Publications by authors named "Zhifei Xu"

96 Publications

Cutaneous toxicity of FDA-approved small-molecule kinase inhibitors.

Expert Opin Drug Metab Toxicol 2021 Nov 26:1-15. Epub 2021 Nov 26.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Introduction: By 1 January 2021, the FDA has approved a total of 62 small-molecule kinase inhibitors (SMKIs). The increasing clinical use of small-molecule kinase inhibitors has led to some side effects, the most common of which is cutaneous toxicity, as reflected by approximately 90% (57 of 62) of the FDA-approved SMKIs have reported treatment-related cutaneous toxicities. Since these cutaneous toxicities may have a crucial influence on the emotional, physical and psychosocial health of the patients, it is of great importance for doctors, patients, oncologists and interrelated researchers to be aware of the cutaneous side effects of these drugs in order to make the diagnosis accurate and the treatment appropriate.

Areas Covered: This review aims to summarize the potential cutaneous toxicities and the frequency of occurrence of FDA-approved 62 SMKIs, and provide a succinct overview of the potential mechanisms of certain cutaneous toxicities. The literature review was performed based on PubMed database and FDA official website.

Expert Opinion: It is significant to determine the risk factors for SMKI-induced cutaneous toxicity. The mechanisms underlying SMKI-induced cutaneous toxicities remain unclear at present. Future research should focus on the mechanisms of SMKI-induced cutaneous toxicities to find out mechanistically driven therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425255.2021.2004116DOI Listing
November 2021

Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation.

Biomed Pharmacother 2021 Dec 12;144:112297. Epub 2021 Oct 12.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, Zhejiang, PR China; Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China. Electronic address:

High incidence of cutaneous toxicity ranging from 29.2% to 71.2% has been reported during clinical use of vandetanib, which is a multi-target kinase inhibitor indicated for the treatment of unresectable medullary thyroid carcinoma. The cutaneous toxicity of vandetanib has limited its clinical benefits, but the underlying mechanisms and protective strategies are not well studied. Hence, we firstly established an in vivo model by continuously administrating vandetanib at 55 mg/kg/day to C57BL/6 for 21 days and verified that vandetanib could induce skin rash in vivo, which was consistent with the clinical study. We further cultured HaCaT and NHEK cells, the immortalized or primary human keratinocyte line, and investigated vandetanib (0-10 μM, 0-24 h)-caused alteration in cellular survival and death processes. The western blot showed that the expression level of apoptotic-related protein, c-PARP, c-Caspase 3 and Bax were increased, while the anti-apoptotic protein Bcl2 and MCL1 level were decreased. Meanwhile, vandetanib downregulated mitochondrial membrane potential which in turn caused the release of Cytochrome C, excessive production of reactive oxygen species and DNA damage. Furthermore, we found that 5 μM bisdemethoxycurcumin partially rescued vandetanib-induced mitochondria pathway-dependent keratinocyte apoptosis via activation of autophagy in vivo and in vitro, thereby ameliorated cutaneous toxicity. Conclusively, our study revealed the mechanisms of vandetanib-induced apoptosis in keratinocytes during the occurrence of cutaneous toxicity, and suggested bisdemethoxycurcumin as a potential protective drug. This work provided a potentially promising therapeutic strategy for the treatment of vandetanib-induced cutaneous toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2021.112297DOI Listing
December 2021

Comparative study on short-term efficacy of single incision plus one (SI+1) port and multiportal 3D laparoscopic minimally invasive esophagectomy.

J Gastrointest Oncol 2021 Aug;12(4):1277-1284

Department of Thoracic Surgery, Shanghai Changzheng Hospital, Navy Military Medical University, Shanghai, China.

Background: To evaluate the safety and efficacy of single incision plus one (SI+1) port three-dimensional (3D) laparoscopic minimally invasive esophagectomy (MIE).

Methods: Clinical data of patients who underwent 3D thoracic laparoscopic MIE in our department from September 2020 to March 2021 were analyzed retrospectively. According to the different methods of laparoscopic surgery, the patients were divided into 2 groups: SI+1 port 3D laparoscopy group and multiportal 3D laparoscopy group. The operation time of the 3D laparoscopy component, amount of intraoperative blood loss, number of celiac lymph node dissections, postoperative abdominal drainage days, postoperative total abdominal drainage, postoperative complications, and length of hospital stay were analyzed.

Results: There was no significant difference between the 2 methods in laparoscopic operation time (30.11±5.86 28.45±4.72 min, P=0.49), intraoperative blood loss (34.44±9.82 35.91±6.25 mL, P=0.69), number of celiac lymph node dissections (8.44±3.13 7.09±2.12, P=0.27), postoperative abdominal drainage days (3.11±0.33 3.00±0.00 days, P=0.28), postoperative total abdominal drainage (95.00±23.33 92.27±11.26 mL, P=0.74), postoperative complications (22.2% 27.3%, P=0.33), and hospital stay (9.67±0.71 10.18±0.87 days, P=0.17). None of the patients enrolled in the study had recurrence or death to date.

Conclusions: The application of SI+1 port 3D laparoscopy in minimally invasive resection of esophageal carcinoma is safe and feasible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jgo-21-441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421880PMC
August 2021

Defining therapeutic targets for renal fibrosis: Exploiting the biology of pathogenesis.

Biomed Pharmacother 2021 Nov 3;143:112115. Epub 2021 Sep 3.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

Renal fibrosis is a failed wound-healing process of the kidney tissue after chronic, sustained injury, which is a common pathway and pathological marker of virtually every type of chronic kidney disease (CKD), regardless of cause. However, there is a lack of effective treatment specifically targeting against renal fibrosis per se to date. The main pathological feature of renal fibrosis is the massive activation and proliferation of renal fibroblasts and the excessive synthesis and secretion of extracellular matrix (ECM) deposited in the renal interstitium, leading to structural damage, impairment of renal function, and eventually end-stage renal disease. In this review, we summarize recent advancements regarding the participation and interaction of many types of kidney residents and infiltrated cells during renal fibrosis, attempt to comprehensively discuss the mechanism of renal fibrosis from the cellular level and conclude by highlighting novel therapeutic targets and approaches for development of new treatments for patients with renal fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2021.112115DOI Listing
November 2021

DNA-Templated Glycan Labeling for Monitoring Receptor Spatial Distribution in Living Cells.

Anal Chem 2021 09 2;93(36):12265-12272. Epub 2021 Sep 2.

MOE Key Laboratory for Analytical Science of Food Safety and Biology, Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety, State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou 350108, People's Republic of China.

Tracking the spatial distribution of receptor tyrosine kinases in their native environment contributes to understanding the homeostatic or pathological states at a molecular level. Conjugation of DNA tags to a specific receptor is a powerful tool for monitoring receptor spatial distribution. However, long-term stable trafficking in live cells without interfering with the intrinsic receptor function remains a challenge. Here, we report a general DNA-templated glycan labeling strategy to track spatial distribution of a specific receptor in living cells. Different from existing target-selective covalent methods, the DNA tags were incorporated in glycan of a specific receptor via aptamer-assisted metabolic glycan labeling, thus resulting in minimal perturbation to the receptor's biological function. As proof of concept, covalent tagging of MET, HER2, and EGFR was achieved, and then the spatial distribution was successfully monitored, including homo-/heterodimerization and internalization. Overall, the proposed strategy will greatly aid in investigating receptor dynamics and is conducive to understanding their biological function in the native environment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.analchem.1c01815DOI Listing
September 2021

Autophagic degradation of CCN2 (cellular communication network factor 2) causes cardiotoxicity of sunitinib.

Autophagy 2021 Aug 25:1-22. Epub 2021 Aug 25.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R.China.

Excessive macroautophagy/autophagy is one of the causes of cardiomyocyte death induced by cardiovascular diseases or cancer therapy, yet the underlying mechanism remains unknown. We and other groups previously reported that autophagy might contribute to cardiomyocyte death caused by sunitinib, a tumor angiogenesis inhibitor that is widely used in clinic, which may help to understand the mechanism of autophagy-induced cardiomyocyte death. Here, we found that sunitinib-induced autophagy leads to apoptosis of cardiomyocyte and cardiac dysfunction as the cardiomyocyte-specific heterozygous mice are resistant to sunitinib. Sunitinib-induced maladaptive autophagy selectively degrades the cardiomyocyte survival mediator CCN2 (cellular communication network factor 2) through the TOLLIP (toll interacting protein)-mediated endosome-related pathway and cardiomyocyte-specific knockdown of through adeno-associated virus serotype 9 (AAV9) mimics sunitinib-induced cardiac dysfunction , suggesting that the autophagic degradation of CCN2 is one of the causes of sunitinib-induced cardiotoxicity and death of cardiomyocytes. Remarkably, deletion of (high mobility group box 1) inhibited sunitinib-induced cardiomyocyte autophagy and apoptosis, and the HMGB1-specific inhibitor glycyrrhizic acid (GA) significantly mitigated sunitinib-induced autophagy, cardiomyocyte death and cardiotoxicity. Our study reveals a novel target protein of autophagic degradation in the regulation of cardiomyocyte death and highlights the pharmacological inhibitor of HMGB1 as an attractive approach for improving the safety of sunitinib-based cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15548627.2021.1965712DOI Listing
August 2021

Autonomic nervous function and low-grade inflammation in children with sleep-disordered breathing.

Pediatr Res 2021 Aug 17. Epub 2021 Aug 17.

Department of Respiratory Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.

Background: The objective of the study was to assess the relationship between autonomic nervous function and low-grade inflammation in children with sleep-disordered breathing.

Methods: We enrolled habitually snoring children aged 3-14 years for overnight polysomnography (PSG) and high-sensitivity C-reactive protein (hsCRP) measurement. Low-grade inflammation was defined as hsCRP >1.0 mg/L to <10.0 mg/L. An electrocardiogram recording was extracted from PSG. Heart rate variability was analyzed using time and frequency domain methods.

Results: In total, 190 children were included, with 61 having primary snoring (PS), 39 mild obstructive sleep apnea (OSA), and 90 moderate-to-severe OSA. The average RR interval displayed a significant decline, whereas the low frequency/high frequency (LF/HF) ratio showed an increasing tendency in children with PS, mild OSA, and moderate-to-severe OSA. Mean RR was mainly influenced by age and the apnea hypopnea index (AHI) (all P < 0.01). AHI was an independent risk factor for the altered LF/HF ratio at all sleep stages except N3 stage (all P < 0.05). In the wake stage, low-grade inflammation was an independent risk factor of altered LF/HF ratio (P = 0.014).

Conclusions: Autonomic nervous function was impaired in children with OSA. The sympathetic-vagal balance was influenced by low-grade inflammation in the wake stage, whereas it was only affected by AHI when falling asleep.

Impact: We found that autonomic nervous function was impaired in children with OSA. We found that there was a negative correlation between systemic inflammation and autonomic nervous function in children with SDB only at wake stage. A negative association between systemic inflammation and autonomic nervous function was demonstrated in children in this study. Furthermore, altered LF/HF ratio maybe a good indicator of autonomic nervous dysfunction in children as it only correlated with the SDB severity, not with age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41390-021-01691-4DOI Listing
August 2021

Clinical and PSG Characteristics of Children with Mild OSA and Respiratory Events Terminated Predominantly with Arousal.

Can Respir J 2021 7;2021:5549423. Epub 2021 Jun 7.

Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China.

Objective: To analyze the clinical and polysomnographic characteristics in children with mild OSA and respiratory events terminated predominantly with arousal.

Methods: Children aged 3-10 yrs who had mild obstructive sleep apnea (OSA) were enrolled. All children underwent polysomnography, and patients' data were collected by using sleep-related breathing disorders (SRBD) questionnaire and OSA-18 quality of life questionnaire.

Results: In total, five hundred and seventy-seven children were eligible. Children in arousal predominant group were younger and showed a lower rate of male and obesity. Compared with that of the nonarousal predominant group, the total arousal index, arousal index related to respiratory event, the percentage of NREM stage 1 (N1%), the fraction of respiratory events that were hypopnea, and the mean and minimum oxygen saturation in the arousal predominant group were significantly greater. The percentage of NREM stage 3 (N%), index of obstructive, central, mixed apnea, the fraction of respiratory events that were obstructive, and central and mixed apnea were significantly lower in arousal predominant group.

Conclusion: Children with mild OSA in the arousal predominant group had specific characteristics, including younger age, lower rate of male and obesity, worse sleep architecture, higher rates of hypopnea events, and better oxygenation. This trial is registered with NCT02447614.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/5549423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203392PMC
June 2021

Generation and characterization of iPSC lines (BCH001) from a boy with intron 14 mutation in the ret proto-oncogene (RET) gene.

Stem Cell Res 2021 05 23;53:102359. Epub 2021 Apr 23.

Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China. Electronic address:

Congenital central hypoventilation syndrome (CCHS) is characterized by an alteration of the ventilatory response to hypercapnia and hypoxia, and is classically presented in neonates with abnormalities of the autonomic nervous system. Here, we generated human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) isolated from a male patient clinically diagnosed with CCHS. These iPSC lines carry a heterozygous RET mutation (c.2608-125C > T), express pluripotency markers, have the capacity to differentiate into the normal teratoma tissue, retain the RET mutation and display the normal karyotype, which will also provide a useful resource to study the pathogenesis of CCHS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scr.2021.102359DOI Listing
May 2021

Effects of obstructive sleep apnoea severity on neurocognitive and brain white matter alterations in children according to sex: a tract-based spatial statistics study.

Sleep Med 2021 06 28;82:134-143. Epub 2020 Aug 28.

Department of Otolaryngology, Head and Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, China. Electronic address:

Objectives: To investigate alterations in neurocognitive, attention, paediatric sleep questionnaire (PSQ) scores and whole brain white matter (WM) integrity between children with mild and severe obstructive sleep apnoea (OSA) according to sex and whether these changes are associated with OSA severity.

Methods: Fifty-seven children (36 males and 21 females) diagnosed with OSA were recruited for this study. Children of both sexes were divided into mild (male-MG, female-MG) and severe (male-SG, female-SG) groups according to OSA severity. Polysomnography (PSG), neurocognitive, attention and PSQ tests were compared between groups by one-way samples analysis of variance (ANOVA) F test. Diffusion tensor imaging (DTI) was scanned using a 3T GE MRI scanner and analysed by Tract-based Spatial Statistics (TBSS). Spearman correlation was calculated between DTI Eigenvalues and clinical characteristics.

Results: Compared to mild OSA patients, severe OSA patients presented greater severity of obstructive apnoea hypopnea index (OAHI), neurocognition, PSQ and attention tests in both male and female patients. Brain WM integrity in the male-SG, compared to the male-MG, demonstrated significantly reduced fractional anisotropy (FA) values in the right middle frontal gyrus and the right frontal sub-gyral regions and increased axial diffusivity (AD) values in the right inferior frontal gyrus, left parietal angular gyrus and sub-gyral regions, while no differences were found between the female-MG and female-SG. Alterations in male-SG brain regions were observably correlated with severity in male OSA patients.

Conclusions: The integrity of WM, which regulates autonomic, cognitive, and attention functions, is impaired in male, but not female, children with severe OSA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sleep.2020.08.026DOI Listing
June 2021

Brain function in children with obstructive sleep apnea: a resting-state fMRI study.

Sleep 2021 08;44(8)

Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, School of Medical Science and Engineering, Beihang University, Beijing, China.

Objective: To explore the neural difference between children with obstructive sleep apnea (OSA) and healthy controls, together with the relation between this difference and cognitive dysfunction of children with OSA.

Methods: Twenty children with OSA (7.2 ± 3.1 years, apnea hypopnea index (AHI): 16.5 ± 16.6 events/h) and 29 healthy controls (7.7 ± 2.8 years, AHI: 1.7 ± 1.2 events/h) were recruited and matched with age, gender, and handedness. All children underwent resting-state fMRI (rs-fMRI) and T1-wighted imaging. Some children were sedated for MRI scanning. We compared amplitude of low frequency fluctuation (ALFF) and regional homogeneity (ReHo) of children with OSA with those of healthy controls. During resting-state, the former reflects the intensity of the spontaneous neural activities, whereas the latter reflects temporal similarity of the spontaneous neural activities within a local brain region. Pearson correlation analysis was performed between these features of rs-fMRI and cognitive scores among children with OSA.

Results: Compared with controls, children with OSA showed decreased ALFF in the left angular gyrus but increased ALFF in the right insula, and decreased ReHo in the left medial superior frontal gyrus, right lingual gyrus, and left precuneus. Additionally, among children with OSA, the ReHo value in the right lingual gyrus was negatively correlated with FIQ and VIQ, whereas that in the left medial superior frontal gyrus was positively correlated with VIQ.

Conclusions: Children with OSA presented abnormal neural activities in some brain regions and impaired cognitive functions with the former possibly being the neural mechanism of the latter.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/sleep/zsab047DOI Listing
August 2021

Adverse events associated with nilotinib in chronic myeloid leukemia: mechanisms and management strategies.

Expert Rev Clin Pharmacol 2021 Apr 28;14(4):445-456. Epub 2021 Feb 28.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

: Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) targeting BCR/ABL, which is used for the first-line treatment of newly diagnosed chronic myeloid leukemia (CML) patients and the second-line treatment of most CML patients who are resistant or intolerant to prior therapy that includes imatinib. In addition to common adverse reactions, long-term use of nilotinib shows some toxicities that are different from those of occurring during other BCR/ABL TKI treatments, such as cardiovascular toxicity. It is life-threatening, which would affect not only the choice of initial treatment of CML patients but also the safety of long-term medication.: Through searching literature and reports from PubMed and clinical trials, here we review a profile of the adverse effects induced by nilotinib. We also discuss the potential molecular toxicological mechanisms and clinical management, which may provide strategies to prevent or intervene the toxicity associated with nilotinib.: Severe adverse effects associated with nilotinib limit its long-term clinical application. However, the exact mechanisms underlying these toxicities remain unclear. Future research should focus on the developing strategies to reduce the toxicities of nilotinib as well as to avoid similar toxicity in the development of new drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17512433.2021.1894129DOI Listing
April 2021

Intra-operative events and countermeasures during esophagectomy via transcervical incision inflatable single-port mediastinoscope combined with laparoscopy.

J Thorac Dis 2021 Jan;13(1):133-139

Department of Thoracic Surgery, Shanghai Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China.

Background: Esophagectomy via transcervical incision inflatable single-port mediastinoscope combined with laparoscopy as a safe and feasible minimally invasive technique has gained attention recently. But the occurrence of Intraoperative events is inevitable. It's necessary to investigate and discuss the intraoperative events and countermeasures during operation.

Methods: Intraoperative events were retrospectively reviewed in 60 patients who underwent esophagectomy via transcervical incision inflatable single-port mediastinoscope combined with laparoscopy in the recent 3 years.

Results: There was no perioperative death and no aortic or bronchial injury. Bronchial artery injury occurred in 2 cases (3.34%), bronchial artery combined with azygos vein hemorrhage occurred in 1 case (1.67%). The pleura were injured in 3 cases (5%). Recurrent laryngeal nerve injury was noticed in 7 cases (11.67%). Thoracic duct injury occurred in 1 case (1.67%).

Conclusions: As a new surgical method, esophagectomy via transcervical incision inflatable single-port mediastinoscope combined with laparoscopy is considered safe and feasible, but requires improvement when compared with traditional surgical methods. Due to the influence of surgical space and with experienced surgeons, the incidence of intraoperative events such as intraoperative bleeding and thoracic duct injury is not dominant when compared with the traditional surgical methods. Thoracic surgeons should continuously improve their clinical knowledge as well as skills. Careful preoperative examination and evaluation of the patients, being familiar with the anatomical structure and various methods, wise selection of energy devices and calmly dealing with all kinds of events are the key factors for successful surgeries with fewer intraoperative events.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jtd-20-2331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867825PMC
January 2021

The efficacy and safety of montelukast in children with obstructive sleep apnea: a systematic review and meta-analysis.

Sleep Med 2021 02 10;78:193-201. Epub 2020 Nov 10.

Department of Respiratory Medicine, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, PR China. Electronic address:

Objective: The efficacy and safety of montelukast in children with obstructive sleep apnea (OSA) remain controversial. Therefore, the aims of this systemic review and meta-analysis are to verify this issue and further provide reference for clinical practice.

Methods: Seven databases were searched for randomized controlled trials (RCTs) up to September 30, 2019. The literature screening and data extraction were performed by two independent researchers. Adverse reactions from trials were also recorded. Meta-analysis was performed and analyzed heterogeneity. Methodological and evidence quality were followed by to evaluate according to Cochrane handbook.

Results: A total of 4 RCTs including 305 children with mild to moderate OSA were involved. Compared with placebo, we found that oral montelukast (OM) significantly improved polysomnography (PSG) monitoring parameters, typical and relevant symptoms including snoring and mouth breathing, and adenoid morphology in children with OSA. When compared with routine drugs, not only PSG monitoring parameters and adenoid morphology, but also sleep-disordered breathing (SDB)-related questionnaire scores were improved in patients with OSA treated by combination of OM and routine drugs. In addition, compared with single nasal spray of mometasone furoate, the present study also showed that OM combined with nasal spray of mometasone furoate significantly improved PSG monitoring parameters, symptoms of snoring and mouth breathing and reduced tonsil morphology in pediatric OSA. In terms of treatment safety, one study reported adverse reactions of OM such as headache, nausea and vomiting, while no adverse events were reported after OM treatment in another study.

Conclusion: As a classic leukotriene receptor antagonist, montelukast can be used to treat children with mild to moderate OSA in the short term and improve clinical characteristics. The promotion and application of OM in clinic is considered to be a noninvasive option to avoid surgical treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sleep.2020.11.009DOI Listing
February 2021

Regulation of p53 stability as a therapeutic strategy for cancer.

Biochem Pharmacol 2021 03 7;185:114407. Epub 2021 Jan 7.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

The tumor suppressor protein p53 participates in the control of key biological functions such as cell death, metabolic homeostasis and immune function, which are closely related to various diseases such as tumors, metabolic disorders, infection and neurodegeneration. The p53 gene is also mutated in approximately 50% of human cancer cells. Mutant p53 proteins escape from the ubiquitination-dependent degradation, gain oncogenic function and promote the carcinogenesis, malignant progression, metastasis and chemoresistance. Therefore, the stability of both wild type and mutant p53 needs to be precisely regulated to maintain normal functions and targeting the p53 stability is one of the therapeutic strategies against cancer. Here, we focus on compound-induced degradation of p53 by both the ubiquitination-dependent proteasome and autophagy-lysosome degradation pathways. We also review other posttranslational modifications which control the stability of p53 and the biological functions involved in these processes. This review provides the current theoretical basis for the regulation of p53 abundance and its possible applications in different diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2021.114407DOI Listing
March 2021

Hepatotoxicity of FDA-approved small molecule kinase inhibitors.

Expert Opin Drug Saf 2021 Mar 27;20(3):335-348. Epub 2020 Dec 27.

Center for Drug Safety Evaluation and Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou China.

: Given their importance in cellular processes and association with numerous diseases, protein kinases have emerged as promising targets for drugs. The FDA has approved greater than fifty small molecule kinase inhibitors (SMKIs) since 2001. Nevertheless, severe hepatotoxicity and related fatal cases have grown as a potential challenge in the advancement of these drugs, and the identification and diagnosis of drug-induced liver injury (DILI) are thorny problems for clinicians.: This article summarizes the progression and analyzes the significant features in the study of SMKI hepatotoxicity, including clinical observations and investigations of the underlying mechanisms.: The understanding of SMKI-associated hepatotoxicity relies on the development of preclinical models and improvement of clinical assessment. With a full understanding of the role of inflammation in DILI and the mediating role of cytokines in inflammation, cytokines are promising candidates as sensitive and specific biomarkers for DILI. The emergence of three-dimensional spheroid models demonstrates potential use in providing clinically relevant data and predicting hepatotoxicity of SMKIs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14740338.2021.1867104DOI Listing
March 2021

PLK1 (polo like kinase 1)-dependent autophagy facilitates gefitinib-induced hepatotoxicity by degrading COX6A1 (cytochrome c oxidase subunit 6A1).

Autophagy 2021 10 14;17(10):3221-3237. Epub 2020 Dec 14.

Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Liver dysfunction is an outstanding dose-limiting toxicity of gefitinib, an EGFR (epidermal growth factor receptor)-tyrosine kinase inhibitor (TKI), in the treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC). We aimed to elucidate the mechanisms underlying gefitinib-induced hepatotoxicity, and provide potentially effective intervention strategy. We discovered that gefitinib could sequentially activate macroautophagy/autophagy and apoptosis in hepatocytes. The inhibition of autophagy alleviated gefitinib-induced apoptosis, whereas the suppression of apoptosis failed to lessen gefitinib-induced autophagy. Moreover, liver-specific heterozygous mice showed less severe liver injury than vehicle, suggesting that autophagy is involved in the gefitinib-promoted hepatotoxicity. Mechanistically, gefitinib selectively degrades the important anti-apoptosis factor COX6A1 (cytochrome c oxidase subunit 6A1) in the autophagy-lysosome pathway. The gefitinib-induced COX6A1 reduction impairs mitochondrial respiratory chain complex IV (RCC IV) function, which in turn activates apoptosis, hence causing liver injury. Notably, this autophagy-promoted apoptosis is dependent on PLK1 (polo like kinase 1). Both AAV8-mediated knockdown and PLK1 inhibitor BI-2536 could mitigate the gefitinib-induced hepatotoxicity by abrogating the autophagic degradation of the COX6A1 protein. In addition, PLK1 inhibition could not compromise the anti-cancer activity of gefitinib. In conclusion, our findings reveal the gefitinib-hepatotoxicity pathway, wherein autophagy promotes apoptosis through COX6A1 degradation, and highlight pharmacological inhibition of PLK1 as an attractive therapeutic approach toward improving the safety of gefitinib-based cancer therapy. 3-MA: 3-methyladenine; AAV8: adeno-associated virus serotype 8; ATG5: autophagy related 5; ATG7: autophagy related 7; B2M: beta-2-microglobulin; CCCP: carbonyl cyanide m-chlorophenylhydrazone; CHX: cycloheximide; COX6A1: cytochrome c oxidase subunit 6A1; c-PARP: cleaved poly(ADP-ribose) polymerase; CQ: chloroquine; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; HBSS: Hanks´ balanced salt solution; H&E: hematoxylin and eosin; MAP1LC3/LC3: microtubule associated proteins 1 light chain 3; PLK1: polo like kinase 1; RCC IV: respiratory chain complex IV; ROS: reactive oxygen species; TUBB8: tubulin beta 8 class VIII.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15548627.2020.1851492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526032PMC
October 2021

Tim-3 is a potential regulator that inhibits monocyte inflammation in response to intermittent hypoxia in children with obstructive sleep apnea syndrome.

Clin Immunol 2021 01 30;222:108641. Epub 2020 Nov 30.

Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China. Electronic address:

The mechanism of the characteristic intermittent hypoxia (IH) of obstructive sleep apnea syndrome (OSAS) on monocyte remain unclear. Our study found that OSAS children had a significantly upregulated expression in circulating proinflammatory cytokines IL-6 and IL-12, and endothelial injury markers VEGF and ICAM1. Association analysis revealed that the plasma TNFα, IL-1β, IL-6, IL-10 and IL-12 concentration were negatively associated with the minimal SpO, a negative index for disease severity. OSAS monocytes presented an inflammatory phenotype with higher mRNA levels of inflammatory cytokines. Importantly, we noted a significant decrease in T-cell immunoglobulin and mucin domain (Tim)-3 expression in OSAS monocytes with the increase of the plasma proinflammatory cytokines. In vitro assay demonstrated that IH induced THP-1 cell overactivation via NF-κB dependent pathway was inhibited by the Tim-3 signal. Our results indicated that activation of monocyte inflammatory responses is closely related to OSAS-induced IH, and negatively mediated by a Tim-3 signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clim.2020.108641DOI Listing
January 2021

Crosstalk between alveolar macrophages and alveolar epithelial cells/fibroblasts contributes to the pulmonary toxicity of gefitinib.

Toxicol Lett 2021 Mar 25;338:1-9. Epub 2020 Nov 25.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address:

Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the first-line treatment of patients with metastatic or advanced non-small cell lung cancer (NSCLC) whose tumors have specific EGFR mutations. Pulmonary toxicity is one of the fatal adverse effects of gefitinib and the underlying mechanism remains unclear. Here we demonstrated that alveolar macrophages contributed to gefitinib-induced pulmonary toxicity through promoting alveolar epithelial cells to undergo epithelial to mesenchymal transition (EMT) and inducing activation and antiapoptotic effect in fibroblasts. Further, we found that alveolar macrophage-secreted MCP-1 worked as a key factor in the pathologic changes of these two cell types. Gefitinib increased Mcp-1 transcription level via the nuclear import of the transcription factor STAT3. In conclusion, our data uncovered the underlying mechanisms of macrophage-promoted pulmonary toxicity in the presence of gefitinib. MCP-1 antibody or inhibition of STAT3 activation may represent novel therapeutic strategies for preventing gefitinib-induced pulmonary toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.toxlet.2020.11.011DOI Listing
March 2021

Analysis of the impact of allergic rhinitis on the children with sleep disordered breathing.

Int J Pediatr Otorhinolaryngol 2020 Nov 12;138:110380. Epub 2020 Sep 12.

Department of Otolaryngology, Head and Neck Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, People's Republic of China. Electronic address:

Objectives: We assessed the influence of allergic rhinitis (AR) on sleep disordered breathing (SDB) in children with adenotonsillar hypertrophy (ATH), and compared sleep quality and polysomnographic data in habitually snoring children with or without AR.

Methods: Children with snoring resulting from adenoid/tonsils hypertrophy were recruited between Jan 1st, 2018 and Jun 30th, 2018. The exclusion criteria were congenital disorders, metabolic disorders, neurological disorders and pulmonary diseases, such as, asthma etc. Overnight polysomnography (PSG) and Sleep Questionnaire (SQ) were assessed on each participant to identify children with obstructive sleep apnea (OSA). Cross-sectional study design was used to examine PSG and SQ data. The diagnosis of AR was based upon history of allergies and positive clinical examinations, then confirmed by allergen test. Participants were categorized into four groups (AR and Non-OSA group; AR and OSA group; Non-AR and Non-OSA group; Non-AR and OSA group). Non-parametric rank sum test was used for statistical analysis.

Results: Six hundred and sixty children (age between 3yrs and 14yrs) with SDB were enrolled in the study (mean age 6.7 ± 2.1yrs, 67.4% male). The number of children diagnosed with OSA was 495 (74.3%). The prevalence of AR among all participating SDB children was 25.8%, and AR with OSA was19.4%. The behavioral problems scores in SQ showed significant difference among SDB children with AR (P<.0001). No difference was observed in the OAHI (obstructive apnea-hypopnea index) and AHI (apnea-hypopnea index) between the groups of children with and without AR regardless whether OSA was coexisting. The percentage of time spent in the rapid eye movement (REM) sleep stage was shortened among children with AR without OSA (P = 0.031), however, the percentage of time spent in the REM sleep stage was not different among children with OSA (P = 0.98). The total sleep time was shorter among children with AR (OSA P = 0.02; without OSA P = 0.03).

Conclusions: Despite the high prevalence of AR in patients with SDB, AR is not an aggravating factor for the severity of AHI. High risk behavioral problems link to SDB with AR. AR is associated with shortened REM sleep stage in children with SDB without sleep apnea, and shortened total sleep time in children with SDB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijporl.2020.110380DOI Listing
November 2020

Research Status and Outlook of PD-1/PD-L1 Inhibitors for Cancer Therapy.

Drug Des Devel Ther 2020 8;14:3625-3649. Epub 2020 Sep 8.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.

PD-1/PD-L1 inhibitors are a group of immune checkpoint inhibitors as front-line treatment of multiple types of cancer. However, the serious immune-related adverse reactions limited the clinical application of PD-1/PD-L1 monoclonal antibodies, despite the promising curative effects. Therefore, it is urgent to develop novel inhibitors, such as small molecules, peptides or macrocycles, targeting the PD-1/PD-L1 axis to meet the increasing clinical demands. Our review discussed the mechanism of action of PD-1/PD-L1 inhibitors and presented clinical trials of currently approved PD-1/PD-L1 targeted drugs and the incidence of related adverse reactions, helping clinicians pay more attention to them, better formulate their intervention and resolution strategies. At last, some new inhibitors whose patent have been published are listed, which provide development ideas and judgment basis for the efficacy and safety of novel PD-1/PD-L1 inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/DDDT.S267433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490077PMC
July 2021

COVID-19 epidemic: a special focus on diagnosis, complications, and management.

Expert Rev Clin Pharmacol 2020 Oct 18;13(10):1085-1093. Epub 2020 Sep 18.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, China.

Introduction: The outbreak of COVID-19 caused by SARS-CoV-2 infection has become a serious hazard to global health. Apart from attacking respiratory system, it can induce multiorgan dysfunction, including cardiovascular system, liver, kidney, gastrointestinal, nervous system, and immune system. However, there are few reviews focusing on summary and comparison of diagnostic methods and complications induced by SARS-CoV-2 infection, which places a significant limit on the effective management.

Areas Covered: This review is a blend of evidence obtained by literature retrieval from PubMed, clinical experience, and the authors' opinions. We searched PubMed using the terms 'COVID-19 & diagnosis' and 'COVID-19 & complications' and selected the most relevant articles. Here we summarize the diagnostic methods that are available in clinic and discuss their different characters. Furthermore, the review offers an insight into the symptoms, incidence, and clinical strategies of complications associated with SARS-CoV-2 infection.

Expert Opinion: COVID-19 has been a global pandemic, which requires rapid response. The comparison between different characters of the diagnostic methods and the summary of the symptoms, incidence, and clinical strategies of complications given in this review are not only significant for the optimal use of diagnostic methods, but also beneficial for the prevention and management of complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17512433.2020.1821651DOI Listing
October 2020

Noninvasive ventilation in a young infant with congenital central hypoventilation and 7-year follow-up.

Pediatr Investig 2019 Dec 21;3(4):261-264. Epub 2019 Dec 21.

Department of Respiratory Medicine Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China.

Introduction: Congenital central hypoventilation syndrome (CCHS) is a rare disorder characterized by alveolar hypoventilation and autonomic system dysregulation secondary to mutations of the gene. Treatment consists of assisted ventilation using positive-pressure ventilators via tracheostomy, bi-level positive airway pressure (BPAP) via a noninvasive interface, negative-pressure ventilators, or diaphragm pacing. The long-term use of BPAP in younger children at home has been less frequently reported.

Case Presentation: We present a case of a 2-month-old infant with CCHS who was successfully managed by BPAP without the need for tracheostomy and followed up for 7 years.

Conclusion: CCHS is a rare disease that manifests as nocturnal desaturation and carbon dioxide retention in early life. Noninvasive ventilation can be successfully used in young infants via an appropriate mask.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ped4.12167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331288PMC
December 2019

Ambulatory blood pressure monitoring in children with obstructive sleep apnea syndrome.

Pediatr Investig 2019 Dec 21;3(4):217-222. Epub 2019 Dec 21.

Department of Otolaryngology Head & Neck Surgery, Beijing Children's Hospital Capital Medical University National Center for Children's Health Beijing China.

Importance: The incidence of obstructive sleep apnea syndrome (OSAS) in children has increased year by year recently. Blood pressure research of OSAS children can help understand the occurrence of OSAS related complications. Early detection and intervention of blood pressure changes in children with OSAS can reduce the incidence of cardiovascular disease in later adulthood.

Objective: To investigate the differences in blood pressure among different groups of snoring children and different sleep stages.

Methods: Habitually snoring children (snoring frequency of ≥ 3 nights per week) aged 3 to 11 years were recruited from Beijing Children's Hospital from 1 January 2017 to 30 June 2018. All children underwent polysomnography, and their blood pressure was monitored and calculated by the pulse transit time. The children were divided into those with primary snoring (PS), mild OSAS, and moderate to severe OSAS according to their obstructive apnea-hypopnea index (OAHI).

Results: In total, 140 children were included. Ninety-seven had PS, 24 had mild OSAS, and 19 had moderate to severe OSAS. There were no differences in age, sex, or body mass index z-score among the groups. Statistically significant differences were found in the OAHI, oxygen desaturation index 3%, respiratory arousal index, and lowest oxygen saturation among the three groups. Children with moderate to severe OSAS had higher systolic and diastolic blood pressure than those with mild OSAS and PS ( < 0.001). In all children, systolic and diastolic blood pressure was higher in the rapid eye movement (REM) sleep stage than in the non-REM sleep stage ( < 0.05).

Interpretation: Children with moderate to severe OSAS had higher blood pressure than those with PS and mild OSAS in all sleep stages. Blood pressure in the REM sleep stage was higher than that in other sleep stages in all groups of children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ped4.12163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331368PMC
December 2019

Long non-coding RNA HEIH suppresses the expression of TP53 through enhancer of zeste homolog 2 in oesophageal squamous cell carcinoma.

J Cell Mol Med 2020 09 30;24(18):10551-10559. Epub 2020 Jul 30.

Department of Minimally Invasive Thoracic Surgery Center, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.

It is increasingly evident that the molecular and biological functions of long non-coding RNAs (lncRNA) are vital for understanding the molecular biology and progression of cancer. The lncRNA-HEIH, a newly identified lncRNA, has been demonstrated to be up-regulated in hepatocellular cancer. However, little is known about its role in oesophageal squamous cell carcinoma (ESCC). In the present study, an obvious up-regulation of lncRNA-HEIH was observed in ESCC compared to the adjacent normal tissues. Meanwhile, patients with high expression of lncRNA-HEIH have significantly poorer prognosis than those with low expression. We further found that lncRNA-HEIH was associated with enhancer of zeste homolog 2 (EZH2) and that this association led to the repression of TP53. These findings indicate that lncRNA-HEIH may serve as a prognostic marker and a potential therapeutic target for ESCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcmm.15673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521320PMC
September 2020

Cardiovascular toxicity induced by anti-VEGF/VEGFR agents: a special focus on definitions, diagnoses, mechanisms and management.

Expert Opin Drug Metab Toxicol 2020 Sep 9;16(9):823-835. Epub 2020 Jul 9.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University , Hangzhou, Zhejiang,China.

Introduction: Vascular endothelial growth factor (VEGF) is a key target in cancer therapy. However, cardiovascular safety has been one of the most challenging aspects of anti-VEGF/VEGF receptor (VEGFR) agent development and therapy. While accurate diagnostic modalities for assessment of cardiac function have been developed over the past few decades, a lack of an optimal definition and precise mechanism still places a significant limit on the effective management of cardiovascular toxicity.

Areas Covered: Here, we report the cardiovascular toxicity profile associated with anti-VEGF/VEGFR agents and summarize the clinical diagnoses as well as management that are already performed in clinical practice or are currently being investigated. Furthermore, the review discusses the potential molecular toxicological mechanisms, which may provide strategies to prevent toxicity and drive drug discovery.

Expert Opinion: Cardiovascular toxicity associated with anti-VEGF/VEGFR agents has been a substantial risk for cancer treatment. To improve its management, the development of guidelines for prevention, monitoring and treatment of cardiovascular toxicity has become a hot topic. The summary of cardiovascular toxicity profile, mechanisms and management given in this review is not only significant for the optimal use of existing anti-VEGF/VEGFR agents to protect patients predisposed to cardiovascular toxicity but is also beneficial for drug development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17425255.2020.1787986DOI Listing
September 2020

A Comprehensive Review of Clinical Cardiotoxicity Incidence of FDA-Approved Small-Molecule Kinase Inhibitors.

Front Pharmacol 2020 12;11:891. Epub 2020 Jun 12.

Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Numerous protein kinases encoded in the genome have become attractive targets for the treatment of different types of cancer. As of January 2020, a total of 52 small-molecule kinase inhibitors (SMKIs) have been approved by the FDA. With the numerous clinical trials and a heavy focus on drug safety, SMKI-induced cardiotoxicity, which is a life-threatening risk, has greatly attracted the attention of researchers. In this review, the SMKIs with cardiotoxicity incidence were described exhaustively. The data were collected from 42 clinical trials, 25 FDA-published documents, seven meta-analysis/systematic reviews, three case reports and more than 50 other types of articles. To date, 73% (38 of 52) of SMKIs have reported treatment-related cardiotoxicity. Among the 38 SMKIs with known cardiotoxicity, the rates of incidence of cardiac adverse events were QT prolongation: 47% (18 of 38), hypertension: 40% (15 of 38), left ventricular dysfunction: 34% (13 of 38), arrhythmia: 34% (13 of 38), heart failure: 26% (10 of 38) and ischemia or myocardial infarction: 29% (11 of 38). In the development process of novel SMKIs, more attention should be paid to balancing the treatment efficacy and the risk of cardiotoxicity. In preclinical drug studies, producing an accurate and reliable cardiotoxicity evaluation model is of key importance. To avoid the clinical potential cardiotoxicity risk and discontinuation of a highly effective drug, patients treated with SMKIs should be proactively monitored on the basis of a global standard. Moreover, the underlying mechanisms of SMKI-induced cardiotoxicity need to be further studied to develop new therapies for SMKI-induced cardiotoxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.00891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303342PMC
June 2020

Determination of 10 Haloacetamides in drinking water by gas chromatography with automated solid phase extraction.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Aug 26;1150:122191. Epub 2020 May 26.

Wuxi Center for Disease Control and Prevention, Wuxi 214023, China; Research Base for Environment and Health in Wuxi, Chinese Center for Disease Control and Prevention, Wuxi 214023, China. Electronic address:

Drinking water disinfection may result in the formation of different classes of toxic disinfection by-products (DBPs). Haloacetamides (HAcAms) are an emerging class of nitrogenous DBPs (N-DBPs), which are generally more prevalent at lower concentrations in disinfected water than carbonaceous DBPs. Herein a fast, convenient, and effective method of analyzing 10 HAcAms in drinking water samples was demonstrated. This method was developed using gas chromatography /electron capture detection (GC/ECD) supplemented with automated solid phase extraction (auto-SPE). The variables for automated SPE procedures were further optimized, including the selection of SPE sorbents, types and volumes of extraction solvents, SPE washing solvents and wash times. Under optimized conditions, the instrumental linearity range was 0.5-150 μg L with correlation coefficients>0.9975. The limits of detection and quantification of this method were 0.002-0.003 μg L and 0.005-0.010 μg L, respectively. The recovery values ranged from 72.4% to 108.5%, and the relative standard deviations ranged from 3.3% to 9.1%. Therefore, the auto-SPE-GC-ECD method showed acceptable linearity and repeatability and was subsequently validated and applied to analyze 10 HAcAms in drinking water.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jchromb.2020.122191DOI Listing
August 2020

s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand-foot skin reaction that can be reversed by nicotinamide.

Cell Res 2020 09 15;30(9):779-793. Epub 2020 Apr 15.

Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China.

Hand-foot skin reaction (HFSR), among the most significant adverse effects of sorafenib, has been limiting the clinical benefits of this frontline drug in treating various malignant tumors. The mechanism underlying such toxicity remains poorly understood, hence the absence of effective intervention strategies. In the present study, we show that vascular endothelial cells are the primary cellular target of sorafenib-induced HFSR wherein soluble heparin-binding epidermal growth factor (s-HBEGF) mediates the crosstalk between vascular endothelial cells and keratinocytes. Mechanistically, s-HBEGF released from vascular endothelial cells activates the epidermal growth factor receptor (EGFR) on keratinocytes and promotes the phosphorylation of c-Jun N-terminal kinase 2 (JNK2), which stabilizes sirtuin 1 (SIRT1), an essential keratinization inducer, and ultimately gives rise to HFSR. The administration of s-HBEGF in vivo could sufficiently induce hyper-keratinization without sorafenib treatment. Furthermore, we report that HBEGF neutralization antibody, Sirt1 knockdown, and a classic SIRT1 inhibitor nicotinamide could all significantly reduce the sorafenib-induced HFSR in the mouse model. It is noteworthy that nicotinic acid, a prodrug of nicotinamide, could substantially reverse the sorafenib-induced HFSR in ten patients in a preliminary clinical study. Collectively, our findings reveal the mechanism of vascular endothelial cell-promoted keratinization in keratinocytes and provide a potentially promising therapeutic strategy for the treatment of sorafenib-induced HFSR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41422-020-0309-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608389PMC
September 2020
-->