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Q134R: Small chemical compound with NFAT inhibitory properties improves behavioral performance and synapse function in mouse models of amyloid pathology.

Aging Cell 2021 Jun 12:e13416. Epub 2021 Jun 12.

Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY, USA.

Inhibition of the protein phosphatase calcineurin (CN) ameliorates pathophysiologic and cognitive changes in aging rodents and mice with aging-related Alzheimer's disease (AD)-like pathology. However, concerns over adverse effects have slowed the transition of common CN-inhibiting drugs to the clinic for the treatment of AD and AD-related disorders. Targeting substrates of CN, like the nuclear factor of activated T cells (NFATs), has been suggested as an alternative, safer approach to CN inhibitors. Read More

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Elevated metallothionein expression in long-lived species mediates the influence of cadmium accumulation on aging.

Geroscience 2021 Jun 11. Epub 2021 Jun 11.

Advanced Technology Center for Aging Research, IRCCS INRCA, 60121, Ancona, Italy.

Cadmium (Cd) accumulates with aging and is elevated in long-lived species. Metallothioneins (MTs), small cysteine-rich proteins involved in metal homeostasis and Cd detoxification, are known to be related to longevity. However, the relationship between Cd accumulation, the role of MTs, and aging is currently unclear. Read More

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The potential of adoptive transfer of γ9δ2 T cells to enhance blinatumomab's antitumor activity against B-cell malignancy.

Sci Rep 2021 Jun 11;11(1):12398. Epub 2021 Jun 11.

Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan, Taiwan.

Blinatumomab, a bispecific T cell engager (BiTE) antibody targeting CD19 and CD3ε, can redirect T cells toward CD19-positive tumor cells and has been approved to treat relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, chemotherapeutic regimens can severely reduce T cells' number and cytotoxic function, leading to an inadequate response to blinatumomab treatment in patients. In addition, it was reported that a substantial portion of R/R B-ALL patients failing blinatumomab treatment had the extramedullary disease, indicating the poor ability of blinatumomab in treating extramedullary disease. Read More

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AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections.

Sci Rep 2021 Jun 11;11(1):12387. Epub 2021 Jun 11.

Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 35294-0012, USA.

Metabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Read More

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Effect of bowel preparation on intestinal permeability and inflammatory response during postoperative ileus in mice.

Surgery 2021 Jun 8. Epub 2021 Jun 8.

Medical Department of General and Visceral Surgery, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin, Germany. Electronic address:

Background: Postoperative ileus entails pathophysiological changes in mucosal permeability and an intestinal inflammatory immune response. We hypothesized that preoperative selective decontamination of the digestive tract combined with preoperative mechanical bowel preparation might be advantageous to prevent or reduce permeability changes and immune response in postoperative ileus.

Methods: Postoperative ileus was induced in mice by standardized small bowel manipulation. Read More

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Photoactivation of TGFβ/SMAD signaling pathway ameliorates adult hippocampal neurogenesis in Alzheimer's disease model.

Stem Cell Res Ther 2021 Jun 11;12(1):345. Epub 2021 Jun 11.

MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.

Background: Adult hippocampal neurogenesis (AHN) is restricted under the pathological conditions of neurodegenerative diseases, especially in Alzheimer's disease (AD). The drop of AHN reduces neural circuit plasticity, resulting in the decrease of the generation of newborn neurons in dentate gyrus (DG), which makes it difficult to recover from learning/memory dysfunction in AD, therefore, it is imperative to find a therapeutic strategy to promote neurogenesis and clarify its underlying mechanism involved.

Methods: Amyloid precursor protein/presenilin 1 (APP/PS1) mice were treated with photobiomodulation therapy (PBMT) for 0. Read More

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Polysaccharide of Atractylodes macrocephala Koidz regulates LPS-mediated mouse hepatitis through the TLR4-MyD88-NFκB signaling pathway.

Int Immunopharmacol 2021 Jun 8;98:107692. Epub 2021 Jun 8.

Zhongkai University of Agriculture and Engineering, Guangzhou, Guangdong 510225, China; Guangdong Province Key Laboratory of Waterfowl Healthy Breeding, Guangzhou, Guangdong 510225, China. Electronic address:

Feed corruption and poor breeding environment could cause widespread bacterial infection which could cause severe liver inflammation and lead to liver damage, even death. It has been proved that Polysaccharide of Atractylodes macrocephala Koidz (PAMK) could improve the immunity of animal, but the mechanism of its protective effect on hepatitis has been rarely reported. This study investigated the protective effect of PAMK on mouse liver through LPS-induced liver inflammatory. Read More

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Danning tablets alleviate high fat diet-induced obesity and fatty liver in mice via modulating SREBP pathway.

J Ethnopharmacol 2021 Jun 8:114320. Epub 2021 Jun 8.

The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, The State Administration of TCM (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China. Electronic address:

Ethnopharmacological Relevance: The traditional Chinese formula Danningtablets exhibit wide clinical applications in liver and gallbladder diseases, and currently it is reported to be effective on fatty liver disease in clinical trials. However, the underlying mechanisms remain elusive.

Aim Of The Study: The purpose of the present study was to assess the effects and potential pharmacological mechanisms of Danning tablet against high fat diet (HFD)-induced obesity, fatty liver, and related metabolic disorders in mice. Read More

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Anneslea fragrans Wall. ameliorates ulcerative colitis via inhibiting NF-κB and MAPK activation and mediating intestinal barrier integrity.

J Ethnopharmacol 2021 Jun 8:114304. Epub 2021 Jun 8.

Faculty of Agriculture and Food, Kunming University of Science and Technology, Kunming, 650500, China. Electronic address:

Ethnopharmacological Relevance: Anneslea fragrans Wall. is traditionally used as a folk medicine in treating indigestion, fever, dysentery, diarrhea, and liver inflammation in China, Vietnam and Cambodia. However, its anti-inflammatory activity and mechanism under a safety therapeutic dose as well as the main chemical components have not yet been fully investigated. Read More

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A physicochemical model of odor sampling.

PLoS Comput Biol 2021 Jun 11;17(6):e1009054. Epub 2021 Jun 11.

Department of Psychology, Cornell University, Ithaca, New York, United States of America.

We present a general physicochemical sampling model for olfaction, based on established pharmacological laws, in which arbitrary combinations of odorant ligands and receptors can be generated and their individual and collective effects on odor representations and olfactory performance measured. Individual odor ligands exhibit receptor-specific affinities and efficacies; that is, they may bind strongly or weakly to a given receptor, and can act as strong agonists, weak agonists, partial agonists, or antagonists. Ligands interacting with common receptors compete with one another for dwell time; these competitive interactions appropriately simulate the degeneracy that fundamentally defines the capacities and limitations of odorant sampling. Read More

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MiR-155 regulates neutrophil extracellular trap formation and lung injury in abdominal sepsis.

J Leukoc Biol 2021 Jun 11. Epub 2021 Jun 11.

Department of Surgery, Clinical Sciences, Malmö, Skåne University Hospital, Lund University, Malmö, Sweden.

Neutrophil extracellular traps (NETs)-mediated tissue damage is a hallmark in abdominal sepsis. Under certain conditions, microRNAs (miRs) can regulate protein expression and cellular functions. The aim of this study was to investigate the role of miR-155 in sepsis-induced NET formation, lung inflammation, and tissue damage. Read More

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Resveratrol ameliorated endothelial injury of thoracic aorta in diabetic mice and Gly-LDL-induced HUVECs through inhibiting TLR4/HIF-1α.

J Cell Mol Med 2021 Jun 10. Epub 2021 Jun 10.

Department of Endocrinology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.

To explore the effects of resveratrol on the levels of inflammatory cytokines and Toll-like receptor-4/ hypoxia-inducible transcription factors-1α (TLR4/HIF-1α) signalling pathway in diabetes mellitus. C57BL/6 mice received intraperitoneal injection of streptozocin for constructing diabetic mice models. Human umbilical vein endothelial cells (HUVECs) were treated with 50 µg/mL Gly-LDL for inducing injury models. Read More

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Vector-mediated expression of Muscle Specific Kinase restores specific force to muscles in the mdx mouse model of Duchenne muscular dystrophy.

Exp Physiol 2021 Jun 10. Epub 2021 Jun 10.

Physiology and Bosch Institute, University of Sydney, Sydney, NSW, Australia.

New Findings: What is the central question of this study? The (dystrophin-deficient) muscles of mdx mice generate less contractile force per cross-sectional area (specific force) than those of healthy wild-type mice. We test the influence of Muscle Specific Kinase (MuSK) upon the properties of the tibialis anterior (TA) muscle in mdx mice. What is the main finding and its importance? Injection of adeno-associated viral vector encoding MuSK into the TA muscle of young mdx mice increased the specific force of the muscle, suggesting the MuSK signalling system has the potential to restore healthy growth to dystrophin-deficient muscles. Read More

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DHODH inhibition modulates glucose metabolism and circulating GDF15, and improves metabolic balance.

iScience 2021 May 1;24(5):102494. Epub 2021 May 1.

Department of Microbiology, Tumor and Cell Biology (MTC), Biomedicum, Karolinska Institutet, SE-171 65 Stockholm, Sweden.

Dihydroorotate dehydrogenase (DHODH) is essential for the synthesis of pyrimidine ribonucleotides, and as such, its inhibitors have been long used to treat autoimmune diseases and are in clinical trials for cancer and viral infections. Interestingly, DHODH is located in the inner mitochondrial membrane and contributes to provide ubiquinol to the respiratory chain. Thus, DHODH provides the link between nucleotide metabolism and mitochondrial function. Read More

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Protective Role of microRNA-200a in Diabetic Retinopathy Through Downregulation of PDLIM1.

J Inflamm Res 2021 4;14:2411-2424. Epub 2021 Jun 4.

Department of Ophthalmology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.

Background: Diabetic retinopathy (DR) is a most common microvascular complication and regarded as the leading cause of blindness in the working age population. The involvement of miR-200a in various disorders has become recognized, and the objective of this study was to identify the protective effect of miR-200a in the development of DR.

Methods: The contents of miR-200a and its potential target gene, PDZ and LIM domain protein 1 (PDLIM1), were detected in both in-vivo and in-vitro DR models. Read More

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Somatostatin neurons control an alcohol binge drinking prelimbic microcircuit in mice.

Neuropsychopharmacology 2021 Jun 10. Epub 2021 Jun 10.

Department of Biology, Pennsylvania State University, University Park, PA, USA.

Somatostatin (SST) neurons have been implicated in a variety of neuropsychiatric disorders such as depression and anxiety, but their role in substance use disorders, including alcohol use disorder (AUD), is not fully characterized. Here, we found that repeated cycles of alcohol binge drinking via the Drinking-in-the-Dark (DID) model led to hypoactivity of SST neurons in the prelimbic (PL) cortex by diminishing their action potential firing capacity and excitatory/inhibitory transmission dynamic. We examined their role in regulating alcohol consumption via bidirectional chemogenetic manipulation. Read More

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TET2 Protects Against VSMC Apoptosis and Intimal Thickening in Transplant Vasculopathy.

Circulation 2021 Jun 11. Epub 2021 Jun 11.

Department of Medicine (Cardiovascular Medicine), Yale University School of Medicine, New Haven, CT.

Coronary allograft vasculopathy (CAV) is a devastating sequelae of heart transplant in which arterial intimal thickening limits coronary blood flow. There are currently no targeted therapies to prevent or reduce this pathology that leads to transplant failure. Vascular smooth muscle cell (VSMC) phenotypic plasticity is critical in CAV neointima formation. Read More

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Activation of Autophagic Flux Blunts Cardiac Ischemia/Reperfusion Injury.

Circ Res 2021 Jun 11. Epub 2021 Jun 11.

Internal Medicine, UT Southwestern Medical Center, UNITED STATES.

Reperfusion injury accounts for up to half of myocardial infarct size, and meaningful clinical therapies targeting it do not exist. We have reported previously that autophagy is reduced during reperfusion and that HDAC inhibition enhances cardiomyocyte autophagy and blunts ischemia/reperfusion (I/R) injury when administered at the time of reperfusion. However, whether inducing autophagy per se, as opposed to other effects triggered by HDAC inhibition, is sufficent to protect against reperfusion injury is not clear. Read More

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Comparative study on the pharmacodynamic difference of oral administration of Xiaojin Pills accompanied with Chinese Baijiu and water.

J Ethnopharmacol 2021 Jun 7:114284. Epub 2021 Jun 7.

State Key Laboratory of Southwestern Chinese Medicine Resources, Pharmacy School, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, PR China. Electronic address:

Ethnopharmacological Relevance: Xiaojin Pills is a classic prescription for the treatment of mammary glands hyperplasia with a history of nearly 300 years, and is also the first choice of Chinese patent medicine for the clinical treatment of mammary glands hyperplasia in contemporary traditional Chinese medicine clinic. Clinical and animal studies have shown that Xiaojin Pills has the effects of anti-mammary glands hyperplasia, promoting blood circulation, anti-inflammation and analgesia. However, its initial administration method was "taking orally after soaked with Chinese Baijiu", the modern method was changed to "taking orally with water" in recent 20 years. Read More

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C2C12 myoblasts are more sensitive to the toxic effects of simvastatin than myotubes and show impaired proliferation and myotube formation.

Biochem Pharmacol 2021 Jun 7:114649. Epub 2021 Jun 7.

Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland; Department of Biomedicine, University of Basel, Switzerland; Swiss Centre for Applied Human Research (SCAHT), Switzerland. Electronic address:

Statins reduce cardiovascular complications in patients with high LDL-cholesterol but are associated with myopathy. We compared the toxicity of simvastatin of C2C12 myoblasts and myotubes. Since myoblasts can proliferate and fuse to myotubes, myoblasts can be considered as satellite cells and myotubes as mature muscle fibers. Read More

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Effect of Vitamin B2-Deficient Diet on Hydroxyproline- or Obesity-Induced Hyperoxaluria in Mice.

Mol Nutr Food Res 2021 Jun 10:e2100226. Epub 2021 Jun 10.

Department of Preventive Environment and Nutrition, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan.

Scope: Hyperoxaluria is a major cause of kidney stone disease. Around half of the oxalate in mammals is supplied from the diet and the other half is endogenously synthesized from glyoxylate. Reduction of hepatic glycolate oxidase (GO) activity is one approach to reduce endogenous production of oxalate. Read More

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Resveratrol affects the expression of uric acid transporter by improving inflammation.

Mol Med Rep 2021 Aug 10;24(2). Epub 2021 Jun 10.

Department of Internal Medicine, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China.

Resveratrol (RSV), a polyphenol, non‑flavonoid plant‑derived antitoxin, ameliorates hyperuricemia and kidney inflammation. The present study aimed to establish a model of high‑fat diet (HFD)‑induced insulin resistance (IR) and to determine the specific mechanism of RSV to improve kidney inflammation and reduce uric acid (UA). C57BL/6J mice were fed a HFD for 12 weeks and their glucose tolerance was evaluated by intraperitoneal glucose tolerance testing. Read More

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Pharmacokinetics-Based Chronoefficacy of and Tripterygium Glycoside Tablet Against Rheumatoid Arthritis.

Front Pharmacol 2021 24;12:673263. Epub 2021 May 24.

Institute of Molecular Rhythm and Metabolism, Guangzhou University of Chinese Medicine, Guangzhou, China.

Rheumatoid arthritis is a systemic autoimmune disease characterized by synovial inflammation and bone destruction. Identifying drugs with time-varying efficacy and toxicity, and elucidating the mechanisms would help to improve treatment efficacy and reduce adverse effects. Here, we aimed to determine the chronoefficacy of (SS) and tripterygium glycoside tablet (TGT) against rheumatoid arthritis in mice, and to investigate a potential role of circadian pharmacokinetics in generating chronoefficacy. Read More

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Niclosamide ethanolamine ameliorates diabetes-related muscle wasting by inhibiting autophagy.

Skelet Muscle 2021 Jun 9;11(1):15. Epub 2021 Jun 9.

Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, 1 Fuhua Road, Futian District, Shenzhen, 518033, Guangdong, China.

Background: Diabetes-related muscle wasting is one of the devastating complications of diabetes, which is associated with muscle autophagy due to insulin-mediated glucose starvation. However, treatment for diabetes-related muscle wasting is limited. Our previous study already found that niclosamide ethanolamine salt has the therapeutic effects on insulin deficiency of type 1 diabetes mice and muscle wasting induced by doxorubicin. Read More

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Glucokinase activation or inactivation: Which will lead to the treatment of type 2 diabetes?

Diabetes Obes Metab 2021 Jun 9. Epub 2021 Jun 9.

Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan.

Glucokinase, which phosphorylates glucose to form glucose-6-phosphate, plays a critical role in regulating the blood glucose levels. On the basis of data of glucokinase-knockout and transgenic mice and humans with glucokinase mutations, glucokinase was targeted for drug development aiming to augment its activity, and thereby reduce hyperglycemia in patients with diabetes. In fact, various small molecule compounds have been developed and clinically tested as glucokinase activators. Read More

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Empagliflozin Alleviates Atherosclerosis Progression by Inhibiting Inflammation and Sympathetic Activity in a Normoglycemic Mouse Model.

J Inflamm Res 2021 31;14:2277-2287. Epub 2021 May 31.

Department of Cardiology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, 210008, Jiangsu, People's Republic of China.

Background: Recent clinical studies have revealed that sodium glucose co-transporter 2 inhibitors (SGLT2i) reduced cardiovascular events in type 2 diabetes. Here, we investigated whether empagliflozin, as a kind of SGLT2i, could alleviate atherosclerosis progression in non-diabetic mice.

Methods: -/- mice were fed on a western diet for 12 weeks to induce atherosclerosis. Read More

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Senolytics reduce coronavirus-related mortality in old mice.

Science 2021 Jun 8. Epub 2021 Jun 8.

Department of Laboratory Medicine and Pathology and Center of Immunology, University of Minnesota, Minneapolis, MN, USA.

The COVID-19 pandemic has revealed the pronounced vulnerability of the elderly and chronically-ill to SARS-CoV-2-induced morbidity and mortality. Cellular senescence contributes to inflammation, multiple chronic diseases, and age-related dysfunction, but effects on responses to viral infection are unclear. Here, we demonstrate that senescent cells (SnC) become hyper-inflammatory in response to pathogen-associated molecular patterns (PAMPs), including SARS-CoV-2 Spike protein-1, increasing expression of viral entry proteins and reducing anti-viral gene expression in non-SnCs through a paracrine mechanism. Read More

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Glucocorticoid induced TNF receptor family-related protein (GITR) - A novel driver of atherosclerosis.

Vascul Pharmacol 2021 Jun 5:106884. Epub 2021 Jun 5.

Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, the Netherlands; Institute of Cardiovascular Prevention (IPEK), Ludwig-Maximilians Universität (LMU Munich), Munich, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany. Electronic address:

Atherosclerosis is a lipid-driven, chronic inflammatory disease. In spite of efficient lipid lowering treatments, such as statins and PCSK9 inhibitors, patients, especially those with elevated inflammatory biomarkers, still have a significant residual cardiovascular disease risk. Novel drugs targeting inflammatory mediators are needed to further reduce this residual risk. Read More

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Guanosine and uridine alleviate airway inflammation via inhibition of the MAPK and NF-κB signals in OVA-induced asthmatic mice.

Pulm Pharmacol Ther 2021 Jun 5;69:102049. Epub 2021 Jun 5.

Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China; Frontiers Science Center for Disease-related Molecular Network, Sichuan University, Chengdu, Sichuan, PR China. Electronic address:

Asthma is one of the most common respiratory diseases. Lack of response or poor adherence to corticosteroids demands the development of new drug candidates for asthma. Endogenous nucleosides could be potential options since uridine has been reported to have an anti-inflammatory effect in asthma model. Read More

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Renal protective effects and mechanisms of the angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome.

Life Sci 2021 Jun 5:119692. Epub 2021 Jun 5.

Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin, China. Electronic address:

Aims: This study investigated the renal protective effects and mechanisms of angiotensin receptor-neprilysin inhibitor LCZ696 in mice with cardiorenal syndrome.

Materials And Methods: Mice were divided into abdominal aortic ligation alone, or treatment with LCZ696 or valsartan, whilst those undergoing sham surgery served as controls. Rat proximal renal tubular epithelial cells from the NRK-52E line were treated with control solution, LCZ696 or valsartan, in the presence or absence of Ang II for 24 h. Read More

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