Publications by authors named "Yan Wang"

12,645 Publications

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Glia maturation factor-β supports liver regeneration by remodeling actin network to enhance STAT3 proliferative signals.

Cell Mol Gastroenterol Hepatol 2022 Aug 8. Epub 2022 Aug 8.

Biomedical Research Center, Southern Medical University, Guangzhou, China; Department of Hepatology, Southern Medical University Affiliated Shenzhen Hospital, Shenzhen, China. Electronic address:

Background & Aims: Glia maturation factor-β (GMFB) is a bona fide member of actin depolymerizing factor homology family. Recently, emerging evidence suggests its implication in liver diseases. But data on its role in liver remain limited.

Methods: Assessment of GMFB in liver histology, impact on liver regeneration and hepatocytes proliferation, and the underlying molecular pathways were conducted using mice models with acute liver injury.

Results: GMFB is widely distributed in normal liver. Its expression increases within 24h following partial hepatectomy (PHx). Adult Gmfb knockout (GKO) mice and wild-type littermates are similar in gross appearance, body weight, liver function and histology. However, compared with wild-type control, GKO mice post-PHx develop more serious liver damage and steatosis and have the delayed liver regeneration; the dominant change in liver transcriptome at 24h post-PHx is the significantly suppressed acute inflammation pathways; the top downregulated gene-sets relate to IL6/JAK/STAT3 signaling. Another mice model intoxicated with carbon tetrachloride replicates the findings. Furthermore, GKO and wild-type groups have the similar numbers of Kupffer cells, but GKO Kupffer cells once stimulated produce less IL6, TNF, and IL1β. In hepatocytes treated with IL6, GMFB positively associates with cell proliferation and STAT3/CyclinD1 activation, but without any direct interaction with STAT3. In GKO hepatocytes, cytoskeleton-related genes expression is significantly changed, appearing abnormal morphology of actin-networks. In hepatocytes modelling actin-filaments turnover, STAT3 activation and metabolite excretion show strong reliance on the status of actin-filaments organization.

Conclusions: GMFB plays a significant role in liver regeneration by promoting acute inflammatory response in Kupffer cells and by intracellularly coordinating the responsive hepatocytes proliferation.
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http://dx.doi.org/10.1016/j.jcmgh.2022.07.016DOI Listing
August 2022

Outer Valence Photoionization and Autoionization of Formaldehyde.

J Phys Chem A 2022 Aug 11. Epub 2022 Aug 11.

School of Physics, Henan Normal University, Xinxiang 453007, Peoples Republic of China.

We investigate photoionization from the ground electronic state of the formaldehyde molecule. Both partial cross sections and asymmetry parameters leading to the , , , and states of HCO ions are studied in the photon region of 10-90 eV using a multichannel -matrix method, which uses the configuration interaction (CI) to describe electronic correlation. We check the sensitivity of the results to change descriptions of the continuum, the different partial waves, and the active spaces in the theoretical model. And we obtain the convergent result of the present calculations. Extensive resonance structures near the ionization threshold are observed for the first time. Our predicted total cross sections and asymmetry parameters differ from these obtained by previous theoretical approaches, all of which neglected correlation effects. The present results were found to agree reasonably well with the available experimental results, suggesting the reliability of our calculations.
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http://dx.doi.org/10.1021/acs.jpca.2c04207DOI Listing
August 2022

Genetic insights into therapeutic targets for aortic aneurysms: A Mendelian randomization study.

EBioMedicine 2022 Aug 8;83:104199. Epub 2022 Aug 8.

Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, PR China; Department of Internal Medicine, Tongji Shanxi Hospital, Taiyuan 030032, Shanxi Province, China. Electronic address:

Background: As aortic aneurysms (AAs) enlarge, they can become life-threatening if left undiagnosed or neglected. At present, there is a lack of radical treatments for preventing disease progression. Therefore, we aimed to identify effective drug targets that slow the progression of AAs.

Methods: A Mendelian randomization (MR) analysis was conducted to identify therapeutic targets which are associated with AAs. Summary statistics for AAs were obtained from two datasets: the UK Biobank (2228 cases and 408,565 controls) and the FinnGen study (3658 cases and 244,907 controls). Cis-expression quantitative trait loci (cis-eQTL) for druggable genes were retrieved from the eQTLGen Consortium and used as genetic instrumental variables. Colocalization analysis was performed to determine the probability that single nucleotide polymorphisms (SNPs) associated with AAs and eQTL shared causal genetic variants.

Findings: Four drug targets (BTN3A1, FASN, PLAU, and PSMA4) showed significant MR results in two independent datasets. Proteasome 20S subunit alpha 4 (PSMA4) and plasminogen activator, urokinase (PLAU) in particular, were found to have strong evidence for colocalization with AAs, and abdominal aortic aneurysm in particular. Additionally, except for the association between PSMA4 and intracranial aneurysms, no association between genetically proxied inhibition of PLAU and PSMA4 was detected in increasing the risk of other cardiometabolic risks and diseases.

Interpretation: This study supports that drug-targeting PLAU and PSMA4 inhibition may reduce the risk of AAs.

Funding: This work was supported by National Key R&D Program of China (NO. 2017YFC0909400), Nature Science Foundation of China (No. 91839302, 81790624), Project supported by Shanghai Municipal Science and Technology Major Project (Grant No. 2017SHZDZX01), and Tongji Hospital Clinical Research Flagship Program (no. 2019CR207).
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http://dx.doi.org/10.1016/j.ebiom.2022.104199DOI Listing
August 2022

Rapid titration with oral sustained-release morphine plus subcutaneous morphine in a multi-center, randomized control study of cancer patients with moderate to severe cancer pain.

Jpn J Clin Oncol 2022 Aug 10. Epub 2022 Aug 10.

Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, China.

Background: Pain is one of the most common concomitant symptoms among cancer patients. Pharmacologic agents are regarded as a cornerstone of cancer pain management. 'Dose titration' with short-acting morphine is widely accepted. Such a titration method is very complicated. The analgesic background establishment is often delayed. Titration based on sustained-release opioids is also recommended, but the onset of analgesic effect requires hours, whereas the rescue analgesia is always needed. This study evaluated the optimized morphine titration scheme with a simultaneous combination of sustained-release morphine and subcutaneous morphine.

Methods: In a multicenter, 7-day, randomized controlled study, patients with moderate to severe cancer pain were assigned to receive either sustained-release morphine and subcutaneous morphine simultaneously (rapid titration) or only subcutaneous morphine to dose titration. The primary outcome was the safety and the number of times of rescue therapy as needed in the first 24 h.

Results: A total of 108 patients with moderate to severe cancer pain were included in the study. The number of times of rescue analgesics in the first 24 h significantly reduced in the rapid titration group (0.4 ± 0.48 vs. 2.3 ± 0.78, P = 0.000). No differences in the intensity of opioid-related symptoms were found between the two groups.

Conclusions: Rapid titration is safe and efficient, which could significantly decrease rescue analgesics in the first 24 h and achieve better analgesic efficacy for cancer pain patients.
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http://dx.doi.org/10.1093/jjco/hyac128DOI Listing
August 2022

Single Institution Evolution in Defining an Algorithm for Prevention and Management of Severe Complications in Direct-to-Implant Breast Reconstruction.

Plast Reconstr Surg 2022 Aug 10. Epub 2022 Aug 10.

Department of Breast Oncoplastic and Reconstructive Surgery, Tianjin Medical University Cancer Institute and Hospital; National Clinical Research Center for Cancer; Sino-Russian Joint Research Center for Oncoplastic Breast Surgery; Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin's Clinical Research Center for Cancer, Tianjin, China.

Background: Complications including infection and wound dehiscence are major concerns for direct-to-implant (DTI) breast reconstruction. However, the risk factors associated with severe complications and implant salvage remain unclear.

Methods: Retrospective study of all patients undergoing unilateral DTI breast reconstruction from 2014 through 2019. The risk factors associated with complications and prosthesis explantation were identified using multivariate logistic regression modeling and interaction analyses.

Results: Among 1027 patients enrolled, 90 experienced severe complications, 41of which underwent prosthesis explantation, while 49 were successfully salvaged. Multivariate analysis demonstrated that patients with larger implant size (p=0.003), use of bovine mesh (p<0.001), adjuvant radiotherapy (p=0.047), low plasma albumin (p=0.013), and elevated blood glucose (p=0.006) were significantly more likely to suffer complications. Adjuvant radiation (OR: 7.44; 95%CI, 1.49-37.18; p = 0.014) and obesity (OR, 4.17; 95%CI, 1.17-14.88; p = 0.028) had significantly lower rates of implant salvage as well as surgical site infection (SSI) and wound dehiscence, while mastectomy skin flap necrosis was not associated with device explanation. There were no differences in complication and explantation rates between nipple-sparing and skin-sparing mastectomies. However, the combined impact of SSI and wound dehiscence added over fourteen-fold higher risk of prosthesis explantation (95%CI, 9.97-19.53).

Conclusion: Success in direct-to-implant breast reconstruction is multifactorial. Larger implant size, adjuvant radiation therapy, diabetes, and malnutrition demonstrate increased risk of complications in the DTI approach. Surgical site infections and wound dehiscence should be treated aggressively, but the combination of both complications portends poor salvage rates.
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http://dx.doi.org/10.1097/PRS.0000000000009490DOI Listing
August 2022

Effect of Intravenous Tirofiban vs Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke: The RESCUE BT Randomized Clinical Trial.

JAMA 2022 08;328(6):543-553

Department of Neurology, Nanyang Central Hospital, Nanyang, China.

Importance: Tirofiban is a highly selective nonpeptide antagonist of glycoprotein IIb/IIIa receptor, which reversibly inhibits platelet aggregation. It remains uncertain whether intravenous tirofiban is effective to improve functional outcomes for patients with large vessel occlusion ischemic stroke undergoing endovascular thrombectomy.

Objective: To assess the efficacy and adverse events of intravenous tirofiban before endovascular thrombectomy for acute ischemic stroke secondary to large vessel occlusion.

Design, Setting, And Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 55 hospitals in China, enrolling 948 patients with stroke and proximal intracranial large vessel occlusion presenting within 24 hours of time last known well. Recruitment took place between October 10, 2018, and October 31, 2021, with final follow-up on January 15, 2022.

Interventions: Participants received intravenous tirofiban (n = 463) or placebo (n = 485) prior to endovascular thrombectomy.

Main Outcomes And Measures: The primary outcome was disability level at 90 days as measured by overall distribution of the modified Rankin Scale scores from 0 (no symptoms) to 6 (death). The primary safety outcome was the incidence of symptomatic intracranial hemorrhage within 48 hours.

Results: Among 948 patients randomized (mean age, 67 years; 391 [41.2%] women), 948 (100%) completed the trial. The median (IQR) 90-day modified Rankin Scale score in the tirofiban group vs placebo group was 3 (1-4) vs 3 (1-4). The adjusted common odds ratio for a lower level of disability with tirofiban vs placebo was 1.08 (95% CI, 0.86-1.36). Incidence of symptomatic intracranial hemorrhage was 9.7% in the tirofiban group vs 6.4% in the placebo group (difference, 3.3% [95% CI, -0.2% to 6.8%]).

Conclusions And Relevance: Among patients with large vessel occlusion acute ischemic stroke undergoing endovascular thrombectomy, treatment with intravenous tirofiban, compared with placebo, before endovascular therapy resulted in no significant difference in disability severity at 90 days. The findings do not support use of intravenous tirofiban before endovascular thrombectomy for acute ischemic stroke.

Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR-IOR-17014167.
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http://dx.doi.org/10.1001/jama.2022.12584DOI Listing
August 2022

N6-methyladenosine-mediated CELF2 regulates CD44 alternative splicing affecting tumorigenesis via ERAD pathway in pancreatic cancer.

Cell Biosci 2022 Aug 8;12(1):125. Epub 2022 Aug 8.

Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350001, Fujian, China.

Background: Alternative splicing (AS) of genes has been found to affect gene stability, and its abnormal regulation can lead to tumorigenesis. CELF2 is a vital splicing factor to participate in mRNA alternative splicing. Its downregulation has been confirmed to promote the occurrence and development of pancreatic cancer (PC). However, the regulatory role and mechanisms in PC has not been elucidated.

Results: CELF2 was downregulated in PC tissues, which affected tumor TNM stage and tumor size, and low expression of CELF2 indicated a poor prognosis of PC. In vivo and in vitro experiments showed that abnormal expression of CELF2 affected the stemness, apoptosis, and proliferation of PC cells. Furthmore, we also found that CELF2 was targeted by ALKBH5 for m6A modification, leading to CELF2 degradation by YTHDF2. Bioinformatic analysis of AS model based on the TCGA database indicated that CELF2 could target CD44 to form different spliceosomes, thereby affecting the biological behavior of PC cells. The conversion of CD44s to CD44V is the key to tumorigenesis. Transcriptomic analysis was conducted to reveal the mechanism of CELF2-mediated CD44 AS in PC. We found that CELF2-mediated splicing of CD44 led to changes in the level of endoplasmic reticulum stress, further regulating the endoplasmic reticulum-associated degradation (ERAD) signaling pathway, thereby affecting apoptosis and cell stemness. In addition, ERAD signaling pathway inhibitor, EerI, could effectively reverse the effect of CD44 on tumors.

Conclusions: This study indicates that N6-methyladenosine-mediated CELF2 promotes AS of CD44, affecting the ERAD pathway and regulating the biological behavior of PC cells. CELF2 is expected to be a new target for targeted-drug development.
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http://dx.doi.org/10.1186/s13578-022-00844-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9361702PMC
August 2022

SIRT7 silencing by miR-152-3p confers cell apoptosis and renal functional impairment induced by renal ischaemia/reperfusion injury.

Int Urol Nephrol 2022 Aug 8. Epub 2022 Aug 8.

Emergency Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China.

Purpose: Acute kidney injury (AKI) induced by renal ischaemia/reperfusion (I/R) during renal transplantation has been reported to be linked to the regulation of SIRT2, one of the members of SIRTUINS family. Current work is attempted to explore the influence and mechanism of SIRT7 in renal cell apoptosis controlled by miR-152-3p during renal I/R injury.

Methods: Three databases were used to select the miRNAs regulating the expression of SIRT7. Overexpression and inhibition of miR-152-3p and Luciferase assay were employed to certify the modulation of miR-152-3p to SIRT7 in cells. RT-qPCR assay was used to measure the mRNA levels. Western blot assay was employed to determine the expression of proteins. TUNEL assay and Flow Cytometry were conducted to analyze cell apoptosis.

Results: SIRT7 expression decreased in tissues of AKI patients and rats underwent renal I/R, which was associated with enhanced impairment of renal function. SIRT7 downregulation was attributed to the direct inhibition by miR-152-3p due to binding and inhibiting its seed sequence in 3'-UTR of SIRT7 mRNA. Consequently, the upregulation of miR-152-3p led to an inhibition of SIRT7 expression, an increase in expression of extrinsic apoptosis molecules containing FOXO3a, Bim, and caspase3, and apoptotic renal cells; while miR-152-3p inhibition abolished these phenotypes.

Conclusion: SIRT7 downregulation by miR-152-3p is a leading cause of renal cell apoptosis and functional impairment induced by renal I/R. Inhibition of miR-152-3p to restore SIRT7 expression can be a promising strategy against renal I/R injury.
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http://dx.doi.org/10.1007/s11255-022-03330-1DOI Listing
August 2022

Microbial transformation of capsaicin by several human intestinal fungi and their inhibitory effects against lysine-specific demethylase 1.

Phytochemistry 2022 Aug 6;202:113365. Epub 2022 Aug 6.

College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, 116044, People's Republic of China. Electronic address:

Capsaicin widely exists in the Capsicum genus (e.g., hot peppers) and is commonly used as a food additive or medicinal material. In this work, microbial transformation of capsaicin was performed based on the three cultivated human intestinal fungi. Fourteen metabolites were obtained, and their chemical structures were elucidated by spectroscopic data analysis, including 13 compounds with undescribed structures. Hydroxylation, lactylation, succinylation, citric acylation, and acetylation were observed for these microbial metabolites derived from capsaicin, which indicated diverse catalytic characteristics of human intestinal fungi. In an in vitro bioassay, four metabolites and capsaicin inhibited the activity of lysine-specific demethylase 1 (LSD1) with a more than 70% inhibitory rate at 10 μM. In particular, 9,5'-dihydroxycapsaicin displayed the strongest inhibitory effect with an IC of 1.52 μM. Therefore, capsaicin analogs displayed potential application as LSD1 inhibitors against the invasion and migration of cancer cells.
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http://dx.doi.org/10.1016/j.phytochem.2022.113365DOI Listing
August 2022

Immunotherapy for EGFR-mutant advanced non-small-cell lung cancer: Current status, possible mechanisms and application prospects.

Front Immunol 2022 22;13:940288. Epub 2022 Jul 22.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.

Immune checkpoint inhibitors (ICIs) are effective against advanced and even perioperative non-small-cell lung cancer (NSCLC) and result in durable clinical benefit, regardless of programmed death ligand-1 (PD-L1) expression status in cancer. Existing clinical evidence shows that the effect of immunotherapy in patients with EGFR-mutant NSCLC after the development of tyrosine kinase inhibitor (TKI) resistance is not satisfactory. However, compared with monotherapy, ICIs combined with chemotherapy can improve the efficacy. Encouragingly, compared with that of patients with sensitive mutations, the progression-free survival of patients with rare mutations who were treated with ICIs was increased. Adequately maximizing the efficacy of ICIs in EGFR-mutant NSCLC patients is worth exploring. In this review, we described preclinical and clinical studies of ICIs or combined therapy for EGFR-mutant NSCLC. We further focused on EGFR mutations and the cancer immune response, with particular attention given to the role of EGFR activation in the cancer-immunity cycle. The mechanisms for the natural resistance to ICIs were explored to identify corresponding countermeasures that made more EGFR-mutant NSCLC patients benefit from ICIs.
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http://dx.doi.org/10.3389/fimmu.2022.940288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353115PMC
August 2022

Therapeutic application of quercetin in aging-related diseases: SIRT1 as a potential mechanism.

Front Immunol 2022 22;13:943321. Epub 2022 Jul 22.

Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu, China.

Quercetin, a naturally non-toxic flavonoid within the safe dose range with antioxidant, anti-apoptotic and anti-inflammatory properties, plays an important role in the treatment of aging-related diseases. Sirtuin 1 (SIRT1), a member of NAD-dependent deacetylase enzyme family, is extensively explored as a potential therapeutic target for attenuating aging-induced disorders. SIRT1 possess beneficial effects against aging-related diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Depression, Osteoporosis, Myocardial ischemia (M/I) and reperfusion (MI/R), Atherosclerosis (AS), and Diabetes. Previous studies have reported that aging increases tissue susceptibility, whereas, SIRT1 regulates cellular senescence and multiple aging-related cellular processes, including SIRT1/Keap1/Nrf2/HO-1 and SIRTI/PI3K/Akt/GSK-3β mediated oxidative stress, SIRT1/NF-κB and SIRT1/NLRP3 regulated inflammatory response, SIRT1/PGC1α/eIF2α/ATF4/CHOP and SIRT1/PKD1/CREB controlled phosphorylation, SIRT1-PINK1-Parkin mediated mitochondrial damage, SIRT1/FoxO mediated autophagy, and SIRT1/FoxG1/CREB/BDNF/Trkβ-catenin mediated neuroprotective effects. In this review, we summarized the role of SIRT1 in the improvement of the attenuation effect of quercetin on aging-related diseases and the relationship between relevant signaling pathways regulated by SIRT1. Moreover, the functional regulation of quercetin in aging-related markers such as oxidative stress, inflammatory response, mitochondrial function, autophagy and apoptosis through SIRT1 was discussed. Finally, the prospects of an extracellular vesicles (EVs) as quercetin loading and delivery, and SIRT1-mediated EVs as signal carriers for treating aging-related diseases, as well as discussed the ferroptosis alleviation effects of quercetin to protect against aging-related disease activating SIRT1. Generally, SIRT1 may serve as a promising therapeutic target in the treatment of aging-related diseases inhibiting oxidative stress, reducing inflammatory responses, and restoring mitochondrial dysfunction.
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http://dx.doi.org/10.3389/fimmu.2022.943321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9355713PMC
August 2022

Alanine Aminotransferase and Bilirubin Dynamic Evolution Pattern as a Novel Model for the Prediction of Acute Liver Failure in Drug-Induced Liver Injury.

Front Pharmacol 2022 22;13:934467. Epub 2022 Jul 22.

Liver Research Center, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Diseases, Beijing, China.

To develop, optimize, and validate a novel model using alanine aminotransferase (ALT) and total bilirubin (TB) dynamic evolution patterns in predicting acute liver failure (ALF) in drug-induced liver injury (DILI) patients. The demographics, clinical data, liver biopsy, and outcomes of DILI patients were collected from two hospitals. According to the dynamic evolution of ALT and TB after DILI onset, the enrolled patients were divided into ALT-mono-peak, TB-mono-peak, double-overlap-peak, and double-separate-peak (DSP) patterns and compared. Logistic regression was used to develop this predictive model in both discovery and validation cohorts. The proportion of ALF was significantly higher in patients with the DSP pattern than in the ALT-mono-peak pattern and DOP pattern (10.0 vs. 0.0% vs. 1.8%, < 0.05). The area under receiver operating characteristic curve (AUROC) of the DSP pattern model was 0.720 (95% CI: 0.682-0.756) in the discovery cohort and 0.828 (95% CI: 0.788-0.864) in the validation cohort in predicting ALF, being further improved by combining with international normalized ratio (INR) and alkaline phosphatase (ALP) (AUROC in the discovery cohort: 0.899; validation cohort: 0.958). Histopathologically, patients with the DSP pattern exhibited a predominantly cholestatic hepatitis pattern (75.0%, < 0.05) with a higher degree of necrosis (29.2%, = 0.084). DILI patients with the DSP pattern are more likely to progress to ALF. The predictive potency of the model for ALF can be improved by incorporating INR and ALP. This novel model allows for better identification of high-risk DILI patients, enabling timely measures to be instituted for better outcome.
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http://dx.doi.org/10.3389/fphar.2022.934467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9355525PMC
July 2022

Metabonomic analysis of abnormal sphingolipid metabolism in rheumatoid arthritis synovial fibroblasts in hypoxia microenvironment and intervention of geniposide.

Front Pharmacol 2022 22;13:969408. Epub 2022 Jul 22.

Key Laboratory of Xin'an Medicine, Ministry of Education, Hefei, China.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by a joint hypoxia microenvironment. Our previous untargeted metabolomics study found that sphingolipid (SPL) metabolism was abnormal in the joint synovial fluid samples from adjuvant arthritis (AA) rats. Geniposide (GE), an iridoid glycoside component of the dried fruit of Ellis, is commonly used for RA treatment in many Asian countries. At present, the mechanism of GE in the treatment of RA, especially in the joint hypoxia microenvironment, is not entirely clear from the perspective of SPL metabolism. The purpose of this research was to explore the potential mechanism of abnormal SPL metabolism in RA joint hypoxia microenvironment and the intervention effect of GE, through the untargeted metabolic analysis based on the ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Arthritis index, foot swelling and histopathology were used to assess whether the AA rat model was successfully established. The SPLs extracts collected from AA rats' synovial tissue, serum and rheumatoid arthritis synovial fibroblasts (RASFs, MH7A cells, hypoxia/normoxia culture) were analyzed by metabolomics and lipdomics approach based on UPLC-Q-TOF/MS, to identify potential biomarkers associated with disorders of GE regulated RA sphingolipid metabolism. As a result, 11 sphingolipid metabolites related to RA were screened and identified. Except for galactosylceramide (d18:1/20:0), GE could recover the change levels of the above 10 sphingolipid biomarkers in varying degrees. Western blotting results showed that the changes in ceramide (Cer) level regulated by GE were related to the down-regulation of acid-sphingomyelinase (A-SMase) expression in synovial tissue of AA rats. To sum up, this research examined the mechanism of GE in the treatment of RA from the perspective of SPL metabolism and provided a new strategy for the screening of biomarkers for clinical diagnosis of RA.
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http://dx.doi.org/10.3389/fphar.2022.969408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353937PMC
July 2022

Decreased modular segregation of the frontal-parietal network in major depressive disorder.

Front Psychiatry 2022 22;13:929812. Epub 2022 Jul 22.

Center for Cognition and Brain Disorders, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.

Major depressive disorder (MDD) is a common psychiatric condition associated with aberrant large-scale distributed brain networks. However, it is unclear how the network dysfunction in MDD patients is characterized by imbalance or derangement of network modular segregation. Fifty-one MDD patients and forty-three matched healthy controls (HC) were recruited in the present study. We analyzed intrinsic brain activity derived from resting-state functional magnetic resonance imaging (R-fMRI) and then examined brain network segregation by computing the participation coefficient (PC). Further intra- and inter-modular connections analysis were preformed to explain atypical PC. Besides, we explored the potential relationship between the above graph theory measures and symptom severity in MDD. Lower modular segregation of the frontal-parietal network (FPN) was found in MDD compared with the HC group. The MDD group exhibited increased inter-module connections between the FPN and cingulo-opercular network (CON), between the FPN and cerebellum (Cere), between the CON and Cere. At the nodal level, the PC of the anterior prefrontal cortex, anterior cingulate cortex, inferior parietal lobule (IPL), and intraparietal sulcus showed larger in MDD. Additionally, the inter-module connections between the FPN and CON and the PC values of the IPL were negatively correlated with depression symptom in the MDD group. These findings might give evidence about abnormal FPN in MDD from the perspective of modular segregation in brain networks.
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http://dx.doi.org/10.3389/fpsyt.2022.929812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9353222PMC
July 2022

Co-occurrence of myeloid neoplasm and plasma cell neoplasm.

Autops Case Rep 2022 21;12:e2021393. Epub 2022 Jul 21.

MetroHealth Medical Center, Department of Pathology, Cleveland, Ohio, USA.

Co-occurrence of myelodysplastic syndrome (MDS) and plasma cell neoplasm in patients with no history of chemo and/or radiotherapy is rarely reported. Herein, we report a case of a female in her seventieth decade of life who was referred to the hospital for pancytopenia. The patient was asymptomatic and was doing well overall. Serum protein electrophoresis was remarkable for a lambda-restricted monoclonal protein (IgG) estimated at 1.8g/dL. Immunoglobulin G serum level was also elevated, and serum Kappa/Lambda free light chain ratio was decreased. At that time, a bone marrow biopsy showed myelodysplastic syndrome with excess blasts-2 (MDS-EB2) and a monoclonal plasma cell proliferation. Some studies have shown that patients with plasma cell neoplasm could be associated with an increased risk of developing MDS compared to the general population. Based on reviewing the literature, to our knowledge, the pathological mechanism of the co-occurrence of both diseases is not yet clear.
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http://dx.doi.org/10.4322/acr.2021.393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9341343PMC
July 2022

Reference intervals of 14 biochemical markers for children and adolescence in China: the PRINCE study.

Clin Chem Lab Med 2022 Aug 8. Epub 2022 Aug 8.

National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, P.R. China.

Objectives: The Pediatric Reference Intervals in China (PRINCE) was initiated to establish the reference intervals (RIs) of Chinese children, as well as to make it possible to compare the variability of biochemical markers among countries internationally.

Methods: Healthy participants, aged up to 20 years, from 11 provinces across China, were enrolled in PRINCE and according to a standard screening procedure, that included a questionnaire survey, physical examinations and laboratory tests. Fasting venous blood specimens were collected. All serum specimens were analyzed with Cobas C702 in the center laboratory, i.e. clinical laboratory of Beijing Children's Hospital, with certified qualification (ISO15189). The nonparametric method recommended by Clinical Laboratory Standards Institute guidelines, was used to calculate the age- and sex-specified RIs.

Results: Among the 15,150 participants enrolled, 12,352 children (6,093 males and 6,259 females) were included to calculate RIs. The RIs for total protein, albumin, globulin, calcium, phosphate, potassium, sodium, chlorine, alkaline phosphatase, γ-glutamyl transpeptadase, alanine aminotransferase, aspartate aminotransferase, creatinine and urea were established by age- or sex-partitions. Most biochemical markers displayed larger variability and higher dispersion during the periods between 28 days and 1 year old, and included 4-6 age partitions commonly during 1 to <20 years old. In addition, differences of RIs between sexes usually occurs around the initiation of puberty at 12-13 years old.

Conclusions: The age- and sex-specified RIs of 14 biochemical markers in PRINCE study can provide a solid reference, which will be transferred into relevant RIs for other clinical laboratory's platforms according to the CLSI guidelines.
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http://dx.doi.org/10.1515/cclm-2022-0299DOI Listing
August 2022

Distribution and driving factors of antibiotic resistance genes in treated wastewater from different types of livestock farms.

Sci Total Environ 2022 Aug 4:157837. Epub 2022 Aug 4.

Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, Guangdong, China; Guangdong Laboratory for Lingnan Modern Agriculture, College of Animal Science, South China Agricultural University, Guangzhou 510642, China; National Engineering Research Center for Breeding Swine Industry, South China Agricultural University, Guangzhou 510642, China; Ministry of Agriculture Key Laboratory of Tropical Agricultural Environment, South China Agricultural University, Guangzhou 510642, China; Guangdong Engineering Technology Research Center of Harmless Treatment and Resource Utilization of Livestock Waste, Yunfu, Xinxing 527400, China. Electronic address:

Treated wastewater from livestock farms is an important reservoir for antibiotic resistance genes (ARGs), and is a main source of ARGs in the environment. However, the distribution and driving factors of ARGs in treated wastewater from different types of livestock farms are rarely reported. In this study, treated wastewater from 69 large-scale livestock farms of different types, including broiler, layer, and pig farms, was collected, and 11 subtypes of ARGs, 2 mobile genetic elements (MGEs) and bacterial community structure were analyzed. The results revealed detection rates of NDM-1 and mcr-1 of 90 % and 43 %, respectively, and the detection rates of other ARGs were 100 %. The relative abundance of ARGs, such as tetA, tetX and strB, in broiler farms was significantly higher than that in layer farms, but the bacterial α diversity was significantly lower than that in other farm types. Furthermore, although the treatment process had a greater impact on the physicochemical properties of the treated wastewater than the livestock type, livestock type was the main factor affecting the bacterial community in the treated wastewater. The analysis of potential host bacteria of ARGs revealed significant differences in the host bacteria of ARGs in treated wastewater from different types of livestock farms. The host bacteria of ARGs in broiler farms mainly belonged to Actinobacteria, layer farms mainly belonged to Proteobacteria, and pig farms mainly belonged to Firmicutes. Additionally, redundancy analysis showed that the distribution of ARGs may have resulted from the combination of multiple driving factors in different types of livestock farms, among which tnpA and NH-N were the main influencing factors. This study revealed multiple driving factors for the distribution of typical ARGs in treated wastewater from different types of livestock farms, providing basic data for the prevention and control of ARG pollution in agricultural environments.
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http://dx.doi.org/10.1016/j.scitotenv.2022.157837DOI Listing
August 2022

Exosomes from human urine-derived stem cells carry NRF1 to alleviate bladder fibrosis via regulating miR-301b-3p/TGFβR1 pathway.

Mol Cell Biochem 2022 Aug 7. Epub 2022 Aug 7.

Department of Urology, The First Affiliated Hospital of Zhengzhou University, Jianshe East Road, No. 1, Zhengzhou, 450052, Henan, China.

Bladder outlet obstruction (BOO) is a common disease that always make the bladder develops from inflammation to fibrosis. This study was to investigate the effect of exosomes from human urine-derived stem cells (hUSCs) on bladder fibrosis after BOO and the underlying mechanism. The BOO mouse model was established by inserting a transurethral catheter, ligation of periurethral wire, and removal of the catheter. Mouse primary bladder smooth muscle cells (BSMCs) were isolated and treated with TGFβ1 to mimic the bladder fibrosis model in vitro. Exosomes from hUSCs (hUSC-Exos) were injected into the bladder of BOO mice and added into the culture of TGFβ1-induced BSMCs. The associated factors in mouse bladder tissues and BSMCs were detected. It was confirmed that the treatment of hUSC-Exos alleviated mouse bladder fibrosis and down-regulated fibrotic markers (a-SMA and collagen III) in bladder tissues and TGFβ1-induced BSMCs. Overexpression of NRF1 in hUSC-Exos further improved the effects of hUSC-Exos on bladder fibrosis both in vivo and in vitro. TGFβR1 was a target of NRF1 and miR-301b-3p, and miR-301b-3p was a target of NRF1. It was next characterized that hUSC-Exos carried NRF1 to up-regulate miR-301B-3p, thereby reducing TGFβR1level. Our results illustrated that hUSC-Exos carried NRF1 to alleviate bladder fibrosis through regulating miR-301b-3p/TGFβR1 pathway.
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http://dx.doi.org/10.1007/s11010-022-04484-3DOI Listing
August 2022

Genistein attenuates memory impairment in Alzheimer's disease via ERS-mediated apoptotic pathway in vivo and in vitro.

J Nutr Biochem 2022 Aug 3:109118. Epub 2022 Aug 3.

School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China; Institute of Integrated Chinese and Western Medicine, Anhui Academy of Chinese Medicine, Hefei 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei 230012, China. Electronic address:

Genistein (GS), an isoflavone compound found in soybean, plays a neuroprotective role in Alzheimer's disease (AD). However, the mechanism of its action remains unclear. Herein, binding ability between GS and GRP78 was predicted by molecular docking, and the effect of GS in vivo and vitro were further studied. In this study, the effects of GS on learning and memory ability, changes of hippocampal neurons and ultrastructure of hippocampal CA3 region in AD rats were investigated. Besides, the protein or mRNA levels of the related proteins were detected. The results showed GS could effectively improve the learning and memory ability, reduce the damage of hippocampal neurons, and decrease the protein or mRNA expression levels of GRP78, CHOP, Caspase-12, Cle-Caspase-9, Cle-Caspase-3, PERK and p-PERK. Taken together, our data reveal GS has a neuroprotective effect by inhibiting the ERS-mediated apoptotic pathway, which may be a new therapeutic target for the treatment of AD.
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http://dx.doi.org/10.1016/j.jnutbio.2022.109118DOI Listing
August 2022

Association between chronic obstructive pulmonary disease and periodontitis: The common role of innate immune cells?

Cytokine 2022 Aug 3;158:155982. Epub 2022 Aug 3.

Guangzhou Medical University, Guangzhou, Guangdong, China; Department of Prosthodontics, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou, Guangdong, China. Electronic address:

Innate immune cells are of broad interest in a variety of diseases. These cells include neutrophils, macrophages, dendritic cells and mast cells, etc. Innate immune cells are often mentioned in inflammatory diseases as the first line of defense against pathogens' invasion. As chronic obstructive pulmonary disease and periodontitis are inflammatory diseases, innate immune cells play an important role in the development of both diseases. COPD and periodontitis are common epidemic diseases with a very high prevalence, thus affecting a large number of people and also reducing the quality of life of patients. In addition, epidemiological studies suggested a link between the two, creating a co-morbid burden, but the mechanism of the link is yet to be explained. This article discusses the possible mechanism of the link between the two diseases in terms of innate immune cells and discusses possible future targeted therapies that could alleviate the burden on patients.
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http://dx.doi.org/10.1016/j.cyto.2022.155982DOI Listing
August 2022

Comparative transcriptome and adaptive evolution analysis on the main liver and attaching liver of Pareuchiloglanis macrotrema.

J Appl Genet 2022 Aug 6. Epub 2022 Aug 6.

College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, 611130, China.

Pareuchiloglanis macrotrema is a glyptosternoid fish belonging to the Siluriform family and is endemic to the Qinghai-Tibet Plateau tributaries. P. macrotrema is an ideal model for studying the adaptive evolution of fish at high altitudes. P. macrotrema has two attaching livers connected to the main liver, a common feature in most Sisoridae fishes but is a special phenomenon relative to other vertebrates. Using RNA-Seq, 42 differentially expressed genes were found between the main liver and attaching liver, of which 31 were upregulated and 11 were downregulated in the main liver. The major differentially expressed genes between the main liver and attaching liver of P. macrotrema are related to metabolism, immunity, and digestive processes. Meanwhile, a comparative transcriptome analysis was carried out on P. macrotrema fish and six non-plateau Siluriformes fishes. We found 268 positively selected genes in P. macrotrema that are related to energy metabolism, immunity, and hypoxic responses. The findings of this study highlight the gene expression differences between the main liver and attaching livers of Sisoridae fishes and provide greater insight into the evolution of Tibetan fishes.
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http://dx.doi.org/10.1007/s13353-022-00712-0DOI Listing
August 2022

Mechanical analysis of deep tissue injury during sitting in patients with spinal cord injury via parametric finite element model.

Biomech Model Mechanobiol 2022 Aug 5. Epub 2022 Aug 5.

Department of Biomedical Engineering, Faculty of Engineering, Hong Kong Polytechnic University, Hong Kong, 999077, Hong Kong SAR, China.

Spinal cord injury patients are prone to develop deep tissue injury because of long-term mechanical load. However, there is a lack of statistical research on the influence of tissue characteristics on the internal mechanical state of soft tissue. This study aimed to investigate the influence of tissue characteristics on the internal mechanical state of buttock in spinal cord injury patients. A three-dimensional reference buttock model was established and a visualization program was generated to modify the parameter values. Through changing the muscle atrophy, body mass index and the radius of curvature of the ischial tuberosity, 96 different model variants were simulated and validated in this study. With body mass index increasing from 16 to 40, the principal shear stress was 10.4 times principal compressive stress, the maximum shear strain and the max cluster volume increased by 1.2 (P < 0.001) and 8.8 times (P < 0.001), respectively. The interaction between BMI and muscle atrophy was significant when BMI was greater than or equal to 22.5 kg/m. In all BMI stages, when the radius of curvature of the ischial tuberosity was 19 mm, the internal stress of the tissue always occupies the highest value. The results demonstrate that body mass index is the most important factor affecting the risk of buttock deep tissue injury. This study provides insights into investigation of inter-individual factors influencing the soft tissue response and assessment of deep tissue injury risk during sitting.
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http://dx.doi.org/10.1007/s10237-022-01607-zDOI Listing
August 2022

Magnetic beads for the evaluation of drug release from biotinylated polymeric micelles in biological media.

J Control Release 2022 Aug 2. Epub 2022 Aug 2.

Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3508 TB Utrecht, the Netherlands. Electronic address:

To improve the reliability of in vitro release studies of drug delivery systems, we developed a novel in vitro method for the evaluation of drug release from polymeric micelles in complex biological media. Polymeric micelles based on poly(N-2-hydroxypropyl methacrylamide)-block-poly(N-2-benzoyloxypropyl methacrylamide) (p(HPMAm)-b-p(HPMAm-Bz)) of which 10% of the chains was functionalized with biotin at the p(HPMAm) terminus were prepared using a solvent extraction method. The size of the micelles when loaded with a hydrophobic agent, namely paclitaxel (a clinically used cytostatic drug) or curcumin (a compound with multiple pharmacological activities), was around 65 nm. The biotin decoration allowed the binding of the micelles to streptavidin-coated magnetic beads which occurred within 10 min and reached a binding efficiency of 90 ± 6%. Drug release in different media was studied after the magnetic separation of micelles bound to the streptavidin-coated beads, by determination of the released drug in the media as well as the retained drug in the micellar fraction bound to the beads. The in vitro release of paclitaxel and curcumin at 37 °C in PBS, PBS containing 2% v/v Tween 80, PBS containing 4.5% w/v bovine serum albumin, mouse plasma, and whole mouse blood was highly medium-dependent. In all media studied, paclitaxel showed superior micellar retention compared to curcumin. Importantly, the presence of serum proteins accelerated the release of both paclitaxel and curcumin. The results presented in this study show great potential for predicting drug release from nanomedicines in biological media which in turn is crucial for their further pharmaceutical development.
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http://dx.doi.org/10.1016/j.jconrel.2022.07.044DOI Listing
August 2022

[Prenatal diagnosis of fetuses with renal anomalies by whole genome sequencing].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2022 Aug;39(8):819-823

Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu 210004, China.

Objective: To explore the genetic basis for fetuses with renal anomalies.

Methods: Genomic DNA of four fetuses and their parents was extracted from amniotic fluid and peripheral blood samples and subjected to whole genome sequencing. Candidate variants were predicted according to the American College of Medical Genetics and Genomics (ACMG) guidelines and validated by SNP-array and Sanger sequencing.

Results: Two fetuses were found to carry a 1.45 Mb pathogenic microdeletion in 17q12 and a pathogenic 1.85 Mb microduplication at 1q21.1-21.2, respectively. One fetus was found to harbor compound heterozygous variants c.8301del (p.Asn2768Thrfs*18) and c.4481del (p.Asn1494Thrfs*6) of the PKHD1 gene, which were predicted to be pathogenic. And one fetus has harbored homozygous c.1372dup (p.Thr458Asnfs*5) variants of the BBS12 gene, which was predicted to be likely pathogenic. All variants were validated by Sanger sequencing.

Conclusion: Whole genome sequencing can enable efficient prenatal diagnosis for fetuses with renal anomalies with high accuracy.
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http://dx.doi.org/10.3760/cma.j.cn511374-20210320-00255DOI Listing
August 2022

The gut microbiome contributes to splenomegaly and tissue inflammation in a murine model of primary biliary cholangitis.

Ann Transl Med 2022 May;10(9):507

Chronic Disease Laboratory, School of Medicine, South China University of Technology, Guangzhou, China.

Background: Splenomegaly is not just a consequence of numerous chronic and acute conditions but may also contribute to their severity, due to the interaction of the spleen with the gut microbiome. This study aimed to explore the effect of the gut microbiome on splenomegaly.

Methods: We used p40IL-2Rα mice as a murine model of primary biliary cholangitis (PBC) as per our previous study. Splenomegaly was evaluated by spleen weight. Severity of liver inflammation was evaluated by hepatic mononuclear cell (MNCs) number and pathological score. Changes of immune cells in the spleen and liver were detected by flow cytometry. The effects of the gut microbiome on splenomegaly and liver inflammation were observed by combined antibiotic treatment in p40IL-2Rα mice.

Results: A proportion of p40IL-2Rα mice developed splenomegaly. The results revealed that liver mononuclear cells infiltration, histological scores of hepatic inflammation, and bile duct damage were positively correlated with the degree of splenomegaly. Hepatic CD4 and CD8 T cells numbers were significantly higher in mice with splenomegaly, and this was particularly observed in activated effector memory CD4 T and CD8 T cells. A proportion of some other immune cells including granulocytes, B, natural killer (NK), and CD8 T effector memory cells were also altered in the enlarged spleen. More importantly, administration of quadruple antibiotics to deplete gut microbiota relieved the splenomegaly of p40IL-2Rα mice, significantly alleviated liver inflammation, and caused a significant reduction of liver and spleen T cell accumulation and activation; however, single antibiotics did not induce these changes.

Conclusions: Splenomegaly was associated with more severe liver inflammation in our PBC murine model, and this effect was reversed by quadruple antibiotic treatment.
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http://dx.doi.org/10.21037/atm-21-5448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9347057PMC
May 2022

Flavonoid Extract from Propolis Provides Cardioprotection following Myocardial Infarction by Activating PPAR-.

Evid Based Complement Alternat Med 2022 5;2022:1333545. Epub 2022 Jul 5.

The Third Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, China.

We have previously reported that flavonoid extract from propolis (FP) can improve cardiac function in rats following myocardial infarction (MI). However, the mechanisms responsible for the cardioprotective effects of FP have not been fully elucidated. In the current study, we explored whether FP can reduce inflammatory cytokines and attenuate sympathetic nerve system activity and antiendoplasmic reticulum (ER) stress and whether the cardioprotective effects are related to peroxisome proliferator-activated receptor gamma (PPAR-) activation. Sprague Dawley rats were randomly divided into six groups: Sham group received the surgical procedure but no artery was ligated; MI group received ligation of the left anterior descending (LAD) branch of the coronary artery; MI + FP group received FP (12.5 mg/kg/d, intragastrically) seven days prior to LAD ligation; FP group (Sham group + 12.5 mg/kg/d, intragastrically); MI + FP + GW9662 group received FP prior to LAD ligation with the addition of a specific PPAR- inhibitor (GW9662), 1 mg/kg/d, orally); and MI + GW9662 group received the PPAR- inhibitor and LAD ligation. The results demonstrated that the following inflammatory markers were significantly elevated following MI as compared with expression in sham animals: IL-1, TNF-, CRP; markers of sympathetic activation: plasma norepinephrine, epinephrine and GAP43, nerve growth factor, thyroid hormone; and ER stress response markers GRP78 and CHOP. Notably, the above changes were attenuated by FP, and GW9662 was able to alleviate the effect of FP. In conclusion, FP induces a cardioprotective effect following myocardial infarction by activating PPAR-, leading to less inflammation, cardiac sympathetic activity, and ER stress.
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http://dx.doi.org/10.1155/2022/1333545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345730PMC
July 2022

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J Pharmacol Exp Ther 2022 Aug 4. Epub 2022 Aug 4.

Neuroscience, Amgen Inc, United States

Ion channels are targets of considerable therapeutic interest to address a wide variety of neurological indications, including pain perception. Current pharmacological strategies have focused mostly on small molecule approaches which can be limited by selectivity requirements within members of a channel family or superfamily. Therapeutic antibodies have been proposed, designed and characterized to alleviate this selectivity limitation, however there are no FDA-approved therapeutic antibody-based drugs targeting ion channels on the market to date. Here, in an effort to identify novel classes of engineered ion channel modulators for potential neurological therapeutic applications, we report the generation and characterization of six (EC < 25nM) Cys-loop receptor family monoclonal antibodies with modulatory function against rat and human glycine receptor alpha 1 (GlyRa1) and/or GlyRa3. These antibodies have activating (; positive modulator) or inhibiting (; negative modulator) profiles. Moreover, GlyRa3 selectivity was successfully achieved for two of the three positive modulators identified. When dosed intravenously, the antibodies achieved sufficient brain exposure to cover their calculated EC values. When compared head-to-head at identical exposures, the GlyRa3-selective antibody showed a more desirable safety profile over the non-selective antibody, thus demonstrating, for the first time, an advantage for GlyRa3-selectivity. Our data show that ligand-gated ion channels of the glycine receptor family within the CNS can be functionally modulated by engineered biologics in a dose-dependent manner and that, despite high protein homology between the alpha subunits, selectivity can be achieved within this receptor family resulting in future therapeutic candidates with more desirable drug safety profiles. We present immunization and multi-platform screening approaches to generate a diverse library of functional antibodies (agonist, potentiator or inhibitory) raised against human glycine receptors (GlyRs). We also demonstrate the feasibility of acquiring alpha subunit selectivity, a desirable therapeutic profile. When tested , these tool molecules demonstrated an increased safety profile in favor of GlyRa3-selectivity. To our knowledge, these are the first reported functional GlyR antibodies that may open new avenues to treating CNS diseases with subunit selective biologics.
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http://dx.doi.org/10.1124/jpet.121.001026DOI Listing
August 2022

Dietary supplementation of salidroside alleviates liver lipid metabolism disorder and inflammatory response to promote hepatocyte regeneration via PI3K/AKT/Gsk3-β pathway.

Poult Sci 2022 Jun 28;101(9):102034. Epub 2022 Jun 28.

Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, P. R. China. Electronic address:

Fatty liver hemorrhagic syndrome (FLHS) is a chronic hepatic disease which occurs when there is a disorder in lipid metabolism. FLHS is often observed in caged laying hens and characterized by a decrease in egg production and dramatic increase of mortality. Salidroside (SDS) is an herbal drug which has shown numerous pharmacological activities, such as protecting mitochondrial function, attenuating cell apoptosis and inflammation, and promoting antioxidant defense system. We aimed to determine the therapeutic effects of SDS on FLHS in laying hens and investigate the underlying mechanisms through which SDS operates these functions. We constructed oleic acid (OA)-induced fatty liver model in vitro and high-fat diet-induced FLHS of laying hens in vivo. The results indicated that SDS inhibited OA-induced lipid accumulation in chicken primary hepatocytes, increased hepatocyte activity, elevated the mRNA expression of proliferation related genes PCNA, CDK2, and cyclinD1 and increased the protein levels of PCNA and CDK2 (P < 0.05), as well as decreased the cleavage levels of Caspase-9, Caspase-8, and Caspase-3 and apoptosis in hepatocytes (P < 0.05). Moreover, SDS promoted the phosphorylation levels of PDK1, AKT, and Gsk3-β, while inhibited the PI3K inhibitor (P < 0.05). Additionally, we found that high-fat diet-induced FLHS hens had heavier body weight, liver weight, and abdominal fat weight, and severe steatosis in histology, compared with the control group (Con). However, hens fed with SDS maintained lighter body weight, liver weight, and abdominal fat weight, as well as normal liver without hepatic steatosis. In addition, high-fat diet-induced FLHS hens had high levels of serum total cholesterol (TC), triglyceride (TG), alanine transaminase (ALT), and aspartate aminotransferase (AST) compared to the Con group, however, in the Model+SDS group, the levels of TC, TG, ALT, and AST decreased significantly, whereas the level of superoxide dismutase (SOD) increased significantly (P < 0.05). We also found that SDS significantly decreased the mRNA expression abundance of PPARγ, SCD, and FAS in the liver, as well as increased levels of PPARα and MTTP, and decreased the mRNA expression of TNF-α, IL-1β, IL-6, and IL-8 in the Model+SDS group (P < 0.05). In summary, this study showed that 0.3 mg/mL SDS attenuated ROS generation, inhibited lipid accumulation and hepatocyte apoptosis, and promoted hepatocyte proliferation by targeting the PI3K/AKT/Gsk3-β pathway in OA-induced fatty liver model in vitro, and 20 mg/kg SDS alleviated high-fat-diet-induced hepatic steatosis, oxidative stress, and inflammatory response in laying hens in vivo.
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http://dx.doi.org/10.1016/j.psj.2022.102034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9356167PMC
June 2022

The reciprocal relationships of social norms and risk perceptions to cigarette, e-cigarette, and cannabis use: Cross-lagged panel analyses among US young adults in a longitudinal study.

Drug Alcohol Depend 2022 Jul 15;238:109570. Epub 2022 Jul 15.

Department of Prevention and Community Health, Milken Institute School of Public Health, George Washington University, Washington, DC 20052, USA; George Washington Cancer Center, George Washington University, Washington, DC 20052, USA. Electronic address:

Introduction: Given the distinct and evolving social norms, research on health implications, and regulations regarding cigarettes, e-cigarettes, and cannabis, it is important to understand the interplay between social norms, risk perceptions, and use of these products.

Methods: We analyzed 3 waves of longitudinal data (Fall 2018, 2019, 2020) from 3006 young adults (M=24.56, 54.8% female, 31.6% sexual minority, 39.6% racial/ethnic minority) from 6 US metropolitan statistical areas. Cross-lagged panel models (CLPMs) examined reciprocal relationships of (a) perceived social norms (i.e., peer use, social acceptability) and risk perceptions (i.e., harm, addictiveness) to (b) number of days of cigarette, e-cigarette, and cannabis use in the past 30 days, respectively.

Results: At baseline, lifetime and past 30-day use prevalence was: 61.8% and 26.9% for cigarettes, 57.7% and 37.7% for e-cigarettes, and 70.7% and 39.2% for cannabis. Perceived social norms and use of cigarettes and e-cigarettes decreased over time, and risk perceptions increased (except cigarettes showed stable perceived harm). Regarding cannabis, perceived social norms and use increased, yet perceived harm and addictiveness also increased. CLPM indicated that greater perceived social norms predicted greater cigarette, e-cigarette, and cannabis use over time, and vice versa. While greater perceived risk predicted less e-cigarette and cannabis use and vice versa, this did not hold true for cigarettes: use predicted lower perceived risk, but risk perceptions did not predict later use.

Conclusions: Tobacco and cannabis intervention and regulatory efforts should address health risks of use, particularly of e-cigarettes and cannabis, as well as denormalizing use.
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http://dx.doi.org/10.1016/j.drugalcdep.2022.109570DOI Listing
July 2022

Microbe-derived non-necrotic glycoside hydrolase family 12 proteins act as immunogenic signatures triggering plant defenses.

J Integr Plant Biol 2022 Aug 4. Epub 2022 Aug 4.

Department of Plant Pathology, Nanjing Agricultural University, Nanjing, 210095, China.

Plant pattern recognition receptors (PRRs) are sentinels at the cell surface sensing microbial invasion and activating innate immune responses. During infection, certain microbial apoplastic effectors can be recognized by plant PRRs, culminating in immune responses accompanied by cell death. However, the intricated relationships between the activation of immune responses and cell death are unclear. Here, we studied the apoplastic glycoside hydrolase family 12 (GH12) protein, Ps109281, secreted by Phytophthora sojae into the plant apoplast during infection. Ps109281 exhibits xyloglucanase activity, and promotes P. sojae infection in a manner dependent on the enzyme activity. Ps109281 is recognized by the membrane-localized receptor-like protein RXEG1 and triggers immune responses in various plant species. Unlike other characterized GH12 members, Ps109281 fails to trigger cell death in plants. The loss of cell death induction activity is closely linked to a sequence polymorphism at the N-terminus. This sequence polymorphism does not affect the in planta interaction of Ps109281 with the recognition receptor RXEG1, indicating that cell death and immune response activation are determined by different regions of the GH12 proteins. Such GH12 protein also exists in other Phytophthora and fungal pathogens. Taken together, these results unravel the evolution of effector sequences underpinning different immune outputs. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/jipb.13337DOI Listing
August 2022
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