Lancet Digit Health. 2023 Aug 1:S2589-7500(23)00093-6. doi: 10.1016/S2589-7500(23)00093-6. Online ahead of print.

ABSTRACT

BACKGROUND: COVID-19 in pregnant people increases the risk for poor maternal-fetal outcomes. However, COVID-19 vaccination hesitancy remains due to concerns over the vaccine's potential effects on maternal-fetal outcomes. Here we examine the impact of COVID-19 vaccination and boosters on maternal SARS-CoV-2 infections and birth outcomes.

METHODS: This was a retrospective multicentre cohort study on the impact of COVID-19 vaccination on maternal-fetal outcomes for people who delivered (n=106 428) at Providence St Joseph Health across seven western US states from Jan 26, 2021 to Oct 26, 2022. Cohorts were defined by vaccination status at delivery: vaccinated (n=35 926; two or more doses of mRNA-1273 Moderna or BNT162b2 Pfizer-BioNTech), unvaccinated (n=55 878), unvaccinated propensity score matched (n=16 771), boosted (n=10 927; three or more doses), vaccinated unboosted (n=13 243; two doses only), and vaccinated unboosted with propensity score matching (n=4414). We built supervised machine learning classification models, which we used to determine which people were more likely to be vaccinated or boosted at delivery. The primary outcome was maternal SARS-CoV-2 infection. COVID-19 vaccination status at delivery, COVID-19-related health care, preterm birth, stillbirth, and very low birthweight were evaluated as secondary outcomes.

FINDINGS: Vaccinated people were more likely to conceive later in the pandemic, have commercial insurance, be older, live in areas with lower household composition vulnerability, and have a higher BMI than unvaccinated people. Boosted people were more likely to have more days since receiving the second COVID-19 vaccine dose, conceive earlier in the pandemic, have commercial insurance, be older, and live in areas with lower household composition vulnerability than vaccinated unboosted people. Vaccinated pregnant people had lower rates of COVID-19 during pregnancy (4·0%) compared with unvaccinated matched people (5·3%; p<0·0001). COVID-19 rates were even lower in boosted people (3·2%) compared with vaccinated unboosted matched people (5·6%; p<0·0001). Vaccinated people were also less likely to have a preterm birth (7·9%; p<0·0001), stillbirth (0·3%; p<0·0002), or very low birthweight neonate (1·0%; p<0·0001) compared with unvaccinated matched people (preterm birth 9·4%; stillbirth 0·6%; very low birthweight 1·5%). Boosted people were less likely to have a stillbirth (0·3%; p<0·025) and have no differences in rates of preterm birth (7·6%; p=0·090) or very low birthweight neonates (0·8%; p=0·092) compared with vaccinated unboosted matched people (stillbirth 0·5%; preterm birth 8·4%; very low birthweight 1·1%).

INTERPRETATION: COVID-19 vaccination protects against adverse maternal-fetal outcomes, with booster doses conferring additional protection. Pregnant people should be high priority for vaccination and stay up to date with their COVID-19 vaccination schedule.

FUNDING: National Institute for Child Health & Human Development and the William O and K Carole Ellison Foundation.

PMID:37537121 | DOI:10.1016/S2589-7500(23)00093-6

J Agric Food Chem. 2023 Aug 3. doi: 10.1021/acs.jafc.3c03412. Online ahead of print.

ABSTRACT

Tomato is a globally important horticultural and economic crop, but its productivity is severely affected by various stresses. Plant small secretory peptides have been identified as crucial mediators in plant resistance. Here, we conducted a comparative transcriptome analysis and identified the prePIP1 gene from Solanum pimpinellifolium (SpprePIP1), as an ortholog of Arabidopsis prePIP1 encoding the precursor protein of PAMP-induced SSP 1. The expression level of SpprePIP1 is transcriptionally induced in tomato upon infection with Phytophthora infestans (P. infestans), the pathogen responsible for late blight. Overexpression of SpprePIP1 resulted in enhanced tomato resistance to P. infestans. In addition, exogenous application of SpPIP1, whether through spraying or irrigation, improved tomato resistance by enhancing the transcript accumulations of pathogenesis-related proteins, as well as reactive oxygen species and the jasmonic acid (JA) levels. Integrated analysis of transcriptomics and metabolomics revealed the potential contributions of JA and phenylpropanoid biosynthesis to SpPIP1-induced tomato immunity. Additionally, SpPIP1 may strengthen tomato resistance to salt stress through the ABA signaling pathway. Overall, our findings demonstrate that SpPIP1 positively regulates tomato tolerance to P. infestans and salt stress, making it a potential plant elicitor for crop protection in an environmentally friendly way.

PMID:37535837 | DOI:10.1021/acs.jafc.3c03412

Science. 2023 Aug 4;381(6657):515-524. doi: 10.1126/science.ade2292. Epub 2023 Aug 3.

ABSTRACT

Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by CXCL9 and SPP1 (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.

PMID:37535729 | DOI:10.1126/science.ade2292

PLoS One. 2023 Aug 3;18(8):e0289535. doi: 10.1371/journal.pone.0289535. eCollection 2023.

ABSTRACT

Acquired resistance to oxaliplatin is considered as the primary reason for failure in colorectal cancer (CRC) therapy. Identifying the underlying resistance mechanisms may improve CRC treatment. The present study aims to identify the key genes involved in acquired oxaliplatin-resistant in CRC by confirming the oxaliplatin resistance index (OX-RI). To this aim, two public microarray datasets regarding oxaliplatin-resistant CRC cells with different OX-RI, GSE42387, and GSE76092 were downloaded from GEO database to identify differentially expressed genes (DEGs). The results indicated that the OX-RI affects the gene expression pattern significantly. Then, 54 common DEGs in both datasets including 18 up- and 36 down-regulated genes were identified. Protein-protein interaction (PPI) analysis revealed 13 up- (MAGEA6, TGM2, MAGEA4, SCHIP1, ECI2, CD33, AKAP12, MAGEA12, CALD1, WFDC2, VSNL1, HMGA2, and MAGEA2B) and 12 down-regulated (PDZK1IP1, FXYD3, ALDH2, CEACAM6, QPRT, GRB10, TM4SF4, LGALS4, ALDH3A1, USH1C, KCNE3, and CA12) hub genes. In the next step, two novel up-regulated hub genes including ECI2 and SCHIP1 were identified to be related to oxaliplatin resistance. Functional enrichment and pathway analysis indicated that metabolic pathways, proliferation, and epithelial-mesenchymal transition may play dominant roles in CRC progression and oxaliplatin resistance. In the next procedure, two in vitro oxaliplatin-resistant sub-lines including HCT116/OX-R4.3 and HCT116/OX-R10 cells with OX-IR 3.93 and 10.06 were established, respectively. The results indicated the up-regulation of TGM2 and HMGA2 in HCT116/OX-R10 cells with high OX-RI and down-regulation of FXYD3, LGALS4, and ECI2 in both cell types. Based on the results, TGM2, HMGA2, FXYD3, and LGALS4 genes are related to oxaliplatin-resistant CRC and may serve as novel therapeutic targets.

PMID:37535601 | DOI:10.1371/journal.pone.0289535

Elife. 2023 Aug 3;12:RP87616. doi: 10.7554/eLife.87616.

ABSTRACT

Gap junction channels (GJCs) mediate intercellular communication by connecting two neighbouring cells and enabling direct exchange of ions and small molecules. Cell coupling via connexin-43 (Cx43) GJCs is important in a wide range of cellular processes in health and disease (Churko and Laird, 2013; Liang et al., 2020; Poelzing and Rosenbaum, 2004), yet the structural basis of Cx43 function and regulation has not been determined until now. Here, we describe the structure of a human Cx43 GJC solved by cryo-EM and single particle analysis at 2.26 Å resolution. The pore region of Cx43 GJC features several lipid-like densities per Cx43 monomer, located close to a putative lateral access site at the monomer boundary. We found a previously undescribed conformation on the cytosolic side of the pore, formed by the N-terminal domain and the transmembrane helix 2 of Cx43 and stabilized by a small molecule. Structures of the Cx43 GJC and hemichannels (HCs) in nanodiscs reveal a similar gate arrangement. The features of the Cx43 GJC and HC cryo-EM maps and the channel properties revealed by molecular dynamics simulations suggest that the captured states of Cx43 are consistent with a closed state.

PMID:37535063 | DOI:10.7554/eLife.87616

J Biomol Struct Dyn. 2023 Aug 3:1-14. doi: 10.1080/07391102.2023.2242500. Online ahead of print.

ABSTRACT

The global health pandemic known as COVID-19, which stems from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a significant concern worldwide. Several treatment methods exist for COVID-19; however, there is an urgent demand for previously established drugs and vaccines to effectively combat the disease. Since, discovering new drugs poses a significant challenge, making the repurposing of existing drugs can potentially reduce time and costs compared to developing entirely new drugs from scratch. The objective of this study is to identify hub genes and associated repurposed drugs targeting them. We analyzed differentially expressed genes (DEGs) by analyzing RNA-seq transcriptomic datasets and integrated with genes associated with COVID-19 present in different databases. We detected 173 Covid-19 associated genes for the construction of a protein-protein interaction (PPI) network which resulted in the identification of the top 10 hub genes/proteins (STAT1, IRF7, MX1, IRF9, ISG15, OAS3, OAS2, OAS1, IRF3, and IRF1). Hub genes were subjected to GO functional and KEGG pathway enrichment analyses, which indicated some key roles and signaling pathways that were strongly related to SARS-CoV-2 infections. We conducted drug repurposing analysis using CMap, TTD, and DrugBank databases with these 10 hub genes, leading to the identification of Piceatannol, CKD-712, and PMID26394986-Compound-10 as top-ranked candidate drugs. Finally, drug-gene interactions analysis through molecular docking and validated via molecular dynamic simulation for 80 ns suggests PMID26394986-Compound-10 as the only potential drug. Our research demonstrates how in silico analysis might produce repurposing candidates to help respond faster to new disease outbreaks.Communicated by Ramaswamy H. Sarma.

PMID:37534820 | DOI:10.1080/07391102.2023.2242500

Mass Spectrom Rev. 2023 Aug 3. doi: 10.1002/mas.21860. Online ahead of print.

ABSTRACT

We are approaching the third decade since the establishment of the very first proteomics repositories back in the mid-'00s. New experimental approaches and technologies continuously enrich the field while producing vast amounts of mass spectrometry data. Together with initiatives to establish standard terminology and file formats, proteomics is rapidly transforming into a mature component of systems biology. Here we describe the ProteomeXchange consortium repositories. We specifically search, collect and evaluate public human tissue datasets (categorized as "complete" by the repository) submitted in 2015-2022, to both map the existing information and assess the data set reusability. Human tissue data are variably represented in the repositories reviewed, ranging between 10% and 25% of the total data submitted, with cancers being the most represented, followed by neuronal and cardiovascular diseases. About half of the retrieved data sets were found to lack annotations or metadata necessary to directly replicate the analysis. This poses a rough challenge to data reusability and highlights the need to increase awareness of the mage-tab file format for metadata in the community. Overall, proteomics repositories have evolved greatly over the past 7 years, as they have grown in size and become equipped with various powerful applications and tools that enable data searching and analytical tasks. However, to make the most of this potential, priority must be given to finding ways to secure detailed metadata for each submission, which is likely the next major milestone for proteomics repositories.

PMID:37534389 | DOI:10.1002/mas.21860

iScience. 2023 Jun 1;26(7):107002. doi: 10.1016/j.isci.2023.107002. eCollection 2023 Jul 21.

ABSTRACT

A combination of yttria stabilized zirconia (YSZ) and Ba(NO3)2 commercial powders was used as electrolytes in the construction of symmetrical SOFC. As X-ray diffraction pattern and Raman spectra revealed, the YSZ-Ba(NO3)2 electrolyte in situ converted into YSZ and yttrium-doped barium zirconate (BZY) composite at 450°C in hydrogen atmosphere. The power maximum (Pmax) of YSZ-BZY based fuel cell can reach 634.06 mW cm-2 at 450°C. Notly, the Pmax can evenly maintain at 300 mW cm-2 as the operational temperature reduced to 390°C. The outstanding cell performance at low temperature indicate the excellent ion conductivity of the composite electrolyte. The promising ion conductivity is originated from the proton conduction of BZY, the oxygen conductivity of YSZ, and the enhanced ion conduction through interface transport. Our work demonstrates that the developed YSZ-BZY electrolyte holds enormous potential for LT-SOFCs.

PMID:37534131 | PMC:PMC10391679 | DOI:10.1016/j.isci.2023.107002

Front Aging Neurosci. 2023 Jul 17;15:1150512. doi: 10.3389/fnagi.2023.1150512. eCollection 2023.

ABSTRACT

Alzheimer's disease (AD) is the most common form of neurological dementia, specified by extracellular β-amyloid plaque deposition, neurofibrillary tangles, and cognitive impairment. AD-associated pathologies like cerebral amyloid angiopathy (CAA) are also affiliated with cognitive impairment and have overlapping molecular drivers, including amyloid buildup. Discerning the complexity of these neurological disorders remains a significant challenge, and the spatiomolecular relationships between pathogenic features of AD and AD-associated pathologies remain poorly understood. This review highlights recent developments in spatial omics, including profiling and molecular imaging methods, and how they are applied to AD. These emerging technologies aim to characterize the relationship between how specific cell types and tissue features are organized in combination with mapping molecular distributions to provide a systems biology view of the tissue microenvironment around these neuropathologies. As spatial omics methods achieve greater resolution and improved molecular coverage, they are enabling deeper characterization of the molecular drivers of AD, leading to new possibilities for the prediction, diagnosis, and mitigation of this debilitating disease.

PMID:37533766 | PMC:PMC10390637 | DOI:10.3389/fnagi.2023.1150512

Front Pharmacol. 2023 Jul 18;14:1222195. doi: 10.3389/fphar.2023.1222195. eCollection 2023.

ABSTRACT

Zingiber and Alpinia species (family: Zingiberaceae) are popularly used in food as spices and flavoring agents and in ethnomedicine to heal numerous diseases, including immune-related disorders. However, their ethnomedicinal uses have not been sufficiently supported by scientific investigations. Numerous studies on the modulating effects of plants and their bioactive compounds on the different steps of the immune system have been documented. This review aimed to highlight up-to-date research findings and critically analyze the modulatory effects and mechanisms of the extracts and secondary compounds of several Zingiber and Alpinia species, namely, Zingiber officinale Roscoe, Z. cassumunar Roxb., Z. zerumbet (L.) Roscoe ex Sm., Alpinia galanga Linn., A. conchigera Griff, A. katsumadai Hayata, A. oxyphylla Miq., A. officinarum Hance, A. zerumbet (Pers.) Burtt. et Smith, and A. purpurata (Viell.) K. Schum. on the immune system, particularly via the inflammation-related signaling pathways. The immunomodulating activities of the crude extracts of the plants have been reported, but the constituents contributing to the activities have mostly not been identified. Among the extracts, Z. officinale extracts were the most investigated for their in vitro, in vivo, and clinical effects on the immune system. Among the bioactive metabolites, 6-, 8-, and 10-gingerols, 6-shogaol, and zerumbone from Zingiber species and cardamomin, 1'-acetoxychavicol acetate, yakuchinone, rutin, 1,8-cineole, and lectin from Alpinia species have demonstrated strong immunomodulating effects. More experimental studies using cell and animal models of immune-related disorders are necessary to further understand the underlying mechanisms, together with elaborate preclinical pharmacokinetics, pharmacodynamics, bioavailability, and toxicity studies. Many of these extracts and secondary metabolites are potential candidates for clinical development in immunomodulating agents or functional foods to prevent and treat chronic inflammatory disorders.

PMID:37533631 | PMC:PMC10391552 | DOI:10.3389/fphar.2023.1222195

Turk J Biol. 2021 Dec 20;46(2):137-144. doi: 10.3906/biy-2107-45. eCollection 2022.

ABSTRACT

The working mechanism of the chemotherapeutic drug doxorubicin, which is frequently used in cancer treatment, its effects on cell metabolism, and pathways activated solely by doxorubicin are not fully known. Understanding these principles is important both in improving existing therapies and in finding new drug targets. Here, I describe a systems-biology approach to find a generalizable working principle for doxorubicin by superimposition of human interactome over gene datasets commonly expressed among various cancer types. The common -in at least two different diseases-transcriptional response of distinctive cancer cell lines to doxorubicin was reflected via 199 significantly and differentially expressed genes, mostly related to the regulation of transcription. Then, by integrating with interactome data, an active network was constructed allowing detection of clusters. Since each cluster defines densely connected regions, another level of understanding of functional principles is provided. Significant clusters were associated with the linked transcription factors and transcriptional factor enrichment analysis within these regulatory networks led to the proposition of Pou5f1b, Znf428, Prmt3, Znf12, Erg, Tfdp1, Foxm1, and Cenpa as new drug targets in drug development that can be applied in different cancer types.

PMID:37533515 | PMC:PMC10393105 | DOI:10.3906/biy-2107-45

Environ Microbiome. 2023 Aug 2;18(1):66. doi: 10.1186/s40793-023-00523-8.

ABSTRACT

The Tri-Service Microbiome Consortium (TSMC) was founded to enhance collaboration, coordination, and communication of microbiome research among DoD organizations and to facilitate resource, material and information sharing amongst consortium members, which includes collaborators in academia and industry. The 6th Annual TSMC Symposium was a hybrid meeting held in Fairlee, Vermont on 27-28 September 2022 with presentations and discussions centered on microbiome-related topics within seven broad thematic areas: (1) Human Microbiomes: Stress Response; (2) Microbiome Analysis & Surveillance; (3) Human Microbiomes Enablers & Engineering; (4) Human Microbiomes: Countermeasures; (5) Human Microbiomes Discovery - Earth & Space; (6) Environmental Micro & Myco-biome; and (7) Environmental Microbiome Analysis & Engineering. Collectively, the symposium provided an update on the scope of current DoD microbiome research efforts, highlighted innovative research being done in academia and industry that can be leveraged by the DoD, and fostered collaborative opportunities. This report summarizes the activities and outcomes from the 6th annual TSMC symposium.

PMID:37533117 | DOI:10.1186/s40793-023-00523-8

Eur J Clin Nutr. 2023 Aug 2. doi: 10.1038/s41430-023-01310-x. Online ahead of print.

ABSTRACT

BACKGROUND: Bioelectrical impedance analysis (BIA) is a technique widely used for estimating body composition and health-related parameters. The technology is relatively simple, quick, and non-invasive, and is currently used globally in diverse settings, including private clinicians' offices, sports and health clubs, and hospitals, and across a spectrum of age, body weight, and disease states. BIA parameters can be used to estimate body composition (fat, fat-free mass, total-body water and its compartments). Moreover, raw measurements including resistance, reactance, phase angle, and impedance vector length can also be used to track health-related markers, including hydration and malnutrition, and disease-prognostic, athletic and general health status. Body composition shows profound variability in association with age, sex, race and ethnicity, geographic ancestry, lifestyle, and health status. To advance understanding of this variability, we propose to develop a large and diverse multi-country dataset of BIA raw measures and derived body components. The aim of this paper is to describe the 'BIA International Database' project and encourage researchers to join the consortium.

METHODS: The Exercise and Health Laboratory of the Faculty of Human Kinetics, University of Lisbon has agreed to host the database using an online portal. At present, the database contains 277,922 measures from individuals ranging from 11 months to 102 years, along with additional data on these participants.

CONCLUSION: The BIA International Database represents a key resource for research on body composition.

PMID:37532867 | DOI:10.1038/s41430-023-01310-x

Nature. 2023 Aug;620(7972):E7-E9. doi: 10.1038/s41586-023-06293-0.

NO ABSTRACT

PMID:37532815 | DOI:10.1038/s41586-023-06293-0

Nature. 2023 Aug;620(7972):47-60. doi: 10.1038/s41586-023-06221-2. Epub 2023 Aug 2.

ABSTRACT

Artificial intelligence (AI) is being increasingly integrated into scientific discovery to augment and accelerate research, helping scientists to generate hypotheses, design experiments, collect and interpret large datasets, and gain insights that might not have been possible using traditional scientific methods alone. Here we examine breakthroughs over the past decade that include self-supervised learning, which allows models to be trained on vast amounts of unlabelled data, and geometric deep learning, which leverages knowledge about the structure of scientific data to enhance model accuracy and efficiency. Generative AI methods can create designs, such as small-molecule drugs and proteins, by analysing diverse data modalities, including images and sequences. We discuss how these methods can help scientists throughout the scientific process and the central issues that remain despite such advances. Both developers and users of AI toolsneed a better understanding of when such approaches need improvement, and challenges posed by poor data quality and stewardship remain. These issues cut across scientific disciplines and require developing foundational algorithmic approaches that can contribute to scientific understanding or acquire it autonomously, making them critical areas of focus for AI innovation.

PMID:37532811 | DOI:10.1038/s41586-023-06221-2

Commun Biol. 2023 Aug 2;6(1):801. doi: 10.1038/s42003-023-05161-x.

ABSTRACT

Molybdenum (Mo) as essential micronutrient for plants, acts as active component of molybdenum cofactor (Moco). Core metabolic processes like nitrate assimilation or abscisic-acid biosynthesis rely on Moco-dependent enzymes. Although a family of molybdate transport proteins (MOT1) is known to date in Arabidopsis, molybdate homeostasis remained unclear. Here we report a second family of molybdate transporters (MOT2) playing key roles in molybdate distribution and usage. KO phenotype-analyses, cellular and organ-specific localization, and connection to Moco-biosynthesis enzymes via protein-protein interaction suggest involvement in cellular import of molybdate in leaves and reproductive organs. Furthermore, we detected a glutathione-molybdate complex, which reveals how vacuolar storage is maintained. A putative Golgi S-adenosyl-methionine transport function was reported recently for the MOT2-family. Here, we propose a moonlighting function, since clear evidence of molybdate transport was found in a yeast-system. Our characterization of the MOT2-family and the detection of a glutathione-molybdate complex unveil the plant-wide way of molybdate.

PMID:37532778 | DOI:10.1038/s42003-023-05161-x

Nat Commun. 2023 Aug 2;14(1):4646. doi: 10.1038/s41467-023-39521-2.

ABSTRACT

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.

PMID:37532724 | DOI:10.1038/s41467-023-39521-2

Methods Enzymol. 2023;686:345-367. doi: 10.1016/bs.mie.2023.02.009. Epub 2023 Apr 6.

ABSTRACT

Protein termini are critical for protein functions. They are often more accessible than internal regions and thus are frequently subjected to various modifications that affect protein function. Protein termini also contribute to regulating protein lifespan. Recent studies have revealed a series of degradation signals located at protein C-termini, termed C-degrons or C-end degrons. C-degrons have been implicated as underlying a protein quality surveillance system that eliminates truncated, cleaved and mislocalized proteins. Despite the importance of C-degrons, our knowledge of them remains sparse. Here, we describe an established framework for the characterization of C-degrons by Global Protein Stability (GPS) profiling assay, a fluorescence-based reporter system for measuring protein stability in cellulo. Furthermore, we apply an approach that couples GPS with random peptide libraries for unbiased and context-independent characterization of C-degron motifs. Our methodology provides a robust and efficient platform for analyzing the degron potencies of C-terminal peptides, which can significantly accelerate our understanding of C-degrons.

PMID:37532407 | DOI:10.1016/bs.mie.2023.02.009

Pestic Biochem Physiol. 2023 Aug;194:105473. doi: 10.1016/j.pestbp.2023.105473. Epub 2023 May 19.

ABSTRACT

Neonicotinoids (neonics) are amongst the most commonly used class of pesticides globally. In the United States, imidacloprid (IMI) is extensively used for agriculture and in other common applications such as house-hold pest control. Regular exposure to IMI, and several of its known metabolites including IMI-olefin and desnitro-imidacloprid (DN-IMI), has been shown to be harmful to many organisms including mammals, birds, and fish. Studies show that neonics bind human nicotinicacetylcholine receptors (nAChRs) and cause cellular toxicity. In the dopaminergic Lund human mesencephalic (LUHMES) cell line, IMI and other neonics (10-100 μM) have been recently shown to activate intracellular calcium signaling through nAChRs. Thus, we examined proteomic responses of LUHMES cells to a 48-h treatment with 50 μM IMI, IMI-olefin, or DN-IMI. Our findings show differential effects of these neonics on cellular protein expression. Bioinformatic analysis of significantly altered proteins indicates an effect of IMI, IMI-olefin, and DN-IMI on protein synthesis and ribosomal function. These findings suggest a role for protein synthesis and transcriptional regulation in neonic-mediated dopaminergic neurotoxicity.

PMID:37532312 | DOI:10.1016/j.pestbp.2023.105473

Phytomedicine. 2023 Jul 22;119:154968. doi: 10.1016/j.phymed.2023.154968. Online ahead of print.

ABSTRACT

BACKGROUND: Immune checkpoint blockade (ICB) induces durable immune responses across a spectrum of advanced cancers and revolutionizes the oncology field. However, only a subset of patients achieves long-lasting clinical benefits. Tumor-associated macrophages (TAMs) usually secrete immunosuppressive cytokines and contribute to the failure of ICB therapy. Therefore, it is crucial to mechanically manipulate the abundance and function of TAMs in the tumor microenvironment (TME), which can offer a promising molecular basis to improve the clinical response efficacy of ICB in cancer patients.

PURPOSE: This study aims to investigate TAMs in the immunosuppressive microenvironment to identify new therapeutic targets, improve the ability to predict and guide responses to clinical immunotherapy, and develop new strategies for immunotherapy of lung tumors.

METHODS: Lewis lung carcinoma (LLC) xenograft-bearing mouse models were established to analyze the antitumor activity of Rhizoma Coptidis (RC) in vivo. A systems pharmacology strategy was used to predict the correlation between RC and M2 macrophages. The effect of RC on the abundance of M2 macrophages was analyzed by flow cytometry of murine samples. Western blot was performed to analyze the expression of Leukotriene A4 hydrolase (LTA4H) and LTB4 receptor 1 (BLT1) in harvested lung cancer tissues. The impact of blocking leukotriene B4 (LTB4) signaling by RC on the recruitment of M2 macrophages was assessed in vitro and in vivo. Transwell migration assays were conducted to clarify the inhibition of macrophage migration by blocking LTB4. Lta4h-/- mice were used to investigate the sensitivity of immunotherapy to lung cancer by blocking the LTB4 signaling.

RESULTS: Here, we report that RC, an herbal medicine from the family Ranunculaceae, suppresses the recruitment and immunosuppressive function of TAMs, which in turn sensitizes lung cancer to ICB therapy. Firstly, a systems pharmacology strategy was proposed to identify combinatorial drugs for ICB therapy with a systems biology perspective of drug-target-pathway-TME phenotype. We predicted and verified that RC significantly inhibits tumor growth and the infiltration of M2-TAMs into TME of LLC tumor-bearing mice. Then, RC inhibits the recruitment of macrophages to the tumor TME via blocking LTB4 signaling, and suppresses the expression of immunosuppressive factors (IL-10, TGF-β and VEGF). As a result, RC enables CD8+ T cells to retain their proliferative and infiltrative abilities within the TME. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumor cells, which is further enhanced by the addition of anti-PD-L1 therapy. Furthermore, we employed LTA4H deficient mice (Lta4h-/- mice) to evaluate the antitumor efficiency, the results showed that the efficacy of immunotherapy was enhanced due to the synergistic effect of LTB4 signaling blockage and ICB inhibition, leading to remarkable inhibition of tumor growth in a mouse model of lung adenocarcinoma.

CONCLUSIONS: Taken together, these findings suggest that RC enhances antitumor immunity, providing a rationale for combining RC with immunotherapies as a potential anti-cancer treatment strategy.

PMID:37531900 | DOI:10.1016/j.phymed.2023.154968