Publications by authors named "Xi Jin"

267 Publications

Tektin4 loss promotes triple-negative breast cancer metastasis through HDAC6-mediated tubulin deacetylation and increases sensitivity to HDAC6 inhibitor.

Oncogene 2021 Mar 2. Epub 2021 Mar 2.

Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China.

Progression of triple-negative breast cancer (TNBC) constitutes a major unresolved clinical challenge, and effective targeted therapies are lacking. Because microtubule dynamics play pivotal roles in breast cancer metastasis, we performed RNA sequencing on 245 samples from TNBC patients to characterize the landscape of microtubule-associated proteins (MAPs). Here, our transcriptome analyses revealed that low expression of one MAP, tektin4, indicated poor patient outcomes. Tektin4 loss led to a marked increase in TNBC migration, invasion, and metastasis and a decrease in microtubule stability. Mechanistically, we identified a novel microtubule-associated complex containing tektin4 and histone deacetylase 6 (HDAC6). Tektin4 loss increased the interaction between HDAC6 and α-tubulin, thus decreasing microtubule stability through HDAC6-mediated tubulin deacetylation. Significantly, we found that tektin4 loss sensitized TNBC cells, xenograft models, and patient-derived organoid models to the HDAC6-selective inhibitor ACY1215. Furthermore, tektin4 expression levels were positively correlated with microtubule stability levels in clinical samples. Together, our findings uncover a metastasis suppressor function of tektin4 and support clinical development of HDAC6 inhibition as a new therapeutic strategy for tektin4-deficient TNBC patients.
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http://dx.doi.org/10.1038/s41388-021-01655-2DOI Listing
March 2021

Efficacy and safety comparison of pharmacotherapies for interstitial cystitis and bladder pain syndrome: a systematic review and Bayesian network meta-analysis.

Int Urogynecol J 2021 Feb 27. Epub 2021 Feb 27.

Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, People's Republic of China.

Introduction And Hypothesis: The objective was to compare the clinical efficacy and safety of pharmacological interventions for interstitial cystitis and bladder pain syndrome (IC/BPS) with direct and indirect evidence from randomized trials.

Methods: We searched PubMed, the Cochrane library, and EMBASE for randomized controlled trials (RCTs) that assessed the pharmacological therapies for IC/BPS. Primary efficacy outcomes included ICSI (O'Leary Sant Interstitial Cystitis Symptom Index), ICPI (O'Leary Sant Interstitial Cystitis Problem Index), 24-h micturition frequency, visual analog scale (VAS), and Likert score for pain. Safety outcomes are total adverse events (AEs, intravesical instillation, and others), gastrointestinal symptoms, headache, pain, and urinary symptoms. A systematic review and Bayesian network meta-analysis were performed.

Results: A total of 23 RCTs with 1,871 participants were identified. The ICSI was significantly reduced in the amitriptyline group (MD = -4.9, 95% CI: -9.0 to -0.76), the cyclosporine A group (MD = -7.9, 95% CI: -13.0 to -3.0) and the certolizumab pegol group (MD = -3.6, 95% CI:-6.5 to -0.63) compared with placebo group. Moreover, for ICPI, cyclosporine A showed superior benefit compared to placebo (MD = -7.6, 95% CI: -13 to -2.3). VAS score improved significantly in cyclosporine A group than pentosan polysulfate sodium (MD = 3.09, 95% CI: 0.13 to 6.07). None of the agents revealed a significant alleviation of 24-h micturition frequency. In terms of safety outcomes, the incidence rate on urinary symptoms for botulinum toxin A was the only variate higher than chondroitin sulfate (MD = -2.02, 95% CI: -4.99 to 0.66) and placebo (MD = -1.60, 95% CI:-3.83 to 0.17). No significant difference was found among the other treatments.

Conclusions: Cyclosporine A might be superior to other pharmacological treatments in efficacy. Amitriptyline and certolizumab pegol were capable of lowering the ICSI as well.
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http://dx.doi.org/10.1007/s00192-020-04659-wDOI Listing
February 2021

Anti-NSCLC activity in vitro of Hsp90 inhibitor KW-2478 and complex crystal structure determination of Hsp90-KW-2478.

J Struct Biol 2021 Feb 19;213(2):107710. Epub 2021 Feb 19.

Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic & Translational Medicine, Xi'an Medical University, Xi'an 710021, China. Electronic address:

KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90  (Hsp90). Absence of complex crystal structure of Hsp90-KW-2478, however, hampered further structure optimization of KW-2478 and understanding on the molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59 Å; PDB ID: 6LT8) and their molecular interaction was analyzed in detail, which suggested that KW-2478 perfectly bound in the N-terminal ATP-binding pocket of Hsp90 to disable its molecular chaperone function, therefore suppressed or killed cancer cells. The results from thermal shift assay (TSA, ΔTm, 18.82 ± 0.51 °C) and isothermal titration calorimetry (ITC, K, 7.30 ± 2.20 nM) suggested that there is an intense binding force and favorable thermodynamic changes during the process of KW-2478 binding with Hsp90. Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC, 8.16 μM for A549; 14.29 μM for H1975) and migration, induced cell cycle arrest and promoted apoptosis. Thirty-six novel KW-2478 derivatives were designed, based on the complex crystal structure and molecular interaction analysis of Hsp90-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90 evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478.
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http://dx.doi.org/10.1016/j.jsb.2021.107710DOI Listing
February 2021

CD90 affects the biological behavior and energy metabolism level of gastric cancer cells by targeting the PI3K/AKT/HIF-1α signaling pathway.

Oncol Lett 2021 Mar 7;21(3):191. Epub 2021 Jan 7.

NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China.

CD90, also known as Thy-1 cell surface antigen, is located on human chromosome 11q23.3, and encodes a glycosylphosphatidylinositol-linked cell surface glycoprotein. CD90 serves a key role in malignancy by regulating cell proliferation, metastasis and angiogenesis. Gastric cancer is one of the most common types of malignancy. Patients with advanced gastric cancer have a poor prognosis. CD90 plays a key role in the occurrence and progression of gastric cancer. However, the molecular mechanism of CD90 in gastric cancer is currently unclear. In order to identify the molecular mechanism by which CD90 affects the biological behavior and energy metabolism of gastric cancer cells, the present study used Cell Counting Kit-8 assays, lactate concentration determination and ATP content determination. The results demonstrated that CD90 promotes proliferation and inhibits senescence in gastric cancer cells. In addition, CD90 enhanced the invasion and migration abilities of AGS gastric cancer cells. Overexpression of CD90 resulted in the accumulation of intracellular lactic acid in AGS cells. CD90 upregulated lactate dehydrogenase levels and increased the NADPH/NADP ratio in AGS cells. CD90 overexpression decreased the ATP concentration in AGS cells. PI3K, PDK1, phosphorylated-AKT-Ser473, HIF-1α, MDM2 and SIRT1 levels were upregulated in CD90-overexpressing AGS cells, compared with AGS cells transfected with the empty vector. In contrast, PTEN, p53, SIRT2, SIRT3 and SIRT6 were downregulated. The results indicate that CD90 affects the biological behavior and levels of energy metabolism of gastric cancer cells by targeting the PI3K/AKT/HIF-1α signaling pathway.
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http://dx.doi.org/10.3892/ol.2021.12451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816286PMC
March 2021

Oncogenic N-Ras mitigates oxidative stress-induced apoptosis of hematopoietic stem cells.

Cancer Res 2021 Jan 13. Epub 2021 Jan 13.

Medicine, University of Michigan–Ann Arbor

Leukemic relapse is believed to be driven by transformed hematopoietic stem cells that harbor oncogenic mutations or have lost tumor suppressor function. Recent comprehensive sequencing studies have shown that mutations predicted to activate Ras signaling are highly prevalent in hematologic malignancies and, notably, in refractory and relapsed cases. To better understand what drives this clinical phenomenon, we expressed oncogenic NrasG12D within the hematopoietic system in mice and interrogated its effects on hematopoietic stem cell (HSC) survival. N-RasG12D conferred a survival benefit to HSC and progenitors following metabolic and genotoxic stress. This effect was limited to HSC and early progenitors and was independent of autophagy and cell proliferation. N-RasG12D-mediated HSC survival was not affected by inhibition of the canonical Ras effectors such as MEK and PI3K. However, inhibition of the non-canonical Ras effector pathway protein kinase C (PKC) ameliorated the protective effects of N-RasG12D. Mechanistically, N-RasG12D lowered levels of reactive oxygen species (ROS), which correlated with reduced mitochondrial membrane potential and ATP levels. Inhibition of PKC restored the levels of ROS to that of control HSC and abrogated the protective effects granted by N-RasG12D. Thus, N-RasG12D activation within HSC promote cell survival through the mitigation of ROS, and targeting this mechanism may represent a viable strategy to induce apoptosis during malignant transformation of HSC.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0118DOI Listing
January 2021

Complex crystal structure determination and anti-non-small-cell lung cancer activity of the Hsp90 inhibitor Debio0932.

Acta Crystallogr D Struct Biol 2021 Jan 1;77(Pt 1):86-97. Epub 2021 Jan 1.

Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an 710021, People's Republic of China.

Debio0932 is a promising lead compound in phase I clinical trials targeting the N-terminal ATP-binding pocket of the molecular chaperone heat-shock protein 90 (Hsp90). The absence of a crystal structure of the Hsp90-Debio0932 complex, however, has impeded further structural optimization of Debio0932 and understanding of the molecular-interaction mechanism. Here, a high-resolution crystal structure of the Hsp90-Debio0932 complex was successfully determined (resolution limit 2.20 Å; PDB entry 6lr9) by X-ray diffraction and the molecular-interaction mechanism was analysed in detail, which suggested that Debio0932 suppresses cancer cells by accommodating itself in the ATP-binding pocket of Hsp90, disabling its molecular-chaperone capability. The results of a thermal shift assay (ΔT = 8.83 ± 0.90°C) and isothermal titration calorimetry (K = 15.50 ± 1.30 nM) indicated strong binding and favourable thermodynamic changes in the binding of Hsp90 and Debio0932. Based on the crystal structure of the complex and on molecular-interaction analysis, 30 new Debio0932 derivatives were designed and nine new derivatives exhibited increased binding to Hsp90, as determined by molecular-docking evaluation. Additionally, Debio0932 suppressed cell proliferation (IC values of 3.26 ± 2.82 µM for A549, 20.33 ± 5.39 µM for H1299 and 3.16 ± 1.04 µM for H1975), induced cell-cycle arrest and promoted apoptosis in three non-small-cell lung cancer (NSCLC) cell lines. These results provide novel perspectives and guidance for the development of new anti-NSCLC drugs based on the lead compound Debio0932.
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http://dx.doi.org/10.1107/S2059798320014990DOI Listing
January 2021

Assessing the changes in childbirth care practices and neonatal outcomes in Western China: pre-comparison and post-comparison study on early essential newborn care interventions.

BMJ Open 2020 12 22;10(12):e041829. Epub 2020 Dec 22.

Child Health Care Department, National Center for Women and Children's Heath China Center for Disease Control, Beijing, China

Objective: To explore the changes in childbirth care practices and health outcomes of newborns after the introduction of early essential newborn care (EENC).

Design: A pre-comparison and post-comparison study.

Setting: The study was conducted in December 2016 and December 2018 in 18 counties in four western provinces of China.

Participants: 46 hospitals that provide delivery services participated in the study.

Interventions: EENC practices were introduced and implemented in the 46 hospitals.

Outcome Measures: The changes of hospital indicators such as incidence of birth asphyxia and neonatal mortality were compared in 2016 and 2018. EENC coverage indicators, such as skin-to-skin (STS) contact, and time of first breast feeding were also compared before and after the intervention via interview with 524 randomly selected postpartum mothers (320 in 2016 and 204 in 2018).

Results: 54 335 newborns were delivered in the pre-EENC period (2016) and 58 057 delivered in the post-EENC period (2018). According to hospital records, the proportion of newborns receiving immediate STS contact increased from 32.6% to 51.2% (Risk Ratio (RR)=1.57,95% CI 1.55 to 1.59) and the percentage of newborns receiving prolonged STS contact for more than 90 min increased from 8.1% to 26.8% (RR=3.31, 95% CI 3.21 to 3.41). No statistically significant changes were found in neonatal mortality, although slight decreases in birth asphyxiate and neonatal intensive care unit admission rates were detected. Among the mothers interviewed, the proportion of newborns receiving immediate STS contact increased from 34.6% to 80.0% (RR=2.31, 95% CI 1.69 to 3.17). The exclusive breastfeeding rate increased from 43% to 73.4% (RR=1.71, 95% CI 1.43 to 2.04). The average length of the first breast feeding increased from 15.8 min to 17.1 min.

Conclusions: The introduction of EENC has yielded significant improvements in newborn care services at the pilot hospitals, including enhanced maternal and newborn care practices, improved STS contact quality and early breastfeeding performance. Further studies are needed to evaluate the long-term impact of EENC on newborn health outcomes.
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http://dx.doi.org/10.1136/bmjopen-2020-041829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757506PMC
December 2020

Na@La-modified zeolite particles for simultaneous removal of ammonia nitrogen and phosphate from rejected water: performance and mechanism.

Water Sci Technol 2020 Dec;82(12):2975-2989

School of Civil Engineering and Architecture, Wuhan University of Technology, Wuhan 430070, China E-mail:

Rejected water from sludge processing in wastewater treatment plants (WWTPs) is very harmful due to its high concentration of ammonia nitrogen and phosphorus. It is therefore necessary to find a low-cost and convenient technique to simultaneously remove ammonia nitrogen and phosphorus from rejected water. In this study, natural granular zeolite was modified by NaCl and La(OH) to obtain a new material (Na@La-MZP), with several advantages compared with powdered zeolite. Na@La-MZP could remove 92.61% ammonia nitrogen (50 mg/L) and 99.01% phosphate (60 mg/L) at the optimal conditions of dosage 12.5 g/L, initial pH 6.0 and reaction time 12 hours, which enabled the effluent to satisfy the discharge standard (GB 18918-2002) for municipal WWTPs in China. The maximum adsorption capacity of Na@La-MZP was determined as 17.92 mg NH-N/g and 9.53 mg P/g by the Langmuir isotherm. Pseudo-second-order kinetics could well illustrate the adsorption process and show that the ammonia nitrogen and phosphate can be degraded by chemical reaction. The characterizations of Na@La-MZP confirmed the removal mechanism of ammonia nitrogen and phosphate. The Na@La-MZP still maintained more than 75% removal efficiency after five reuses. Furthermore, the estimated cost of this treatment method was 0.22 $/m rejected water.
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http://dx.doi.org/10.2166/wst.2020.541DOI Listing
December 2020

Barriers to Adolescent Health Care in Maternal and Children's Healthcare Hospitals: Based on a National Survey in China.

J Adolesc Health 2020 Nov 24;67(5S):S32-S37. Epub 2020 Nov 24.

National Center for Women and Children's Health, Chinese Center for Disease Control and Prevention, Beijing, China.

Purpose: Adolescence is a critical period for physical and psychological development; therefore, health interventions at this phase may be especially beneficial. In this study, we aim to describe the distribution of the adolescent health care system in China and to compare the perceived barriers of running an adolescent clinic (AC) proposed by hospitals with corresponding government entities.

Methods: A nationwide online survey was launched by the National Health Commission of China in December 2015, among 116 Maternal and Children's Healthcare (MCH) hospitals located across 24 randomized selected provinces. The online survey included management questionnaires filled out by health administrators from local health commissions and service questionnaires filled out by adolescent care providers from MCH hospitals.

Results: Among the surveyed provinces, only 7% have special funding for adolescent health care, 13% have a supporting policy, 8% have guidelines/service standards, and 16% provide adolescent health care based in MCH hospitals. Among the 116 MCH hospitals investigated, 31 (27%) had a functioning AC and 15 (13%) used to have an AC. Compared with the MCH hospitals that never have an AC, those that previously had an AC were more likely to perceive demand as a barrier (odds ratio = 8.02; p value < .05) but less likely to perceive guidelines/service standards as a problem (odds ratio = .09; p value < .01). The perceptions of health administrators and adolescent health care providers differed markedly on demand and profits: both were ranked highly by supply side (health providers) but ranked low by the health administrators.

Conclusions: This national survey, for the first time, presents a whole picture of adolescent health care in MCH hospital settings in China. Among the surveyed MCH hospitals, major areas of discordance between administrators and health care providers were barriers in demand and profits, which health administrators tend to overlook. A number of strategic priorities are proposed to best guide the development of the adolescent health care system in China, including improved linkage between health and education and community systems, comprehensive approaches move beyond sexual and reproductive education, as well as the workforce development and capacity-building.
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http://dx.doi.org/10.1016/j.jadohealth.2020.07.024DOI Listing
November 2020

Multicenter Evaluation of Xpert Carba-R Assay for Detection and Identification of the Carbapenemase Genes in Rectal Swabs and Clinical Isolates.

J Mol Diagn 2021 Jan 16;23(1):111-119. Epub 2020 Nov 16.

Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China; Regional Medical Center for National Institute of Respiratory Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address:

Rapid detection of carbapenemase-producing organisms is clinically desirable for hospital infection control and antibiotic stewardship. In this multicenter study, the Xpert Carba-R assay was evaluated for detection of the five carbapenemase genes (bla, bla, bla, bla, and bla) in 2404 nonduplicate rectal swabs of admitted inpatients and 521 Gram-negative isolates from four tertiary hospitals in China, compared with the reference growth-based method with DNA sequence analysis of colonies. All suspected false-positive results in rectal swabs were resolved by supplementary sequencing from broth cultures. A total of 197 bla, 171 bla, 142 bla, 6 bla, and 5 bla genes were detected by Xpert Carba-R in 417 rectal swabs, with overall positive and negative percentage agreements ranging from 94.5% to 100% and from 94.8% to 99.9%, respectively. Notably, 17.5% (263/1500) of inpatients had rectal colonization with carbapenem-nonsusceptible organisms detected in intensive care units, and 63.1% (166/263) were Xpert Carba-R positive. Among the 469 carbapenem-nonsusceptible and 52 carbapenem-susceptible isolates examined, 373 were Enterobacteriaceae, 55 were Pseudomonas aeruginosa, and 93 were Acinetobacter baumannii. Compared with the reference isolate sequencing, overall positive and negative percentage agreements were 99.7% and 98.0%, respectively. The intra-assay and interassay coefficient of variability values were both <2%. Thus, we show that Xpert Carba-R assay provides good reproducibility and reliable results for detection and differentiation of five carbapenemase genes in both rectal swabs and clinical isolates.
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http://dx.doi.org/10.1016/j.jmoldx.2020.10.017DOI Listing
January 2021

Kappa Opioid Receptor on Pulmonary Macrophages and Immune Function.

Transl Perioper Pain Med 2020 20;7(3):225-233. Epub 2020 Feb 20.

Department of Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Background: Respiratory failure significantly increases mortality in critically ill patients. While opioids are often used during the perioperative period and in critically ill situations, little is known about how opioids are involved in pulmonary immune function and the inflammatory response. There is currently no clear information on the role of the kappa opioid receptor (KOR) in pulmonary inflammation. Here we evaluate whether KORs are involved in the modulation of lung macrophages by the use of selective KOR agonists in lipopolysaccharide (LPS) activated alveolar macrophages.

Method: The inflammatory response in rat NR8383 macrophages was induced by stimulation with LPS (100 ng/ml) at different time-points. The effects of the KOR agonists Salvinorin A (SA) and U50488 on inflammatory factors such as nitrite, TNF-α, IL-1β, iNOS and COX-2 were investigated. Nor-binaltorphimine, a selective KOR antagonist, was used to investigate the specific role of KOR.

Results: Stimulation of NR8383 cells with LPS (100 ng/ml) significantly increased the level of TNF-α at 1h, 2h and 6h compared to un-stimulated cells. SA attenuated the inflammatory response by reducing the levels of TNF-α and IL-1β after LPS treatment. SA co-treatment reduced the elevated levels of NO induced by LPS and also alleviated the over-expression of iNOS and COX-2 within 2 hours after LPS activation, and such effects can be partially blocked by KOR antagonist, nor-binaltorphimine. Similar results from U50488 were observed.

Conclusion: Our results indicate that KORs may play a critical role in the modulation of the pulmonary inflammatory process by their activation in macrophages. Selective KOR agonists exert their anti-inflammatory effects acutely on lung macrophages, within 1-2 hours of LPS-stimulated inflammation .
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http://dx.doi.org/10.31480/2330-4871/117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668421PMC
February 2020

The role of interleukin-6/interleukin-6 receptor signaling in the mechanical stress-induced extracellular matrix remodeling of bladder smooth muscle.

Arch Biochem Biophys 2020 Nov 12:108674. Epub 2020 Nov 12.

Department of Urology, Institute of Urology, Laboratory of Reconstructive Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China. Electronic address:

Extracellular matrix (ECM) remodeling is strongly associated with pathological changes induced by bladder outlet obstruction (BOO). In this study, we investigated the role of interleukin-6 (IL-6) in mechanical stretch-induced ECM remodeling of bladder smooth muscle. To construct a BOO animal model, the urethras of female Sprague-Dawley rats were partially ligated. In addition, increased hydrostatic pressure and mechanical stretching were applied to human bladder smooth muscle cells (HBSMCs) as an in vitro model. The expression of rat inflammatory genes was analyzed using DNA microarrays. We used quantitative RT-PCR (qRT-PCR) and immunohistochemical staining to detect IL-6 in the bladder smooth muscle of rats. To determine the specificity of IL-6, small interfering ribonucleic acid (siRNA) transfection and IL-6 receptor inhibitor (SC144) were applied to HBSMCs. qRT-PCR with siRNA transfection was also used to determine the specificity of downstream signaling. Moreover, western blotting was conducted to verify the expression results. In the animal model, the expression of ECM components and inflammatory genes was significantly upregulated. The expression of IL-6 was increased at both the mRNA level and the protein level in BOO rats. In vitro, hydrostatic pressure, and mechanical stretching both promoted MMP7 and MMP11 expression. Additionally, downregulation of collagen III occurred in both the hydrostatic pressure group and the mechanical stretch group. However, the expression of fibronectin exhibited opposing patterns between the hydrostatic pressure and mechanical stretch groups. The application of targeted siRNA transfection and an inhibitor (SC144) that targeted IL-6 significantly reversed the changes in MMP7 and MMP11 under mechanical stress and partially increased the expression of collagen III and fibronectin. In summary, IL-6 participated in the ECM remodeling of HBSMCs under mechanical stress, indicating that IL-6 may play an essential role in BOO.
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http://dx.doi.org/10.1016/j.abb.2020.108674DOI Listing
November 2020

Autophagy Inhibition Preserves Tight Junction of Human Cerebral Microvascular Endothelium Under Oxygen Glucose Deprivation.

Curr Neurovasc Res 2020 ;17(5):644-651

Department of Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA, United States.

Aims: To investigate the role of autophagy in the tight junction of human brain endothelial cells during hypoxia and ischemia.

Background: Endothelial cells play an important role in the initiation, progression and recovery from ischemic stroke. The role of autophagy on human brain endothelial cells (HBECs) subjected to oxygen-glucose deprivation (OGD) is not fully elucidated.

Objective: The objective of this study was to investigate the effect of autophagy on HBECs during OGD.

Methods: HBECs were cultured in a 96-well plate and underwent 4 hours of OGD. For drug treatment, 3-Methyladenine (3-MA) (5mmol/L), an inhibitor of autophagy, was added at the start of OGD. Cell viability and cytotoxicity were tested by cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) assays. Morphological changes in cells were examined by immunofluorescence microscopy. The protein expression of light chain 3 (LC3) was measured. Autophagosomes and endothelial cell tight junctions were observed using transmission electron microscopy.

Results: The results showed that OGD induced serious damage to HBECs. Cell viability was decreased significantly and LDH release increased significantly (p<0.05) following OGD. 3-MA protected HBECs from damage. Immunostaining further confirmed these results. Since 3-MA is an inhibitor of autophagy, we chose to examine alterations in the amount of LC3, a marker of autophagy. The ratios of LC3-II to LC3-I were significantly lower in the 3-MA treated OGD group than in the non-3-MA treated OGD group (p<0.05). Electron microscopy showed that 3-MA inhibited the formation of autophagolysosomes and revealed that the tight junction ultrastructure of HBECs, which was destroyed by OGD, was significantly protected by treatment with 3-MA.

Conclusion: Autophagy is a key response to oxygen-glucose deprivation stress and its detrimental effects are closely related to the destruction of tight junctions of human brain endothelial cells. Strategies to inhibit autophagy could help to preserve tight junctions.
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http://dx.doi.org/10.2174/1567202617999201103200705DOI Listing
January 2020

ER-associated degradation preserves hematopoietic stem cell quiescence and self-renewal by restricting mTOR activity.

Blood 2020 Dec;136(26):2975-2986

Department of Internal Medicine.

Hematopoietic stem cells (HSC) self-renew to sustain stem cell pools and differentiate to generate all types of blood cells. HSCs remain in quiescence to sustain their long-term self-renewal potential. It remains unclear whether protein quality control is required for stem cells in quiescence when RNA content, protein synthesis, and metabolic activities are profoundly reduced. Here, we report that protein quality control via endoplasmic reticulum-associated degradation (ERAD) governs the function of quiescent HSCs. The Sel1L/Hrd1 ERAD genes are enriched in the quiescent and inactive HSCs, and conditional knockout of Sel1L in hematopoietic tissues drives HSCs to hyperproliferation, which leads to complete loss of HSC self-renewal and HSC depletion. Mechanistically, ERAD deficiency via Sel1L knockout leads to activation of mammalian target of rapamycin (mTOR) signaling. Furthermore, we identify Ras homolog enriched in brain (Rheb), an activator of mTOR, as a novel protein substrate of Sel1L/Hrd1 ERAD, which accumulates upon Sel1L deletion and HSC activation. Importantly, inhibition of mTOR, or Rheb, rescues HSC defects in Sel1L knockout mice. Protein quality control via ERAD is, therefore, a critical checkpoint that governs HSC quiescence and self-renewal by Rheb-mediated restriction of mTOR activity.
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http://dx.doi.org/10.1182/blood.2020007975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770563PMC
December 2020

Effects of baby-friendly practices on breastfeeding duration in China: a case-control study.

Int Breastfeed J 2020 11 3;15(1):92. Epub 2020 Nov 3.

National Center for Women and Children's Health, Chinese Center for Disease Control and Prevention, Beijing, 100081, China.

Background: The Baby-Friendly Hospital Initiative is generally considered an effective way to promote breastfeeding. Although China has the largest number of baby-friendly hospitals in the world, research on baby-friendly practices in China is limited, and the rate of exclusive breastfeeding (EBF) at 6 months, 20.7%, compared to the 2025 global goal of 50% is low. It is, therefore, important to determine the factors that remain significant barriers to EBF in China. To explore how the key baby-friendly practices affect EBF duration in China, we used a case-control study to compare the effects of baby-friendly-related practices on both EBF and non-breastfeeding (NBF) mothers at 3 months and to investigate the effects of both single and comprehensive baby-friendly practices in promoting EBF duration at 3 months, which is one step toward EBF at 6 months.

Methods: Participants were recruited from four maternal and child health hospitals in western (Chongqing), eastern (Qingdao), southern (Liuzhou), and central China (Maanshan). A total of 421 mothers (245 in the EBF group, 176 in the NBF group) of infants aged 3 months were surveyed through a self-reported questionnaire from April 2018 to March 2019. The experience of baby-friendly practices and breastfeeding during hospitalization were assessed with yes/no questions. Socio-demographic factors that influenced breastfeeding at 3 months were analyzed using bivariate and multivariate logistic regression analyses.

Results: Of mothers in the EBF group, 65.57% reported engaging in at least seven baby-friendly practices compared to 47.72% of mothers in the NBF group. Significantly more mothers in the EBF group engaged in baby-friendly practices than in the NBF group. These practices included "breastfeeding within one hour after birth" (74.29% vs. 59.09%), "breastfeeding on demand" (86.48% vs. 75.00%), and "never use a pacifier" (46.53% vs. 31.25%). After adjusting for confounding variables, we found that the mothers who engaged in fewer than seven baby-friendly practices were about 1.7 times less likely to breastfeed than were those who engaged in seven or more baby-friendly practices (odds ratio [OR] 1.720, 95% confidence interval [CI] 1.106, 2.667). Further, the mothers who did not breastfeed on demand were as likely to not breastfeed up to 3 months (OR 2.263, 95% CI 1.265, 4.049), as were mothers who did not breastfeed during hospitalization (OR 4.379, 95% CI 1.815, 10.563).

Conclusions: These data from hospitals in China suggest that higher compliance with baby-friendly practices may have a positive impact on EBF at 3 months, particularly in terms of promoting the implementation of breastfeeding on demand and breastfeeding during hospitalization in China.
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http://dx.doi.org/10.1186/s13006-020-00334-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640486PMC
November 2020

Fra-1 Inhibits Cell Growth and the Warburg Effect in Cervical Cancer Cells via STAT1 Regulation of the p53 Signaling Pathway.

Front Cell Dev Biol 2020 30;8:579629. Epub 2020 Sep 30.

Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.

The oncogenesis of cervical cancer is a multi-factor and multi-step process, and major risk factors include oncogene activation with tumor suppressor gene inactivation, viral factors, and immune factors. For example, the human papillomavirus (HPV) has been linked to the occurrence of cervical cancer. At present, the pathogenesis of cervical cancer remains unclear. Fra-1 (Fos-related antigen 1, also known as FOSL1) is a member of the Fos family and an important nuclear transcription factor that regulates normal cell growth, differentiation, and apoptosis. In the present study, we found that Fra-1 inhibited the proliferation of cervical cancer cells while also promoting apoptosis and affecting cell cycle distribution. Moreover, Fra-1 up-regulated STAT1 expression and modulated p53 signal pathway activity in cervical cancer cells. Overexpression of Fra-1 inhibited cell senescence by altering sirtuin 1 (SIRT1) expression in HeLa cells, and Fra-1 overexpression restored mitochondrial disorder and suppressed metabolic reprogramming in HeLa cells. Silencing of STAT1 impaired the inhibitory effect of Fra-1 on cervical cancer cell growth, while knock-down of STAT1 reversed the effect on cell senescence and mitochondrial dysfunction caused by Fra-1 in HeLa cells. Silencing of STAT1 also recovered metabolic reprogramming in cervical cancer cells. In summary, our results show that Fra-1 inhibited cervical cancer cell growth and the Warburg effect via STAT1-mediated regulation of the p53 signaling pathway.
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http://dx.doi.org/10.3389/fcell.2020.579629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554318PMC
September 2020

Urological second malignant neoplasms in testicular nonseminoma survivors: a population-based analysis.

Int Urol Nephrol 2021 Mar 14;53(3):471-477. Epub 2020 Oct 14.

Laboratory of Reconstructive Urology, Department of Urology, Institute of Urology, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu, Sichuan, 610041, People's Republic of China.

Purpose: Patients with testicular non-seminomatous germ cell tumors in the modern cisplatin-based chemotherapy era show favorable outcomes, yielding survivors exposed to increased risk of second malignant neoplasms. The carcinogenic effects of cisplatin were well established, and its side effects had shown close connections with the urinary system. The study aimed to evaluate how the characteristics of the primary testicular nonseminoma are associated with urological second malignant neoplasms and survival outcomes.

Methods: Using the Surveillance, Epidemiology and End Results database, standardized incidence ratios (SIR) for three major urological tumors including kidney, bladder, and prostate cancer were calculated for 10,734 patients with testicular nonseminoma from 1975 to 2016. The survival analyses were performed using the Kaplan-Meier method and log-rank test, risk factors for overall survival were determined by Cox regression.

Results: We identified a total of 197 patients with secondary urological neoplasms. Patients with previous testicular nonseminoma had elevated risk of kidney cancer (SIR 2.13, 95% CI 1.59-2.79), bladder cancer (SIR 1.47, 95% CI 1.07-1.59), and decreased risks of prostate cancer (SIR 0.75, 95% CI 0.61-0.91) compared with the general population. Patients diagnosed with testicular nonseminoma had favorable prognosis with 10-year overall survival reaching 91.8%, and patients with urological second malignant neoplasms showed better prognoses than patients with other second malignant neoplasms (log-rank P < 0.001).

Conclusion: Testicular nonseminoma survivors showed higher risks of kidney and bladder cancer associated with chemotherapy and decreased risk of prostate cancer. The prognosis of urological second neoplasms was better than other tumor origins.
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http://dx.doi.org/10.1007/s11255-020-02659-9DOI Listing
March 2021

Randomized phase II clinical trial and biomarker analysis of paclitaxel plus epirubicin versus vinorelbine plus epirubicin as neoadjuvant chemotherapy in locally advanced HER2-negative breast cancer with TEKT4 variations.

Breast Cancer Res Treat 2021 Jan 25;185(2):371-380. Epub 2020 Sep 25.

Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, People's Republic of China.

Purpose: Resistance to paclitaxel remains a major challenge in treating breast cancer. Our preclinical study suggested that TEKT4 germline variations in breast cancer are associated with paclitaxel resistance and increase vinorelbine sensitivity. This clinical trial compared the efficacy of paclitaxel and vinorelbine in breast cancer neoadjuvant chemotherapy.

Methods: In this open-label, single-center, phase II trial, female patients with human epidermal growth factor receptor 2 (HER2)-negative, stage IIB-IIIC breast cancer harboring TEKT4 germline variations were randomly assigned to the paclitaxel plus epirubicin (PE) or vinorelbine plus epirubicin (NE). The primary endpoint was the pathologic complete response (pCR) rate, and the secondary endpoints were the objective response rate (ORR) and safety. Targeted sequencing of a panel comprising 484 breast-related genes was performed to identify pCR-associated somatic mutations in each group.

Results: 91 Patients were assigned to PE (46 patients) or NE (45 patients). NE numerically increased the pCR rate (22.2% versus 8.7%, P = 0.074). The ORRs for NE and PE were 82.2% and 76.1%, respectively. Interestingly, NE (15.4%) showed a significantly higher pCR rate than PE (0%) in the hormone receptor (HR)-positive subgroup (P = 0.044). Both regimens were well tolerated, with grade 3 and 4 toxicities reported at the expected levels. The biomarker analysis showed that UNC13D mutation predicted the pCR rate in NE (P = 0.011).

Conclusions: Although the primary endpoint was not met, NE might bring clinical benefit to HR-positive patients or patients simultaneously carrying UNC13D mutations.
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http://dx.doi.org/10.1007/s10549-020-05940-8DOI Listing
January 2021

Efficacy and Safety of External Physical Vibration Lithecbole After Extracorporeal Shock Wave Lithotripsy or Retrograde Intrarenal Surgery for Urinary Stone: A Systematic Review and Meta-analysis.

J Endourol 2020 Nov 5. Epub 2020 Nov 5.

Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, People's Republic of China.

The current study evaluated the efficacy and safety of external physical vibration lithecbole (EPVL) after extracorporeal shock wave lithotripsy (SWL) or retrograde intrarenal surgery (RIRS) for urolithiasis. Publicized literature was systematically searched from EMBASE, Cochrane Library, PubMed, ScienceDirect, ClinicalTrials.gov, and Web of Science up to February 2020. Fixed-effects or random-effects model was chosen in risk ratio (RR) calculation according to heterogeneity. Quality of evidence was estimated under the guidance of Cochrane handbook. Stone expulsion rate, stone-free rates (SFRs), and complication rates were set as end points. Six randomized controlled trials, including 853 patients, were eligible for analysis. EPVL significantly increased SFR within 3 weeks (RR = 1.17, 95% CI: 1.06-1.29,  = 0.001) and above 3 weeks (RR = 1.19, 95% CI: 1.03-1.37,  = 0.02) after SWL. EPVL also improved SFR within 3 weeks (RR = 1.84, 95% CI: 1.35-2.49,  < 0.0001) and above 3 weeks (RR = 1.53, 95% CI: 1.33-1.77,  < 0.00001) after RIRS. Besides, EPVL can significantly increase SFRs for stones in renal pelvis, lower calix, and multiple locations (all -value <0.05). Although the overall complication rate was not significantly higher in EPVL + RIRS group, it was found to be 1.38 times higher in EPVL+SWL group (RR = 1.38, 95% CI: 1.06-1.79,  = 0.02), especially the incidence of flank pain (RR = 3.11, 95% CI: 1.02-9.46,  = 0.05). EPVL is effective and safe with high SFRs (especially in renal pelvis, lower calix, and multiple locations) after SWL or RIRS and lower overall complication rate after RIRS in patients with urolithiasis. However, the overall complication rate (especially the incidence of flank pain) was higher after EPVL + SWL.
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http://dx.doi.org/10.1089/end.2020.0820DOI Listing
November 2020

β-Adrenoceptor regulates contraction and inflammatory cytokine expression of human bladder smooth muscle cells via autophagy under pathological hydrostatic pressure.

Neurourol Urodyn 2020 11 19;39(8):2128-2138. Epub 2020 Sep 19.

Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan, China.

Aims: Abnormal intravesical pressure created by partial bladder outlet obstruction (PBOO) triggered the progression from chronic inflammation to fibrosis, initiating structural and functional alterations of bladder. To elucidate the underlying mechanisms of contraction and inflammatory response, we investigated the isolated human bladder smooth muscle cells (hBSMC) under pathological hydrostatic pressure (HP) mimicking the in vivo PBOO condition.

Methods: hBSMCs were subjected to HP of 200 cm H O to explore the contraction and inflammatory cytokine expression of hBSMC treated with β-adrenoceptors (ADRBs) and/or autophagy signaling pathway agonists and/or antagonists.

Results: We showed that pathological HP induced the release of the proinflammatory cytokines, including monocyte chemotactic protein-1, regulated upon activation normal T cell expressed and secreted factor, and interleukin-6. HP downregulated ADRB2 and ADRB3 expression, which was consistent with the results of the PBOO rat model. ADRB2 or autophagy activation repressed pathological HP-induced proinflammatory cytokine production. ADRB2, ADRB3 or autophagy activation ameliorated the HP-enhanced contraction. The increased contraction and autophagy activity by ADRB2 agonist under HP conditions were reversed by pretreatment with antagonists of adenosine monophosphate-activated protein kinase (AMPK).

Conclusion: The present study provides evidence that the ADRB3 agonist suppresses hBSMC contraction under pathological HP conditions. Moreover, the ADRB2 agonist negatively regulates the contraction and inflammatory response of hBSMCs through AMPK/mTOR-mediated autophagy under pathological HP. These findings provide a theoretical basis for potential therapeutic strategies for patients with PBOO.
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http://dx.doi.org/10.1002/nau.24517DOI Listing
November 2020

Achieving enhanced biological nitrogen removal via 2450 MHz electromagnetic wave loading on returned sludge in anaerobic-anoxic-oxic process.

Water Sci Technol 2020 Jul;82(2):373-385

School of Civil Engineering, Southeast University, Nanjing 210096, China.

To evaluate the enhancing of the biological nitrogen removal effectiveness by electromagnetic wave loading on returned sludge in the A/A/O reactor, some experiments were completed with the returned sludge loaded by 2,450 MHz electromagnetic wave. The excess sludge yield and pollutant removal effect of the system were evaluated. Results showed that stronger denitrification effect and less sludge yield were achieved. When 30% of the returned sludge was loaded by electromagnetic wave, the actual denitrification efficiency increased by 7% without dosage. The dissolution of carbon, nitrogen and phosphorus from loaded returned sludge was detected, thus providing the system with a supplemental carbon source of 4.6 g/d SCOD. The specific oxygen uptake rate of the oxic activated sludge increased by 14%, and the denitrification rate of the anoxic activated sludge increased by 29%. Illumina MiSeq analysis showed that the microbial richness increased obviously, and denitrifying bacteria (i.e. Dechloromonas, Zoogloea and Azospira, etc.) were accumulated.
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http://dx.doi.org/10.2166/wst.2020.328DOI Listing
July 2020

Adipose-derived mesenchymal stem cells alleviate TNBS-induced colitis in rats by influencing intestinal epithelial cell regeneration, Wnt signaling, and T cell immunity.

World J Gastroenterol 2020 Jul;26(26):3750-3766

Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.

Background: Conventional Crohn's disease (CD) treatments are supportive rather than curative and have serious side effects. Adipose-derived mesenchymal stem cells (ADSCs) have been gradually applied to treat various diseases. The therapeutic effect and underlying mechanism of ADSCs on CD are still not clear.

Aim: To investigate the effect of ADSC administration on CD and explore the potential mechanisms.

Methods: Wistar rats were administered with 2,4,6-trinitrobenzene sulfonic acid (TNBS) to establish a rat model of CD, followed by tail injections of green fluorescent protein (GFP)-modified ADSCs. Flow cytometry, qRT-PCR, and Western blot were used to detect changes in the Wnt signaling pathway, T cell subtypes, and their related cytokines.

Results: The isolated cells showed the characteristics of ADSCs, including spindle-shaped morphology, high expression of CD29, CD44, and CD90, low expression of CD34 and CD45, and osteogenic/adipogenic ability. ADSC therapy markedly reduced disease activity index and ameliorated colitis severity in the TNBS-induced rat model of CD. Furthermore, serum anti-sacchromyces cerevisiae antibody and p-anti-neutrophil cytoplasmic antibody levels were significantly reduced in ADSC-treated rats. Mechanistically, the GFP-ADSCs were colocalized with intestinal epithelial cells (IECs) in the CD rat model. GFP-ADSC delivery significantly antagonized TNBS-induced increased canonical Wnt pathway expression, decreased noncanonical Wnt signaling pathway expression, and increased apoptosis rates and protein level of cleaved caspase-3 in rats. In addition, ADSCs attenuated TNBS-induced abnormal inflammatory cytokine production, disturbed T cell subtypes, and their related markers in rats.

Conclusion: Successfully isolated ADSCs show therapeutic effects in CD by regulating IEC proliferation, the Wnt signaling pathway, and T cell immunity.
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http://dx.doi.org/10.3748/wjg.v26.i26.3750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383848PMC
July 2020

[Construction of a novel lentiviral vector knocking down PD-1 via microRNA and its application in CAR-T cells].

Sheng Wu Gong Cheng Xue Bao 2020 Jul;36(7):1395-1404

School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou 325035, Zhejiang, China.

By inserting microRNAs into the intron of EF1α promoter, we constructed a novel lentiviral vector knocking down PD-1 gene via microRNA and applied it to CAR-T cells. Lentiviral transduction efficiency and PD-1-silencing efficiency were detected by flow cytometry. PD-1 expression was detected by Western blotting. Relative expression of microRNA was measured by Q-PCR. Cytotoxicity of CAR-T cells based on this vector was tested by luciferase bioluminescence and flow cytometry. Compared with lentiviral vector with microRNA transcribed by U6 promotor, the transduction efficiency of lentiviral vector with microRNA which was inserted into the intron of EF1α promoter was more significant, and the knockdown rate of PD-1 was more than 90%, which was validated by flow cytometry and Western blotting. And the relative expression level of microRNA in Jurkat cells transduced with this novel lentiviral vector was shown by Q-PCR. Compared with normal CAR-T cells, CAR-T cells based on this vector showed stronger cytotoxicity against PD-L1 positive Raji cells. We successfully constructed a novel lentiviral vector that knocked down PD-1 via microRNA and verified the superiority of its transduction efficiency and knockdown efficiency of PD-1. CAR-T cells based on this vector can exert a more powerful cytotoxicity, thus providing theoretical support for the subsequent treatment of PD-L1 positive tumors.
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http://dx.doi.org/10.13345/j.cjb.200193DOI Listing
July 2020

Auranofin mitigates systemic iron overload and induces ferroptosis via distinct mechanisms.

Signal Transduct Target Ther 2020 07 31;5(1):138. Epub 2020 Jul 31.

Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University, 450001, Zhengzhou, China.

Iron homeostasis is essential for health; moreover, hepcidin-deficiency results in iron overload in both hereditary hemochromatosis and iron-loading anemia. Here, we identified iron modulators by functionally screening hepcidin agonists using a library of 640 FDA-approved drugs in human hepatic Huh7 cells. We validated the results in C57BL/6J mice and a mouse model of hemochromatosis (Hfe mice). Our screen revealed that the anti-rheumatoid arthritis drug auranofin (AUR) potently upregulates hepcidin expression. Interestingly, we found that canonical signaling pathways that regulate iron, including the Bmp/Smad and IL-6/Jak2/Stat3 pathways, play indispensable roles in mediating AUR's effects. In addition, AUR induces IL-6 via the NF-κB pathway. In C57BL/6J mice, acute treatment with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling and decreased serum iron and transferrin saturation. Whereas chronically treating male Hfe mice with 5 mg/kg AUR activated hepatic IL-6/hepcidin signaling, decreasing systemic iron overload, but less effective in females. Further analyses revealed that estrogen reduced the ability of AUR to induce IL-6/hepcidin signaling in Huh7 cells, providing a mechanistic explanation for ineffectiveness of AUR in female Hfe mice. Notably, high-dose AUR (25 mg/kg) induces ferroptosis and causes lipid peroxidation through inhibition of thioredoxin reductase (TXNRD) activity. We demonstrate the ferroptosis inhibitor ferrostatin significantly protects liver toxicity induced by high-dose AUR without comprising its beneficial effect on iron metabolism. In conclusion, our findings provide compelling evidence that TXNRD is a key regulator of ferroptosis, and AUR is a novel activator of hepcidin and ferroptosis via distinct mechanisms, suggesting a promising approach for treating hemochromatosis and hepcidin-deficiency related disorders.
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http://dx.doi.org/10.1038/s41392-020-00253-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393508PMC
July 2020

High neutrophil-to-lymphocyte ratio associated with progression to critical illness in older patients with COVID-19: a multicenter retrospective study.

Aging (Albany NY) 2020 07 30;12(14):13849-13859. Epub 2020 Jul 30.

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

This retrospective cohort study aimed to investigate the correlation of the neutrophil-to-lymphocyte ratio (NLR) with critical illness in older patients with COVID-19, and evaluate the prognostic power of the NLR at admission. We enrolled 232 patients with COVID-19, aged ≥60 y, in Zhejiang province from January 17 to March 3, 2020. Primary outcomes were evaluated until April 13. Cox regression was performed for prognostic factors. Twenty-nine (12.5%) patients progressed to critical illness. Age, shortness of breath, comorbidities including hypertension, heart disease, and chronic obstructive pulmonary disease, higher NLR, lower albumin levels, and multiple mottling and ground-glass opacity were associated with progression. In the multivariate analysis, older age (hazard ratio [HR] 1.121, confidence interval [CI] 1.070-1.174, P<0.001), heart disease (HR 2.587, CI 1.156-5.787, P=0.021), higher NLR (HR 1.136, CI 1.094-1.180, P < 0.001), and multiple mottling and ground-glass opacity (HR 4.518, CI 1.906-10.712, P<0.001) remained critical illness predictors. The NLR was independently associated with progression to critical illness; the relationship was significant and graded (HR: 1.16 per unit; 95% CI: 1.10-1.22; P for trend < 0.001). Therefore, NLR can be adopted as a prognostic tool to assist healthcare providers predict the clinical outcomes of older patients suffering from COVID-19.
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http://dx.doi.org/10.18632/aging.103582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425510PMC
July 2020

Molecular Interaction Between Butorphanol and κ-Opioid Receptor.

Anesth Analg 2020 09;131(3):935-942

Department of Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Background: The misuse of opioids stems, in part, from inadequate knowledge of molecular interactions between opioids and opioid receptors. It is still unclear why some opioids are far more addictive than others. The κ-opioid receptor (KOR) plays a critical role in modulating pain, addiction, and many other physiological and pathological processes. Butorphanol, an opioid analgesic, is a less addictive opioid with unique pharmacological profiles. In this study, we investigated the interaction between butorphanol and KOR to obtain insights into the safe usage of this medication.

Methods: We determined the binding affinity of butorphanol to KOR with a naltrexone competition study. Recombinant KORs expressed in mammalian cell membranes (Chem-1) were used for G-protein activation studies, and a human embryonic kidney-293 (HEK-293) cell line stably transfected with the human KOR was used for β-arrestin study as previously described in the literature. The effects of butorphanol on KOR internalization were investigated using mouse neuroblastoma Neuro2A cells stably transfected with mKOR-tdTomato fusion protein (N2A-mKOR-tdT) cells overexpressing KOR. The active-state KOR crystal structure was used for docking calculation of butorphanol to characterize the ligand binding site. Salvinorin A, a full KOR agonist, was used as a control for comparison.

Results: The affinity of KOR for butorphanol is characterized by Kd of 0.1 ± 0.02 nM, about 20-fold higher compared with that of the µ-opioid receptor (MOR; 2.4 ± 1.2 nM). Our data indicate that butorphanol is more potent on KOR than on MOR. In addition, butorphanol acts as a partial agonist of KOR in the G-protein activation pathway and is a full agonist on the β-arrestin recruitment pathway, similar to that of salvinorin A. The activation of the β-arrestin pathway is further confirmed by KOR internalization. The in silico docking model indicates that both salvinorin A and butorphanol share the same binding cavity with the KOR full agonist MP1104. This cavity plays an important role in determining either agonist or antagonist effects of the ligand.

Conclusions: In conclusion, butorphanol is a partial KOR agonist in the G-protein activation pathway and a potent KOR full agonist in the β-arrestin recruitment pathway. The structure analysis offers insights into the molecular mechanism of KOR interaction and activation by butorphanol.
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http://dx.doi.org/10.1213/ANE.0000000000005017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668422PMC
September 2020

Percutaneous tibial nerve stimulation for overactive bladder syndrome: a systematic review and meta-analysis.

Int Urogynecol J 2020 Dec 17;31(12):2457-2471. Epub 2020 Jul 17.

Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, People's Republic of China.

Introduction And Hypothesis: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of percutaneous tibial nerve stimulation (PTNS) for the treatment of overactive bladder (OAB) syndrome.

Methods: PubMed, Embase, Web of Science and Cochrane Library were searched systematically to identify all the relevant studies. Void frequency per day, nocturia frequency per day, urgency episodes per day, incontinence episodes per day, urodynamic values, success rate and side effects, etc., were extracted from the included studies and analyzed.

Results: Twenty-eight studies with 2461 patients in total were included. Results showed that there was a significant clinical effect on the voiding frequency per day (MD = -2.48; 95% CI -3.19, -1.76; P < 0.001), nocturia frequency per day (MD = -1.57; 95% CI -2.16, -0.99; P < 0.001), urgency episodes per day (MD = -2.20; 95% CI -3.77, -0.62; P = 0.006), incontinence episodes per day (MD = -1.37; 95% CI -1.71, -1.02; P < 0.001), maximum cystometric capacity (MD = 63.76; 95% CI 31.90, 95.61; P < 0.001) and compliance (MD = 7.62; 95% CI 0.61, 14.63; P = 0.033). The pooled success rate was 0.68 (95% CI 0.59, 0.78). The major complication was the pain at the puncture site, but the incidence was low.

Conclusions: PTNS is effective and safe in treating OAB symptoms.
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http://dx.doi.org/10.1007/s00192-020-04429-8DOI Listing
December 2020

Effect of nano zero-valent iron addition on caproate fermentation in carboxylate chain elongation system.

Sci Total Environ 2020 Nov 2;743:140664. Epub 2020 Jul 2.

School of Environment, Tsinghua University, Beijing 100084, China. Electronic address:

Carboxylate chain elongation is a burgeoning research area for producing added value bio-products from organic fraction of municipal solid waste. Effect of nano zero-valent iron (NZVI) on chain elongation and its possible mechanism was investigated. Highest caproate concentration, 28.0 mmol·L was achieved with 2 g·L NZVI amendment, which is about 16.7% higher than the control. Promoted ethanol utilization was considered as the main reason for the increment of caproate production and hydrogen generation. Electron balance analysis shows that NZVI did not improve the total electron recovery efficiency but favoured the electron flow toward longer carboxylate chain product, i.e. caproate. Finally, full-length 16s rRNA sequencing of bacterial community showed NZVI reshaped the bacterial community by exerting reduction selectivity. And Oscillibacter and Clostridium could be the potential functional species for carboxylate chain elongation.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140664DOI Listing
November 2020

The relationship between gut microbiota and short chain fatty acids in the renal calcium oxalate stones disease.

FASEB J 2020 08 9;34(8):11200-11214. Epub 2020 Jul 9.

Department of Urology, Laboratory of Reconstructive Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.

The relationship of gut microbiota and calcium oxalate stone has been limited investigated, especially with no study of gut microbiota and short chain fatty acids (SCFAs) in nephrolithiasis. We provided Sprague Dawley rats of renal calcium oxalate stones with antibiotics and examined the renal crystals deposition. We also performed a case-control study by analyzing 16S rRNA microbial profiling, shotgun metagenomics and SCFAs in 153 fecal samples from non-kidney stone (NS) controls, patients with occasional renal calcium oxalate stones (OS) and patients with recurrent stones (RS). Antibiotics reduced bacterial load in feces and could promote the formation of renal calcium crystals in model rats. In addition, both OS and RS patients exhibited higher fecal microbial diversity than NS controls. Several SCFAs-producing gut bacteria, as well as metabolic pathways associated with SCFAs production, were considerably lower in the gut microbiota among the kidney stone patients compared with the NS controls. Representation of genes involved in oxalate degradation showed no significance difference among groups. However, fecal acetic acid concentration was the highest in RS patients with high level of urinary oxalate, which was positively correlated with genes involvement in oxalate synthesis. Administration of SCFAs reduced renal crystals. These results shed new light on bacteria and SCFAs, which may promote the development of treatment strategy in nephrolithiasis.
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http://dx.doi.org/10.1096/fj.202000786RDOI Listing
August 2020

Liver Enzyme Elevation in Coronavirus Disease 2019: A Multicenter, Retrospective, Cross-Sectional Study.

Am J Gastroenterol 2020 07;115(7):1075-1083

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Department of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.

Introduction: Elevated liver enzyme levels are observed in patients with coronavirus disease 2019 (COVID-19); however, these features have not been characterized.

Methods: Hospitalized patients with COVID-19 in Zhejiang Province, China, from January 17 to February 12, 2020, were enrolled. Liver enzyme level elevation was defined as alanine aminotransferase level >35 U/L for men and 25 U/L for women at admission. Patients with normal alanine aminotransferase levels were included in the control group. Reverse transcription polymerase chain reaction was used to confirm severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and patients symptomatic with SARS-CoV-2 infection were defined as patients with COVID-19. Epidemiological, demographic, clinical, laboratory, treatment, and outcome data were collected and compared.

Results: Of 788 patients with COVID-19, 222 (28.2%) patients had elevated liver enzyme levels (median [interquartile range {IQR}] age, 47.0 [35.0-55.0] years; 40.5% women). Being male, overweight, and smoking increased the risk of liver enzyme level elevation. The liver enzyme level elevation group had lesser pharyngalgia and more diarrhea than the control group. The median time from illness onset to admission was 3 days for liver enzyme level elevation groups (IQR, 2-6), whereas the median hospitalization time for 86 (38.7%) discharged patients was 13 days (IQR, 11-16). No differences in disease severity and clinical outcomes were noted between the groups.

Discussion: We found that 28.2% of patients with COVID-19 presented with elevated liver enzyme levels on admission, which could partially be related to SARS-CoV-2 infection. Male patients had a higher risk of liver enzyme level elevation. With early medical intervention, liver enzyme level elevation did not worsen the outcomes of patients with COVID-19.
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http://dx.doi.org/10.14309/ajg.0000000000000717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288765PMC
July 2020