11,201 results match your criteria proteasome system

Proteasomal activator 28 gamma stabilizes hepatitis B virus X protein by competitively inhibiting the Siah-1-mediated proteasomal degradation.

Biochem Biophys Res Commun 2021 Sep 16;578:97-103. Epub 2021 Sep 16.

Department of Microbiology, College of Natural Science, Pusan National University, Busan, 46241, Republic of Korea; Microbiological Resource Research Institute, Pusan National University, Busan, 46241, Republic of Korea. Electronic address:

Proteasomal activator 28 gamma (PA28γ) upregulates the levels of HBx, a regulatory protein of hepatitis B virus (HBV) to stimulate HBV replication; however, the detailed mechanism remains unknown. Here, we found that PA28γ impaired the ability of seven in absentia homolog 1 (Siah-1) as an E3 ubiquitin ligase of HBx. PA28γ competitively inhibited the binding of Siah-1 to HBx in human hepatoma cells. Read More

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September 2021

Cereblon: promise and challenges for combating human diseases.

Pflugers Arch 2021 Sep 22. Epub 2021 Sep 22.

Department of Physiology, College of Medicine, Cardiovascular and Metabolic Disease Center, Smart Marine Therapeutic Center, Department of Health Sciences and Technology, Graduate School, Inje University, 47392, Busan, Korea.

Cereblon (CRBN) is a substrate recognition protein in the E3-ligase ubiquitin complex. The binding target of CRBN varies according to tissues and cells, and the protein regulates various biological functions by regulating tissue-specific targets. As new endogenous targets of CRBN have been identified over the past decade, the physiological and pathological functions of CRBN and its potential as a therapeutic target in various diseases have greatly expanded. Read More

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September 2021

Synthesis and Evaluation of Ubiquitin-Dioxetane Conjugate as a Chemiluminescent Probe for Monitoring Deubiquitinase Activity.

Bioconjug Chem 2021 Sep 22. Epub 2021 Sep 22.

School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv 69978, Israel.

The removal of ubiquitin (Ub) from a modified protein or Ub chain is a process that occurs regularly by the ubiquitin-proteasome system. This process is known to be mediated by various deubiquitinating enzymes (DUBs) in order to control the protein's half-life and its expression levels among many other signaling processes. Since the function of DUBs is also involved in numerous human diseases, such as cancer, there is an obvious need for an effective diagnostic probe that can monitor the activity of these enzymes. Read More

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September 2021

Ubiquitin Proteasome Activity Measurement in Total Plant Extracts.

Bio Protoc 2017 Sep 5;7(17):e2532. Epub 2017 Sep 5.

Plant Metabolism Group, Leibniz-Institute of Vegetable and Ornamental Crops (IGZ), Großbeeren, Germany.

The fine-tuned balance of protein level, conformation and location within the cell is vital for the dynamic changes required for a cell to respond to a given stimulus. This requires the regulated turnover of damaged or short-lived proteins through the ubiquitin proteasome system (UPS). Thus, the protease activity of the proteasome is adjusted to meet the current demands of protein degradation via the UPS within the cell. Read More

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September 2017

Parasitic modulation of host development by ubiquitin-independent protein degradation.

Cell 2021 Sep 10. Epub 2021 Sep 10.

Department of Crop Genetics, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK. Electronic address:

Certain obligate parasites induce complex and substantial phenotypic changes in their hosts in ways that favor their transmission to other trophic levels. However, the mechanisms underlying these changes remain largely unknown. Here we demonstrate how SAP05 protein effectors from insect-vectored plant pathogenic phytoplasmas take control of several plant developmental processes. Read More

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September 2021

Ubiquitin pathways regulate the pathogenesis of chronic liver disease.

Biochem Pharmacol 2021 Sep 13;193:114764. Epub 2021 Sep 13.

College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju 28160, South Korea. Electronic address:

Chronic liver disease (CLD) is considered the leading cause of global mortality. In westernized countries, increased consumption of alcohol and overeating foods with high fat/ high glucose promote progression of CLD such as alcoholic liver disease (ALD) and non-alcoholic liver disease (NAFLD). Accumulating evidence and research suggest that ubiquitin, a 75 amino acid protein, plays crucial role in the pathogenesis of CLD through dynamic post-translational modifications (PTMs) exerting diverse cellular outcomes such as protein degradation through ubiquitin-proteasome system (UPS) and autophagy, and regulation of signal transduction. Read More

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September 2021

The Intertwining of Autophagy and the Ubiquitin Proteasome System in Podocyte (Patho)Physiology.

Cell Physiol Biochem 2021 Sep;55(S4):68-95

Institute of Cellular and Integrative Physiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,

Protein homeostasis strongly depends on the targeted and selective removal of unneeded or flawed proteins, of protein aggregates, and of damaged or excess organelles by the two main intracellular degradative systems, namely the ubiquitin proteasomal system (UPS) and the autophagosomal lysosomal system. Despite representing completely distinct mechanisms of degradation, which underlie differing regulatory mechanisms, growing evidence suggests that the UPS and autophagy strongly interact especially in situations of overwhelming and impairment, and that both are involved in podocyte proteostasis and in the pathogenesis of podocyte injury. The differential impact of autophagy and the UPS on podocyte biology and on podocyte disease development and progression is not understood. Read More

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September 2021

Neurotoxicity of a pyrethroid pesticide deltamethrin is associated with the imbalance in proteolytic systems caused by mitophagy activation and proteasome inhibition.

Toxicol Appl Pharmacol 2021 Sep 11:115723. Epub 2021 Sep 11.

Life Science Research Center, University of Toyama, 2630 Sugitani, Toyama, Toyama 930-0194, Japan.

Pyrethroids are one of the most commonly used classes of synthetic pesticides in the world. Recent laboratory and epidemiological evidence suggested that pyrethroids have potential adverse effects in the mammalian brain; however, the underlying mechanisms of the neurotoxic effects of pyrethroids have not been fully elucidated. In the present study, we investigated the mechanisms of effects of a type II pyrethroid deltamethrin (DM) in a neuronal cell model focusing on the proteolytic function, including autophagy and the ubiquitin-proteasome system. Read More

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September 2021

Biochemical strategies of E3 ubiquitin ligases target viruses in critical diseases.

J Cell Biochem 2021 Sep 14. Epub 2021 Sep 14.

Department of Bioscience and Bioengineering, Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, India.

Viruses are known to cause various diseases in human and also infect other species such as animal plants, fungi, and bacteria. Replication of viruses depends upon their interaction with hosts. Human cells are prone to such unwanted viral infections. Read More

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September 2021

Harnessing the E3 Ligase KEAP1 for Targeted Protein Degradation.

J Am Chem Soc 2021 Sep 14;143(37):15073-15083. Epub 2021 Sep 14.

Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

Proteolysis targeting chimeras (PROTACs) represent a new class of promising therapeutic modalities. PROTACs hijack E3 ligases and the ubiquitin-proteasome system (UPS), leading to selective degradation of the target proteins. However, only a very limited number of E3 ligases have been leveraged to generate effective PROTACs. Read More

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September 2021

Using Phage Display to Develop Ubiquitin Variant Modulators for E3 Ligases.

J Vis Exp 2021 Aug 27(174). Epub 2021 Aug 27.

Department of Molecular and Cellular Biology, College of Biological Science, University of Guelph;

Ubiquitin is a small 8.6 kDa protein that is a core component of the ubiquitin-proteasome system. Consequently, it can bind to a diverse array of proteins with high specificity but low affinity. Read More

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E3 Ubiquitin Ligase-Mediated Regulation of Osteoblast Differentiation and Bone Formation.

Front Cell Dev Biol 2021 27;9:706395. Epub 2021 Aug 27.

Guangdong Innovation Platform for Translation of 3D Printing Application, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.

The ubiquitin-proteasome system (UPS) is an essential pathway that regulates the homeostasis and function of intracellular proteins and is a crucial protein-degradation system in osteoblast differentiation and bone formation. Abnormal regulation of ubiquitination leads to osteoblast differentiation disorders, interfering with bone formation and ultimately leading to osteoporosis. E3 ubiquitin ligases (E3) promote addition of a ubiquitin moiety to substrate proteins, specifically recognizing the substrate and modulating tyrosine kinase receptors, signaling proteins, and transcription factors involved in the regulation of osteoblast proliferation, differentiation, survival, and bone formation. Read More

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Activation of Antioxidant and Proteolytic Pathways in the Nigrostriatal Dopaminergic System After 3,4-Methylenedioxymethamphetamine Administration: Sex-Related Differences.

Front Pharmacol 2021 27;12:713486. Epub 2021 Aug 27.

Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Bologna, Italy.

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is an amphetamine-related drug that may damage the dopaminergic nigrostriatal system. To investigate the mechanisms that sustain this toxic effect and ascertain their sex-dependence, we evaluated in the nigrostriatal system of MDMA-treated (4 × 20 mg/kg, 2 h apart) male and female mice the activity of superoxide dismutase (SOD), the gene expression of SOD type 1 and 2, together with SOD1/2 co-localization with tyrosine hydroxylase (TH)-positive neurons. In the same mice and brain areas, activity of glutathione peroxidase (GPx) and of β2/β5 subunits of the ubiquitin-proteasome system (UPS) were also evaluated. Read More

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Implications of FBXW7 in Neurodevelopment and Neurodegeneration: Molecular Mechanisms and Therapeutic Potential.

Front Cell Neurosci 2021 25;15:736008. Epub 2021 Aug 25.

Shandong Collaborative Innovation Center for Diagnosis, Treatment and Behavioral Interventions of Mental Disorders, Institute of Mental Health, Jining Medical University, Jining, China.

The ubiquitin-proteasome system (UPS) mediated protein degradation is crucial to maintain quantitive and functional homeostasis of diverse proteins. Balanced cellular protein homeostasis controlled by UPS is fundamental to normal neurological functions while impairment of UPS can also lead to some neurodevelopmental and neurodegenerative disorders. Functioning as the substrate recognition component of the SCF-type E3 ubiquitin ligase, FBXW7 is essential to multiple aspects of cellular processes via targeting a wide range of substrates for proteasome-mediated degradation. Read More

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Implications of Valosin-containing Protein in Promoting Autophagy to Prevent Tau Aggregation.

Neuroscience 2021 Sep 10. Epub 2021 Sep 10.

Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411008, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.

Chaperones and cellular degradative mechanisms modulate Tau aggregation. During aging and neurodegenerative disorders, the cellular proteostasis is disturbed due to impaired protective mechanisms. This results in accumulation of aberrant Tau aggregates in the neuron that leads to microtubule destabilization and neuronal degeneration. Read More

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September 2021

Mutation of a Ubiquitin Carboxy Terminal Hydrolase L1 Lipid Binding Site Alleviates Cell Death, Axonal Injury, and Behavioral Deficits After Traumatic Brain Injury in Mice.

Neuroscience 2021 Sep 8. Epub 2021 Sep 8.

Geriatric Research Educational and Clinical Center, V.A. Pittsburgh Healthcare System, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address:

Ubiquitin carboxy terminal hydrolase L1 (UCHL1) is a protein highly expressed in neurons that may play important roles in the ubiquitin proteasome pathway (UPP) in neurons, axonal integrity, and motor function after traumatic brain injury (TBI). Binding of reactive lipid species to cysteine 152 of UCHL1 results in unfolding, aggregation, and inactivation of the enzyme. To test the role of this mechanism in TBI, mice bearing a cysteine to alanine mutation at site 152 (C152A mice) that renders UCHL1 resistant to inactivation by reactive lipids were subjected to the controlled cortical impact model (CCI) of TBI and compared to wild type (WT) controls. Read More

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September 2021

Chirality and asymmetry increase the potency of candidate ADRM1/RPN13 inhibitors.

PLoS One 2021 10;16(9):e0256937. Epub 2021 Sep 10.

Department of Pathology, The Johns Hopkins University, Baltimore, Maryland, United States of America.

Bortezomib and the other licensed 20S proteasome inhibitors show robust activity against liquid tumors like multiple myeloma, but have disappointed against solid tumors including ovarian cancer. Consequently, interest is mounting in alternative non-peptide based drugs targeting the proteasome's 19S regulatory particle subunit, including its ubiquitin receptor RPN13. RA183 and RA375 are more potent analogs of the prototypic inhibitor of RPN13 (iRPN13) called RA190, and they show promise for the treatment of ovarian cancer. Read More

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September 2021

Integration of Mass Spectrometry Data for Structural Biology.

Chem Rev 2021 Sep 10. Epub 2021 Sep 10.

Institute of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom.

Mass spectrometry (MS) is increasingly being used to probe the structure and dynamics of proteins and the complexes they form with other macromolecules. There are now several specialized MS methods, each with unique sample preparation, data acquisition, and data processing protocols. Collectively, these methods are referred to as structural MS and include cross-linking, hydrogen-deuterium exchange, hydroxyl radical footprinting, native, ion mobility, and top-down MS. Read More

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September 2021

Knockdown of PSMC2 contributes to suppression of cholangiocarcinoma development by regulating CDK1.

Aging (Albany NY) 2021 09 9;13(17):21325-21344. Epub 2021 Sep 9.

Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China.

Cholangiocarcinoma (CCA) has been well known as the second most common primary tumor of hepatobiliary system. PSMC2 (proteasome 26S subunit ATPase 2) is a key member of the 19S regulatory subunit of 26S proteasome, responsible for catalyzing the unfolding and translocation of substrates into the 20S proteasome, whose role in CCA is totally unknown. In this study, the results of immunohistochemistry analysis showed the upregulation of PSMC2 in CCA tissues compared with normal tissues, which was statistically analyzed to be associated with CCA tumor grade. Read More

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September 2021

Innate Immune Evasion of Porcine Epidemic Diarrhea Virus through Degradation of F-box and WD repeat domain-containing 7 protein via Ubiquitin-proteasome Pathway.

J Virol 2021 Sep 8:JVI0088921. Epub 2021 Sep 8.

State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.

Porcine epidemic diarrhea virus (PEDV) causes a porcine disease associated with swine epidemic diarrhea. Different antagonistic strategies have been identified, and the mechanism by which PEDV infection impairs the production of interferon (IFN) and delays the activation of the IFN response to escape host innate immunity has been determined, but the pathogenic mechanisms of PEDV infection remain enigmatic. Our preliminary results revealed that endogenous F-box and WD repeat domain-containing 7 (FBXW7), the substrate recognition component of the SCF-type E3 ubiquitin ligase, is downregulated in PEDV-infected Vero E6 cells, according to the results from an isobaric tags for relative and absolute quantification (iTRAQ) analysis. Read More

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September 2021

Recent Developments in PROTAC-Mediated Protein Degradation: From Bench to Clinic.

Chembiochem 2021 Sep 8. Epub 2021 Sep 8.

Department of Molecular, Cellular and Developmental Biology, Yale University, 260 Whitney Avenue, New Haven, CT 06511, USA.

Proteolysis-targeting chimeras (PROTACs), an emerging paradigm-shifting technology, hijacks the ubiquitin-proteasome system for targeted protein degradation. PROTACs induce ternary complexes between an E3 ligase and POI, and this induced proximity leads to polyUb chain formation on substrates and eventual proteasomal-mediated POI degradation. PROTACs have shown great therapeutic potential by degrading many disease-causing proteins, such as the androgen receptor and BRD4. Read More

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September 2021

The OMM-severed and IMM-ubiquitinated mitochondria are intermediates of mitochondrial proteotoxicity-induced autophagy in PRKN/parkin-deficient cells.

Autophagy 2021 Sep 5:1-3. Epub 2021 Sep 5.

Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD, USA.

Among other mechanisms, mitochondrial membrane dynamics including mitochondrial fission and fusion, and the activity of the ubiquitin (Ub)-proteasome system (UPS) both are critical for maintaining mitochondrial function. To advance our knowledge of the role of mitochondrial fission, the UPS, and how they coordinatively affect mitochondrial response to proteotoxicity, we analyzed mitochondrial ubiquitination and mitochondria-specific autophagy (mitophagy) in E3 Ub ligase PRKN/parkin-expressing and -deficient cells. Through imaging, biochemical, and genetic analyses, we found that in a model of acute reduction of mitochondrial translation fidelity (MTF) some population of mitochondria within a single cell are enriched, while some showed reduced levels of CYCS (cytochrome c, somatic) and CPOX (coproporphyrinogen oxidase) proteins, both located in the intermembrane space (IMS); henceforth called "mosaic distribution". Read More

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September 2021

Regulation of Ferroptosis Pathway by Ubiquitination.

Front Cell Dev Biol 2021 13;9:699304. Epub 2021 Aug 13.

Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, China.

Ferroptosis is an iron-dependent form of programmed cell death, which plays crucial roles in tumorigenesis, ischemia-reperfusion injury and various human degenerative diseases. Ferroptosis is characterized by aberrant iron and lipid metabolisms. Mechanistically, excess of catalytic iron is capable of triggering lipid peroxidation followed by Fenton reaction to induce ferroptosis. Read More

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Long-time progression-free survival in relapsed, refractory multiple myeloma with the oral ixazomib-lenalidomide-dexamethasone regime

Orv Hetil 2021 09 5;162(36):1451-1458. Epub 2021 Sep 5.

1 Dél-pesti Centrumkórház, Országos Hematológiai és Infektológiai Intézet, Hematológiai és Őssejt-transzplantációs Osztály, Budapest.

Összefoglaló. Bevezetés: A myeloma multiplex mindmáig alapvetően gyógyíthatatlan betegség, ezért nagy klinikai jelentőségük van az eredményes mentő kezeléseknek. A szájon át adható első proteaszómagátlóval, az ixazomibbal kiegészített lenalidomid-dexametazon terápia jól tolerálható, csak orális szerekből álló kombináció, mely hazánkban 2015 áprilisától kezdődően a "Named Patient Program" keretén belül vált elérhetővé relabált, refrakter myeloma multiplexes betegek kezelésére. Read More

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September 2021

Rag GTPases suppress PRL-3 degradation and predict poor clinical diagnosis of cancer patients with low PRL-3 mRNA expression.

Biochem Biophys Res Commun 2021 Oct 31;576:108-116. Epub 2021 Aug 31.

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute of Molecular and Cell Biology, A∗STAR (Agency for Science, Technology and Research), Singapore, Singapore; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA. Electronic address:

Ras-related GTP binding (Rag) GTPases are required to activate mechanistic target of rapamycin complex 1 (mTORC1), which plays a central role in cell growth and metabolism and is considered as one of the most important oncogenic pathways. Therefore, Rag GTPases have been speculated to play a pro-cancer role via mTOR induction. However, aside from stimulation of mTOR signaling, firm links connecting Rag GTPase activity and their downstream effectors with cancer progression, remain largely unreported. Read More

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October 2021

Regulation of topoisomerase II stability and activity by ubiquitination and SUMOylation: clinical implications for cancer chemotherapy.

Mol Biol Rep 2021 Sep 2;48(9):6589-6601. Epub 2021 Sep 2.

HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, 315010, China.

DNA topoisomerases II (TOP2) are peculiar enzymes (TOP2α and TOP2β) that modulate the conformation of DNA by momentarily breaking double-stranded DNA to allow another strand to pass through, and then rejoins the DNA phosphodiester backbone. TOP2α and TOP2β play vital roles in nearly all events involving DNA metabolism, including DNA transcription, replication, repair, and chromatin remodeling. Beyond these vital functions, TOP2 enzymes are therapeutic targets for various anticancer drugs, termed TOP2 poisons, such as teniposide, etoposide, and doxorubicin. Read More

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September 2021

Mechanistic and thermodynamic characterization of oxathiazolones as potent and selective covalent immunoproteasome inhibitors.

Comput Struct Biotechnol J 2021 9;19:4486-4496. Epub 2021 Aug 9.

Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Magyar tudósok körútja 2, Budapest 1117, Hungary.

The ubiquitin-proteasome system is responsible for the degradation of proteins and plays a critical role in key cellular processes. While the constitutive proteasome (cPS) is expressed in all eukaryotic cells, the immunoproteasome (iPS) is primarily induced during disease processes, and its inhibition is beneficial in the treatment of cancer, autoimmune disorders and neurodegenerative diseases. Oxathiazolones were reported to selectively inhibit iPS over cPS, and the inhibitory activity of several oxathiazolones against iPS was experimentally determined. Read More

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In silico analysis and molecular identification of an anaphase-promoting complex homologue from human pathogen Entamoeba histolytica.

J Genet Eng Biotechnol 2021 Sep 1;19(1):133. Epub 2021 Sep 1.

Department of Microbiology, The University of Burdwan , Burdwan, West Bengal, 713104, India.

Background: Amoebiasis, being endemic worldwide, is the second leading cause of parasite-associated morbidity and mortality after malaria. The human parasite Entamoeba histolytica is responsible for the disease. Metronidazole is considered as the gold standard for the treatment of amoebiasis, but this antibiotic is carcinogenic and the development of antibiotic resistance against E. Read More

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September 2021

A Chemical Toolbox for Labeling and Degrading Engineered Cas Proteins.

JACS Au 2021 Jun 12;1(6):777-785. Epub 2021 May 12.

Buchmann Institute for Molecular Life Sciences, Pharmaceutical Chemistry, Goethe University Frankfurt am Main, Max-von-Laue-Strasse 15. R. 3.652, D-60438 Frankfurt am Main, Germany.

The discovery of clustered regularly interspaced short palindromic repeats and their associated proteins (Cas) has revolutionized the field of genome and epigenome editing. A number of new methods have been developed to precisely control the function and activity of Cas proteins, including fusion proteins and small-molecule modulators. Proteolysis-targeting chimeras (PROTACs) represent a new concept using the ubiquitin-proteasome system to degrade a protein of interest, highlighting the significance of chemically induced protein-E3 ligase interaction in drug discovery. Read More

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The molecular and cellular insight into the toxicology of bortezomib-induced peripheral neuropathy.

Biomed Pharmacother 2021 Oct 24;142:112068. Epub 2021 Aug 24.

Department of Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. Electronic address:

The proteasome inhibitor bortezomib (BTZ) is a first-line antitumor drug, mainly used for multiple myeloma treatment. However, BTZ shows prominent toxicity in the peripheral nervous system, termed BTZ-induced peripheral neuropathy (BIPN). BIPN is characterized by neuropathic pain, resulting in a dose reduction or even treatment withdrawal. Read More

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October 2021