Publications by authors named "Siwei Chen"

71 Publications

Behavior and mechanism of the adsorption of lead by an eco-friendly porous double-network hydrogel derived from keratin.

Chemosphere 2021 Nov 27:133086. Epub 2021 Nov 27.

School of Medical Instrument and Food Engineering, Shanghai Engineering Research Center for Food Rapid Detection, University of Shanghai for Science and Technology, P.O. Box 454, No. 516, Jungong Road, Shanghai, 200093, PR China. Electronic address:

In this study, a novel eco-friendly porous double-network keratin/polyacrylic acid (keratin-PAA) hydrogel was prepared using the one-pot method to improve the adsorption performance of the hydrogel toward Pb(II). The obtained porous keratin-PAA hydrogel was then characterized using nitrogen adsorption-desorption isotherms, thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). The interaction mechanism of Pb(II) and the keratin-PAA hydrogel was further investigated using X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). The results showed that keratin-PAA hydrogel was successfully synthesized, with a specific surface area of 49.35 m/g and a uniform pore distribution of 6.20 nm. The synthesized keratin-PAA hydrogel only took 6 min to adsorb nearly 70% of Pb(II) from the solution because of the interconnected porous network. The keratin-PAA hydrogel also showed a maximal adsorption amount of 234.6 mg/g, and satisfactory selectivity toward Pb(II). The adsorption kinetics of the keratin-PAA hydrogel binding to Pb(II) could be better described by the pseudo-second-order model, whereas the adsorption isotherms could be fitted using the Langmuir equation; this suggested that chemisorption was the main rate-limiting step. The XPS and FT-IR analysis results indicated that the sulfur-, nitrogen- and oxygen-containing groups in the keratin-PAA hydrogel were the main binding sites for Pb(II). In real aqueous samples, the keratin-PAA hydrogel could remove 93-104% of Pb(II). It is clear that the keratin-PAA hydrogel is an outstanding adsorbent material for the removal of Pb(II) from aqueous samples.
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http://dx.doi.org/10.1016/j.chemosphere.2021.133086DOI Listing
November 2021

Transcriptome Profiling of Dysregulated GPCRs Reveals Overlapping Patterns across Psychiatric Disorders and Age-Disease Interactions.

Cells 2021 Oct 31;10(11). Epub 2021 Oct 31.

Department of Pharmaceutical Sciences, School of Pharmacy, University of California Irvine, Irvine, CA 92697, USA.

G-protein-coupled receptors (GPCRs) play an integral role in the neurobiology of psychiatric disorders. Almost all neurotransmitters involved in psychiatric disorders act through GPCRs, and GPCRs are the most common targets of therapeutic drugs currently used in the treatment of psychiatric disorders. However, the roles of GPCRs in the etiology and pathophysiology of psychiatric disorders are not fully understood. Using publically available datasets, we performed a comprehensive analysis of the transcriptomic signatures of G-protein-linked signaling across the major psychiatric disorders: autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BP), and major depressive disorder (MDD). We also used the BrainSpan transcriptomic dataset of the developing human brain to examine whether GPCRs that exhibit chronological age-associated expressions have a higher tendency to be dysregulated in psychiatric disorders than age-independent GPCRs. We found that most GPCR genes were differentially expressed in the four disorders and that the GPCR superfamily as a gene cluster was overrepresented in the four disorders. We also identified a greater amplitude of gene expression changes in GPCRs than other gene families in the four psychiatric disorders. Further, dysregulated GPCRs overlapped across the four psychiatric disorders, with SCZ exhibiting the highest overlap with the three other disorders. Finally, the results revealed a greater tendency of age-associated GPCRs to be dysregulated in ASD than random GPCRs. Our results substantiate the central role of GPCR signaling pathways in the etiology and pathophysiology of psychiatric disorders. Furthermore, our study suggests that common GPCRs' signaling may mediate distinct phenotypic presentations across psychiatric disorders. Consequently, targeting these GPCRs could serve as a common therapeutic strategy to treat specific clinical symptoms across psychiatric disorders.
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http://dx.doi.org/10.3390/cells10112967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616384PMC
October 2021

Modulating CRISPR/Cas9 genome-editing activity by small molecules.

Drug Discov Today 2021 Nov 22. Epub 2021 Nov 22.

Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen 9713 AV, the Netherlands. Electronic address:

Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genome engineering has become a standard procedure for creating genetic and epigenetic changes of DNA molecules in basic biology, biotechnology, and medicine. However, its versatile applications have been hampered by its overall low precise gene modification efficiency and uncontrollable prolonged Cas9 activity. Therefore, overcoming these problems could broaden the therapeutic use of CRISPR/Cas9-based technologies. Here, we review small molecules with the clinical potential to precisely modulate CRISPR/Cas9-mediated genome-editing activity and discuss their mechanisms of action. Based on these data, we suggest that direct-acting small molecules for Cas9 are more suitable for precisely regulating Cas9 activity. These findings provide useful information for the identification of novel small-molecule enhancers and inhibitors of Cas9 and Cas9-associated endonucleases.
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http://dx.doi.org/10.1016/j.drudis.2021.11.018DOI Listing
November 2021

HDAC/MIF dual inhibitor inhibits NSCLC cell survival and proliferation by blocking the AKT pathway.

Bioorg Chem 2021 Dec 4;117:105396. Epub 2021 Oct 4.

Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, the Netherlands. Electronic address:

Non-small-cell lung carcinoma (NSCLC) is one of the most common forms of lung cancer, and a leading cause of cancer death among human beings. There is an urgent demand for novel therapeutics for the treatment of NSCLC to enhance the efficacy of the currently applied Tyrosine kinase inhibitors (TKIs) therapy and to overcome therapy-resistance. Here, we report a novel small-molecule inhibitor that simultaneously targets histone deacetylase (HDAC) and macrophage migration inhibitory factor (MIF). The HDAC/MIF dual inhibitor proved to be toxic for EGFR mutated (H1650, TKI-resistant) or knock out (A549 EGFR) NSCLC cell lines. Further experiments showed that HDAC inhibition inhibits cell survival and proliferation, while MIF inhibition downregulates pAKT or AKT expression level, which both interfere with cell survival. Furthermore, the combination treatment of TKI and HDAC/MIF dual inhibitor showed that the dual inhibitor enhanced TKI inhibitory efficacy, highlighting the advantages of HDAC/MIF dual inhibitor for more effective treatment of NSCLC.
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http://dx.doi.org/10.1016/j.bioorg.2021.105396DOI Listing
December 2021

Dynamic Changes of Brain Cilia Transcriptomes across the Human Lifespan.

Int J Mol Sci 2021 Sep 27;22(19). Epub 2021 Sep 27.

Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California-Irvine, Irvine, CA 92617, USA.

Almost all brain cells contain primary cilia, antennae-like microtubule sensory organelles, on their surface, which play critical roles in brain functions. During neurodevelopmental stages, cilia are essential for brain formation and maturation. In the adult brain, cilia play vital roles as signaling hubs that receive and transduce various signals and regulate cell-to-cell communications. These distinct roles suggest that cilia functions, and probably structures, change throughout the human lifespan. To further understand the age-dependent changes in cilia roles, we identified and analyzed age-dependent patterns of expression of cilia's structural and functional components across the human lifespan. We acquired cilia transcriptomic data for 16 brain regions from the BrainSpan Atlas and analyzed the age-dependent expression patterns using a linear regression model by calculating the regression coefficient. We found that 67% of cilia transcripts were differentially expressed genes with age (DEGAs) in at least one brain region. The age-dependent expression was region-specific, with the highest and lowest numbers of DEGAs expressed in the ventrolateral prefrontal cortex and hippocampus, respectively. The majority of cilia DEGAs displayed upregulation with age in most of the brain regions. The transcripts encoding cilia basal body components formed the majority of cilia DEGAs, and adjacent cerebral cortices exhibited large overlapping pairs of cilia DEGAs. Most remarkably, specific α/β-tubulin subunits (, , and and exhibited the highest rates of downregulation and upregulation, respectively, across age in almost all brain regions. α/β-tubulins and expressions are known to be dysregulated in age-related neurodevelopmental and neurodegenerative disorders. Our results support a role for the high dynamics of cilia structural and functional components across the lifespan in the normal physiology of brain circuits. Furthermore, they suggest a crucial role for cilia signaling in the pathophysiological mechanisms of age-related psychiatric/neurological disorders.
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http://dx.doi.org/10.3390/ijms221910387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509004PMC
September 2021

Impact of Increased Hemoglobin on Spontaneous Intracerebral Hemorrhage.

Neurocrit Care 2021 Jul 27. Epub 2021 Jul 27.

Department of Neurology, People's Hospital of Tibet Autonomous Region, Lhasa, Tibet, China.

Background: Studies of the impact of increased hemoglobin on spontaneous intracerebral hemorrhage (ICH) are limited. The present study aimed to explore the effect of increased hemoglobin on ICH.

Methods: A retrospective single-center study using medical records from a database processed by univariate and multivariate analyses was performed in the People's Hospital of Tibet Autonomous Region in Lhasa, Tibet, China.

Results: The mean hemoglobin level in 211 patients with ICH was 165.03 ± 34.12 g/l, and a median hematoma volume was 18.5 ml. Eighty-eight (41.7%) patients had large hematomas (supratentorial hematoma ≥ 30 ml; infratentorial hematoma ≥ 10 ml). No differences in ICH risk factors between the groups with different hemoglobin levels were detected. Increased hemoglobin was independently associated with large hematomas [odds ratio (OR) 1.013, P = 0.023]. Increased hemoglobin was independently associated with ICH with subarachnoid hemorrhage (OR 1.014, P = 0.016), which was more pronounced in men (OR 1.027, P = 0.002). Increased hemoglobin was independently associated with basal ganglia hemorrhage and lobar hemorrhage in men (OR 0.986, P = 0.022; OR 1.013, P = 0.044, respectively) but not in women (P > 0.1).

Conclusions: Increased hemoglobin was independently associated with large hemorrhage volume. Increased hemoglobin was independently associated with lobar hemorrhage in men and ICH with subarachnoid hemorrhage, which was more pronounced in men. Additional studies are needed to confirm our findings and explore potential mechanisms.
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http://dx.doi.org/10.1007/s12028-021-01305-1DOI Listing
July 2021

Large-scale analysis reveals spatiotemporal circadian patterns of cilia transcriptomes in the primate brain.

J Neurosci Res 2021 10 26;99(10):2610-2624. Epub 2021 Jul 26.

Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California-Irvine, Irvine, CA, USA.

Cilia are dynamic subcellular systems, with core structural and functional components operating in a highly coordinated manner. Since many environmental stimuli sensed by cilia are circadian in nature, it is reasonable to speculate that genes encoding cilia structural and functional components follow rhythmic circadian patterns of expression. Using computational methods and the largest spatiotemporal gene expression atlas of primates, we identified and analyzed the circadian rhythmic expression of cilia genes across 22 primate brain areas. We found that around 73% of cilia transcripts exhibited circadian rhythmicity across at least one of 22 brain regions. In 12 brain regions, cilia transcriptomes were significantly enriched with circadian oscillating transcripts, as compared to the rest of the transcriptome. The phase of the cilia circadian transcripts deviated from the phase of the majority of the background circadian transcripts, and transcripts coding for cilia basal body components accounted for the majority of cilia circadian transcripts. In addition, adjacent or functionally connected brain nuclei had large overlapping complements of circadian cilia genes. Most remarkably, cilia circadian transcripts shared across the basal ganglia nuclei and the prefrontal cortex peaked in these structures in sequential fashion that is similar to the sequential order of activation of the basal ganglia-cortical circuitry in connection with movement coordination, albeit on completely different timescales. These findings support a role for the circadian spatiotemporal orchestration of cilia gene expression in the normal physiology of the basal ganglia-cortical circuit and motor control. Studying orchestrated cilia rhythmicity in the basal ganglia-cortical circuits and other brain circuits may help develop better functional models, and shed light on the causal effects cilia functions have on these circuits and on the regulation of movement and other behaviors.
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http://dx.doi.org/10.1002/jnr.24919DOI Listing
October 2021

Age-Related Neurometabolomic Signature of Mouse Brain.

ACS Chem Neurosci 2021 08 20;12(15):2887-2902. Epub 2021 Jul 20.

Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California-Irvine, Irvine, California 92697, United States.

Neurometabolites are the ultimate gene products in the brain and the most precise biomolecular indicators of brain endophenotypes. Metabolomics is the only "omics" that provides a moment-to-moment "snapshot" of brain circuits' biochemical activities in response to external stimuli within the context of specific genetic variations. Although the expression levels of neurometabolites are highly dynamic, the underlying metabolic processes are tightly regulated during brain development, maturation, and aging. Therefore, this study aimed to identify mouse brain metabolic profiles in neonatal and adult stages and reconstruct both the active metabolic network and the metabolic pathway functioning. Using high-throughput metabolomics and bioinformatics analyses, we show that the neonatal mouse brain has its distinct metabolomic signature, which differs from the adult brain. Furthermore, lipid metabolites showed the most profound changes between the neonatal and adult brain, with some lipid species reaching 1000-fold changes. There were trends of age-dependent increases and decreases among lipids and non-lipid metabolites, respectively. A few lipid metabolites such as HexCers and SHexCers were almost absent in neonatal brains, whereas other non-lipid metabolites such as homoarginine were absent in the adult brains. Several molecules that act as neurotransmitters/neuromodulators showed age-dependent levels, with adenosine and GABA exhibiting around 100- and 10-fold increases in the adult compared with the neonatal brain. Of particular interest is the observation that purine and pyrimidines nucleobases exhibited opposite age-dependent changes. Bioinformatics analysis revealed an enrichment of lipid biosynthesis pathways in metabolites, whose levels increased in adult brains. In contrast, pathways involved in the metabolism of amino acids, nucleobases, glucose (glycolysis), tricarboxylic acid cycle (TCA) were enriched in metabolites whose levels were higher in the neonatal brains. Many of these pathways are associated with pathological conditions, which can be predicted as early as the neonatal stage. Our study provides an initial age-related biochemical directory of the mouse brain and warrants further studies to identify temporal brain metabolome across the lifespan, particularly during adolescence and aging. Such neurometabolomic data may provide important insight about the onset and progression of neurological/psychiatric disorders and may ultimately lead to the development of precise diagnostic biomarkers and more effective preventive/therapeutic strategies.
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http://dx.doi.org/10.1021/acschemneuro.1c00259DOI Listing
August 2021

Atractylenolide III induces apoptosis by regulating the Bax/Bcl-2 signaling pathway in human colorectal cancer HCT-116 Cells in vitro and in vivo.

Anticancer Drugs 2021 Sep 13. Epub 2021 Sep 13.

Department of Pharmacology, School of Pharmacy, Southwest Medical University Pharmaceutical Department of Traditional Chinese Medicine, School of Pharmacy, Southwest Medical University Department of Pharmacy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.

Atractylodes is the dry root of atractylodes macrocephala koidz and has been commonly used as a traditional Chinese medicine (TCM). Atractylenolide III, a main component of atractylodes, has displayed significant effects on anti-inflammation and anticancer. However, the effects of atractylenolide III on growth inhibition and apoptosis induction in colon cancer remain unclear. The results showed that atractylenolide III significantly inhibited the cell growth and induce cellular apoptosis in HCT-116 cells in a concentration dependence manner in vitro. Mechanistic studies further showed that atractylenolide III could regulate the Bax/Bcl-2 apoptotic signaling pathway through promoting the expression of proapoptotic related gene/proteins Bax, caspase-9 and caspase-3 but inhibiting the expression of antiapoptotic related gene/protein Bcl-2 in HCT-116 cells. Furthermore, atractylenolide III also significantly inhibited the tumor growth of HCT-116 tumor xenografts bearing in nude mice through inducing apoptosis by upregulation of the expressions of Bax, cleaved caspase-3 and p53 but downregulation of the expressions of Bcl-2 in HCT-116 tumor tissues in vivo. The studies may provide the scientific rationale for the understanding of the anticancer effect of atractylenolide III. Therefore, atractylenolide III may have the potential to be developed as a promising novel anticancer agent for the treatment of colorectal cancer clinically.
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http://dx.doi.org/10.1097/CAD.0000000000001136DOI Listing
September 2021

Fabrication and Characterization of Collagen/PVA Dual-Layer Membranes for Periodontal Bone Regeneration.

Front Bioeng Biotechnol 2021 9;9:630977. Epub 2021 Jun 9.

National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, Shanghai, China.

Guided tissue regeneration (GTR) is a promising treatment for periodontal tissue defects, which generally uses a membrane to build a mechanical barrier from the gingival epithelium and hold space for the periodontal regeneration especially the tooth-supporting bone. However, existing membranes possess insufficient mechanical properties and limited bioactivity for periodontal bone regenerate. Herein, fish collagen and polyvinyl alcohol (Col/PVA) dual-layer membrane were developed via a combined freezing/thawing and layer coating method. This dual-layer membrane had a clear but contact boundary line between collagen and PVA layers, which were both hydrophilic. The dual membrane had an elongation at break of 193 ± 27% and would undergo an degradation duration of more than 17 days. Further cell experiments showed that compared with the PVA layer, the collagen layer not only presented good cytocompatibility with rat bone marrow-derived mesenchymal stem cells (BMSCs), but also promoted the osteogenic genes (RUNX2, ALP, OCN, and COL1) and protein (ALP) expression of BMSCs. Hence, the currently developed dual-layer membranes could be used as a stable barrier with a stable degradation rate and selectively favor the bone tissue to repopulate the periodontal defect. The membranes could meet the challenges encountered by GTR for superior defect repair, demonstrating great potential in clinical applications.
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http://dx.doi.org/10.3389/fbioe.2021.630977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8219956PMC
June 2021

Intergenerational trauma transmission is associated with brain metabotranscriptome remodeling and mitochondrial dysfunction.

Commun Biol 2021 06 24;4(1):783. Epub 2021 Jun 24.

Department of Pharmaceutical Sciences, University of California, Irvine, CA, USA.

Intergenerational trauma increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational trauma transmission is a consequence of in-utero neurodevelopmental disruptions versus early-life mother-infant interaction is unknown. Here, we demonstrate that trauma exposure during pregnancy induces in mouse offspring social deficits and depressive-like behavior. Normal pups raised by traumatized mothers exhibited similar behavioral deficits to those induced in pups raised by their biological traumatized mothers. Good caregiving by normal mothers did not reverse prenatal trauma-induced behaviors, indicating a two-hit stress mechanism comprising both in-utero abnormalities and early-life poor parenting. The behavioral deficits were associated with profound changes in the brain metabotranscriptome. Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid in the brains of neonates and adults exposed prenatally to trauma indicated mitochondrial dysfunction and epigenetic mechanisms. Bioinformatic analyses revealed stress- and hypoxia-response metabolic pathways in the neonates, which produced long-lasting alterations in mitochondrial energy metabolism and epigenetic processes (DNA and chromatin modifications). Most strikingly, early pharmacological interventions with acetyl-L-carnitine (ALCAR) supplementation produced long-lasting protection against intergenerational trauma-induced depression.
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http://dx.doi.org/10.1038/s42003-021-02255-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225861PMC
June 2021

Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area.

Neuropsychopharmacology 2021 09 21;46(10):1768-1779. Epub 2021 Jun 21.

Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, CA, USA.

During the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.
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http://dx.doi.org/10.1038/s41386-021-01031-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357835PMC
September 2021

Predicting Brain Regions Related to Alzheimer's Disease Based on Global Feature.

Front Comput Neurosci 2021 21;15:659838. Epub 2021 May 21.

Academy of Mathematics and Systems Science, Chinese Academy of Sciences, Beijing, China.

Alzheimer's disease (AD) is a neurodegenerative disease that commonly affects the elderly; early diagnosis and timely treatment are very important to delay the course of the disease. In the past, most brain regions related to AD were identified based on imaging methods, and only some atrophic brain regions could be identified. In this work, the authors used mathematical models to identify the potential brain regions related to AD. In this study, 20 patients with AD and 13 healthy controls (non-AD) were recruited by the neurology outpatient department or the neurology ward of Peking University First Hospital from September 2017 to March 2019. First, diffusion tensor imaging (DTI) was used to construct the brain structural network. Next, the authors set a new local feature index 2hop-connectivity to measure the correlation between different regions. Compared with the traditional graph theory index, 2hop-connectivity exploits the higher-order information of the graph structure. And for this purpose, the authors proposed a novel algorithm called 2hopRWR to measure 2hop-connectivity. Then, a new index global feature score (GFS) based on a global feature was proposed by combing five local features, namely degree centrality, betweenness centrality, closeness centrality, the number of maximal cliques, and 2hop-connectivity, to judge which brain regions are related to AD. As a result, the top ten brain regions identified using the GFS scoring difference between the AD and the non-AD groups were associated to AD by literature verification. The results of the literature validation comparing GFS with the local features showed that GFS was superior to individual local features. Finally, the results of the canonical correlation analysis showed that the GFS was significantly correlated with the scores of the Mini-Mental State Examination (MMSE) scale and the Montreal Cognitive Assessment (MoCA) scale. Therefore, the authors believe the GFS can also be used as a new biomarker to assist in diagnosis and objective monitoring of disease progression. Besides, the method proposed in this paper can be used as a differential network analysis method for network analysis in other domains.
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http://dx.doi.org/10.3389/fncom.2021.659838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175859PMC
May 2021

Ferroptosis-Related Gene Signature: A New Method for Personalized Risk Assessment in Patients with Diffuse Large B-Cell Lymphoma.

Pharmgenomics Pers Med 2021 26;14:609-619. Epub 2021 May 26.

Department of Lymphoma & Hematology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China.

Purpose: Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease, which makes prognostic prediction challenging. The rapid development of research on ferroptosis provides the possibility of its use in prognosis in cancer patients. The aim of the current investigation was to perform a systematic study of ferroptosis and DLBCL prognosis to identify prognostic biomarkers in DLBCL.

Materials And Methods: A total of 884 DLBCL patients from the Gene Expression Omnibus database were included in this study and were divided into a training set and a validation set. Univariate Cox regression analysis was used to investigate relationships between gene expression and prognostic values. Ferroptosis-related genes associated with overall survival in the training set were then extracted, and the least absolute shrinkage and selection operator Cox regression model was used to establish an eight-gene signature, comprising ZEB1, PSAT1, NGB, NFE2L2, LAMP2, HIF1A, FH, and CXCL2.

Results: The signature exhibited significant independent prognostic value in both the training set and the validation set. It also exhibited strong prognostic value in subgroup analysis. A nomogram integrating the eight-gene signature and components of the International Prognostic Index facilitated reliable prognostic prediction.

Conclusion: A novel and reliable ferroptosis-related gene signature that can effectively classify DLBCL patients into high-risk and low-risk groups in terms of survival rate was developed. It could be used for prognostic prediction in DLBCL patients. Targeting ferroptosis may be a therapeutic alternative in DLBCL.
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http://dx.doi.org/10.2147/PGPM.S309846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165657PMC
May 2021

Primary Mediastinal B-Cell Lymphoma: Novel Precision Therapies and Future Directions.

Front Oncol 2021 22;11:654854. Epub 2021 Mar 22.

Department of Lymphoma and Hematology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.

Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct clinicopathologic disease from other types of diffuse large B-cell lymphoma (DLBCL) with unique prognostic features and limited availability of clinical data. The current standard treatment for newly diagnosed PMBCL has long been dependent on a dose-intensive, dose-adjusted multi-agent chemotherapy regimen of rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH). Recent randomized trials have provided evidence that R-CHOP followed by consolidation radiotherapy (RT) is a valuable alternative option to first-line treatment. For recurrent/refractory PMBCL (rrPMBCL), new drugs such as pembrolizumab and CAR-T cell therapy have proven to be effective in a few studies. Positron emission tomography-computed tomography (PET-CT) is the preferred imaging modality of choice for the initial phase of lymphoma treatment and to assess response to treatment. In the future, baseline quantitative PET-CT can be used to predict prognosis in PMBCL. This review focuses on the pathology of PMBCL, underlying molecular basis, treatment options, radiotherapy, targeted therapies, and the potential role of PET-CT to guide treatment choices in this disease.
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http://dx.doi.org/10.3389/fonc.2021.654854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044947PMC
March 2021

Identification and Validation of a Prognostic Gene Signature for Diffuse Large B-Cell Lymphoma Based on Tumor Microenvironment-Related Genes.

Front Oncol 2021 22;11:614211. Epub 2021 Feb 22.

Department of Lymphoma & Hematology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.

Diffuse large B-cell lymphoma (DLBCL) is an extremely heterogeneous tumor entity, which makes prognostic prediction challenging. The tumor microenvironment (TME) has a crucial role in fostering and restraining tumor development. Consequently, we performed a systematic investigation of the TME and genetic factors associated with DLBCL to identify prognostic biomarkers for DLBCL. Data for a total of 1,084 DLBCL patients from the Gene Expression Omnibus database were included in this study, and patients were divided into a training group, an internal validation group, and two external validation groups. We calculated the abundance of immune-stromal components of DLBCL and found that they were related to tumor prognosis and progression. Then, differentially expressed genes were obtained based on immune and stromal scores, and prognostic TME-related genes were further identified using a protein-protein interaction network and univariate Cox regression analysis. These genes were analyzed by the least absolute shrinkage and selection operator Cox regression model to establish a seven-gene signature, comprising , , , , , , and . The signature was shown to have critical prognostic value in the training and validation sets and was also confirmed to be an independent prognostic factor. Subgroup analysis also indicated the robust prognostic ability of the signature. A nomogram integrating the seven-gene signature and components of the International Prognostic Index was shown to have value for prognostic prediction. Gene set enrichment analysis between risk groups demonstrated that immune-related pathways were enriched in the low-risk group. In conclusion, a novel and reliable TME relevant gene signature was proposed and shown to be capable of predicting the survival of DLBCL patients at high risk of poor survival.
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http://dx.doi.org/10.3389/fonc.2021.614211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938316PMC
February 2021

Cobalt-Catalyzed Dearomatization of Indoles via Transfer Hydrogenation To Afford Polycyclic Indolines.

Org Lett 2021 03 8;23(6):2212-2216. Epub 2021 Mar 8.

State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Bioactive Natural Product Research, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, P. R. China.

A cobalt-catalyzed dearomatization of indoles via transfer hydrogenation with HBpin and HO has been developed. This reaction offered a straightforward platform to access hexahydropyrido[1,2-]indoles in high regio- and chemoselectivity. A preliminary reaction mechanism was proposed on the basis of deuterium-labeling experiments, and a cobalt hydride species was involved in the reaction.
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http://dx.doi.org/10.1021/acs.orglett.1c00354DOI Listing
March 2021

Patterns of cilia gene dysregulations in major psychiatric disorders.

Prog Neuropsychopharmacol Biol Psychiatry 2021 07 27;109:110255. Epub 2021 Jan 27.

Departments of Pharmaceutical Sciences, School of Pharmacy, University of California-, Irvine, CA 92697, USA; Department of Computer Science, School of Information and Computer Sciences, University of California-Irvine, Irvine, CA 92697, USA. Electronic address:

Primary cilia function as cells' antennas to detect and transduce external stimuli and play crucial roles in cell signaling and communication. The vast majority of cilia genes that are causally linked with ciliopathies are also associated with neurological deficits, such as cognitive impairments. Yet, the roles of cilia dysfunctions in the pathogenesis of psychiatric disorders have not been studied. Our aim is to identify patterns of cilia gene dysregulation in the four major psychiatric disorders: schizophrenia (SCZ), autism spectrum disorder (ASD), bipolar disorder (BP), and major depressive disorder (MDD). For this purpose, we acquired differentially expressed genes (DEGs) from the largest and most recent publicly available databases. We found that 42%, 24%, 17%, and 15% of brain-expressed cilia genes were significantly differentially expressed in SCZ, ASD, BP, and MDD, respectively. Several genes exhibited cross-disorder overlap, suggesting that typical cilia signaling pathways' dysfunctions determine susceptibility to more than one psychiatric disorder or may partially underlie their pathophysiology. Our study revealed that genes encoding proteins of almost all sub-cilia structural and functional compartments were dysregulated in the four psychiatric disorders. Strikingly, the genes of 75% of cilia GPCRs and 50% of the transition zone proteins were differentially expressed in SCZ. The present study is the first to draw associations between cilia and major psychiatric disorders, and is the first step toward understanding the role that cilia components play in their pathophysiological processes, which may lead to novel therapeutic targets for these disorders.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110255DOI Listing
July 2021

The Association between Neprilysin gene polymorphisms and Alzheimer's disease in Tibetan population.

Brain Behav 2021 03 13;11(3):e02002. Epub 2020 Dec 13.

Department of Neurology, Peking University First Hospital, Beijing, China.

Objectives: Alzheimer's disease (AD) is a well-known neurodegenerative disease, of which the hallmark is the disposition of β-amyloid (Aβ) in the form of plaque in the brain. Neprilysin (NEP) is the major enzyme to degrade Aβ and prevent accumulation of Aβ. The present study was undertaken to elucidate the correlation between the NEP gene polymorphisms and AD in Chinese Tibetan population.

Methods: Ninety-nine sporadic AD Tibetan patients and 113 healthy Tibetan controls were enrolled in this study. The genotype frequencies and allele frequencies of multiple NEP gene loci were analyzed using the case-control association analysis.

Results: No significant correlation was found between polymorphisms of NEP gene loci (rs9829757, rs1816558, rs6776185, rs3736187, rs701109, rs989692) and the occurrence of AD in Tibetan population. However, allele C of NEP gene locus (rs701109) and allele T of gene locus (rs3736187) were possible risk factors of male AD patients in Tibetan population.

Conclusions: NEP gene loci (rs701109, rs989692, rs9829757, rs3736187, rs1816558, rs6776185) were polymorphic in Tibetan population. No difference was found between these loci but for that male gender combined with allele C of NEP gene locus (rs701109) and T of gene locus (rs3736187) might be risk factors for AD in Tibet.
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http://dx.doi.org/10.1002/brb3.2002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994707PMC
March 2021

Data on making uniform lignin building blocks via in-situ real-time monitoring of hydroxyethyl modification.

Data Brief 2020 Dec 10;33:106512. Epub 2020 Nov 10.

Department of Wood Science, The University of British Columbia, 2424 Main Mall, Vancouver, British Columbia, Canada.

In this work, a lab-designed apparatus was developed to collect and record the CO amount during the hydroxyethyl modification of lignin. We presented the CO volume amount and the production rate under different reaction conditions (80 - 120 °C and 2 - 6 hrs). Nuclear magnetic resonance spectroscopy was performed to analyze the chemical structure of the hydroxyethyl lignin corresponding with different amounts of CO that evolved during the reaction. The aliphatic hydroxyl, aromatic hydroxyl, and carboxylic acid groups were analyzed and tabulated. The acetylated hydroxyethyl lignin samples were characterized by C NMR to obtain the aliphatic hydroxyl (primary and secondary), phenol (ortho substituted and ortho-free), hydroxyethyl, methoxy, and aromatic hydrogen groups semi-quantitatively. Fourier-transform infrared (FTIR) spectroscopy was adopted to analyze the surface functional groups including alkyl aryl ether bond, carboxylic acid groups, and aromatic hydroxyl groups. Gel permeation chromatography combined with a multi-angle light scattering detector and differential refractive index detector were used to obtain the molar mass of lignin before and after the modification.
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http://dx.doi.org/10.1016/j.dib.2020.106512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718129PMC
December 2020

Evaluation of Microalgae as Immunostimulants and Recombinant Vaccines for Diseases Prevention and Control in Aquaculture.

Front Bioeng Biotechnol 2020 16;8:590431. Epub 2020 Nov 16.

State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.

Microalgae are often used as nutritional supplements for aquatic animals and are widely used in the aquaculture industry, providing direct or indirect nutrients for many aquatic animals. Microalgae are abundant in nature, of high nutritional value, and some of them are non-toxic and rich in antioxidants so that they can be explored as a medicinal carrier for human or animals. Natural wild-type microalgae can be adopted as an immunostimulant to enhance non-specific immune response and improve growth performance, among which spp. are commonly used. At present, there have been some successful cases of using microalgae to develop oral vaccines in the aquaculture industry. Researchers usually develop recombinant vaccines based on , and cyanobacteria. Among them, in the genetic modification of eukaryotic microalgae, many examples are expressing antigen genes in chloroplasts. They are all used for the prevention and control of single infectious diseases and most of them are resistant to shrimp virus infection. However, there is still no effective strategy targeting polymicrobial infections and few commercial vaccines are available. Although several species of microalgae are widely developed in the aquaculture industry, many of them have not yet established an effective and mature genetic manipulation system. This article systematically analyzes and discusses the above problems to provide ideas for the future development of highly effective microalgae recombinant oral vaccines.
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http://dx.doi.org/10.3389/fbioe.2020.590431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701134PMC
November 2020

Effect of dithiocyano-methane on hexose monophosphate pathway in the respiratory metabolism of Escherichia coli.

AMB Express 2020 Nov 11;10(1):205. Epub 2020 Nov 11.

Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, Key Laboratory of Animal Molecular Design and Precise Breeding of Guangdong Higher Education Institutes, School of Life Science and Engineering, Foshan University, Foshan, 528231, China.

This paper studied the inhibitory effects of dithiocyano-methane (DM) on the glucose decomposition pathway in the respiratory metabolism of Escherichia coli. We investigated the effects of DM on the activities of key enzymes (ATPase and glucose-6-phosphate dehydrogenase, G6PDH), the levels of key product (nicotinamide adenosine denucleotide hydro-phosphoric acid, NADPH), and gene expression in the hexose monophosphate pathway (HMP). The results showed that the minimum inhibitory concentration (MIC) and the minimum bactericide concentration (MBC) of DM against the tested strains were 5.86 mg/L and 11.72 mg/L, respectively. Bacteria exposed to DM at MIC demonstrated an increase in bacterial ATPase and G6PDH activities, NADPH levels, and gene expression in the HMP pathway compared to bacteria in the control group, which could be interpreted as a behavioral response to stress introduced by DM. However, DM at a lethal concentration of 10 × MIC affected glucose decomposition by inhibiting mainly the HMP pathway in E. coli.
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http://dx.doi.org/10.1186/s13568-020-01142-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658277PMC
November 2020

TMT-based quantitative proteomics analyses of sterile/fertile anthers from a genic male-sterile line and its maintainer in cotton (Gossypium hirsutum L.).

J Proteomics 2021 02 28;232:104026. Epub 2020 Oct 28.

Industrial Crop Research Institute, Sichuan Academy of Agricultural Science, No.159 Huajin Avanue, Qingbaijiang District, Chengdu 610300, China. Electronic address:

Genetic male sterility (GMS) in cotton is important for utilization of heterosis. However, the molecular mechanism of GMS is poorly known. In this study, cytological and proteomics analyses of anthers were conducted in three stages (stage 3 to 5) between GMS line (GA18) and its maintainer (GA18M). The cross-section observation revealed that the tapetal layer in stage 3 was thinner in GA18 compared to GA18M, and the tapetum cells did not degrade in stage 4 in GA18, thus providing no material for microspore development. A total of 1952 differentially expressed proteins (DEPs) were identified between GA18 and GA18M anthers. They were annotated to 52 gene ontology (GO) terms and enriched in 115 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, which formed several complex regulator networks, and dozens of important nodes were identified. Moreover, DEPs were also identified between two consecutive stages of GA18 and GA18M, with functional analyses indicating that numerous developmental differences existed between fertile and sterile anthers. The metabolic pathways were significantly altered, including decreased carbohydrate metabolism, ribosome defects, disturbed protein synthesis, disrupted flavonoids synthesis, etc., that may be involved in male sterility. Overall, these results provide genetic resources that help decipher the molecular mechanisms behind GMS. SIGNIFICANCE: Male sterility is a common phenomenon in flowering plant species, and plays a role in the application of heterosis. However, the molecular mechanism of it remains to be elucidated. Using cytological and proteomics approaches, we found that the tapetal layer development retardation may be the reason of male sterility, which was different from the delayed degradation described in previous studies. More than one thousand differentially expressed proteins were identified between male sterile line and its maintainer, forming a complex regulatory network, and the key nodes were remarked that could be used as candidate proteins related to male sterility in future study. Dozens of metabolic pathways were significantly altered, among them, ribosome defects was a novel pathway that may be involved in male sterility. These results enhance our understanding of the molecular mechanism governing male sterility and lay a foundation for clone of genes association with male sterility.
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http://dx.doi.org/10.1016/j.jprot.2020.104026DOI Listing
February 2021

De novo missense variants disrupting protein-protein interactions affect risk for autism through gene co-expression and protein networks in neuronal cell types.

Mol Autism 2020 10 8;11(1):76. Epub 2020 Oct 8.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.

Background: Whole-exome sequencing studies have been useful for identifying genes that, when mutated, affect risk for autism spectrum disorder (ASD). Nonetheless, the association signal primarily arises from de novo protein-truncating variants, as opposed to the more common missense variants. Despite their commonness in humans, determining which missense variants affect phenotypes and how remains a challenge. We investigate the functional relevance of de novo missense variants, specifically whether they are likely to disrupt protein interactions, and nominate novel genes in risk for ASD through integrated genomic, transcriptomic, and proteomic analyses.

Methods: Utilizing our previous interactome perturbation predictor, we identify a set of missense variants that are likely disruptive to protein-protein interactions. For genes encoding the disrupted interactions, we evaluate their expression patterns across developing brains and within specific cell types, using both bulk and inferred cell-type-specific brain transcriptomes. Connecting all disrupted pairs of proteins, we construct an "ASD disrupted network." Finally, we integrate protein interactions and cell-type-specific co-expression networks together with published association data to implicate novel genes in ASD risk in a cell-type-specific manner.

Results: Extending earlier work, we show that de novo missense variants that disrupt protein interactions are enriched in individuals with ASD, often affecting hub proteins and disrupting hub interactions. Genes encoding disrupted complementary interactors tend to be risk genes, and an interaction network built from these proteins is enriched for ASD proteins. Consistent with other studies, genes identified by disrupted protein interactions are expressed early in development and in excitatory and inhibitory neuronal lineages. Using inferred gene co-expression for three neuronal cell types-excitatory, inhibitory, and neural progenitor-we implicate several hundred genes in risk (FDR [Formula: see text]0.05), ~ 60% novel, with characteristics of genuine ASD genes. Across cell types, these genes affect neuronal morphogenesis and neuronal communication, while neural progenitor cells show strong enrichment for development of the limbic system.

Limitations: Some analyses use the imperfect guilt-by-association principle; results are statistical, not functional.

Conclusions: Disrupted protein interactions identify gene sets involved in risk for ASD. Their gene expression during brain development and within cell types highlights how they relate to ASD.
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http://dx.doi.org/10.1186/s13229-020-00386-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545940PMC
October 2020

MiR-29 coordinates age-dependent plasticity brakes in the adult visual cortex.

EMBO Rep 2020 11 7;21(11):e50431. Epub 2020 Oct 7.

[email protected] Lab, Scuola Normale Superiore, Pisa, Italy.

Visual cortical circuits show profound plasticity during early life and are later stabilized by molecular "brakes" limiting excessive rewiring beyond a critical period. The mechanisms coordinating the expression of these factors during the transition from development to adulthood remain unknown. We found that miR-29a expression in the visual cortex dramatically increases with age, but it is not experience-dependent. Precocious high levels of miR-29a blocked ocular dominance plasticity and caused an early appearance of perineuronal nets. Conversely, inhibition of miR-29a in adult mice using LNA antagomirs activated ocular dominance plasticity, reduced perineuronal nets, and restored their juvenile chemical composition. Activated adult plasticity had the typical functional and proteomic signature of critical period plasticity. Transcriptomic and proteomic studies indicated that miR-29a manipulation regulates the expression of plasticity brakes in specific cortical circuits. These data indicate that miR-29a is a regulator of the plasticity brakes promoting age-dependent stabilization of visual cortical connections.
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http://dx.doi.org/10.15252/embr.202050431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645255PMC
November 2020

Modulating oxygen coverage of TiCT MXenes to boost catalytic activity for HCOOH dehydrogenation.

Nat Commun 2020 Aug 25;11(1):4251. Epub 2020 Aug 25.

State Key Laboratory for Powder Metallurgy, Key Laboratory of Electronic Packing and Advanced Functional Materials of Hunan Province, School of Materials Science and Engineering, Central South University, 410083, Changsha, Hunan, P. R. China.

As a promising hydrogen carrier, formic acid (HCOOH) is renewable, safe and nontoxic. Although noble-metal-based catalysts have exhibited excellent activity in HCOOH dehydrogenation, developing non-noble-metal heterogeneous catalysts with high efficiency remains a great challenge. Here, we modulate oxygen coverage on the surface of TiCT MXenes to boost the catalytic activity toward HCOOH dehydrogenation. Impressively, TiCT MXenes after treating with air at 250 °C (TiCT-250) significantly increase the amount of surface oxygen atoms without the change of crystalline structure, exhibiting a mass activity of 365 mmol·g·h with 100% of selectivity for H at 80 °C, which is 2.2 and 2.0 times that of commercial Pd/C and Pt/C, respectively. Further mechanistic studies demonstrate that HCOO* is the intermediate in HCOOH dehydrogenation over TiCT MXenes with different coverages of surface oxygen atoms. Increasing the oxygen coverage on the surface of TiCT MXenes not only promotes the conversion from HCOO* to CO* by lowering the energy barrier, but also weakens the adsorption energy of CO and H, thus accelerating the dehydrogenation of HCOOH.
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http://dx.doi.org/10.1038/s41467-020-18091-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447762PMC
August 2020

A non-pharmacological therapeutic approach in the gut triggers distal metabolic rewiring capable of ameliorating diet-induced dysfunctions encompassed by metabolic syndrome.

Sci Rep 2020 07 31;10(1):12915. Epub 2020 Jul 31.

Natural Bio-Medicine SpA, Loc. Aboca 20, 52037, Sansepolcro, AR, Italy.

Metabolic syndrome has increased at a worrisome level. Lifestyle changes are not sufficient to prevent and improve the adverse effects of obesity, thus novel interventions are necessary. The aim of this study was to investigate the use and metabolic outcomes of a non-pharmacological intervention in a high-fat diet (HFD) fed mouse model, capable of recapitulating key aspects of metabolic syndrome. We show that Policaptil Gel Retard has remarkable, beneficial effects on metabolic dysfunction caused by consumption of HFD. We describe the mechanism by which such effects are obtained, highlighting the fact that the amelioration of metabolic function observed upon Policaptil Gel Retard administration is profound and of systemic nature, despite being originated by sequestering, therefore non-pharmacological events elicited in the gut lumen.
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http://dx.doi.org/10.1038/s41598-020-69469-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395094PMC
July 2020

Metabolomic and transcriptomic signatures of prenatal excessive methionine support nature rather than nurture in schizophrenia pathogenesis.

Commun Biol 2020 07 30;3(1):409. Epub 2020 Jul 30.

Institute for Genomics and Bioinformatics, School of Information and Computer Sciences, University of California-Irvine, Irvine, CA, 92697, USA.

The imbalance of prenatal micronutrients may perturb one-carbon (C1) metabolism and increase the risk for neuropsychiatric disorders. Prenatal excessive methionine (MET) produces in mice behavioral phenotypes reminiscent of human schizophrenia. Whether in-utero programming or early life caregiving mediate these effects is, however, unknown. Here, we show that the behavioral deficits of MET are independent of the early life mother-infant interaction. We also show that MET produces in early life profound changes in the brain C1 pathway components as well as glutamate transmission, mitochondrial function, and lipid metabolism. Bioinformatics analysis integrating metabolomics and transcriptomic data reveal dysregulations of glutamate transmission and lipid metabolism, and identify perturbed pathways of methylation and redox reactions. Our transcriptomics Linkage analysis of MET mice and schizophrenia subjects reveals master genes involved in inflammation and myelination. Finally, we identify potential metabolites as early biomarkers for neurodevelopmental defects and suggest therapeutic targets for schizophrenia.
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http://dx.doi.org/10.1038/s42003-020-01124-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393105PMC
July 2020
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