308,192 results match your criteria therapeutic target

Discovery of pyrrolo[2,3-d]pyrimidine derivatives as potent Axl inhibitors: Design, synthesis and biological evaluation.

Eur J Med Chem 2021 Apr 25;220:113497. Epub 2021 Apr 25.

Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address:

Axl has emerged as an attractive target for cancer therapy due to its strong correlation with tumor growth, metastasis, poor survival, and drug resistance. Herein, we report the design, synthesis and structure-activity relationship (SAR) investigation of a series of pyrrolo[2,3-d]pyrimidine derivatives as new Axl inhibitors. Among them, the most promising compound 13b showed high enzymatic and cellular Axl potencies. Read More

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Identification of non-covalent 3C-like protease inhibitors against severe acute respiratory syndrome coronavirus-2 via virtual screening of a Korean compound library.

Bioorg Med Chem Lett 2021 May 3:128067. Epub 2021 May 3.

Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon 34113, Republic of Korea. Electronic address:

The outbreak of coronavirus (CoV) disease 2019 (COVID-19) caused by the severe acute respiratory syndrome CoV-2 (SARS-CoV-2) has turned into a pandemic. The enzyme 3C-like protease (3CL) is essential for the maturation of viral polyproteins in SARS-CoV-2 and is therefore regarded as a key drug target for treating the disease. To identify 3CL inhibitors that can suppress SARS-CoV-2 replication, we performed a virtual screening of 500,282 compounds in a Korean compound bank. Read More

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Th17/Treg cell imbalance played an important role in respiratory syncytial virus infection compromising asthma tolerance In mice.

Microb Pathog 2021 May 3:104867. Epub 2021 May 3.

Department of Pulmonary and Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai, 200240, China; Center of Community-Based Health Research, Fudan University, China. Electronic address:

Mucosal tolerance is induced early in life and is an important mechanism of protection from diseases, such as asthma. Respiratory syncytial virus (RSV) is a main cause of bronchiolitis and pneumonia in infants. Clinical studies have found that there is a strong association between RSV infection in infancy and later development of asthma, but the underlying mechanisms are unclear. Read More

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In silico network pharmacology and in vivo analysis of berberine-related mechanisms against type 2 diabetes mellitus and its complications.

J Ethnopharmacol 2021 May 3:114180. Epub 2021 May 3.

Endocrinology Department, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin, China. Electronic address:

Ethnopharmacological Relevance: Berberine (BBR), extracted from the traditional medicinal plant Coptis chinensis Franch., has been widely used for the treatment of type 2 diabetes mellitus (T2DM) and its complications.

Aim Of The Study: To determine the potential pharmacological mechanisms underlying BBR therapeutic effect on T2DM and its complications by in silico network pharmacology and experimental in vivo validation. Read More

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Long noncoding RNA TP53TG1 suppresses the growth and metastasis of hepatocellular carcinoma by regulating the PRDX4/β-catenin pathway.

Cancer Lett 2021 May 3. Epub 2021 May 3.

Department of Hepatobiliary Surgery, Tianjin Medical University General Hospital, Tianjin, 300052, PR China. Electronic address:

Emerging evidence has shown that aberrant expression of lncRNA-TP53TG1 plays important roles in various malignancies. However, the biological functions of lncRNA-TP53TG1 in hepatocarcinogenesis, as well as the underlying mechanisms, remain largely unknown. Here, we assessed whether lncRNA-TP53TG1 plays a key role in the progression of hepatocellular carcinoma (HCC). Read More

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Electrohydrodynamic Atomisation Driven Design and Engineering of Opportunistic Particulate Systems For Applications in Drug Delivery, Therapeutics and Pharmaceutics.

Adv Drug Deliv Rev 2021 May 3. Epub 2021 May 3.

The Leicester School of Pharmacy, De Montfort University, Leicester, UK. Electronic address:

Electrohydrodynamic atomisation (EHDA) technologies have evolved significantly over the past decade; branching into several established and emerging healthcare remits through timely advances in the engineering sciences and tailored conceptual process designs. More specifically for pharmaceutical and drug delivery spheres, electrospraying (ES) has presented itself as a high value technique enabling a plethora of different particulate structures. However, when coupled with novel formulations (e. Read More

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DEP-induced ZEB2 promotes nasal polyp formation via epithelial-to-mesenchymal transition.

J Allergy Clin Immunol 2021 May 3. Epub 2021 May 3.

Obstructive Upper airway Research (OUaR) Laboratory, Department of Pharmacology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea; Ischemic/hypoxic disease institute, Seoul National University College of Medicine, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea;; Department of Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea. Electronic address:

Background: Diesel exhaust particles (DEP) are associated with the prevalence and exacerbation of allergic respiratory diseases, including allergic rhinitis and allergic asthma. However, DEP-induced mechanistic pathways promoting upper airway disease and their clinical implications remain unclear OBJECTIVE: We sought to investigate the mechanisms by which DEP exposure contributes to nasal polyposis using human-derived epithelial cells and a murine nasal polyp (NP) model.

Methods: Gene set enrichment and weighted gene co-expression network analyses were performed. Read More

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Human cells and networks of pain: Transforming pain target identification and therapeutic development.

Neuron 2021 May;109(9):1426-1429

Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA. Electronic address:

Chronic pain is a disabling disease with limited treatment options. While animal models have revealed important aspects of pain neurobiology, therapeutic translation of this knowledge requires our understanding of these cells and networks of pain in humans. We propose a multi-institutional collaboration to rigorously and ethically address this challenge. Read More

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Faster lipid β-oxidation rate by acetyl-CoA carboxylase 2 inhibition alleviates high-glucose-induced insulin resistance via SIRT1/PGC-1α in human podocytes.

J Biochem Mol Toxicol 2021 May 6:e22797. Epub 2021 May 6.

Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.

Diabetic nephropathy (DN) is becoming a research hotspot in recent years because the prevalence is high and the prognosis is poor. Lipid accumulation in podocytes induced by hyperglycemia has been shown to be a driving mechanism underlying the development of DN. However, the mechanism of lipotoxicity remains unclear. Read More

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Intracranial Stenting: Angioplasty Basic Technique, Indications, and Sizing: 2-Dimensional Operative Video.

Oper Neurosurg (Hagerstown) 2021 May 6. Epub 2021 May 6.

Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York, USA.

Intracranial atherosclerotic disease (ICAD) is a common cause of stroke. Antiplatelet therapy is the mainstay for symptomatic ICAD treatment. Endovascular management with submaximal angioplasty and/or intracranial stenting is reserved for patients with repeated ischemic events despite optimal medical therapy. Read More

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Integrin α2β1 regulates collagen I tethering to modulate hyperresponsiveness in reactive airway disease models.

J Clin Invest 2021 May 6. Epub 2021 May 6.

Department of Medicine, University of California, San Francisco, San Francisco, United States of America.

Severe asthma remains challenging to manage with limited treatment options. We have previously shown that targeting smooth muscle integrin α5β1 interaction with fibronectin can mitigate the effects of airway hyperresponsiveness by impairing force transmission. In this paper we show that another member of the integrin superfamily, integrin α2β1, is present in airway smooth muscle and capable of regulating force transmission via cellular tethering to the matrix protein collagen I, and to a lesser degree, laminin-111. Read More

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Inhibitors of immuno-oncology target HPK1 - a patent review (2016 to 2020).

Expert Opin Ther Pat 2021 May 6. Epub 2021 May 6.

Nimbus Therapeutics, 130 Prospect Street, Suite 301, Cambridge, MA 02139, USA.

Introduction: Hematopoietic progenitor kinase (HPK1), a serine/threonine kinase, which is primarily expressed in hematopoietic cells is a negative regulator of T-cell receptor and B cell signaling. Studies using genetic disruption of HPK1 function show enhanced T-cell signaling, cytokine production and tumor growth inhibition. This profile of enhanced immune response highlights small molecule inhibition of HPK1 as an attractive approach for the immunotherapy of cancer. Read More

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p70S6K on astrocytes protects dopamine neurons from 1-methyl-4-phenylpyridinium neurotoxicity.

Glia 2021 May 6. Epub 2021 May 6.

Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, South Korea.

Our recent finding has demonstrated that astrocytes confer neuroprotection by endogenously producing ciliary neurotrophic factor (CNTF) via transient receptor potential vanilloid 1 (TRPV1) in Parkinson's disease (PD). In this study, the possible molecular target for TRPV1-mediated CNTF production and its neuroprotective effects on dopamine neurons were further investigated. For comparison, glial cell-line derived neurotrophic factor (GDNF) was also examined. Read More

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HDAC inhibitor, MS-275, increases vascular permeability by suppressing Robo4 expression in endothelial cells.

Tissue Barriers 2021 May 6:1911195. Epub 2021 May 6.

Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.

Roundabout guidance receptor 4 (Robo4) is an endothelial-specific membrane protein that suppresses pathological angiogenesis and vascular hyperpermeability by stabilizing endothelial cells. Robo4 suppresses severe systemic inflammation induced by pathogens and endotoxins and inhibits tumor growth and metastasis, therefore serving as a potential therapeutic target. Although the regulation of Robo4 expression through transcription factors and epigenetic mechanisms has been studied, the role of histone deacetylases (HDACs) has not been explored. Read More

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Discovery of Natural Products Targeting NQO1 via an Approach Combining Network-Based Inference and Identification of Privileged Substructures.

J Chem Inf Model 2021 May 6. Epub 2021 May 6.

Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.

NAD(P)H:quinone oxidoreductase 1 (NQO1) has been shown to be a potential therapeutic target for various human diseases, such as cancer and neurodegenerative disorders. Recent advances in computational methods, especially network-based methods, have made it possible to identify novel compounds for a target with high efficiency and low cost. In this study, we designed a workflow combining network-based methods and identification of privileged substructures to discover new compounds targeting NQO1 from a natural product library. Read More

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Discovery of Highly Specific Catalytic-Site-Targeting Fluorescent Probes for Detecting Lysosomal PDE10A in Living Cells.

ACS Chem Biol 2021 May 6. Epub 2021 May 6.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.

A challenge for sensors targeting specific enzymes of interest in their native environment for direct imaging is that they rationally exploit a highly selective fluorescent probe with a high binding affinity to provide real-time detection. Immunohistochemical staining, proteomic analysis, or recent enzymatic fluorescent probes are not optimal for tracking specific enzymes directly in living cells. Herein, we introduce the concept of designing a highly effective fluorescent probe () targeting phosphodiesterase 10A with a highly potent affinity and a >1000-fold subfamily selectivity by gaining insights into the three-dimensional structural information of the active site of the catalytic pocket. Read More

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Chemogenetic suppression of anterior cingulate cortical neurons projecting to the visual cortex disrupts attentional behavior in mice.

Neuropsychopharmacol Rep 2021 May 6. Epub 2021 May 6.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Aim: Attention is a goal-directed cognitive process that facilitates the detection of task-relevant sensory stimuli from dynamic environments. Anterior cingulate cortical area (ACA) is known to play a key role in attentional behavior, but the specific circuits mediating attention remain largely unknown. As ACA modulates sensory processing in the visual cortex (VIS), we aim to test a hypothesis that frontal top-down neurons projecting from ACA to VIS (ACA ) contributes to visual attention behavior through chemogenetic approach. Read More

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Despite large choice of effective therapies: Individuals with psoriasis still seem undertreated.

J Dtsch Dermatol Ges 2021 May 6. Epub 2021 May 6.

Department of Dermatology, University Hospital, Friedrich-Alexander-University of Erlangen-Nuremberg (FAU), Erlangen, Germany.

Background And Objectives: Due to the development of new anti-psoriatic drugs in combination with improved structures for implementation throughout Germany, the medical care of psoriasis patients has markedly improved. In this study we investigated the real-life utilization of the health care system and identified reasons for dissatisfaction in affected individuals.

Patients And Methods: This non-interventional cross-sectional study was conducted as an anonymous online survey from 12/2018 to 01/2019 in Germany. Read More

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Inhibition of hyperactivity of the dorsal raphe 5-HTergic neurons ameliorates hippocampal seizure.

CNS Neurosci Ther 2021 May 6. Epub 2021 May 6.

Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, China.

Aims: Epilepsy, frequently comorbid with depression, easily develops drug resistance. Here, we investigated how dorsal raphe (DR) and its 5-HTergic neurons are implicated in epilepsy.

Methods: In mouse hippocampal kindling model, using immunochemistry, calcium fiber photometry, and optogenetics, we investigated the causal role of DR 5-HTergic neurons in seizure of temporal lobe epilepsy (TLE). Read More

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Transforming growth factor‑β1 functions as a competitive endogenous RNA that ameliorates intracranial hemorrhage injury by sponging microRNA‑93‑5p.

Mol Med Rep 2021 Jul 6;24(1). Epub 2021 May 6.

Department of Neurology, The Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi 332000, P.R. China.

Intracerebral hemorrhage (ICH) has the highest mortality rate of all stroke subtypes but an effective treatment has yet to be clinically implemented. Transforming growth factor‑β1 (TGF‑β1) has been reported to modulate microglia‑mediated neuroinflammation after ICH and promote functional recovery; however, the underlying mechanisms remain unclear. Non‑coding RNAs such as microRNAs (miRNAs) and competitive endogenous RNAs (ceRNAs) have surfaced as critical regulators in human disease. Read More

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Downregulation of microRNA‑221 facilitates H1N1 influenza A virus replication through suppression of type‑IFN response by targeting the SOCS1/NF‑κB pathway.

Mol Med Rep 2021 Jul 6;24(1). Epub 2021 May 6.

Department of Respiratory Medicine and Intensive Care Unit, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471009, P.R. China.

Accumulating data has indicated that host microRNAs (miRNAs/miRs) play essential roles in innate immune responses to viral infection; however, the roles and the underlying mechanisms of miRNAs in influenza A virus (IAV) replication remain unclear. The present study examined on the effects of miRNAs on hemagglutinin (H)1 neuraminidase (N)1 replication and antiviral innate immunity. Using a microarray assay, the expression profiles of miRNA molecules in IAV‑infected A549 cells were analyzed. Read More

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Unique C-terminal extension and interactome of Mycobacterium tuberculosis GlmU impacts its in vivo function and the survival of the pathogen.

Biochem J 2021 May 6. Epub 2021 May 6.

National Institute of Immunology, New Delhi, India.

N-acetyl glucosamine-1-phosphate uridyltransferase (GlmU) is a bifunctional enzyme involved in the biosynthesis of Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is a critical precursor for the synthesis of peptidoglycan and other cell wall components. The absence of a homolog in eukaryotes makes GlmU an attractive target for therapeutic intervention. Read More

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So you want to express your protein in Escherichia coli?

Essays Biochem 2021 May 6. Epub 2021 May 6.

Protein and Structural Biology Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu 90220, Finland.

Recombinant proteins have been extensively employed as therapeutics for the treatment of various critical and life-threatening diseases and as industrial enzymes in high-value industrial processes. Advances in genetic engineering and synthetic biology have broadened the horizon of heterologous protein production using multiple expression platforms. Selection of a suitable expression system depends on a variety of factors ranging from the physicochemical properties of the target protein to economic considerations. Read More

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Therapeutic cancer vaccine therapy for acute myeloid leukemia.

Immunotherapy 2021 May 6. Epub 2021 May 6.

Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.

Antitumor function of the immune system has been harnessed to eradicate tumor cells as cancer therapy. Therapeutic cancer vaccines aim to help immune cells recognize tumor cells, which are difficult to target owing to immune escape. Many attempts at vaccine designs have been conducted throughout the last decades. Read More

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Molecular docking-guided synthesis of NSAID-glucosamine bioconjugates and their evaluation as COX-1/COX-2 inhibitors with potentially reduced gastric toxicity.

Chem Biol Drug Des 2021 May 5. Epub 2021 May 5.

Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL, 32611-7200, USA.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a powerful class of inhibitors targeting two isoforms of the family of cyclooxygenase enzymes (COX-1, COX-2). While NSAIDs are widely used in the management of pain, in particular as a treatment for osteo- and rheumatoid arthritis, their long-term use has associated with numerous on- and off-target effects. As the carboxylic acid moiety present in common NSAIDs is responsible for some of their adverse effects, but is not required for their anti-inflammatory activity, we sought to mask this group through direct coupling to glucosamine, which is thought to prevent cartilage degradation. Read More

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Enhanced anti-angiogenic activity of novel melatonin-like agents.

J Pineal Res 2021 May 5:e12739. Epub 2021 May 5.

School of Pharmacy, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea.

Hypoxia-inducible factor-1 (HIF-1) plays an important role in cellular responses to hypoxia, including the transcriptional activation of several genes involved in tumor angiogenesis. Melatonin, also known as N-acetyl-5-methopxytryptamine, is produced naturally by the pineal gland and has anti-angiogenic effects in cancer through its ability to modulate HIF-1α activity. However, the use of melatonin as a therapeutic is limited by its low oral bioavailability and short half-life. Read More

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Glucagon-like peptide-1 receptor agonist inhibits aeroallergen-induced activation of ILC2 and neutrophilic airway inflammation in obese mice.

Allergy 2021 May 6. Epub 2021 May 6.

Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Background: Obesity is a risk factor for the development of asthma. However, pharmacologic therapeutic strategies that specifically target obese asthmatics have not been identified. We hypothesize that glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment inhibitsaeroallergen-induced early innate airway inflammation in a mouse model of asthma in the setting of obesity. Read More

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PD-1 blocking antibodies moonlighting as killers.

Eur J Immunol 2021 May 5. Epub 2021 May 5.

Division of Immune Receptor and T cell Activation, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.

Therapeutic antibodies that block PD-1-mediated inhibition of T cells have revolutionized cancer therapy. Murine cancer models are an essential tool for testing the efficacy of PD-1 blockers alone or in combination with other treatments. Depending on the isotype of the antibody and the host-species, blocking antibodies can also exert cytotoxic activity towards cells expressing the target molecule. Read More

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Trachyspermum ammi and Cinnamomum verum as nutraceuticals: Spices rich in therapeutically significant protein tyrosine phosphatases.

J Food Biochem 2021 May 5:e13750. Epub 2021 May 5.

Centre for Biotechnology and Biochemical Engineering, Amity Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India.

Nutraceuticals need special attention as preventive molecules to create a natural barrier against various dreadful diseases like cancer and to regulate metabolism. In the present study, two spices, Trachyspermum ammi and Cinnamomum verum, been identified as excellent Protein Tyrosine Phosphatases (PTPases) sources that play significant role in the regulation of cell signal transduction and developmental processes in plants as well as animals, being lucrative and potential targets for pharmacological modulation. PTPases from both cases were partially purified into 0%-40% and 40%-80% fractions based on ammonium sulfate saturation levels. Read More

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A Critical Review of the Efficacy and Safety of Inclisiran.

Am J Cardiovasc Drugs 2021 May 6. Epub 2021 May 6.

East Coast Institute for Research, Jacksonville, FL, USA.

The association between low-density cholesterol (LDL-C) and cardiovascular disease (CVD) is well-established, with an emphasis on lowering LDL-C levels to reduce cardiovascular events. Statin therapy has been the traditional treatment for LDL-C reduction, in addition to lifestyle modifications, but studies have shown that a substantial proportion of patients does not reach target LDL-C goals despite receiving maximally tolerated statin medications. Additionally, statin therapy is associated with a few shortcomings as many patients initiated on these medications discontinue treatment within 1 year because of lack of tolerability. Read More

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