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New insights into the therapeutic approaches for the treatment of tauopathies

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Neural Regeneration Research 2024年第5期19卷 1020-1026页

作者： Himanshi Singh Asmita Das Mohammad Moshahid Khan Tayebeh Pourmotabbed Department of Microbiology Immunology and BiochemistryUniversity of Tennessee Health Science CenterMemphisTNUSA Department of Biotechnology Delhi Technological UniversityShahbad DaulatpurDelhiIndia Department of Neurology College of MedicineUniversity of Tennessee Health Science CenterMemphisTNUSA Neuroscience Institute University of Tennessee Health Science CenterMemphisTNUSA center for Muscle Metabolism and NeuropathologyDivision of Regenerative and Rehabilitation Sciences and Department of Physical TherapyCollege of Health ProfessionsUniversity of Tennessee Health Science CenterMemphisTNUSA

Tauopathies are a group of neurological disorders,including Alzheimer’s disease and frontotemporal dementia,which involve progressive neurodegeneration,cognitive deficits,and aberrant tau protein *** development of tauopathies cannot currently be stopped or slowed down by treatment *** the significant contribution of tau burden in primary tauopathies and the strong association between pathogenic tau accumulation and cognitive deficits,there has been a lot of interest in creating therapies that can alleviate tau pathology and render neuroprotective ***,small molecules,immunotherapies,and gene therapy have been used to reduce the pathological tau burden and prevent neurodegeneration in animal models of ***,the major pitfall of the current therapeutic approach is the difficulty of drugs and gene-targeting modalities to cross the blood-brain barrier and their unintended side *** this review,the current therapeutic strategies used for tauopathies including the use of oligonucleotide-based gene therapy approaches that have shown a promising result for the treatment of tauopathies and Alzheimer’s disease in preclinical animal models,have been discussed.

关键词： dementia gene therapies immunotherapy neurodegeneration oligonucleotides tau tauopathies therapies

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Structural changes in the conversion of an Arabidopsis outward-rectifying K+channel into an inward-rectifying channel

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Plant Communications 2024年第6期5卷 5-8页

作者： Xudong Gao Xia Xu Tengfei Sun Yuhan Lu Yutian Jia Jiaqi Zhou Peng Fu Yanming Zhang Guanghui Yang State Key Laboratory of Plant Environmental Resilience Frontiers Science Center for Molecular Design BreedingDepartment of Nutrition and HealthCollege of Biological SciencesChina Agricultural UniversityBeijing 100193China

Dear Editor,By using cryo-electron microscopy and electrophysiology,this study characterizes the structural and functional dynamics of the K+outward-rectifying channel SKOR in Arabidopsis and the structural changes associated with a double mutation that transforms SKOR into an inward-rectifying K+channel,*** findings have implications for understanding and manipulating crop K+nutrition.

关键词： channel Arabidopsis changes

Cardiac energy metabolism disorder mediated by energy substrate imbalance and mitochondrial damage upon tebuconazole exposure

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Journal of Environmental sciences 2024年第2期136卷 270-278页

作者： Tingting Ku Jindong Hu Mengmeng Zhou Yuanyuan Xie Yutong Liu Xin Tan Lin Guo Guangke Li Nan Sang College of Environmental science and Resources Research Center of Environment and HealthShanxi UniversityTaiyuan 030006China

Tebuconazole exposure has been described as an increasing hazard to human *** increasing number of recent studies have shown a positive association between tebuconazole exposure and cardiovascular disease risk,which is characterized by the reduction of adenosine triphosphate(ATP)***,researches on the damage of tebuconazole exposure to energy metabolism and the related molecular mechanisms are *** the present study,male C57BL/6 mice were treated with tebuconazole at different low concentrations for 4 *** results indicated that tebuconazole could accumulate in the heart and further induce the decrease of ATP content in the mouse ***,tebuconazole induced an obvious shift in substrate utilization of fatty acid and glucose by disrupting their corresponding transporters(GLUT1,GLUT4,CD36,FABP3 and FATP1)expression,and significantly repressed the expression of mitochondrial biogenesis(Gabpa and Tfam)and oxidative phosphorylation(CS,Ndufa4,Sdhb,Cox5a and Atp5b)related genes in a dosedependent *** investigation revealed that these alterations were related to the IRS1/AKT and PPARγ/RXRα*** findings contribute to a better understanding of triazole fungicide-induced cardiovascular disease by revealing the key indicators associated with this phenomenon.

关键词： Tebuconazole Cardiotoxicity Energy metabolic disorders Energy substrate Mitochondrial damage

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Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosome-lysosomal fusion in hepatocellular carcinoma

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Journal of Pharmaceutical Analysis 2024年第2期14卷 211-224页

作者： Jingjing Wang Qi Su Kun Chen Qing Wu Jiayan Ren Wenjuan Tang Yu Hu Zeren Zhu Cheng Cheng Kaihui Tu Huaizhen He Yanmin Zhang School of Pharmacy Health Science CenterXi'an Jiaotong UniversityXi'an710061China

Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit synaptosomal-associated protein 29 (SNAP29)-vesicle-associated membrane protein 8 (VAMP8) interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.

关键词： Pyrimethamine BNIP3 SNARE Autophagosome-lysosome fusion Hepatocellular carcinoma Sorafenib

Highly efficient expression of human extracellular superoxide dismutase(rhEcSOD)with ultraviolet-B-induced damage-resistance activity in transgenic silkworm cocoons

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Insect science 2024年第4期31卷 1150-1164页

作者： Feng Wang Ri-Yuan Wang De-Bin Zhong Ping Zhao Qing-You Xia Integrative science center of Germplasm Creation in Western China(CHONGQING)science City Biological Science Research CenterSouthwest UniversityChongqingChina Century Legend Biotechnology Research Institute(Chongqing)Co. Ltd.ChongqingChina

Extracellular superoxide dismutase(EcSOD)protects tissues from oxidative stress,and thus is considered as a therapeutic agent for many diseases such as atherosclerosis,hypertension,and ***,cost-effective production of bioactive recombinant human EcSOD(rhEcSOD)remains a ***,we developed an efficient strategy for producing active rhEcSOD by transgenic *** was successfully synthesized as homodimers and homotetramers in the middle silk gland and spun into the cocoons with a concentration of 9.48±0.21 mg/*** of rhEcSOD from the cocoons could be conveniently achieved with a purity of 99.50%and a yield of 3.5±0.5 mg/***,N-glycosylation at the only site of N89 in rhEcSOD with 10 types were *** purified rhEcSOD gained the potent enzymatic activity of 4162±293 U/mg after Cu/Zn ions *** importantly,rhEcSOD was capable of penetrating and accumulating in the nuclei of cells to maintain cell morphology and attenuate ultraviolet B-induced cell apoptosis by eliminating reactive oxygen species and inhibiting the C-Jun N-terminal kinase signaling *** results demonstrated that the transgenic silkworm could successfully produce rhEcSOD with enzymatic and biological activities for biomedical applications.

关键词： antioxidant human extracellular superoxide dismutase recombinant expression silkworm silk gland

JW-1-283 inhibits melanoma tumor growth via stabilization of the p53 pathway

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Genes & Diseases 2024年第3期11卷 18-21页

作者： Yang Xie Ruida Hou Kelli LHartman Jianxiong Jiang Zhongzhi Wu Wei Li Drug Discovery center College of PharmacyUniversity of Tennessee Health Science CenterMemphisTN38163USA

Melanoma is a lethal skin malignancy and the fifth most diagnosed cancer in the United States.1 Currently,for unresectable melanoma,the recommended treatment options include checkpoint inhibitor immunotherapy targeting programmed cell death 1(PD-1),and inhibitors targeting the mitogen-activated protein kinase(MAPK)***,the response rate may vary among the patients,and therefore demanding the development of novel treatment *** suppressor TP53has been suggested as one of the critical regulators mediating the aggressiveness and progression of melanoma.

关键词： melanoma suppressor death

Limited Social Support,but Comparable health Literacy and Service Utilization,Among Elderly People Living Alone—Six PLADs,China,May-September 2020

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China CDC weekly 2024年第39期6卷 1011-1016页

作者： Hao Lin Meijun Chen Yuhui Shi Ying Ji Yuting Lin Wangnan Cao Chun Chang Department of Social Medicine and health Education School of Public HealthPeking University Health Science CenterBeijingChina center for healthy Aging Peking University Health Science CenterBeijingChina School of Public health The University of Hong KongHong Kong Special Administrative RegionChina

What is already known about this topic?The proportion of elderly living alone in China is approximately 10%.Living away from family poses enormous challenges for older *** is added by this report?Compared to those living with family,elderly individuals living alone exhibit a lower registration rate with general practitioners and have less social *** are the implications for public health practice?While the current health service system for elderly people living alone is working relatively well,there is a need for additional programs to enhance social support and improve their social well-being.

关键词： alone elderly service

Mixed plastics waste valorization to high-added value products via thermally induced phase separation and spin-casting

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Green Energy & Environment 2024年第10期9卷 1627-1640页

作者： Junaid Saleem Moghal Zubair Khalid Baig Usman Bin Shahid Rafael Luque Gordon McKay Division of Sustainable Development College of Science and EngineeringHamad Bin Khalifa University center for Advanced Materials Qatar University Department of Chemical and biological Engineering The Hong Kong University of Science and Technology Universidad ECOTEC

Plastic waste is an underutilized resource that has the potential to be transformed into value-added ***,its chemical diversity leads to cost-intensive sorting techniques,limiting recycling and upcycling ***,we report an open-loop recycling method to produce graded feedstock from mixed polyolefins waste,which makes up 60%of total plastic *** method uses heat flow scanning to quantify the composition of plastic waste and resolves its compatibility through controlled *** resulting feedstock is then used to synthesize blended pellets,porous sorbents,and superhydrophobic coatings via thermally induced phase separation and *** hybrid approach broadens the opportunities for reusing plastic waste,which is a step towards creating a more circular economy and better waste management practices.

关键词： Plastic waste Valorization Superhydrophobic coatings Blended pellets Porous materials Sorbents

Genome-wide CRISPR screening reveals key genes and pathways associated with 20-hydroxyecdysone signal transduction in the silkworm(Bombyx mori)

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Insect science 2024年第1期31卷 47-58页

作者： Hao Sun Jingya Chen Ruolin Wang Dan Liu Na Zhang Tong Zhang Ling Jia Sanyuan Ma Qingyou Xia State Key Laboratory of Silkworm Genome Biology Southwest UniversityChongqingChina biological science Research center Southwest UniversityChongqingChina

Metamorphosis is a complex developmental process involving multiple pathways and a large number of genes that are regulated by juvenile hormone(JH)and 20-hydroxyecdysone(20E).Despite important progress in understanding various aspects of silkworm biology,the hormone signaling pathway in the silkworm remains poorly ***-wide screening using clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)-based libraries has recently emerged as a novel method for analyzing genome function,enabling further research into essential genes,drug targets,and virus-host ***,we constructed a genome-wide CRISPR/Cas9-based library of the silkworm(Bombyx mori)and successfully revealed the genes involved in biotic or abiotic stress factor *** this study,we used our silkworm CRISPR library and large-scale genome-wide screening to analyze the key genes in the silkworm 20E signaling pathway and their mechanisms of *** annotation showed that 20E regulates key proteins in processes that mainly occur in the cytoplasm and *** enrichment analysis showed that 20E can activate phosphorylation and may affect innate immunity,interfere with intracellular nutrition and energy metabolism,and eventually cause cell *** screening results were experimentally validated by generating cells with knockout alleles of the relevant genes,which had increased tolerance to *** findings provide a panoramic overview of signaling in response to 20E in the silkworm,underscoring the utility of genome-wide CRISPR mutant libraries in deciphering hormone signaling pathways and the mechanisms that regulate metamorphosis in insects.

关键词： CRISPR/Cas9 CRISPR library screening ecdysone 20E signal transduction silkworm whole genome editing