Induced Stem Cells as a Novel Multiple Sclerosis Therapy.

Stem cell replacement is providing hope for many degenerative diseases that lack effective therapeutic methods including multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. Transplantation of neural stem cells or mesenchymal stem cells is a potential therapy for MS thanks to their capacity for cell repopulation as well as for their immunomodulatory and neurotrophic properties. Induced pluripotent stem cell (iPSC), an emerging cell source in regenerative medicine, is also being tested for the treatment of MS. Remarkable improvement in mobility and robust remyelination have been observed after transplantation of iPSC-derived neural cells into demyelinated models. Direct reprogramming of somatic cells into induced neural cells, such as induced neural stem cells (iNSCs) and induced oligodendrocyte progenitor cells (iOPCs), without passing through the pluripotency stage, is an alternative for transplantation that has been proved effective in the congenital hypomyelination model. iPSC technology is rapidly progressing as efforts are being made to increase the efficiency of iPSC therapy and reduce its potential side effects. In this review, we discuss the recent advances in application of stem cells, with particular focus on induced stem/progenitor cells (iPSCs, iNSC, iOPCs), which are promising in the treatment of MS

Facile Synthesis of Highly Dispersed WO 3

The highly dispersed WO3·H2O nanoplates have been synthesized by a facile hydrothermal reaction assisted by citrate acid. WO3 nanoplates have been prepared by the calcination of as-prepared WO3·H2O at 450°C. XRD data show that WO3·H2O and WO3 have good crystal structure and high purity. SEM images show that WO3·H2O and WO3 have the uniform nanoplates morphology with the edge length of about 100–150 nm. The selective absorbance of citrate acid with many OH groups onto [010] facet of tungsten oxide precursors can result in the controlled growth of WO3·H2O, thus leading to the good dispersion and small size of WO3·H2O nanoplates. The electrocatalytic activity of WO3·H2O and WO3 for hydrogen evolution reaction (HER) has been investigated in detail. The good electrocatalytic activity for HER has been obtained, which may be attributed to the good dispersion and small size of nanoplates. And the growth mechanisms of WO3·H2O and WO3 nanoplates have been discussed

PI3K/Akt pathway: a potential therapeutic target for chronic pain

Chronic pain is among the most disabling and costly disorders, with prevalence ranging from 10% to 55%. However, current therapeutic strategies for chronic pain are unsatisfactory due to our poor understanding of its mechanisms. Thus, novel therapeutic targets need to be found in order to improve these patients' quality of life. PI3K and its downstream Akt are widely expressed in the spinal cord, particularly in the laminae I-IV of the dorsal horn, where nociceptive C and Aδ fibers of primary afferents principally terminate. Recent studies have demonstrated their critical roles in the development and maintenance of chronic pain. In this review, we summarized the roles and mechanisms of PI3K/Akt pathway in the progression of chronic pain through sciatic nerve injury, diabetic neuropathy, spinal cord injury, bone cancer, opioid tolerance, or opioid-induced hyperalgesia

Lysine-5 Acetylation Negatively Regulates Lactate Dehydrogenase A and Is Decreased in Pancreatic Cancer

SummaryTumor cells commonly have increased glucose uptake and lactate accumulation. Lactate is produced from pyruvate by lactate dehydrogenase A (LDH-A), which is frequently overexpressed in tumor cells and is important for cell growth. Elevated transcription by c-Myc or HIF1α may contribute to increased LDH-A in some cancer types. Here, we show that LDH-A is acetylated at lysine 5 (K5) and that this acetylation inhibits LDH-A activity. Furthermore, the K5-acetylated LDH-A is recognized by the HSC70 chaperone and delivered to lysosomes for degradation. Replacement of endogenous LDH-A with an acetylation mimetic mutant decreases cell proliferation and migration. Importantly, K5 acetylation of LDH-A is reduced in human pancreatic cancers. Our study reveals a mechanism of LDH-A upregulation in pancreatic cancers

Anti-cancer treatment within two weeks serves as a risk factor for clinical outcomes among cancer patients with COVID-19

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has resulted in infections among patients with cancer. Our study aimed to investigate the potential adverse impact of anti-cancer treatments within 2 weeks of COVID-19 infection on clinical outcomes in patients with cancer.MethodsThis retrospective cohort study analyzed 70 cancer patients with COVID-19 infection from the First Hospital of Jilin University in Changchun City, Jilin Province, between March and June 2022. Data on demographic characteristics, vaccination status, COVID-19 clinical classification, symptoms, complications, tumor-related characteristics, laboratory examinations and medical interventions were extracted from electronic medical record. The primary outcome of our study was Intensive Care Unit (ICU) admission. Logistic regression model was performed to investigate the association between anti-cancer treatments within 2 weeks after COVID-19 infection and the risk of ICU admission.ResultsOf the 70 patients enrolled in this study, 37 received anti-cancer treatments within 2 weeks after COVID-19 infection. Patients receiving anti-cancer treatment were more likely to experience non-mild COVID-19, require oxygen therapy, develop acute respiratory distress syndrome (ARDS) and exhibit elevated inflammatory levels. The risk of ICU admission (P<0.001) and 30-day mortality after reverse transcriptase polymerase chain reaction (RT-PCR) negative conversion (P=0.007) was significantly higher in patients receiving anti-cancer treatments. In multivariate Logistic regression analysis, non-mild classification of COVID-19, anti-cancer treatments within 2 weeks and ECOG > 1were all independently associated with ICU admission after adjusting for confounder factors. The risk of ICU admission rose to 43.63 times (95% confidence interval=1.31–1452.94, P=0.035) in patients receiving anti-cancer treatments within 2 weeks.ConclusionAnti-cancer treatments within 2 weeks of COVID-19 infection increase the risk of ICU admission and 30-day mortality after RT-PCR negative conversion in patients with cancer. It may be recommended to postpone cancer-related treatments for more than 2 weeks in cancer patients with COVID-19 infection

The N-terminal Phosphodegron Targets TAZ/WWTR1 Protein for SCF β-TrCP -dependent Degradation in Response to Phosphatidylinositol 3-Kinase Inhibition

The Hippo tumor suppressor pathway plays a major role in development and organ size control, and its dysregulation contributes to tumorigenesis. TAZ (transcriptional co-activator with PDZ-binding motif; also known as WWTR1) is a transcription co-activator acting downstream of the Hippo pathway, and increased TAZ protein levels have been associated with human cancers, such as breast cancer. Previous studies have shown that TAZ is inhibited by large tumor suppressor (LATS)-dependent phosphorylation, leading to cytoplasmic retention and ubiquitin-dependent degradation. The LATS kinase, a core component of the Hippo pathway, phosphorylates the C-terminal phosphodegron in TAZ to promote its degradation. In this study, we have found that the N-terminal phosphodegron of TAZ also plays a role in TAZ protein level regulation, particularly in response to different status of cellular PI3K signaling. GSK3, which can be inhibited by high PI3K via AKT-dependent inhibitory phosphorylation, phosphorylates the N-terminal phosphodegron in TAZ, and the phosphorylated TAZ binds to β-TrCP subunit of the SCFβ-TrCP E3 ubiquitin ligase, thereby leading to TAZ ubiquitylation and degradation. We observed that the TAZ protein level is elevated in tumor cells with high PI3K signaling, such as in PTEN mutant cancer cells. This study provides a novel mechanism of TAZ regulation and suggests a role of TAZ in modulating tissue growth and tumor development in response to PI3K signaling

Glyceraldehyde-3-phosphate Dehydrogenase Is Activated by Lysine 254 Acetylation in Response to Glucose Signal

The altered metabolism in most tumor cells consists of elevated glucose uptake and increased glycolysis even in the presence of high oxygen tension. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an obligatory enzyme in glycolysis. Here, we report that acetylation at lysine 254 (K254) increases GAPDH activity in response to glucose. Furthermore, acetylation of GAPDH (K254) is reversibly regulated by the acetyltransferase PCAF and the deacetylase HDAC5. Substitution of K254 to glutamine compromises the ability of GAPDH to support cell proliferation and tumor growth. Our study reveals a mechanism of GAPDH enzyme activity regulation by acetylation and its critical role in cellular regulation

A Non-Canonical Function of Gβ as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation

G protein-coupled receptors (GPCRs) comprise the largest family of cell-surface receptors, regulate a wide range of physiological processes, and are the major targets of pharmaceutical drugs. Canonical signaling from GPCRs is relayed to intracellular effector proteins by trimeric G proteins, composed of α, β, and γ subunits (Gαβγ). Here, we report that G-protein β subunits (Gβ) bind to DDB1 and that Gβ2 targets GRK2 for ubiquitylation by the DDB1-CUL4A-ROC1 ubiquitin ligase. Activation of GPCR results in PKA-mediated phosphorylation of DDB1 at Ser645 and its dissociation from Gβ2, leading to increase of GRK2 protein. Deletion of Cul4a results in cardiac hypertrophy in male mice that can be partially rescued by the deletion of one Grk2 allele. These results reveal a non-canonical function of the Gβ protein as a ubiquitin ligase component and a mechanism of feedback regulation of GPCR signaling

Theoretical Study on Electrical Properties of Molecular Junctions of Viologen Derivatives

本文基于密度泛函(DFT)结合非平衡格林函数(NEGF)的方法,以具有氧化还原中心的紫罗碱衍生物(N,N′-bis(4-thioalkyl)-4,4′-bipyridinium, HS-4V4-SH)功能分子构造Au(111)/S-4V4-S/Au(111)分子结,详细分析了分子在三种价态V、V+和V2+下的电学性质与分子的几何结构和电子结构的关系。基于对三种价态透射系数分析结果表明,在零偏压下,V与V+的电导值比V2+高了两个数量级,4V4分子结的电导随两个吡啶环之间夹角的增大呈线性减小。同时,理论计算结果也表明,增加烷基链(HS-nVn-SH, n = 2 ~ 7)的数目,发现分子结电导值呈指数形式衰减,其每个亚甲基的衰减因子约为1,与烷基二硫醇分子的接近。In this paper, the electrical properties of molecular junctions formed N,N′-bis(4-thioalkyl)-4,4′-bipyridinium (viologen) moiety between two gold (Au) electrodes have been investigated by combining density functional theory and non-equilibrium Green’s functional approach. To modulate the viologen molecule to be a cation with one and two positive charges (V+ and V2+), we introduce one and two trifluoroacetic acid ions (TFA-) around the molecule, respectively. The valence states of V+ and V2+ are confirmed by checking Mulliken and NBO charges. Then the relationship between molecular conductance and electronic structures of the neutral state V, the radical state V+ and dication V2+ are analyzed in detail. The results in analyzing transmission spectra of the three states reveal that the conductance values of V and V+ are two orders of magnitude larger than that of V2+. This suggests that the redox states of viologen molecules can be used to realize the function of molecular switches. Our calculated results also show that increasing the torsion angle between two pyridine rings of the S-4V4-S molecule will decrease the conductance. By comparing different ions of TFA、PF6 and BF4, the calculated results show that the molecular junction conductance decreases about 3 times when the torsion angle increases by about 6°. It indicates that increasing the torsion angle of the dication V2+ can improve significantly switching ratio of viologen derivatives molecules. At the same time, the calculated results show that increasing the number of methylene groups in alky chains (HS-nVn-SH, n = 2 ~ 7), the conductance values of molecular junctions decrease exponentially, and the attenuation factor of each methylene is about 1 close to alkanedithiol molecules in literatures experimentally and theoretically. This also shows that as the alkyl chain length increases, the DFT-NEGF theoretical method can better predict the zero-bias conductance of the viologen derivative molecule.国家自然科学基金项目(21533006);国家自然科学基金项目(21621091);国家自然科学基金项目(21773197);福建省创新人才通讯作者:吴德印E-mail:[email protected]:De-YinWuE-mail:[email protected]厦门大学化学化工学院化学系,固体表面物理化学国家重点实验室,福建 厦门 361005Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, Fujian, Chin

Acetylation Targets the M2 Isoform of Pyruvate Kinase for Degradation through Chaperone-Mediated Autophagy and Promotes Tumor Growth

Most tumor cells take up more glucose than normal cells but metabolize glucose via glycolysis even in the presence of normal levels of oxygen, a phenomenon known as the Warburg effect. Tumor cells commonly express the embryonic M2 isoform of pyruvate kinase (PKM2) that may contribute to the metabolism shift from oxidative phosphorylation to aerobic glycolysis and tumorigenesis. Here we show that PKM2 is acetylated on lysine 305 and that this acetylation is stimulated by high glucose concentration. PKM2 K305 acetylation decreases PKM2 enzyme activity and promotes its lysosomal-dependent degradation via chaperone-mediated autophagy (CMA). Acetylation increases PKM2 interaction with HSC70, a chaperone for CMA, and association with lysosomes. Ectopic expression of an acetylation mimetic K305Q mutant accumulates glycolytic intermediates and promotes cell proliferation and tumor growth. These results reveal an acetylation regulation of pyruvate kinase and the link between lysine acetylation and CMA