Publications by authors named "Qi Wu"

1,178 Publications

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and Serve as Potential Diagnostic Biomarkers of Acute Myocardial Infarction Based on Integrated Bioinformatics Analyses.

DNA Cell Biol 2021 Jun 10. Epub 2021 Jun 10.

Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.

This study aimed to explore the potential diagnostic biomarkers and mechanisms underlying acute myocardial infarction (AMI). We downloaded four datasets (GSE19339, GSE48060, GSE66360, and GSE97320) from the Gene Expression Omnibus database and combined them as an integrated dataset. A total of 153 differentially expressed genes (DEGs) were analyzed by the linear models for microarray analysis (LIMMA) package. Weighted gene co-expression network analysis was used to screen for the significant gene modules. The intersection of DEGs and genes in the most significant module was termed "common genes" (CGs). CGs were mainly enriched in "inflammatory response," "neutrophil chemotaxis," and "IL-17 signaling pathway" through functional enrichment analyses. Subsequently, 15 genes were identified as the hub genes in the protein-protein interaction network. The Fc fragment of IgE receptor Ig () and prostaglandin-endoperoxide synthase 2 () showed significantly increased expression in AMI patients and mice at the 12-h time point in our experiments. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of and . The area under ROC curve of and was 77.6% and 80.7%, respectively. Moreover, the micro (mi)RNA-messenger (m)RNA network was also visualized; the results showed that miRNA-143, miRNA-144, and miRNA-26 could target in AMI progression.
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http://dx.doi.org/10.1089/dna.2020.6447DOI Listing
June 2021

Ratiometric sensing of Zn with a new benzothiazole-based fluorescent sensor and living cell imaging.

Analyst 2021 Jun 11. Epub 2021 Jun 11.

School of Chemistry and Chemical Engineering, Shanxi University, Taiyuan 030006, PR China.

A new fluorescent probe, 3-(benzo[d]thiazol-2-yl)-5-bromosalicylaldehyde-4N-phenyl thiosemicarbazone (BTT), for ratiometric sensing of Zn2+ ions in methanol/HEPES buffer solution (3 : 2, pH = 7.4) is reported in this paper. The presence of Zn2+ ions yields a significant blue shift in the maximum emission of BTT from 570 nm to 488 nm, accompanied by a clear color change from orange to green. This emission change of BTT upon binding to Zn2+ in a 1 : 1 ratio may be due to the block of excited state intramolecular proton transfer (ESIPT) as well as chelation enhanced fluorescence (CHEF) on complex formation. The limit of detection (LOD) determined for Zn2+ quantitation was down to 37.7 nM. In addition, the probe BTT displays the ability to image both exogenous Zn2+ ions loaded into HeLa cells and endogenous Zn2+ distribution in living SH-SY5Y neuroblastoma cells.
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http://dx.doi.org/10.1039/d1an00749aDOI Listing
June 2021

Deciphering an AgRP-serotoninergic neural circuit in distinct control of energy metabolism from feeding.

Nat Commun 2021 06 10;12(1):3525. Epub 2021 Jun 10.

USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA.

Contrasting to the established role of the hypothalamic agouti-related protein (AgRP) neurons in feeding regulation, the neural circuit and signaling mechanisms by which they control energy expenditure remains unclear. Here, we report that energy expenditure is regulated by a subgroup of AgRP neurons that send non-collateral projections to neurons within the dorsal lateral part of dorsal raphe nucleus (dlDRN) expressing the melanocortin 4 receptor (MC4R), which in turn innervate nearby serotonergic (5-HT) neurons. Genetic manipulations reveal a bi-directional control of energy expenditure by this circuit without affecting food intake. Fiber photometry and electrophysiological results indicate that the thermo-sensing MC4R neurons integrate pre-synaptic AgRP signaling, thereby modulating the post-synaptic serotonergic pathway. Specifically, the MC4R signaling elicits profound, bi-directional, regulation of body weight mainly through sympathetic outflow that reprograms mitochondrial bioenergetics within brown and beige fat while feeding remains intact. Together, we suggest that this AgRP neural circuit plays a unique role in persistent control of energy expenditure and body weight, hinting next-generation therapeutic approaches for obesity and metabolic disorders.
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http://dx.doi.org/10.1038/s41467-021-23846-xDOI Listing
June 2021

Autophagy induction by IGF1R inhibition with picropodophyllin and linsitinib.

Autophagy 2021 Jun 10:1-2. Epub 2021 Jun 10.

Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, Institut Universitaire de France, Paris, France.

Induction of macroautophagy (hereafter termed autophagy) is a strategy to improve the outcome of antineoplastic therapies by facilitating the induction of immunogenic cancer cell death and the consequent immune recognition of malignant cells. We analyzed 65,000 distinct compounds by means of a phenotypic discovery platform for autophagy induction and identified the IGF1R (insulin like growth factor 1 receptor) inhibitor picropodophyllin (PPP) as a potent inducer of autophagic flux. We found that PPP acts on-target, as an inhibitor of the tyrosine kinase activity of IGF1R and enhances the release of adenosine triphosphate, ATP, from stressed and dying cancer cells in vitro, thereby improving the therapeutic efficacy of chemoimmunotherapy in cancer-bearing mice. This PPP effect was phenocopied by another IGF1R inhibitor, linsitinib. Moreover, in human triple-negative breast cancer, phosphorylation of IGF1R correlates with reduced autophagy, an unfavorable local immune profile and poor prognosis. In summary, IGF1R inhibition may constitute a novel strategy for the treatment of cancer in the context of chemoimmunotherapy.
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http://dx.doi.org/10.1080/15548627.2021.1936934DOI Listing
June 2021

Divergence of a genomic island leads to the evolution of melanization in a halophyte root fungus.

ISME J 2021 Jun 9. Epub 2021 Jun 9.

Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, Beijing Forestry University, Beijing, China.

Understanding how organisms adapt to extreme living conditions is central to evolutionary biology. Dark septate endophytes (DSEs) constitute an important component of the root mycobiome and they are often able to alleviate host abiotic stresses. Here, we investigated the molecular mechanisms underlying the beneficial association between the DSE Laburnicola rhizohalophila and its host, the native halophyte Suaeda salsa, using population genomics. Based on genome-wide Fst (pairwise fixation index) and Vst analyses, which compared the variance in allele frequencies of single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs), respectively, we found a high level of genetic differentiation between two populations. CNV patterns revealed population-specific expansions and contractions. Interestingly, we identified a ~20 kbp genomic island of high divergence with a strong sign of positive selection. This region contains a melanin-biosynthetic polyketide synthase gene cluster linked to six additional genes likely involved in biosynthesis, membrane trafficking, regulation, and localization of melanin. Differences in growth yield and melanin biosynthesis between the two populations grown under 2% NaCl stress suggested that this genomic island contributes to the observed differences in melanin accumulation. Our findings provide a better understanding of the genetic and evolutionary mechanisms underlying the adaptation to saline conditions of the L. rhizohalophila-S. salsa symbiosis.
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http://dx.doi.org/10.1038/s41396-021-01023-8DOI Listing
June 2021

Adaptation and validation of the European cyberbullying intervention project questionnaire with and for Chinese adolescents.

Health Soc Care Community 2021 Jun 5. Epub 2021 Jun 5.

Department of Social Work, School of Sociology and Anthropology, Xiamen University, Xiamen, China.

Cyberbullying is a global and growing phenomenon, which affects the wellbeing of millions of adolescents around the world including Chinese adolescents. However, there is a lack of valid and reliable measures of cyberbullying behaviours in Chinese. To address this research gap, this study aims to adapt and validate a well-known, reliable and validated instrument: the European Cyberbullying Intervention Project Questionnaire (ECIPQ) among Chinese adolescents. A 14-item (seven for cyber aggression and seven for cyber victimisation) of the Chinese version of ECIPQ was developed based on its relevance and appropriateness to the Chinese culture. After its cultural and linguistic adaptation, the measure was norm with a sample of Chinese adolescents. A total sample of 452 adolescents was randomly split into two evenly subsamples for exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). The EFA results indicated that the Chinese version of ECIPQ had a good convergent validity and satisfactory discriminant validity, and a two-factor model was identified. CFA results showed a good fit of the measurement model in assessing cyber aggression and cyber victimisation. This adapted Chinese version of ECIPQ can be used to facilitate future research on cyberbullying screening, and that research may in turn promote proactive screening and better coordination of community responses for victims as well as perpetrators. Future comparative studies may use the validated scale to assess the prevalence of cyberbullying and the results of interventions to reduce cyberbullying among Chinese adolescents.
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http://dx.doi.org/10.1111/hsc.13466DOI Listing
June 2021

Hollow CoP/FeP Heterostructural Nanorods Interwoven by CNT as a Highly Efficient Electrocatalyst for Oxygen Evolution Reactions.

Nanomaterials (Basel) 2021 May 30;11(6). Epub 2021 May 30.

College of Science, Institute of Oxygen Supply, Tibet University, Lhasa 850000, China.

Electrolysis of water to produce hydrogen is crucial for developing sustainable clean energy and protecting the environment. However, because of the multi-electron transfer in the oxygen evolution reaction (OER) process, the kinetics of the reaction is seriously hindered. To address this issue, we designed and synthesized hollow CoP/FeP heterostructural nanorods interwoven by carbon nanotubes (CoP/[email protected]) via a hydrothermal reaction and a phosphorization process. The CoP/[email protected] hybrid catalyst delivers prominent OER electrochemical performances: it displays a substantially smaller Tafel slope of 48.0 mV dec and a lower overpotential of 301 mV at 10 mA cm, compared with an RuO commercial catalyst; it also shows good stability over 20 h. The outstanding OER property is mainly attributed to the synergistic coupling between its unique CNT-interwoven hollow nanorod structure and the CoP/FeP heterojunction, which can not only guarantee high conductivity and rich active sites, but also greatly facilitate the electron transfer, ion diffusion, and O gas release and significantly enhance its electrocatalytic activity. This work offers a facile method to develop transition metal-based phosphide heterostructure electrocatalysts with a unique hierarchical nanostructure for high performance water oxidation.
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http://dx.doi.org/10.3390/nano11061450DOI Listing
May 2021

A hindbrain dopaminergic neural circuit prevents weight gain by reinforcing food satiation.

Sci Adv 2021 May 26;7(22). Epub 2021 May 26.

USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

The neural circuitry mechanism that underlies dopaminergic (DA) control of innate feeding behavior is largely uncharacterized. Here, we identified a subpopulation of DA neurons situated in the caudal ventral tegmental area (cVTA) directly innervating DRD1-expressing neurons within the lateral parabrachial nucleus (LPBN). This neural circuit potently suppresses food intake via enhanced satiation response. Notably, this cohort of DA neurons is activated immediately before the cessation of each feeding bout. Acute inhibition of these DA neurons before bout termination substantially suppresses satiety and prolongs the consummatory feeding. Activation of postsynaptic DRD1 neurons inhibits feeding, whereas genetic deletion of within the LPBN causes robust increase in food intake and subsequent weight gain. Furthermore, the DRD1 signaling manifests the central mechanism in methylphenidate-induced hypophagia. In conclusion, our study illuminates a hindbrain DAergic circuit that controls feeding through dynamic regulation in satiety response and meal structure.
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http://dx.doi.org/10.1126/sciadv.abf8719DOI Listing
May 2021

Barbadin potentiates long-term effects of lorcaserin on POMC neurons and weight loss.

J Neurosci 2021 May 24. Epub 2021 May 24.

Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030

Obesity is a serious global health problem due to its increasing prevalence and comorbidities, but its treatments are limited. The serotonin 2C receptor (5-HTR), a G protein-coupled receptor, activates pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus (ARH) to reduce appetite and weight gain. However, several 5-HT analogs targeting this receptor, e.g. lorcaserin, suffer from diminished efficacy to reduce weight after prolonged administration. Here we show that barbadin, a novel β-arrestin/β2-adaptin inhibitor, can prevent 5-HTR internalization in cells and potentiate long-term effects of lorcaserin to reduce appetite and body weight in male mice. Mechanistically, we demonstrate that barbadin co-treatment can effectively maintain the sensitivity of the 5-HTR in POMC neurons, despite prolonged lorcaserin exposure, thereby allowing these neurons to be activated through opening the transient receptor potential cation channels. Thus, our results prove the concept that inhibition of 5-HTR desensitization can be a valid strategy to improve the long-term weight loss effects of lorcaserin or other 5-HTR agonists, and also provide an intellectual framework to develop effective long-term management of weight by targeting 5-HTR desensitization.By demonstrating that the combination of barbadin with a GPCR agonist can provide prolonged weight-lowering benefits in a preclinical setting, our work should call for additional efforts to validate barbadin as a safe and effective medicine or to use barbadin as a lead compound to develop more suitable compounds for obesity treatment. These results prove the concept that inhibition of 5-HTR desensitization can be a valid strategy to improve the long-term weight loss effects of lorcaserin or other 5-HTR agonists. Since GPCRs represent a major category as therapeutic targets for various human diseases and desensitization of GPCRs is a common issue, our work may provide a conceptual framework to enhance effects of a broad range of GPCR medicines.
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http://dx.doi.org/10.1523/JNEUROSCI.3210-20.2021DOI Listing
May 2021

Hypoxia-induced increase in GABA content is essential for restoration of membrane potential and preventing ROS-induced disturbance to ion homeostasis.

Plant Commun 2021 May 1;2(3):100188. Epub 2021 May 1.

International Research Centre for Environmental Membrane Biology, Foshan University, Foshan 528000, China.

When plants are exposed to hypoxic conditions, the level of γ-aminobutyric acid (GABA) in plant tissues increases by several orders of magnitude. The physiological rationale behind this elevation remains largely unanswered. By combining genetic and electrophysiological approach, in this work we show that hypoxia-induced increase in GABA content is essential for restoration of membrane potential and preventing ROS-induced disturbance to cytosolic K homeostasis and Ca signaling. We show that reduced O availability affects H-ATPase pumping activity, leading to membrane depolarization and K loss via outward-rectifying GORK channels. Hypoxia stress also results in HO accumulation in the cell that activates ROS-inducible Ca uptake channels and triggers self-amplifying "ROS-Ca hub," further exacerbating K loss via non-selective cation channels that results in the loss of the cell's viability. Hypoxia-induced elevation in the GABA level may restore membrane potential by pH-dependent regulation of H-ATPase and/or by generating more energy through the activation of the GABA shunt pathway and TCA cycle. Elevated GABA can also provide better control of the ROS-Ca hub by transcriptional control of RBOH genes thus preventing over-excessive HO accumulation. Finally, GABA can operate as a ligand directly controlling the open probability and conductance of K efflux GORK channels, thus enabling plants adaptation to hypoxic conditions.
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http://dx.doi.org/10.1016/j.xplc.2021.100188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132176PMC
May 2021

Mimosine functionalized gold nanoparticles (Mimo-AuNPs) suppress β-amyloid aggregation and neuronal toxicity.

Bioact Mater 2021 Dec 10;6(12):4491-4505. Epub 2021 May 10.

Departments of Medicine and University of Alberta, Edmonton, Alberta, T6G 2M8, Canada.

Evidence suggests that increased level/aggregation of beta-amyloid (Aβ) peptides initiate neurodegeneration and subsequent development of Alzheimer's disease (AD). At present, there is no effective treatment for AD. In this study, we reported the effects of gold nanoparticles surface-functionalized with a plant-based amino acid mimosine (Mimo-AuNPs), which is found to cross the blood-brain barrier, on the Aβ fibrillization process and toxicity. Thioflavin T kinetic assays, fluorescence imaging and electron microscopy data showed that Mimo-AuNPs were able to suppress the spontaneous and seed-induced Aβ aggregation. Spectroscopic studies, molecular docking and biochemical analyses further revealed that Mimo-AuNPs stabilize Aβ to remain in its monomeric state by interacting with the hydrophobic domain of Aβ (i.e., Lys to Ala) there by preventing a conformational shift towards the β-sheet structure. Additionally, Mimo-AuNPs were found to trigger the disassembly of matured Aβ fibers and increased neuronal viability by reducing phosphorylation of tau protein and the production of oxyradicals. Collectively, these results reveal that the surface-functionalization of gold nanoparticles with mimosine can attenuate Aβ fibrillization and neuronal toxicity. Thus, we propose Mimo-AuNPs may be used as a potential treatment strategy towards AD-related pathologies.
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http://dx.doi.org/10.1016/j.bioactmat.2021.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131740PMC
December 2021

Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions.

Cell 2021 Jun 21;184(12):3178-3191.e18. Epub 2021 May 21.

Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Gasdermin B (GSDMB) belongs to a large family of pore-forming cytolysins that execute inflammatory cell death programs. While genetic studies have linked GSDMB polymorphisms to human disease, its function in the immunological response to pathogens remains poorly understood. Here, we report a dynamic host-pathogen conflict between GSDMB and the IpaH7.8 effector protein secreted by enteroinvasive Shigella flexneri. We show that IpaH7.8 ubiquitinates and targets GSDMB for 26S proteasome destruction. This virulence strategy protects Shigella from the bacteriocidic activity of natural killer cells by suppressing granzyme-A-mediated activation of GSDMB. In contrast to the canonical function of most gasdermin family members, GSDMB does not inhibit Shigella by lysing host cells. Rather, it exhibits direct microbiocidal activity through recognition of phospholipids found on Gram-negative bacterial membranes. These findings place GSDMB as a central executioner of intracellular bacterial killing and reveal a mechanism employed by pathogens to counteract this host defense system.
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http://dx.doi.org/10.1016/j.cell.2021.04.036DOI Listing
June 2021

Influence of Perceptual and Conceptual Information on Fear Generalization: A Behavioral and Event-Related Potential Study.

Cogn Affect Behav Neurosci 2021 May 21. Epub 2021 May 21.

Institute of Brain and Psychological Sciences, Sichuan Normal University, Chengdu, 610066, China.

Learned fear can be generalized through both perceptual and conceptual information. This study investigated how perceptual and conceptual similarities influence this generalization process. Twenty-three healthy volunteers completed a fear-generalization test as brain activity was recorded in the form of event-related potentials (ERPs). Participants were exposed to a de novo fear acquisition paradigm with four categories of conditioned stimuli (CS): two conceptual cues (animals and furniture); and two perceptual cues (blue and purple shapes). Animals (C+) and purple shapes (P+) were paired with the unconditioned stimulus (US), whereas furniture (C-) and blue shapes (P-) never were. The generalized stimuli were thus blue animals (C+P+, determined danger), blue furniture (C-P+, perceptual danger), purple animals (C+P-, conceptual danger), and purple furniture (C-P-, determined safe). We found that perceptual cues elicited larger fear responses and shorter reaction times than did conceptual cues during fear acquisition. This suggests that a perceptually related pathway might evoke greater fear than a conceptually based route. During generalization, participants were more afraid of C+ exemplars than of C- exemplars. Furthermore, C+ trials elicited greater N400 amplitudes. Thus, participants appear able to use conceptually based cues to infer the value of the current stimuli. Additionally, compared with C+ exemplars, we found an enhanced late positive potential effect in response to C- exemplars, which seems to reflect a late inhibitory process and might index safety learning. These findings may offer new insights into the pathological mechanism of anxiety disorders.
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http://dx.doi.org/10.3758/s13415-021-00912-xDOI Listing
May 2021

Sensitivity, specificity, and safety of a novel ESAT6-CFP10 skin test for tuberculosis infection in China: two randomized, self-controlled, parallel-group phase 2b trials.

Clin Infect Dis 2021 May 22. Epub 2021 May 22.

Center for Disease Control and Prevention of Jiangsu Province, Nanjing, Jiangsu Province, PR, China.

Background: Diagnostics to identify tuberculosis infection are limited. We aimed to assess the diagnostic accuracy and safety of the novel ESAT6-CFP10 (EC) skin test for tuberculosis infection in Chinese adults.

Methods: We conducted two randomized, parallel-group clinical trials in healthy participants and tuberculosis patients. All participants were tested with the T-SPOT.TB test, then received EC skin test and tuberculin skin test (TST). The diameter of skin indurations and/or redness at injection sites were measured at different time periods. A Bacillus Calmette Guerin (BCG) model was also established to assess the diagnosis of tuberculosis infection using EC skin test.

Results: In total, 777 healthy participants and 96 tuberculosis patients were allocated to receive the EC skin test at 1.0μg/0.1ml or 0.5μg/0.1ml. The area under the curve was 0.95 (95% CI, 0.91-0.97) from the EC skin test at a dose of 1.0μg/0.1ml at 24-72 hours. Compared to the T-SPOT.TB test, the EC skin test demonstrated similar sensitivity (87.5, 95% CI 77.8-97.2 versus 86.5, 95% CI 79.5-93.4) and specificity (98.9, 95% CI 96.0-99.9 versus 96.1, 95% CI 93.5-97.8). Among BCG vaccinated participants, the EC skin test had high consistency with the T-SPOT.TB test (96.3, 95% CI, 92.0-100.0). No serious adverse events related to the EC skin test were observed.

Conclusions: The EC skin test demonstrated both high specificity and sensitivity at a dose of 1.0μg/0.1ml, comparable to the T-SPOT.TB test. The diagnostic accuracy of the EC skin test was not impacted by BCG vaccination.
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http://dx.doi.org/10.1093/cid/ciab472DOI Listing
May 2021

Pyroptosis: A New Frontier in Kidney Diseases.

Oxid Med Cell Longev 2021 28;2021:6686617. Epub 2021 Apr 28.

Department of Pathophysiology, Xuzhou Medical University, Xuzhou 221009, China.

Pyroptosis is a pattern of programmed cell death that significantly differs from apoptosis and autophagy in terms of cell morphology and function. The process of pyroptosis is characterized predominantly by the formation of gasdermin protein family-mediated membrane perforation, cell collapse, and the release of inflammatory factors, including IL-1 and IL-18. In recent years, with the rise of pyroptosis research, scholars have devoted time to study the mechanism of pyroptosis in kidney-related diseases. Pyroptosis is probably involved in kidney diseases through two pathways: the caspase-1-mediated canonical pathway and the caspase-4/5/11-mediated noncanonical pathway. In addition, some scholars have identified targets for the treatment of kidney-related diseases from the viewpoint of pyroptosis and developed corresponding medicines, which may become a recommendation for prognosis, targeted treatment, and clinical diagnosis of kidney diseases. This paper focuses on the up-to-date advances in the field of pyroptosis, especially on the key pathogenic role of pyroptosis in the development and progression of kidney diseases. It presents a more in-depth understanding of the pathogenesis of kidney diseases and introduces novel therapeutic targets for the prevention and clinical treatment of kidney diseases.
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http://dx.doi.org/10.1155/2021/6686617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102120PMC
April 2021

Syntheses, structure and properties of a new series of organic-inorganic Hg-based halides: adjusting halogens resulted in huge performance mutations.

Dalton Trans 2021 Jun;50(22):7563-7570

Institute of Materials Science, TU Darmstadt, 64287 Darmstadt, Germany.

Three new organic-inorganic hybrid perovskite (OIHP) halides, [N(CH3)4]HgCl0.63Br2.37 (I), [N(CH3)4]HgBrI2 (II) and [N(CH3)4]HgCl0.45I2.55 (III), were synthesized by a hydrothermal reaction. They feature different crystal structures, in which both II and III are isomorphic and contain a one-dimensional chain with organic cation [N(CH3)4]+ interspersed in the space, whereas II has a similar one-dimensional chain but significantly different spatial arrangement due to the enhanced hydrogen bond interaction. The experimental results show that the divergent second-order nonlinear optical (NLO) effect from Br(Cl) to I and the arrangement of anion groups change dramatically from the presence of hydrogen bonds to the absence of hydrogen bonds, leading to a sharply increased NLO response of II and III (18 and 25 times that of I) compared with that of I. Moreover, the phase matching ability disappeared and the band gap decreased significantly. Meanwhile, a high temperature phase transition was observed in II and III, which is rare in common OIHPs. All these results indicate that the regulation of halogen bonds plays a crucial role in the structural and property mutations of OIHP halides.
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http://dx.doi.org/10.1039/d1dt01085aDOI Listing
June 2021

Paeoniflorin ameliorates ischemic injury in rat brain via inhibiting cytochrome c/caspase3/HDAC4 pathway.

Acta Pharmacol Sin 2021 May 11. Epub 2021 May 11.

CAS Key Laboratory of Receptor Research, Department of Neuropharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.

Paeoniflorin (PF), a bioactive monoterpene glucoside, has shown a variety of pharmacological effects such as anti-inflammation and autophagy modulation etc. In this study, we investigated whether and how PF exerted a protective effect against ischemic brain injury in vivo and in vitro. Primary rat cortical neurons underwent oxygen/glucose deprivation/reperfusion (OGD/R) for 90 min. We showed that after OGD/R, a short fragment of histone deacetylase 4 (HDAC4) produced by caspase3-mediated degradation was markedly accumulated in the nucleus and the activity of caspase3 was increased. Treatment with PF (100 nM, 1 μM) significantly improved the viability of cortical neurons after OGD/R. Furthermore, PF treatment could maintain HDAC4 intrinsic subcellular localization and reduce the caspase3 activity without changing the HDAC4 at the transcriptional level. PF treatment significantly reduced OGD/R-caused inhibition of transcriptional factor MEF2 expression and increased the expression of downstream proteins such as GDNF, BDNF, and Bcl-xl, thus exerting a great anti-apoptosis effect as revealed by TUNEL staining. The beneficial effects of PF were almost canceled in HDAC4 (D289E)-transfected PC12 cells after OGD/R. In addition, PF treatment reduced the caspase9 activity, rescued the release of cytochrome c from mitochondria, and maintained the integrity of mitochondria membrane. We conducted in vivo experiments in 90-min-middle cerebral artery occlusion (MCAO) rat model. The rats were administered PF (20, 40 mg/kg, ip, 3 times at the reperfusion, 24 h and 48 h after the surgery). We showed that PF administration dose-dependently reduced infarction area, improved neurological symptoms, and maintained HDAC4 localization in rats after MCAO. These results demonstrate that PF is effective in protecting against ischemic brain injury and inhibit apoptosis through inhibiting the cytochrome c/caspase3/HDAC4 pathway.
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http://dx.doi.org/10.1038/s41401-021-00671-yDOI Listing
May 2021

A neural basis for brain leptin action on reducing type 1 diabetic hyperglycemia.

Nat Commun 2021 05 11;12(1):2662. Epub 2021 May 11.

Brown Foundation of Molecular Medicine for the Prevention of Human Diseases of McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Central leptin action rescues type 1 diabetic (T1D) hyperglycemia; however, the underlying mechanism and the identity of mediating neurons remain elusive. Here, we show that leptin receptor (LepR)-expressing neurons in arcuate (LepR) are selectively activated in T1D. Activation of LepR neurons, Arc GABAergic (GABA) neurons, or arcuate AgRP neurons, is able to reverse the leptin's rescuing effect. Conversely, inhibition of GABA neurons, but not AgRP neurons, produces leptin-mimicking rescuing effects. Further, AgRP neuron function is not required for T1D hyperglycemia or leptin's rescuing effects. Finally, T1D LepR neurons show defective nutrient sensing and signs of cellular energy deprivation, which are both restored by leptin, whereas nutrient deprivation reverses the leptin action. Our results identify aberrant activation of LepR neurons owing to energy deprivation as the neural basis for T1D hyperglycemia and that leptin action is mediated by inhibiting LepR neurons through reversing energy deprivation.
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http://dx.doi.org/10.1038/s41467-021-22940-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113586PMC
May 2021

Peripheral-specific Y1 receptor antagonism increases thermogenesis and protects against diet-induced obesity.

Nat Commun 2021 05 11;12(1):2622. Epub 2021 May 11.

Neuroscience Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW, Australia.

Obesity is caused by an imbalance between food intake and energy expenditure (EE). Here we identify a conserved pathway that links signalling through peripheral Y1 receptors (Y1R) to the control of EE. Selective antagonism of peripheral Y1R, via the non-brain penetrable antagonist BIBO3304, leads to a significant reduction in body weight gain due to enhanced EE thereby reducing fat mass. Specifically thermogenesis in brown adipose tissue (BAT) due to elevated UCP1 is enhanced accompanied by extensive browning of white adipose tissue both in mice and humans. Importantly, selective ablation of Y1R from adipocytes protects against diet-induced obesity. Furthermore, peripheral specific Y1R antagonism also improves glucose homeostasis mainly driven by dynamic changes in Akt activity in BAT. Together, these data suggest that selective peripheral only Y1R antagonism via BIBO3304, or a functional analogue, could be developed as a safer and more effective treatment option to mitigate diet-induced obesity.
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http://dx.doi.org/10.1038/s41467-021-22925-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113522PMC
May 2021

Investigation of differentially expressed gene profile for cisplatin-treated lung cancer patients.

Anticancer Drugs 2021 May 6. Epub 2021 May 6.

Tianjin Medical University Tianjin Medical University General Hospital Department of Respiratory and Critical Care Medicine, Tianjin Chest Hospital, Tianjin, China.

The purpose of the study was to establish a comprehensive differential gene profile for lung cancer patients treated with cisplatin compared with control patients without any chemotherapy drug treatment. The RNA sequencing data and miRNA sequencing data of 108 lung cancer patients treated with cisplatin only and 232 lung cancer patients treated without any chemotherapeutic drugs, were analyzed using differential expression, protein-protein interaction, and immune cell infiltration ratio analysis. Compared with control patients, the cisplatin-treated patients demonstrated 336 differentially expressed genes, which included 48 upregulated genes and 288 downregulated genes. Meanwhile, 12 differentially expressed miRNAs (DEMs), including 7 upregulated miRNAs and 5 downregulated miRNAs showed a differentially expressed pattern. With further instigation, five miRNAs (hsa-miR-548ah, hsa-miR-466, hsa-miR-552, hsa-miR-371a, and hsa-miR-4445) were suggested to be the key targets in the cisplatin-treated patients. At the same time, we also found a significant correlation between the cisplatin treatment and six immune checkpoints including programmed cell death ligand. This study helped us better understand the potential targets and underline molecular mechanisms for cisplatin treatment and provided references to eliminate existing side effects in the future.
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http://dx.doi.org/10.1097/CAD.0000000000001075DOI Listing
May 2021

ROC1 promotes the malignant progression of bladder cancer by regulating p-IκBα/NF-κB signaling.

J Exp Clin Cancer Res 2021 May 7;40(1):158. Epub 2021 May 7.

Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.100 Haining Road, Hongkou District, Shanghai, 200080, China.

Background: Regulator of cullins 1 (ROC1) is an important catalytic subunit of cullin-RING E3 ligase. Nuclear factor-kappa B (NF-κB) signaling is closely related to tumor invasion and metastasis. Earlier, we reported that ROC1 was associated with a poor prognosis in patients with bladder cancer (BCa). However, it is unclear whether ROC1 is involved in the NF-κB signaling associated with malignant BCa progression.

Methods: The expression of ROC1 and p65 in bladder cancer and paracancerous tissues were detected by immunohistochemistry (IHC). Pearson correlation was used to assess correlation between ROC1 and p65 protein expressions. The wound-healing and transwell assays were used to monitor cell invasion and migration. The effect of ROC1 on the expression of key proteins in the NF-κB signaling was determined by immunofluorescence and western blot (WB). Cycloheximide (CHX), MG132 and immunoprecipitation assays were used to evaluate the effect of ROC1 on the ubiquitination of phosphorylated inhibitor of kappa B alpha (p-IκBα). A lung metastasis mouse model was generated to detect the role of ROC1 in tumor metastasis.

Results: We found that ROC1 was up-regulated in BCa tissues and cell lines, and high ROC1 levels were positively correlated with higher tumour grade, lymph node metastasis, distant metastasis and poor prognosis. Linear-regression analysis showed significant a Pearson correlation between ROC1 and nuclear p65 expression in BCa tissue microarray (TMA) samples. Functional studies demonstrated that ROC1 promoted BCa cell invasion and migration. In vitro and in vivo experiments showed that ROC1 activated NF-κB signaling by enhancing the ubiquitination of p-IκBα, which caused p65 nuclear translocation and promoted the transcription of some metastasis-related target genes, such as urokinase-type plasminogen activator receptor (uPAR), intracellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), and matrix metalloproteinase 9 (MMP9), resulting in promoting BCa metastasis.

Conclusion: ROC1 plays an important role in the progression of BCa and serves as a potential diagnostic and therapeutic target for patients with BCa.
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http://dx.doi.org/10.1186/s13046-021-01935-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106150PMC
May 2021

Efficacy and Safety of a Combination of Shenmai Injection plus Chemotherapy for the Treatment of Lung Cancer: A Meta-Analysis.

Evid Based Complement Alternat Med 2021 13;2021:7929165. Epub 2021 Apr 13.

Department of Pathophysiology, Xuzhou Medical University, Xuzhou 221009, China.

Objective: To perform a systematic evaluation of the efficacy and safety of combined treatment of Shenmai injection and chemotherapy for lung cancer.

Methods: A literature search for randomized controlled trials (RCTs) describing the treatment of lung cancer by Shenmai injection and chemotherapy or chemotherapy alone was performed using the PubMed, Cochrane Library, China National Knowledge Infrastructure (CNKI), Value In Paper (VIP), China BioMed, and Wanfang databases. The databases were searched for entries published before September 1, 2019.

Results: Thirty-seven RCTs, comprising a total of 2808 cases, were included in the present meta-analysis. Of these, 1428 cases were treated by Shenmai injection plus chemotherapy, and 1380 cases were treated only by chemotherapy. The results of meta-analysis showed that the combined treatment (Shenmai injection plus chemotherapy) increased the short-term efficacy of treatment (relative risk [RR] = 1.183, 95% confidence interval [CI] = 1.043-1.343, < 0.01) and improved patients' quality of life (RR = 1.514, 95%CI = 1.211-1.891, < 0.01) compared with chemotherapy alone. With regard to the adverse effects, the combined treatment markedly reduced the incidence of white blood cell (WBC) reduction (RR = 0.846, 95%CI = 0.760-0.941, < 0.01), platelet reduction (RR = 0.462, 95% CI = 0.330-0.649, < 0.01), and hemoglobin reduction (RR = 0.462, 95% CI = 0.330-0.649, < 0.01) and alleviated drug-induced liver injury (RR = 0.677, 95%CI = 0.463-0.990, < 0.05). However, it did not offer a significant protective effect (RR = 0.725, 95%CI = 0.358-1.468, < 0.05). The effect of the combined treatment on the occurrence of vomiting was considerable (RR = 0.889, 95%CI = 0.794-0.996, < 0.05), and the combined treatment markedly increased the immunity of patients with lung cancer.

Conclusion: The combined treatment of Shenmai injection plus chemotherapy enhanced the short-term efficacy of chemotherapy, improved the patient quality of life, alleviated the adverse effects of chemotherapeutics, and increased the patient immunity. These results should be confirmed by large-scale, high-quality RCTs.
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http://dx.doi.org/10.1155/2021/7929165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8060114PMC
April 2021

Quinoa sprouts as potential vegetable source: Nutrient composition and functional contents of different quinoa sprout varieties.

Food Chem 2021 Apr 8;357:129752. Epub 2021 Apr 8.

Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengluo road 2025, Shiling town, Longquanyi District, Chengdu 610106, Sichuan Province, People's Republic of China; Sichuan Engineering & Technology Research Center of Coarse Cereal Industralization, School of Food and Biological Engineering, Chengdu University, Chengdu 610106, Sichuan Province, People's Republic of China. Electronic address:

Quinoa has a long history of cultivation and unique nutritional value. Quinoa sprouts can be eaten as leafy vegetables, but their nutritional quality is unknown. Ten quinoa sprout varieties (lines) were evaluated and compared for nutrient and functional composition. All quinoa sprout varieties had high contents of moisture content, reducing sugar, potassium, magnesium, and vitamin C. All varieties contained all essential amino acids, with leucine present in abundance. They had high contents of phenolics, flavonoids, carotenoids (β-carotene and lycopene) as well as chlorophylls a and b. Overall, var. LL-01 had better nutrient and phytochemical composition than other varieties. The potential nutritionalhealth benefits of quinoa sprouts as a vegetable are important for both traditional and contemporary diets.
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http://dx.doi.org/10.1016/j.foodchem.2021.129752DOI Listing
April 2021

Molecular Classification Based on Prognostic and Cell Cycle-Associated Genes in Patients With Colon Cancer.

Front Oncol 2021 7;11:636591. Epub 2021 Apr 7.

Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.

The molecular classification of patients with colon cancer is inconclusive. The gene set enrichment analysis (GSEA) of dysregulated genes among normal and tumor tissues indicated that the cell cycle played a crucial role in colon cancer. We performed univariate Cox regression analysis to find out the prognostic-related genes, and these genes were then intersected with cell cycle-associated genes and were further recognized as prognostic and cell cycle-associated genes. Unsupervised non-negative matrix factorization (NMF) clustering was performed based on cell cycle-associated genes. Two subgroups were identified with different overall survival, clinical features, cell cycle enrichment profile, and mutation profile. Through nearest template prediction (NTP), the molecular classification could be effectively repeated in the original data set and validated in several independent data sets indicating that the classification is highly repeatable. Furthermore, we constructed two prognostic signatures in two subgroups, respectively. Our molecular classification based on cell cycle may provide novel insight into the treatment and the prognosis of colon cancer.
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http://dx.doi.org/10.3389/fonc.2021.636591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059408PMC
April 2021

Endoscopic resection with adjuvant treatment versus esophagectomy for early-stage esophageal cancer.

Surg Endosc 2021 Apr 23. Epub 2021 Apr 23.

Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai, China.

Objective: To evaluate the outcome following the strategy of endoscopic R0 resection (ER) plus adjuvant treatment (AT) versus esophagectomy for esophageal squamous cell cancer in T1a invading muscularis mucosa (M3)-T1b stage.

Methods: We evaluated the outcomes of 46 esophageal squamous cell cancer (ESCC) patients with T1aM3-T1b stage who underwent ER + AT from the Esophageal Cancer Endoscopic Therapy Consortium (ECETC) and compared these outcomes to 92 patients who underwent esophagectomy. Propensity score matching (1:2) was used, with overall survival (OS) and relapse-free survival (RFS) being compared between the two groups.

Results: During a median follow-up of 32 months, there were no statistical differences (P = 0.226) in OS between the two groups. The 1-, 2-, and 3-year overall survival in the esophagectomy group was 95%, 91%, and 84%, respectively. There were no mortalities within three years in the ER + AT group. The RFS between the two groups was also not significantly different (P = 0.938). The 1-, 2-, and 3-year RFS of patients in the esophagectomy group was 90%, 90%, and 83%, respectively, while it was 97%, 94%, and 74% in the ER + AT group, respectively. The local recurrence rates between the two groups were not significantly different (P = 0.277).

Conclusions: This first multicenter analysis showed similar outcomes were found regarding OS and RFS between the two groups in T1aM3-T1b stage patients. ER + AT may be considered in high-risk patients or for those who refuse esophagectomy.
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http://dx.doi.org/10.1007/s00464-021-08466-2DOI Listing
April 2021

Surgery may not benefit patients with locally advanced rectal cancer who achieved clinical complete response following neoadjuvant chemoradiotherapy.

Asian J Surg 2021 Apr 19. Epub 2021 Apr 19.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, China; Peking University International Cancer Institute, China; Department of General Surgery, Peking University Shougang Hospital, Beijing, China; Peking-Tsinghua Center for Life Science, China. Electronic address:

Purpose: We compared the long-term outcome of the watch and wait (WW) strategy and surgery in patients with locally advanced rectal cancer.

Patients And Methods: This prospective cohort study included 84 patients who achieved clinical complete response (cCR) after neoadjuvant chemoradiotherapy (NCRT). They were divided into the WW group (n = 58) and surgery group (SG, n = 26). Patients in the SG underwent total mesorectal excision. The study site was the Peking University Cancer Hospital.

Results: Eighty-four patients were included (58 and 26 in the WW group and SG, respectively). A total of 76·9% of the patients in the SG achieved pathological complete response (pCR) and 23·1% of the patients had a residual tumor. The total recurrence and metastasis rate was 15·4% (4/26) in the SG and 18·9% (11/58) in the WW group. There was no significant difference in the recurrence and metastasis rate between the two groups. In the WW group, 9 cases developed tumor regrowth during follow-up and underwent salvage surgery. The overall survival rate of the WW group (96·6% vs 92·3%) was not significantly different from that of the SG (P > 0·05). The WW patients also retained their anal sphincter function and avoided surgery-related complications.

Conclusion: The WW strategy is a feasible treatment option in patients with cCR after NCRT. Surgery may not bring benefits to these cCR patients.
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http://dx.doi.org/10.1016/j.asjsur.2021.03.025DOI Listing
April 2021

Acentric Organic-Inorganic Hybrid Halide [N(CH)]HgBrI Featuring an Isolated [HgBrI] Tetrahedron and Second-Order Nonlinearity.

Inorg Chem 2021 May 22;60(9):6829-6835. Epub 2021 Apr 22.

State Key Laboratory of Crystal Materials and Institute of Crystal Materials, Shandong University, Jinan 250100, P. R. China.

A new hybrid compound [N(CH)]HgBrI, obtained by a hydrothermal reaction, crystallized in the noncentrosymmetric space group 222. Its structure contains an isolated asymmetric [HgBrI] tetrahedron with net polarization, connected by hydrogen bonds to form pseudo-one-dimensional chain structures. Moreover, its optical band gap, nonlinear optical (NLO) property, fluorescence property, and thermal property were characterized in detail. A rare high-temperature phase transition was observed in the compound. In addition, theoretical calculations were performed to elaborate the relation between electronic state, band structure, and their nonlinear optical response. These results indicate that [N(CH)]HgBrI is a new potential candidate for future photoelectronic applications in fluorescence and nonlinear optics.
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http://dx.doi.org/10.1021/acs.inorgchem.1c00756DOI Listing
May 2021

AKT as a therapeutic target for autophagy induction and cancer therapy.

Oncoscience 2021 19;8:34-36. Epub 2021 Mar 19.

Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France.

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http://dx.doi.org/10.18632/oncoscience.526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045973PMC
March 2021

Identification of the specific long-noncoding RNAs involved in night-break mediated flowering retardation in Chenopodium quinoa.

BMC Genomics 2021 Apr 19;22(1):284. Epub 2021 Apr 19.

Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Sichuan Engineering & Technology Research Center of Coarse Cereal Industralization, School of Food and Biological Engineering, Chengdu University, Chengluo road 2025, Shiling town, Longquanyi District, Chengdu, 610106, Sichuan Province, P.R. China.

Background: Night-break (NB) has been proven to repress flowering of short-day plants (SDPs). Long-noncoding RNAs (lncRNAs) play key roles in plant flowering. However, investigation of the relationship between lncRNAs and NB responses is still limited, especially in Chenopodium quinoa, an important short-day coarse cereal.

Results: In this study, we performed strand-specific RNA-seq of leaf samples collected from quinoa seedlings treated by SD and NB. A total of 4914 high-confidence lncRNAs were identified, out of which 91 lncRNAs showed specific responses to SD and NB. Based on the expression profiles, we identified 17 positive- and 7 negative-flowering lncRNAs. Co-expression network analysis indicated that 1653 mRNAs were the common targets of both types of flowering lncRNAs. By mapping these targets to the known flowering pathways in model plants, we found some pivotal flowering homologs, including 2 florigen encoding genes (FT (FLOWERING LOCUS T) and TSF (TWIN SISTER of FT) homologs), 3 circadian clock related genes (EARLY FLOWERING 3 (ELF3), LATE ELONGATED HYPOCOTYL (LHY) and ELONGATED HYPOCOTYL 5 (HY5) homologs), 2 photoreceptor genes (PHYTOCHROME A (PHYA) and CRYPTOCHROME1 (CRY1) homologs), 1 B-BOX type CONSTANS (CO) homolog and 1 RELATED TO ABI3/VP1 (RAV1) homolog, were specifically affected by NB and competed by the positive and negative-flowering lncRNAs. We speculated that these potential flowering lncRNAs may mediate quinoa NB responses by modifying the expression of the floral homologous genes.

Conclusions: Together, the findings in this study will deepen our understanding of the roles of lncRNAs in NB responses, and provide valuable information for functional characterization in future.
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http://dx.doi.org/10.1186/s12864-021-07605-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056640PMC
April 2021

Inhibition of dual leucine zipper kinase prevents chemotherapy-induced peripheral neuropathy and cognitive impairments.

Pain 2021 Apr 15. Epub 2021 Apr 15.

The Neurodegeneration Consortium, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, United States Laboratories of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, United States Cancer Neuroscience Lab, School of Nursing, Department of Diagnostic Medicine, LIVESTRONG Cancer Institutes, University of Texas at Austin, Austin, TX, United States Institute for Applied Cancer Science, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, United States Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

Abstract: Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairments (CICI) are common, often severe neurotoxic side effects of cancer treatment that greatly reduce quality of life of cancer patients and survivors. Currently, there are no Food and Drug Administration-approved agents for the prevention or curative treatment of CIPN or CICI. The dual leucine zipper kinase (DLK) is a key mediator of axonal degeneration that is localized to axons and coordinates the neuronal response to injury. We developed a novel brain-penetrant DLK inhibitor, IACS'8287, which demonstrates potent and highly selective inhibition of DLK in vitro and in vivo. Coadministration of IACS'8287 with the platinum derivative cisplatin prevents mechanical allodynia, loss of intraepidermal nerve fibers in the hind paws, cognitive deficits, and impairments in brain connectivity in mice, all without interfering with the antitumor activity of cisplatin. The protective effects of IACS'8287 are associated with preservation of mitochondrial function in dorsal root ganglion neurons and in brain synaptosomes. In addition, RNA sequencing analysis of dorsal root ganglia reveals modulation of genes involved in neuronal activity and markers for immune cell infiltration by DLK inhibition. These data indicate that CIPN and CICI require DLK signaling in mice, and DLK inhibitors could become an attractive treatment in the clinic when coadministered with cisplatin, and potentially other chemotherapeutic agents, to prevent neurotoxicities as a result of cancer treatment.
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http://dx.doi.org/10.1097/j.pain.0000000000002256DOI Listing
April 2021