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Long way up:rethink diseases in light of phase separation and phase transition

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Protein & cell 2024年第7期15卷 475-492页

作者： Mingrui Ding Weifan Xu Gaofeng Pei Pilong Li State Key laboratory of Membrane biology&Frontier Research Center for Biological Structure School of Life SciencesTsinghua UniversityBeijing 100084China Tsinghua-Peking Center for Life Sciences Beijing 100084China NuPhase Therapeutics Beijing 100083China

Biomolecular condensation, driven by multivalency, serves as a fundamental mechanism within cells, facilitating the formation of distinct compartments, including membraneless organelles that play essential roles in various cellular processes. Perturbations in the delicate equilibrium of condensation, whether resulting in gain or loss of phase separation, have robustly been associated with cellular dysfunction and physiological disorders. As ongoing research endeavors wholeheartedly embrace this newly acknowledged principle, a transformative shift is occurring in our comprehension of disease. Consequently, significant strides have been made in unraveling the profound relevance and potential causal connections between abnormal phase separation and various diseases. This comprehensive review presents compelling recent evidence that highlight the intricate associations between aberrant phase separation and neurodegenerative diseases, cancers, and infectious diseases. Additionally, we provide a succinct summary of current efforts and propose innovative solutions for the development of potential therapeutics to combat the pathological consequences attributed to aberrant phase separation.

关键词： multivalency compartments aberant phase separation therapeutics gain or loss of phase separation diseases

Inhibition of DNA-dependent Protein Kinase Catalytic Subunit by Small Molecule Inhibitor NU7026 Sensitizes Human Leukemic K562 cells to Benzene Metabolite-induced Apoptosis

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2013年第1期33卷 43-50页

作者：游浩孔萌萌王立萍肖潇廖汉林毕卓悦燕虹王红汪春红马强刘燕群毕勇毅 School of Public Health Wuhan University School of Medicine Jianghan University School of Pharmaceutical Science Wuhan University Receptor biology laboratory Toxicology and Molecular Biology BranchHealth Effects Laboratory DivisionNational Institute for Occupational Safety and Health

Benzene is an established leukotoxin and leukemogen in humans. We have previously re- ported that exposure of workers to benzene and to benzene metabolite hydroquinone in cultured cells induced DNA-dependent protein kinase catalytic subunit （DNA-PKcs） to mediate the cellular response to DNA double strand break （DSB） caused by DNA-damaging metabolites. In this study, we used a new, small molecule, a selective inhibitor of DNA-PKcs, 2-（morpholin-4-yl）-benzo[h]chomen-4-one （NU7026）, as a probe to analyze the molecular events and pathways in hydroquinone-induced DNA DSB repair and apoptosis. Inhibition of DNA-PKcs by NU7026 markedly potentiated the apoptotic and growth inhibitory effects of hydroquinone in proerythroid leukemic K562 cells in a dose-dependent manner. Treatment with NU7026 did not alter the production of reactive oxygen species and oxidative stress by hydroquinone but repressed the protein level of DNA-PKcs and blocked the induction of the kinase mRNA and protein expression by hydroquinone. Moreover, hydroquinone increased the phos- phorylation of Akt to activate Akt, whereas co-treatment with NU7026 prevented the activation of Akt by hydroquinone. Lastly, hydroquinone and NU7026 exhibited synergistic effects on promoting apop- tosis by increasing the protein levels of pro-apoptotic proteins Bax and caspase-3 but decreasing the protein expression of anti-apoptotic protein Bcl-2. Taken together, the findings reveal a central role of DNA-PKcs in hydroquinone-induced hematotoxicity in which it coordinates DNA DSB repair, cell cycle progression, and apoptosis to regulate the response to hydroquinone-induced DNA damage.

关键词： benzene DNA-dependent protein kinase catalytic subunit 2-(morpholin-4-yl)- benzo[h]chomen-4-one Akt DNA double strand break

Association of Host Interferon-γ Gene Polymorphism with Toxoplasma gondii Infection in Pregnant Women of Bangladesh

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American Journal of Molecular biology 2023年第3期13卷 156-169页

作者： Nasrin Akter Sonia Tamanna Molie Rahman Atiqur Rahman Akm Mahbub Hasan Taibur Rahman laboratory of Infection biology Department of Biochemistry and Molecular Biology University of Dhaka Dhaka Bangladesh laboratory of Reproductive Health Department of Biochemistry and Molecular Biology University of Dhaka Dhaka Bangladesh Bangladesh Institute of Research and Rehabilitation in Diabetes Endocrine and Metabolic Disorders Dhaka Bangladesh

Human toxoplasmosis is caused by the intracellular protozoan parasite Toxoplasma gondii. Although T. gondii infection is generally asymptomatic for most of the immunocompetent adults, severe complications may occur particularly in pregnant women and immunocompromised individual. Host cell immunity plays a critical role in parasite differentiation and persistence in the host. Therefore, genetic polymorphism in the host immune genes, for instance interferon-γ gene could be linked with possibility of T. gondii infection. The objective of the study was to verify the link between the single nucleotide polymorphisms (SNPs) in the IFN-γ gene of pregnant women and T. gondii infection through correlating with anthropometric and sociodemographic parameters. In this study, ninety-two (N = 92) pregnant women (16 - 40 years) and healthy controls (N = 95) with similar age ranges were included. Among them, 25% (n = 23) pregnant women were seropositive for T. gondii IgG antibodies by Rapid Test Assay. Allelic and genotypic frequencies of IFN-γ +874T/A (rs2430561) SNPs were evaluated by using ARMS-PCR. The distribution of the A and T alleles in the specific position of the IFN-γ gene in the T. gondii-infected pregnant women and the control groups did not differ significantly, according to the data. However, we found a higher frequency (13.04%) of A/A genotype in T. gondii infected pregnant women as compared to non-infected individuals (8.70%), demonstrating that T. gondii infection susceptibility may be increased by homozygosity for the A allele. Further studies are to be needed to find out the link between host gene polymorphism and T. gondii infection in Bangladesh.

关键词： T. gondii Pregnant Women Seroprevalence IFN-γ Gene Polymorphism

Signaling pathways downstream to receptor tyrosine kinases:targets for cancer treatment

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 556-574页

作者： Emma Cordover Audrey Minden Susan Lehman Cullman laboratory for Cancer Research Department of Chemical BiologyErnest Mario School of PharmacyRutgersThe State University of New JerseyPiscatawayNJ 08854USA

Mammalian cells have the ability to respond to a myriad of diverse extracellular stimuli that modulate cell *** often involves ligands binding to cell surface receptors and subsequent activation of intracellular signaling *** pathways can lead to changes in gene expression patterns that in turn regulate cell growth,differentiation,migration,and *** important type of cell surface receptor is the receptor tyrosine kinase(RTK).In response to in response to ligand binding,RTKs dimerize,then trans-phosphorylate each other,leading to activation of downstream *** the signaling proteins in these pathways are important for normal cell growth control,when improperly regulated they can lead to uncontrolled growth and sometimes *** this reason,they are often considered to be good candidates for drug targets for chemotherapeutic *** can activate multiple different signaling *** of the signaling proteins in these pathways can have crosstalk with other RTK activated pathways,and some of them can be activated by multiple mechanisms in addition to activation by *** there is a wide array of different signaling proteins and pathways activated by RTKs,in this review we will discuss components of several key pathways including the MAPK pathway,the Her2/Neu pathway,mTOR,and Pak *** provide an overview of the roles for these pathways in cell signaling and discuss how different components of these pathways are being considered as targets for cancer treatment.

关键词： Receptor tyrosine kinases signaling pathways targeted cancer therapeutics oncogenes cell signaling

Promoting neuronal regeneration using extracellular vesicles loaded with superparamagnetic iron oxide nanoparticles

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Neural Regeneration Research 2016年第1期11卷 61-63页

作者： Jenni Neubert Jana Glumm Institute of cell biology and Neurobiology Center for AnatomyCharité-Universit?tsmedizin Berlin Department of Neurosurgery HELIOS Klinikum Berlin Buch

Intercellular communication between neurons and glial cells via extracellular vesicles（EVs）as a novel mechanism of information transfer has been shown to be involved in regeneration processes within the central nervous system（CNS）（Rajendran et al.,2014）.Hence,to take advantage of EV signaling for therapeutic applications appears to be a completely new approach to promote regeneration.

关键词： vesicles regeneration neuronal loaded glial instance targeting synaptic exosome hippocampal

Posterior interosseous nerve localization within the proximal forearm-a patient normalized parameter

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World Journal of Orthopedics 2017年第4期8卷 310-316页

作者： Srinath Kamineni Crystal R Norgren Evan M Davidson Ellora P Kamineni Andrew S Deane Elbow Shoulder Research Centre Depart-ment of Orthopaedics and Sports MedicineUniversity of Kentucky University of Kentucky College of Medicine Paul Laurence Dunbar High School Department of Anatomy and cell biology Indiana University School of Medicine

AIM To provide a "patient-normalized" parameter in the proximal forearm. METHODS Sixty-three cadaveric upper extremities from thirty-five cadavers were studied. A muscle splitting approach was utilized to locate the posterior interosseous nerve(PIN) at the point where it emerges from beneath the supinator. The supinator was carefully incised to expose the midpoint length of the nerve as it passes into the forearm while preserving the associated fascial connections, thereby preserving the relationship of the nerve with the muscle. We measured the transepicondylar distance(TED), PIN distance in the forearm's neutral rotation position, pronation position, supination position, and the nerve width. Two individuals performed measurements using a digital caliper with inter-observer and intraobserver blinding. The results were analyzed with the Wilcoxon-Mann-Whitney test for paired samples. RESULTS In pronation, the PIN was within two confidence intervals of 1.0 TED in 95% of cases(range 0.7-1.3 TED); in neutral, within two confidence intervals of 0.84 TED in 95% of cases(range 0.5-1.1 TED); in supination,within two confidence intervals of 0.72 TED in 95% of cases(range 0.5-0.9 TED). The mean PIN distance from the lateral epicondyle was 100% of TED in a pronated forearm, 84% in neutral, and 72% in supination. Predictive accuracy was highest in supination; in all cases the majority of specimens(90.47%-95.23%) are within 2 cm of the forearm position-specific percentage of TED. When comparing right to left sides for TEDs with the signed Wilcoxon-Mann-Whitney test for paired samples as well as a significance test(with normal distribution), the P-value was 0.0357(significance-0.05) indicating a significant difference between the two *** This "patient normalized" parameter localizes the PIN crossing a line drawn between the lateral epicondyle and the radial styloid. Accurate PIN localization will aid in diagnosis, injections, and surgical approaches.

关键词： Posterior interosseous nerve Radial nerve Transepicondylar distance Radial tunnel syndrome Supinator syndrome

Evolution of the DHRS4 gene cluster and antisense AS1DHRS4

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Evolution of the DHRS4 gene cluster and antisense AS1DHRS4

Streptococcal Protein G Enhances Antibody Binding to Platinum Sensor Surfaces

第五届全国生物信息学与系统生物学学术大会暨国际生物信息学前沿研讨会高通量时代的生物信息学与系统生物学

作者： Lei Feng Dongyang Huang Department of cell biology 22 Xinling RoadShantou University Medical College

Background:The DHRS4 gene encodes an NADP(H)-dependent retinol dehydrogenase /***4 and two genes(DHRS4L2 and DHRS4L1) that recently arose from gene duplication in human,an antisense transcript AS1DHRS4,devoted of the DHRS4 gene negatively regulates expression of all three *** order to analysis the evolution of the DHRS4 gene cluster and antisense AS1DHRS4,bioinformatics methods were performed to analysis it. Methods:Infernal-1.0.2 was run to searching DNA sequence databases for RNA structure and sequence similarities homologous sequences of AS1DHRS4 in fifteen species. Multiple sequence alignments and evolution analysis were completed by ClustalX2.0. Mega5.0 was used to estimate rates of molecular evolution.3’-RACE and 5’-RACE were conducted to obtain the full length of *** also transfected rhesus monkey siRNA to knockdown CO048964,and detected the knockdown effect by real-time PCR. Results:Sequence alignment of Infernal-1.0.2 shows that DHRS4 sequences are conserved in *** the sequence alignments,we realized that most primates have a single ***,human and rhesus monkeys contain two duplications,while marmosets and other vertebrates contain only one *** alignment showed that the AS1DHRS4 does not exist in mouse and rat even though both genomes have high similarity with the human ***1DHRS4 is conserved in all primates except in marmosets, but exists in the *** found an EST sequence CO048964 in rhesus monkey that transcribed at the opposite chain of the DHRS4 gene ***’s exon structure is extremely different from *** rhesus monkeys full length CO048964 was obtained through 3’-RACE and 5’-RACE in Frhk-4 cell line RNA,and devoted it *** ID: JQ686618,JQ686619,*** of rheASlDHRS4 in Frhk-4 cell led significant down regulation of DHRS4,which is opposite to AS1DHRS4 in human cells. Conclusions:The sequence of DHRS4 gene is conserved among the fifteen spec

关键词： long noncoding RNA evolution nature antisense transcripts DHRS4

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Journal of Sensor Technology 2015年第1期5卷 1-6页

作者： Michael E. Stephens Terri N. Ellis Jay S. Huebner Erica M. Kelly Doria F. Bowers Department of Molecular and cell biology University of Connecticut Storrs USA Department of biology University of North Florida Jacksonville USA Department of Physics University of North Florida Jacksonville USA

Photo-Electric Microbe Sensor is a patented biotechnology that detects microbes in aqueous solution by measuring the change in photo-voltage in response to UV light stimulation of a platinum (Pt) disk surface on an electrode before and after immunoprecipitation of microbes. This study aimed to increase the sensitivity of microbe detection by pre-adsorbing recombinant Streptococcal Protein G (PG), to the Pt sensor surface. Streptococcal PG binds the Fc region of mammalian IgG molecules and we investigated the association of PG to Pt and the resulting ability to tether antibodies to the Pt-PG surface. An ELISA protocol was optimized to detect the presence of mouse monoclonal antibodies tethered to Pt immunoaffinity disks, and to determine the recommended blocking solution and reagent concentrations. Our results demonstrate that PG binds to bare Pt, increases IgG affinity to the Pt surface following Superblock Buffer application, and together offers design-options for Pt-based sensor technologies.

关键词： Platinum Sensor Surface Microbe Photo-Voltages Immunoaffinity

nitiation of ER Body Formation and Indole Glucosinolate Metabolism by the Plastidia Retrograde Signaling Metabolite, MEcPP

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Molecular Plant 2017年第11期10卷 1400-1416页

作者： Jin-Zheng Wang Baohua Li Yanmei Xiao Yu Ni Haiyan Ke Panyu Yang Amancio de Souza Marta Bjornson Xiang He Zhouxin Shen Gerd Ulrich Balcke Steve P. Briggs Alain Tissier Daniel J. Kliebenstein Katayoon Dehesh Institute for Integrative Genome biology and Department of Botany and Plant Sciences University of California Riverside CA 92521 USA Department of Plant biology University of California Davis CA 95616 USA Department of Plant Sciences University of California Davis CA 95616 USA Division of Biological Sciences University of California San Diego La Jolla CA 92093 USA Department of cell and Metabolic biology Leibniz-lnstitute of Plant Biochemistry Halle Germany Present address: College of Agronomy and Biotechnology Southwest University Chongqing P.R. China Present address: Rice Research Institute Sichuan Agricultural University Changdu Sichuan 611130 China

Plants have evolved tightly regulated signaling networks to respond and adapt to environmental perturbations, but the nature of the signaling hub（s） involved have remained an enigma. We have previously established that methylerythritol cyclodiphosphate （MEcPP）, a precursor of plastidial isoprenoids and a stress- specific retrograde signaling metabolite, enables cellular readjustments for high-order adaptive functions. Here, we specifically show that MEcPP promotes two Brassicaceae-specific traits, namely endoplasmic reticulum （ER） body formation and induction of indole glucosinolate （IGs） metabolism selectively, via tran- scriptional regulation of key regulators NAIl for ER body formation and MYB51/122 for IGs biosynthesis）. The specificity of MEcPP is further confirmed by the lack of induction of wound-inducible ER body genes as well as IGs by other altered methylerythritol phosphate pathway enzymes. Genetic analyses revealed MEcPP-mediated COil-dependent induction of these traits. Moreover, MEcPP signaling integrates the biosynthesis and hydrolysis of IGs through induction of nitrile-specifier protein1 and reduction of the sup- pressor, ESM1, and production of simple nitriles as the bioactive end product. The findings position the plastidial metabolite, MEcPP, as the initiation hub, transducing signals to adjust the activity of hard- wired gene circuitry to expand phytochemical diversity and alter the associated subcellular structure required for functionality of the secondary metabolites, thereby tailoring plant stress responses.

关键词： glucosinolates ER body retrograde signaling MEP pathway MEcPP stress