicol 2021 Jun 20;152:112213. Epub 2021 Apr 20.

Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang 110122, Liaoning, China. Electronic address:

Chronic manganese (Mn) exposure is related to elevated risks of neurodegenerative diseases, and mitochondrial dysfunction is considered a critical pathophysiological feature of Mn neurotoxicity. Although previous research has demonstrated Mn-induced alpha-synuclein (α-Syn) overexpression, the role of α-Syn in mitochondrial dysfunction remains unclear. Here, we used Wistar rats and human neuroblastoma cells (SH-SY5Y cells) to elucidate the molecular mechanisms underlying how α-Syn overexpression induced by different doses of Mn (15, 30, and 60 mg/kg) results in mitochondrial dysfunction. We found that Mn-induced neural cell injury was associated with mitochondrial damage. Furthermore, Mn upregulated α-Syn protein levels and increased the interaction between α-Syn and mitochondria. We then used a lentivirus vector containing α-Syn shRNA to examine the effect of Mn-induced α-Syn protein on PINK1/Parkin-mediated mitophagy in SH-SY5Y cells. Our data demonstrated that the knockdown of α-Syn decreased the interaction between α-Syn and PINK1. The enhanced level of phosphorylated Parkin (p-Parkin) was due to the decrease of the interaction between α-Syn and PINK1. Moreover, the knockdown of α-Syn increased recruitment of p-Parkin to mitochondria. Collectively, these observations revealed that Mn-induced α-Syn overexpression repressed PINK1/Parkin-mediated mitophagy and exacerbated mitochondrial damage.
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http://dx.doi.org/10.1016/j.fct.2021.112213DOI Listing
June 2021

Chromosome Unipolar Division and Low Expression of May Cause Parthenogenesis of Rice Water Weevil ( Kuschel).

Insects 2021 Mar 24;12(4). Epub 2021 Mar 24.

Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.

Rice water weevil (RWW) is divided into two types of population, triploid parthenogenesis and diploid bisexual reproduction. In this study, we explored the meiosis of triploid parthenogenesis RWW (Shangzhuang Town, Haidian District, Beijing, China) by marking the chromosomes and microtubules of parthenogenetic RWW oocytes via immunostaining. The immunostaining results show that there is a canonical meiotic spindle formed in the triploid parthenogenetic RWW oocytes, but chromosomes segregate at only one pole, which means that there is a chromosomal unipolar division during the oogenesis of the parthenogenetic RWW. Furthermore, we cloned the conserved sequences of parthenogenetic RWW and , and designed primers based on the parthenogenetic RWW sequence to detect expression patterns by quantitative PCR (Q-PCR). Q-PCR results indicate that the expression of and in ovarian tissue of bisexual is 0.98 and 10,000.00 times parthenogenetic RWW, respectively ( < 0.01). The results show that had low expression in parthenogenetic RWW ovarian tissue, and was expressed normally. Our study suggests that the chromosomal unipolar division and deletion of may cause parthenogenesis in RWW.
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http://dx.doi.org/10.3390/insects12040278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064085PMC
March 2021

Islet organoid as a promising model for diabetes.

Protein Cell 2021 Mar 10. Epub 2021 Mar 10.

National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.

Studies on diabetes have long been hampered by a lack of authentic disease models that, ideally, should be unlimited and able to recapitulate the abnormalities involved in the development, structure, and function of human pancreatic islets under pathological conditions. Stem cell-based islet organoids faithfully recapitulate islet development in vitro and provide large amounts of three-dimensional functional islet biomimetic materials with a morphological structure and cellular composition similar to those of native islets. Thus, islet organoids hold great promise for modeling islet development and function, deciphering the mechanisms underlying the onset of diabetes, providing an in vitro human organ model for infection of viruses such as SARS-CoV-2, and contributing to drug screening and autologous islet transplantation. However, the currently established islet organoids are generally immature compared with native islets, and further efforts should be made to improve the heterogeneity and functionality of islet organoids, making it an authentic and informative disease model for diabetes. Here, we review the advances and challenges in the generation of islet organoids, focusing on human pluripotent stem cell-derived islet organoids, and the potential applications of islet organoids as disease models and regenerative therapies for diabetes.
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http://dx.doi.org/10.1007/s13238-021-00831-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943334PMC
March 2021

Bedaquiline-containing regimens in patients with pulmonary multidrug-resistant tuberculosis in China: focus on the safety.

Infect Dis Poverty 2021 Mar 19;10(1):32. Epub 2021 Mar 19.

Department of Tuberculosis, The Second Affiliated Hospital of Hainan Medical University, Haikou, People's Republic of China.

Background: World Health Organization recommends countries introducing new drug and short treatment regimen for drug resistant tuberculosis (DR-TB) should develop and implement a system for active pharmacovigilance that allows for detection, reporting and management of adverse events. The aim of the study is to evaluate the frequency and severity of adverse events (AEs) of bedaquiline-containing regimen in a cohort of Chinese patients with multidrug-resistant (MDR)/extensively drug-resistant (XDR)-TB based on active drug safety monitoring (aDSM) system of New Drug Introduction and Protection Program (NDIP).

Methods: AEs were prospectively collected with demographic, bacteriological, radiological and clinical data from 54 sites throughout China at patient enrollment and during treatment between February, 2018 and December, 2019. This is an interim analysis including patients who are still on treatment and those that have completed treatment. A descriptive analysis was performed on the patients evaluated in the cohort.

Results: By December 31, 2019, a total of 1162 patients received bedaquiline-containing anti-TB treatment. Overall, 1563 AEs were reported, 66.9% were classified as minor (Grade 1-2) and 33.1% as serious (Grade 3-5). The median duration of bedaquiline treatment was 167.0 [interquartile range (IQR): 75-169] days. 86 (7.4%) patients received 36-week prolonged treatment with bedaquiline. The incidence of AEs and serious AEs was 47.1% and 7.8%, respectively. The most frequently reported AEs were QT prolongation (24.7%) and hepatotoxicity (16.4%). There were 14 (1.2%) AEs leading to death. Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 3.1% (32/1044) experienced a post-baseline QTcF ≥ 500 ms, and 15.7% (132/839) had at least one change of QTcF ≥ 60 ms from baseline. 49 (4.2%) patients had QT prolonged AEs leading to bedaquiline withdrawal. One hundred and ninety patients reported 361 AEs with hepatotoxicity ranking the second with high occurrence. Thirty-four patients reported 43 AEs of hepatic injury referred to bedaquiline, much lower than that referred to protionamide, pyrazinamide and para-aminosalicylic acid individually.

Conclusions: Bedaquiline was generally well-tolerated with few safety concerns in this clinical patient population without any new safety signal identified. The mortality rate was generally low. These data inform significant positive effect to support the WHO recent recommendations for the wide use of bedaquiline.
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http://dx.doi.org/10.1186/s40249-021-00819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7977294PMC
March 2021

Cropland connectivity affects genetic divergence of Colorado potato beetle along an invasion front.

Evol Appl 2021 Feb 8;14(2):553-565. Epub 2020 Oct 8.

Key Laboratory of Zoological Systematics and Evolution Institute of Zoology Chinese Academy of Sciences Beijing China.

The population genetic structure of invasive species can be strongly affected by environmental and landscape barriers to dispersal. Disentangling the relative contributions of these factors to genetic divergence among invading populations is a fundamental goal of landscape genetics with important implications for invasion management. Here, we relate patterns of genetic divergence in a global invasive agricultural pest, Colorado potato beetle (CPB; ), to environmental and landscape factors along an invasion front in Northwestern China. We first used microsatellite markers and spatial-temporal samples to assess broad patterns of genetic diversity as well as fine-scale changes in patterns of genetic divergence. We then distinguished the relative contributions of five factors to genetic divergence among front populations: geographic distance (isolation by distance), climate dissimilarity (isolation by environment), and least-cost distances (isolation by resistance) modeled with three factors: climate suitability, cropland cover, and road networks. Genetic diversity broadly decreased from West to East, with the exception being Eastern China. Low levels of genetic diversity and varying degrees of divergence were observed in Northwestern China, reflecting the potential effect of landscape heterogeneity. Least-cost distance across cropland cover was most positively correlated with genetic divergence, suggesting a role of croplands in facilitating gene flow. The contribution of climate to genetic divergence was secondary, whether modeled in terms of local adaptability or connectivity of the climatic landscape, suggesting that constraints to CPB gene flow imposed by a harsh climate may be ameliorated in agricultural landscapes. No evidence was found for an obvious effect of road networks on genetic divergence and population structuring. Our study provides an example of how agricultural landscape connectivity can facilitate the spread of invasive pests, even across a broad climatic gradient. More broadly, our findings can guide decisions about future land management for mitigating further spread.
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http://dx.doi.org/10.1111/eva.13140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896701PMC
February 2021

Association of Gene Polymorphisms and Amlodipine-Induced Peripheral Edema in Chinese Han Patients with Essential Hypertension.

Pharmgenomics Pers Med 2021 2;14:189-197. Epub 2021 Feb 2.

Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People's Republic of China.

Background: Amlodipine is one of the most used members of calcium channel blockers (CCB), available to treat hypertension. It is mainly metabolized by the Cytochrome P450 3A4/5 (CYP3A4/5) in the liver. Peripheral edema emerges as the major adverse drug reaction to amlodipine and is the primary reason for discontinuation of amlodipine therapy. However, genetic changes in may lead to changes in the tolerability of amlodipine.

Purpose: In this study, we were interested whether variants in CYP3A5 have a role to play in amlodipine-induced peripheral edema.

Methods: A total number of 240 Chinese Han patients that have experienced hypertension were included in the study. Sixty-four patients had experienced amlodipine-induced peripheral edema, while the remaining 176 patients with no history of edema formed the control group. Twenty-four single-nucleotide polymorphisms (SNPs) of gene were sequenced by targeted region sequencing method. The relationship of these genetic variants with amlodipine-induced peripheral edema risk was assessed using logistic regression.

Results: The allele frequencies of (rs15524), (rs4646453) and (rs776746) were significantly different between cases and controls (<0.05). The (CC) or (AA) carriers showed an increased risk of amlodipine-induced peripheral edema in dominant model. Meanwhile, patients carrying (AC/AA) showed a reduced risk of peripheral edema. Furthermore, we found a strong linkage disequilibrium among rs15524, rs4646453 and rs776746.

Conclusion: Our study reveals for the first time that and were associated with amlodipine-induced peripheral edema in Chinese Han patients with hypertension. However, further studies comprising larger number of samples, more related genes and other factors are wanted.
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http://dx.doi.org/10.2147/PGPM.S291277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866951PMC
February 2021

The Association of Metabolic Syndrome with the development of cardiovascular disease among Kazakhs in remote rural areas of Xinjiang, China: a cohort study.

BMC Public Health 2021 01 26;21(1):216. Epub 2021 Jan 26.

Department of Public Health, Shihezi University School of Medicine, Shihezi, 832000, Xinjiang, China.

Background: Metabolic syndrome (MS) can promote the development of cardiovascular disease (CVD). The objective of this study was to examine the association of MS and its components with CVD, to further prevent and control CVD in Kazakhs.

Methods: In the cohort study, a total of 2644 participants completed the baseline survey between April 2010 and December 2012.The follow-up survey was conducted from April 2016 to December 2016 and was completed by 2286 participants (86.46% follow-up rate). Cox regression was used to evaluate the association of each component and the number of combinations of MS components on the development of CVD.

Results: A total of 278 CVD patients were enrolled from rural residents of Xinjiang. The average age of the MS and non-MS groups was 46.33 and 38.71 years, respectively. Independent associations with CVD were found for elevated blood pressure (BP) (adjusted hazard ratio (HR) [aHR] = 1.50,95%confidence interval [CI]: 1.08-2.08), elevated waist circumference (WC) (aHR = 1.60, 95%CI: 1.19-2.15), and elevated triglycerides (TG) (aHR = 1.44, 95%CI: 1.04-2.01). Participants with one to 5 MS components had an increased HR for developing CVD, from 1.82to 8.59 (P for trend < 0.001), compared with those with no MS components. The risk of developing CVD increased when TG and WC coexisted (aHR = 2.16, 95%CI: 1.54-3.04)), when TG and BP coexisted ((aHR = 1.92, 95%CI: 1.32-2.79), and when WC and BP coexisted (aHR = 1.93, 95%CI: 1.33-2.82)). However, no significant interactions were found between BP, WC, and TG.

Conclusions: Elevations of BP, WC, and TG were independent risk factors for CVD in Kazakhs. Control of these factors is important to prevent CVD in this population.
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http://dx.doi.org/10.1186/s12889-021-10241-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836449PMC
January 2021

Impact of pharmacist-led medication therapy management in ambulatory elderly patients with chronic diseases.

Br J Clin Pharmacol 2021 Jul 20;87(7):2937-2944. Epub 2021 Jan 20.

Department of Pharmacy, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.

Aims: This study aimed to assess the impact of pharmacist-led medication therapy management (MTM) performed on ambulatory elderly patients with chronic diseases.

Methods: Patients who came to a pharmacist-led outpatient clinic between January 2016 and June 2018 were enrolled in this study. Eligible subjects received MTM services from the pharmacists at least twice a year and the clinical data of these patients were complete. Drug-related problems (DRPs) and recommendations were evaluated using The Pharmaceutical Care Network Europe Classification for Drug related problems V8.03.

Results: A total of 525 DRPs were identified during the study period. Treatment effectiveness (53.71%) was the most common DRP. The most frequently recommended intervention was changing the drug (48.76%). There were 92.38% patients accepting the interventions and 90.48% patients completely implemented. The number of drugs taken was the significant associated factor for DRPs. Postintervention data collection showed lower levels in systolic blood pressure (BP) and diastolic BP compared to the preintervention data collection. There were statistically significant changes in total cholesterol, low-density lipoprotein cholesterol and triglycerides between the pre- and postintervention data collections. The average cost of medications per patient for every month decreased from 387.72 to 355.17 renminbi (P = .009).

Conclusion: We confirmed that pharmacists had a valuable role to perform MTM services for ambulatory elderly patients, not only in identifying and solving the DRPs, but also in improving clinical outcomes (BP and lipid level) and cost-saving effect.
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http://dx.doi.org/10.1111/bcp.14709DOI Listing
July 2021

Coaxial [email protected] Carbon Nanofibers Derived Hierarchical Electrodes for Efficient H Production Urea Electrolysis.

ACS Appl Mater Interfaces 2021 Jan 13;13(3):3937-3948. Epub 2021 Jan 13.

Key Laboratory of Micro-Systems and Microstructures Manufacturing, Ministry of Education, Harbin Institute of Technology, Harbin 150080, P. R. China.

Electrochemical water splitting into hydrogen is a promising strategy for hydrogen production powered by solar energy. However, the cell voltage of an electrolyzer is still too high for practical application, which is mainly limited by the sluggish oxygen evolution reaction process. To this end, hybrid water electrolyzers have drawn tremendous attention. Herein, coaxial Ni/[email protected] nanofibers are directly grown on nickel foam (NF), which is highly active for hydrogen evolution reaction. Meanwhile, the [email protected] nanofibers on NF prepared in an Ar atmosphere display superior urea oxidation reaction performance to previously reported catalysts. The cell voltage is about 1.50 V in urea electrolysis to deliver a current density of 20 mA cm, lower than that of a traditional water electrolyzer (1.82 V). The current density is around 77% relative to its initial value of 20 mA cm after 20 h, superior to Pt/C|Ir/C-based urea electrolysis (14%). It is found that the synergistic effect between metallic Ni and NiS, as well as the interfacial effect between metal centers and N-doped carbon, favors the initial dissociation of HO and the adsorption/desorption of H* with thermal neutral Gibbs free energy. Meanwhile, the in-situ generated NiOOH on the outer surface of NiS possessed lower electrochemical activation energy for urea decomposition. Meanwhile, the abundant oxygen vacancies in electrodes could expose more active sites for the adsorption of intermediates, including H* and OOH*. It is also found that the hierarchical nanostructure of densely packed nanowires provides ideal electronic and ionic transport paths for fast electrocatalytic kinetics. The present work indicated that the modulation of compositions and hierarchical nanostructure is effective to prepare efficient catalysts for H production urea electrolysis.
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http://dx.doi.org/10.1021/acsami.0c19117DOI Listing
January 2021

One-pot method based on deep eutectic solvent for extraction and conversion of polydatin to resveratrol from Polygonum cuspidatum.

Food Chem 2021 May 11;343:128498. Epub 2020 Nov 11.

Key Laboratory of Fermentation Engineering (Ministry of Education), Bioengineering and Food College, Hubei University of Technology, Wuhan, Hubei, China; National 111 Center for Cellular Regulation and Molecular Pharmaceutics, Wuhan, Hubei, China. Electronic address:

The acquisition of resveratrol from Polygonum cuspidatum is complicated and costs organic solvents due to extraction and hydrolysis of its corresponding glycoside (polydatin). In this work, a novel one-pot method based on deep eutectic solvent (DES) was developed for simultaneous extraction and conversion of polydatin to resveratrol from Polygonum cuspidatum for the first time. The extraction yield of resveratrol by DES-based one-pot method were significantly higher than that of water, methanol and ethanol. After optimization by One-Variable-at-a-Time and response surface methodology, the extraction yield of resveratrol reached 12.26 ± 0.14 mg/g within 80 min. The conversation efficiency of polydatin to resveratrol in Polygonum cuspidatum from five different origins was more than 96.3%. Scanning electron microscope results indicated the selected DES disrupted plant cell walls to enhance the yield of resveratrol. The results indicated that one green method was successfully established for efficient extraction and conversion of polydatin to resveratrol from Polygonum cuspidatum.
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http://dx.doi.org/10.1016/j.foodchem.2020.128498DOI Listing
May 2021

Magnetic double-network composite capable of large recoverable deformation.

Soft Matter 2021 Jan 12;17(3):554-562. Epub 2020 Nov 12.

Department of Mechanics and Aerospace Engineering, Southern University of Science and Technology, Shenzhen 518055, China. and Soft Matter GI-CoRE, Hokkaido University, Sapporo 060-0810, Japan.

This paper presents the design and fabrication of a magnetic double network (DN) composite, which consists of permanent magnet chains embedded in an elastomer matrix, and was capable of large yet fully recoverable deformation. The initially connected magnets served as reusable sacrificial components in the composite. The strong magnetic attraction between neighboring magnetics endowed the composite with the high strength while the compliance of the elastomer matrix provided the high extensibility. Having a similar mechanism as DN gels, the composite was found to be significantly tougher than either of the constituents. The nonlinear behavior in the composite separated it into two coexisting phases - a softer phase with separated magnet links and a stiffer phase with connected magnet links - which led to the stress plateau on the tensile curve. Further stretching was manifested by the growth of the disconnected softer phase at the expense of the linked stiffer phase, until all magnets were separated. The unloading curves appeared drastically different from the loading curves, as the force needed to separate two magnets was much higher than the force at which two separated magnets snapped back. Such asymmetry between loading and unloading was the main cause of the hysteresis in the stress-strain curve and the energy dissipation. To further understand the physical mechanism and the damage process of the magnetic DN composite, a simple model was developed to examine the deformation and damage dissipation process of composite. With very few parameters, the model predictions agree qualitatively with the measured properties of the material, and the difference can be further reduced by accounting for the interfacial friction/adhesion, a second means of energy dissipation. With a combination of desired properties including high stretchability, self-healing, and high toughness, the magnetic DN composite is a viable candidate for various applications.
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http://dx.doi.org/10.1039/d0sm01613fDOI Listing
January 2021

Therapeutic Erythrocytapheresis Is Effective in Treating High Altitude Polycythemia on the Qinghai-Tibet Plateau.

Wilderness Environ Med 2020 Dec 29;31(4):426-430. Epub 2020 Oct 29.

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shigatse People's Hospital, Tibet, China. Electronic address:

Introduction: High altitude polycythemia (HAPC) is a common chronic disease at high altitudes. It is characterized by excessive erythrocytosis (≥190 g·L in females or ≥210 g·L in males). HAPC severely jeopardizes the health status of plateau dwellers. The Qinghai-Tibet plateau, with an elevation above 4000 m, is the highest plateau in the world. Both Han and Tibetan populations residing there face the threat of HAPC. Therapeutic erythrocytapheresis (TE) was introduced to Tibet as an alternative to phlebotomy in 2015.

Methods: In this study, we retrospectively analyzed 155 patients with HAPC treated with TE in Tibet. Routine blood testing values before and after TE were compared to evaluate treatment efficacy. The efficiency rate, defined as the rate of increase in red blood cell depletion attained by TE compared with 450 mL whole blood phlebotomy, was calculated using whole blood volume and hematocrit before and after treatment and used to identify patients who maintained a normal hemoglobin level in the year after the TE procedure.

Results: On average, TE reduced red blood cell levels by 1.5×10·L, hemoglobin concentration by 52 g·L, and hematocrit by 14% (P<0.001 for each). Patients who underwent TE with an efficiency rate ≥1.9 were more likely to maintain a normal hemoglobin level in the following year than those who underwent TE with an efficiency rate <1.9 (90 vs 28%, P<0.01).

Conclusions: TE is a feasible therapeutic method to treat HAPC on the Qinghai-Tibet plateau. The efficiency rate is a useful tool to predict the expected interval between TE procedures.
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http://dx.doi.org/10.1016/j.wem.2020.07.006DOI Listing
December 2020

Production of high sensory quality Shiitake mushroom (Lentinus edodes) by pulsed air-impingement jet drying (AID) technique.

Food Chem 2021 Mar 5;341(Pt 2):128290. Epub 2020 Oct 5.

College of Food Science & Nutritional Engineering, China Agricultural University, Beijing 100083, China; National Engineering Research Centre for Fruit and Vegetable Processing, Key Laboratory of Fruit and Vegetable Processing, Ministry of Agriculture and Rural Affairs, Beijing 100083, China; Beijing Key Laboratory for Food Nonthermal Processing, Beijing 100083, China; Xinghua Industrial Research Centre for Food Science and Human Health, China Agricultural University, Xinghua 225700, Jiangsu, China. Electronic address:

The effect of pulsed air-impingement jet drying (AID) on the sensory qualities of Shiitake mushroom was comprehensively examined compared with hot air drying (HAD) and vacuum freeze-drying (VFD). AID considerably improved the characteristic flavors (onion-like odor and umami) of dried mushrooms by partially inhibiting enzymatic and Maillard reactions. The texture characteristics (rehydration and shrinkage) of AID mushrooms had no significant difference to VFD ones and were better than HAD ones. AID combined the advantages of HAD and VFD technologies and outperformed HAD and VFD in terms of overall quality, though the total content of free amino acids and soluble sugars of AID mushrooms dropped slightly. In summary, AID is a promising drying technology for obtaining high sensory quality Shiitake mushrooms compared to prevailing drying methods.
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http://dx.doi.org/10.1016/j.foodchem.2020.128290DOI Listing
March 2021

Alpha-synuclein is involved in manganese-induced spatial memory and synaptic plasticity impairments via TrkB/Akt/Fyn-mediated phosphorylation of NMDA receptors.

Cell Death Dis 2020 10 8;11(10):834. Epub 2020 Oct 8.

Department of Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, 110122, Shenyang, Liaoning Province, People's Republic of China.

Manganese (Mn) overexposure produces long-term cognitive deficits and reduces brain-derived neurotrophic factor (BDNF) in the hippocampus. However, it remains elusive whether Mn-dependent enhanced alpha-synuclein (α-Syn) expression, suggesting a multifaceted mode of neuronal toxicities, accounts for interference with BDNF/TrkB signaling. In this study, we used C57BL/6J WT and α-Syn knockout (KO) mice to establish a model of manganism and found that Mn-induced impairments in spatial memory and synaptic plasticity were related to the α-Syn protein. In addition, consistent with the long-term potentiation (LTP) impairments that were observed, α-Syn KO relieved Mn-induced degradation of PSD95, phosphorylated CaMKIIα, and downregulated SynGAP protein levels. We transfected HT22 cells with lentivirus (LV)-α-Syn shRNA, followed by BDNF and Mn stimulation. In vitro experiments indicated that α-Syn selectively interacted with TrkB receptors and inhibited BDNF/TrkB signaling, leading to phosphorylation and downregulation of GluN2B. The binding of α-Syn to TrkB and Fyn-mediated phosphorylation of GluN2B were negatively regulated by BDNF. Together, these findings indicate that Mn-dependent enhanced α-Syn expression contributes to further exacerbate BDNF protein-level reduction and to inhibit TrkB/Akt/Fyn signaling, thereby disturbing Fyn-mediated phosphorylation of the NMDA receptor GluN2B subunit at tyrosine. In KO α-Syn mice treated with Mn, spatial memory and LTP impairments were less pronounced than in WT mice. However, the same robust neuronal death was observed as a result of Mn-induced neurotoxicity.
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http://dx.doi.org/10.1038/s41419-020-03051-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545185PMC
October 2020

Propofol Attenuates Inflammatory Damage via Inhibiting NLRP1-Casp1-Casp6 Signaling in Ischemic Brain Injury.

Biol Pharm Bull 2020 ;43(10):1481-1489

China-Japan Union Hospital of Jilin University.

Stroke is a common cerebrovascular disease. Inflammation-induced neuronal death is one of the key factors in stroke pathology. Propofol has been shown to ameliorate neuroinflammatory injury, but the exact mechanism of its neuroprotective role remains to be fully elucidated. In the present study, we found that inflammation was activated in ischemic cortical neurons, and the expression of nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 1 (NLRP1), NLRP3 inflammasome and effectors in primary cortical neurons increased. However, we found that propofol could inhibit the increased expression of NLRP1 and NLRP3 inflammasome induced by oxygen-glucose deprivation (OGD). Furthermore, the effector molecule caspase-1 (casp1) was revealed to be the downstream target of NLRP1 and propofol repressed the activation of caspase-1 via inhibiting NLRP1 in cortical neurons. Moreover, propofol inhibits caspase-6 activation in neurons through the NLRP1-caspase-1 pathway. Once the expression of caspase6 increases, propofol reduced its neuroprotective effect in OGD-treated cortical neurons. In the stroke middle cerebral artery occlusion (MCAO) model, infusion of caspase-6 inhibitors enhanced the protective effect of propofol on infarct size and neurological function. In conclusion, our results suggest that propofol plays a neuroprotective role in stroke by inhibiting the inflammatory pathway of NLRP1-caspase-1-caspase-6. Overall, these data suggest that propofol plays a key role in the inflammatory-dependent pathway after stroke, providing an important evidence for propofol as an effective strategy for neuroprotection in stroke.
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http://dx.doi.org/10.1248/bpb.b20-00050DOI Listing
July 2021

Characteristics of drug-related problems and pharmacists' interventions in a geriatric unit in China.

Int J Clin Pharm 2021 Feb 29;43(1):270-274. Epub 2020 Aug 29.

Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.

Background Data is lacking on the characteristics of drug-related problems in Chinese elderly inpatients and the impacts of clinical pharmacy activities in the geriatric ward in China. Objective To describe the nature of drug-related problems in elderly inpatients based on the Pharmaceutical Care Network Europe classification, and identify the correlates of the drug-related problems. Setting Geriatric ward of a tertiary hospital in Beijing, China. Method Pharmacists reviewed medication orders over a 12-month period with drug-related problems and interventions documented. Drug-related problems were categorized respectively according to the Pharmaceutical Care Network Europe classification. A multivariate logistic regression analysis was carried out to determine factors associated with drug-related problems. Main outcome measure The causes, interventions proposed and risk factors of potential drug-related problems. Results A total of 335 interventions associated with possible drug-related problems for 184 older patients were recorded. The incidence of patients experiencing at least one drug-related problem was 34.5%. Drug therapy problems were most commonly classified within the treatment effectiveness domain. Drug selection accounted for most cause of possible drug-related problems. The most common intervention was starting a drug and the acceptance rate was 91.9%. The factors associated with drug-related problems were the number of prescribed medications, Charlson Comorbidity Index and length of stay (P < 0.05). Conclusion Drug-related problems are common in elderly inpatients. Clinical pharmacy service is necessary to the optimization of drug therapy in older inpatients.
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http://dx.doi.org/10.1007/s11096-020-01128-8DOI Listing
February 2021

"Political blue sky" in fog and haze governance: evidence from the local major international events in China.

Environ Sci Pollut Res Int 2021 Jan 21;28(1):775-788. Epub 2020 Aug 21.

School of Economics and Management, China University of Geosciences, No. 388 Lumo Road, Wuhan, 430074, Hubei, China.

The trade-off between economic development and environmental protection has always been a significant and tough issue for local governments. Studies found that some local governments took temporary measures to control air pollution and created "political blue sky" in certain periods. We collected daily air quality index (AQI) data and individual pollutant concentration data of four cities in China which have hosted major international events in 2019. The air quality of the cities taken temporary measures to control air pollution had an obvious improvement during the events. Furthermore, the improvement mainly occurred in pollution indicators, such as PM and PM, which are more valued and sensitive to the public. The sustainability analysis demonstrates that the air quality deteriorated again after the event, indicating that "political blue sky" comes at the cost of retaliatory pollution.
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http://dx.doi.org/10.1007/s11356-020-10483-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441305PMC
January 2021

Corrigendum to "Resveratrol prevents benzo(a)pyrene-induced disruption of mitochondrial homeostasis via the AMPK signaling pathway in primary cultured neurons" [Environ. Pollut. 261 (2020) 114207].

Environ Pollut 2020 10;265(Pt A):115331

Department of Environmental Health, School of Public Health, China Medical University, Shenyang, 110122, Liaoning, China. Electronic address:

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http://dx.doi.org/10.1016/j.envpol.2020.115331DOI Listing
October 2020

Potentially inappropriate medications and potentially prescribing omissions in Chinese older patients: Comparison of two versions of STOPP/START.

J Clin Pharm Ther 2020 Dec 10;45(6):1405-1413. Epub 2020 Aug 10.

Pharmacy Department of Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.

What Is Known And Objective: The aim of this study was to compare the prevalence of potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) in elderly Chinese patients identified by the Screening Tool of Older Persons' Prescriptions/Screening Tool to Alert to Right Treatment (STOPP/START) version 2 (v2) and version 1 (v1). The secondary objective was to analyse the risk factors associated with the PIMs/PPOs.

Methods: This was a retrospective cross-sectional study, and all patients were aged ≥65 years and discharged from internal medical wards of Beijing Chaoyang Hospital in December 2018. STOPP/START v2 and STOPP/START v1 were used to detect PIMs/PPOs. The concordance between the two versions was calculated using kappa tests. A logistic regression analysis was carried out to determine variables independently associated with PIM/PPO use.

Results And Discussion: In the 662 patients included, the median age was 73 years and 361 were male (54.53%). PIMs were present in 36.1% and 47.7% of participants according to the STOPP v1 and STOPP v2, respectively. The prevalence of PPOs was 42.0% and 64.2% according to the START v1 and START v2, respectively. Drug prescribed without indication was the most common item in PIMs, whereas ACEIs were the drugs most frequently involved with PPOs according to the STOPP/START v2. Two versions of the STOPP criteria indicated a moderate coherence, whereas two versions of the START criteria showed poor accordance. Age (OR 1.029, 1.004-1.054), gender (OR 1.536, 1.103-2.138) and the number of prescribed medications (<5: OR 1; 5-9: OR 2.503, 1.173-5.342; ≥10: OR 4.324, 2.204-9.235) were associated factors with PIMs identified by the STOPP v2, whereas PPOs identified by the START v2 were independently associated with age (OR 1.039, 1.012-1.066), activities of daily living (ADL) score (OR 2.713, 1.818-4.048), the number of prescribed medications (<5: OR 1; 5-9: OR 2.704, 1.524-4.795; ≥10: OR 3.075, 1.704-5.549) and Charlson Comorbidity Index (OR 1.302, 1.110-1.529).

What Is New And Conclusion: This study showed a high prevalence of PIMs/PPOs in aged internal medical ward inpatients in China, which was associated with various correlates. The STOPP/START v2 had a higher detection rate than v1.
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http://dx.doi.org/10.1111/jcpt.13237DOI Listing
December 2020

Oxygen Vacancy-rich Ni/[email protected] Nanosheets with Schottky Heterointerface for Efficient Urea Oxidation Reaction.

ChemSusChem 2020 Sep 4;13(18):5004-5014. Epub 2020 Aug 4.

School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin, 150001, P. R. China.

H production via electrocatalytic water splitting is greatly hindered by the sluggish oxygen evolution reaction (OER). The urea oxidation reaction (UOR) draws specific attention not only because of its lower theoretical voltage of 0.37 V compared with OER (1.23 V), but also for treating sewage water. Herein, Ni/NiO nanosheets with an ultrathin N-doped C layer containing a Schottky Ni and NiO heterointerface is constructed. Because of the self-driven charge redistribution at the heterointerface, janus charge domains are successfully created to drive the cleavage of urea molecules. Meanwhile, the synergistic effect between N-doped C and Ni/NiO restrains the deactivation of active sites in alkaline solution. The catalyst displays 1.35 V for UOR at 10 mA/cm , 0.27 V lower than that of OER. The final potential increase is only 2 mV after long-term stability test of 12 h for UOR, much smaller than the uncoated sample (38 mV). The present work shows that C-coated transition metal nanomaterials with oxygen vacancies and a Schottky heterointerface are promising candidates for simultaneously boosting UOR with both high activity and long-term stability.
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http://dx.doi.org/10.1002/cssc.202001185DOI Listing
September 2020

Resveratrol ameliorates disorders of mitochondrial biogenesis and mitophagy in rats continuously exposed to benzo(a)pyrene from embryonic development through adolescence.

Toxicology 2020 09 30;442:152532. Epub 2020 Jun 30.

Department of Environmental Health, School of Public Health, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, 110122, People's Republic of China. Electronic address:

Exposure to benzo(a)pyrene (BaP) is associated with poor neurodevelopment in children and memory impairment in adults. Previous research has demonstrated that mitochondrial damage plays an important role in BaP-induced neurotoxicity. Of interest, increasing evidence has suggested that resveratrol (RSV) can alleviate nerve cell damage, however the exact mechanisms of biological activity in mitochondria are not fully understood. In the current study, Wistar rats were exposed to BaP (1, 2, 4 mg/kg) and/or RSV (15, 30 mg/kg) during embryonic development and adolescence, and learning and memory ability, mitochondrial damage, and the expression of proteins associated with mitochondrial biogenesis and mitophagy were evaluated. These studies indicated that 2 and 4 mg/kg BaP could induce disorders of mitochondrial biogenesis and mitophagy, which leads to abnormal nerve cell development. However, pretreatment with 30 mg/kg RSV alleviated cell damage and the disorder of mitochondrial biogenesis by activating the AMPK/PGC-1α signaling pathway and promoting mitophagy. These findings suggested that RSV had utility in promoting mitochondrial homeostasis against BaP-induced nerve cell damage in the hippocampus of rats.
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http://dx.doi.org/10.1016/j.tox.2020.152532DOI Listing
September 2020

p70S6K Promotes Acquired Resistance of Erlotinib Through Induction of Epithelial-Mesenchymal Transition in Non-Small Cell Lung Carcinoma.

Onco Targets Ther 2020 9;13:5257-5270. Epub 2020 Jun 9.

Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China, 210029.

Background: Lung cancer is the leading cause of cancer-related deaths. EGFR tyrosine kinase inhibitors, such as erlotinib, were approved for non-small cell lung carcinoma patients with EGFR mutations. However, the acquired resistance of these inhibitors has not been fully clarified. Therefore, clarifying the mechanism and developing new rationales to overcome the drug resistance are urgently needed.

Methods: A pair of erlotinib sensitive and resistant cells was used to identify the key molecules in mediating erlotinib resistance. Loss- or gain-of-function study was used to confirm the effects of the key molecules. Xenograft mouse model and human cancer tissue sample studies were conducted for further corroboration.

Results: HCC827 cells with acquired resistance to erlotinib underwent epithelial-mesenchymal transition and exhibited enhanced p70S6K signaling compared to parental sensitive cells. Moreover, in erlotinib resistant cells, downregulation of p70S6K expression using either siRNA or shRNA reversed EMT and partially overcame erlotinib resistance. Meanwhile, in erlotinib sensitive cells, overexpression of p70S6K promoted EMT and induced erlotinib resistance. Upregulation of p70S6K signaling in erlotinib resistant cells was caused by reduced GSK3β-mediated protein degradation of mTOR and raptor. Additionally, p70S6K silencing suppressed the growth of erlotinib resistant cells in a xenograft mouse model. Finally, we found a correlation between p70S6K and E-cadherin expression in human non-small-cell lung cancer (NSCLC) tissue samples.

Conclusion: Our findings suggest that p70S6K-induced EMT plays an important role in the acquired resistance of erlotinib and provides a novel therapeutic rationale of targeting p70S6K in NSCLC therapy.
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http://dx.doi.org/10.2147/OTT.S249695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295111PMC
June 2020
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