The effect of mycophenolate mofetil on podocytes in nephrotoxic serum nephritis.

Mycophenolate mofetil (MMF) is applied in proteinuric kidney diseases, but the exact mechanism of its effect on podocytes is still unknown. Our previous in vitro experiments suggested that MMF can ameliorate podocyte damage via restoration of the Ca2+-actin cytoskeleton axis. The goal of this study was to characterize podocyte biology during MMF treatment in nephrotoxic serum (NTS) nephritis (NTN). NTN was induced in three-week old wild-type mice. On day 3, half of the mice were treated with MMF (100 mg/kgBW/d p.o.) for one week. On day 10, we performed proteomic analysis of glomeruli as well as super-resolution imaging of the slit diaphragm. For multiphoton imaging of Ca2+ concentration ([Ca2+]i), the experimental design was repeated in mice expressing podocyte-specific Ca2+ sensor. MMF ameliorated the proteinuria and crescent formation induced by NTS. We identified significant changes in the abundance of proteins involved in Ca2+ signaling and actin cytoskeleton regulation, which was further confirmed by direct [Ca2+]i imaging in podocytes showing decreased Ca2+ levels after MMF treatment. This was associated with a tendency to restoration of podocyte foot process structure. Here, we provide evidence that MPA has a substantial direct effect on podocytes. MMF contributes to improvement of [Ca2+]i and amelioration of the disorganized actin cytoskeleton in podocytes. These data extend the knowledge of direct effects of immunosuppressants on podocytes that may contribute to a more effective treatment of proteinuric glomerulopathies with the least possible side effects.

Lipoylation is dependent on the ferredoxin FDX1 and dispensable under hypoxia in human cells.

Iron-sulfur clusters (ISC) are essential cofactors that participate in electron transfer, environmental sensing, and catalysis. Amongst the most ancient ISC-containing proteins are the ferredoxin (FDX) family of electron carriers. Humans have two FDXs- FDX1 and FDX2, both of which are localized to mitochondria, and the latter of which is itself important for ISC synthesis. We have previously shown that hypoxia can eliminate the requirement for some components of the ISC biosynthetic pathway, but FDXs were not included in that study. Here, we report that FDX1, but not FDX2, is dispensable under 1% O2 in cultured human cells. We find that FDX1 is essential for production of the lipoic acid cofactor, which is synthesized by the ISC-containing enzyme lipoyl synthase. While hypoxia can rescue the growth phenotype of either FDX1 or lipoyl synthase KO cells, lipoylation in these same cells is not rescued, arguing against an alternative biosynthetic route or salvage pathway for lipoate in hypoxia. Our work reveals the divergent roles of FDX1 and FDX2 in mitochondria, identifies a role for FDX1 in lipoate synthesis, and suggests that loss of lipoic acid can be tolerated under low oxygen tensions in cell culture.

Pharos 2023: an integrated resource for the understudied human proteome.

The Illuminating the Druggable Genome (IDG) project aims to improve our understanding of understudied proteins and our ability to study them in the context of disease biology by perturbing them with small molecules, biologics, or other therapeutic modalities. Two main products from the IDG effort are the Target Central Resource Database (TCRD) (http://juniper.health.unm.edu/tcrd/), which curates and aggregates information, and Pharos (https://pharos.nih.gov/), a web interface for fusers to extract and visualize data from TCRD. Since the 2021 release, TCRD/Pharos has focused on developing visualization and analysis tools that help reveal higher-level patterns in the underlying data. The current iterations of TCRD and Pharos enable users to perform enrichment calculations based on subsets of targets, diseases, or ligands and to create interactive heat maps and UpSet charts of many types of annotations. Using several examples, we show how to address disease biology and drug discovery questions through enrichment calculations and UpSet charts.

The importance of transcriptomics and proteomics for studying molecular mechanisms of mycotoxin exposure: A review.

This review aims to highlight recent advances where transcriptomics and proteomics have been used as a key tool to understand molecular toxicity of mycotoxins. The most studied mycotoxin by using transcriptomic approach is deoxynivalenol (DON), followed by aflatoxins (AFs) and zearalenone (ZEA). Instead, proteomics mostly focuses on AFs but also in this case, mildly to ZEA and DON. However, in both omics approaches, fewer studies investigated the toxicological effect of emerging mycotoxins, patulin, ochratoxin A, T-2 toxin, alternariol and amino-14,16-dimethyloctadecan-3-ol. The study of changes in the expression of genes involved in immune system are the most common purposes for transcriptomics whereas cellular processes in proteomics field. Concerning the techniques used to perform the experiments, RT-qPCR is the most employed in gene expression analysis whereas liquid chromatography coupled with mass spectrometry is the master technique for proteomics assays. The gathered data have reported that the interest in using these omic approaches has increased in the last five years. However, in vitro models take precedence over the in vivo and ex vivo ones. Therefore, there is a need to enhance the use of in vivo models and alternative methods to better understand mycotoxins mode of action on animal and human health.

Bisphenol A replacement chemicals, BPF and BPS, induce protumorigenic changes in human mammary gland organoid morphology and proteome.

SignificanceBisphenol A (BPA), found in many plastic products, has weak estrogenic effects that can be harmful to human health. Thus, structurally related replacements-bisphenol S (BPS) and bisphenol F (BPF)-are coming into wider use with very few data about their biological activities. Here, we compared the effects of BPA, BPS, and BPF on human mammary organoids established from normal breast tissue. BPS disrupted organoid architecture and induced supernumerary branching. At a proteomic level, the bisphenols altered the abundance of common targets and those that were unique to each compound. The latter included proteins linked to tumor-promoting processes. These data highlighted the importance of testing the human health effects of replacements that are structurally related to chemicals of concern.

Quantitative Proteomics Analysis Expands the Roles of Lysine ß-Hydroxybutyrylation Pathway in Response to Environmental ß-Hydroxybutyrate.

Lysine ß-hydroxybutyrylation (Kbhb) is a newly identified protein posttranslational modification (PTM) derived from ß-hydroxybutyrate (BHB), a product of ketone body metabolism in liver. BHB could serve as an energy source and play a role in the suppression of oxidative stress. The plasma concentration of BHB could increase up to 20 mM during starvation and in pathological conditions. Despite the progress, how the cells derived from extrahepatic tissues respond to elevated environmental BHB remains largely unknown. Given that BHB can significantly drive Kbhb, we characterized the BHB-induced lysine ß-hydroxybutyrylome and acetylome by quantitative proteomics. A total of 840 unique Kbhb sites on 429 proteins were identified, with 42 sites on 39 proteins increased by more than 50% in response to BHB. The results showed that the upregulated Kbhb induced by BHB was involved in aminoacyl-tRNA biosynthesis, 2-oxocarboxylic acid metabolism, citrate cycle, glycolysis/gluconeogenesis, and pyruvate metabolism pathways. Moreover, some BHB-induced Kbhb substrates were significantly involved in diseases such as cancer. Taken together, we investigate the dynamics of lysine ß-hydroxybutyrylome and acetylome induced by environmental BHB, which reveals the roles of Kbhb in regulating various biological processes and expands the biological functions of BHB.

Pterostilbene Promotes Mean Lifespan in Both Male and Female Drosophila Melanogaster Modulating Different Proteins in the Two Sexes.

Aging is a multifactorial phenomenon characterized by degenerative processes closely connected to oxidative damage and chronic inflammation. Recently, many studies have shown that natural bioactive compounds are useful in delaying the aging process. In this work, we studied the effects of an in vivo supplementation of the stilbenoid pterostilbene on lifespan extension in Drosophila melanogaster. We found that the average lifespan of flies of both sexes was increased by pterostilbene supplementation with a higher effect in females. The expression of longevity related genes (Sir2, Foxo, and Notch) was increased in both sexes but with different patterns. Pterostilbene counteracted oxidative stress induced by ethanol and paraquat and up-regulated the antioxidant enzymes Ho e Trxr-1 in male but not in female flies. On the other hand, pterostilbene decreased the inflammatory mediators dome and egr only in female flies. Proteomic analysis revealed that pterostilbene modulates 113 proteins in male flies and only 9 in females. Only one of these proteins was modulated by pterostilbene in both sexes: vacuolar H[+] ATPase 68 kDa subunit 2 (Vha68-2) that was strongly down-regulated. These findings suggest a potential role of pterostilbene in increasing lifespan both in male and female flies by mechanisms that seem to be different in the two sexes, highlighting the need to conduct nutraceutical supplementation studies on males and females separately in order to give more reliable results.

What Worth the Garlic Peel.

Plants have two types of reproduction: sexual, resulting in embryo production, and asexual, resulting in vegetative bodies commonly derived from stems and roots (e.g., bulb, tuber). Dead organs enclosing embryos (DOEEs, such as seed coat and pericarp) are emerging as central components of the dispersal unit acting to nurture the embryo and ensure its survival in the habitat. Here we wanted to investigate the properties of dead organs enclosing plant asexual reproductive bodies, focusing on the garlic (Allium sativum) bulb. We investigated the biochemical and biological properties of the outer peel enclosing the bulb and the inner peel enclosing the clove using various methodologies, including bioassays, proteomics, and metabolomics. The garlic peels differentially affected germination and post-germination growth, with the outer peel demonstrating a strong negative effect on seed germination of Sinapis alba and on post-germination growth of Brassica juncea. Proteome analysis showed that dead garlic peels possess 67 proteins, including chitinases and proteases, which retained their enzymatic activity. Among primary metabolites identified in garlic peels, the outer peel accumulated multiple sugars, including rhamnose, mannitol, sorbitol, and trehalose, as well as the modified amino acid 5-hydroxylysine, known as a major component of collagen, at a higher level compared to the clove and the inner peel. Growth of Escherichia coli and Staphylococcus aureus was promoted by garlic peel extracts but inhibited by clove extract. All extracts strongly inhibited spore germination of Fusarium oxysporum f.sp. melonis. Thus, the garlic peels not only provide physical protection to vegetative offspring but also appear to function as a refined arsenal of proteins and metabolites for enhancing growth and development, combating potential pathogens, and conferring tolerance to abiotic stresses.

TCDD-induced IL-24 secretion in human chorionic stromal cells inhibits placental trophoblast cell migration and invasion.

Environmental pollutant dioxins are potentially harmful to pregnant women and can lead to severe adverse outcomes in pregnancy, such as spontaneous abortion and stillbirth. However, little is currently known about the underlying toxicological mechanism. Our previous study reported that the IL-24 gene is a dioxin response gene during 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) treatment. Here, we further tested the effect of TCDD on IL-24 expression in human chorionic stromal cells. We also investigated the effect of IL-24 on the behaviors of human placental trophoblast cells and predicted the potential mechanism underlying these behaviors using functional network analysis. We found that TCDD stimulates IL-24 expression in human chorionic stromal cells in an AhR (aromatic hydrocarbon receptor)-related manner. We also found that IL-24 inhibits the migration and invasion of human placental trophoblast cells, the possible mechanism of which involves thirteen key proteins and mitochondrial function. Our findings suggest that IL-24 is a potential factor induced by TCDD to regulate trophoblast cell invasion, which potentially involves in TCDD-induced abortion.

Effects of long-term fluoride exposure are associated with oxidative biochemistry impairment and global proteomic modulation, but not genotoxicity, in parotid glands of mice.

BACKGROUND: Fluoride has become widely used in dentistry because of its effectiveness in caries control. However, evidence indicates that excessive intake interferes with the metabolic processes of different tissues. Thus, this study aimed to investigate the effects of long-term exposure to F on the parotid salivary gland of mice, from the analysis of oxidative, proteomic and genotoxic parameters. MATERIALS AND METHODS: The animals received deionized water containing 0, 10 or 50 mg/L of F, as sodium fluoride, for 60 days. After, parotid glands were collected for analysis of oxidative biochemistry, global proteomic profile, genotoxicity assessment and histopathological analyses. RESULTS: The results revealed that exposure to fluoride interfered in the biochemical homeostasis of the parotid gland, with increased levels of thiobarbituric acid reactive species and reduced glutathione in the exposed groups; as well as promoted alteration of the glandular proteomic profile in these groups, especially in structural proteins and proteins related to oxidative stress. However, genotoxic assessment demonstrated that exposure to fluoride did not interfere with DNA integrity in these concentrations and durations of exposure. Also, it was not observed histopathological alterations in parotid gland. CONCLUSIONS: Thus, our results suggest that long-term exposure to fluoride promoted modulation of the proteomic and biochemical profile in the parotid glands, without inducing damage to the genetic component. These findings reinforce the importance of rationalizing the use of fluorides to maximize their preventative effects while minimizing the environmental risks.

The proteomic landscape of ovarian cancer cells in response to melatonin.

Ovarian cancer (OC) is the most lethal gynecological malignancy with a highly negative prognosis. Melatonin is an indoleamine secreted by the pineal gland during darkness and has shown antitumor activity in both in vitro and in vivo experiments. Herein, we investigated the influence of melatonin on the proteome of human ovarian carcinoma cells (SKOV-3 cell line) using the Ultimate 3000 LC Liquid NanoChromatography equipment coupled to a Q-Exactive mass spectrometry. After 48 h of treatment, melatonin induced a significant cytotoxicity especially with the highest melatonin concentration. The proteomic profile revealed 639 proteins in the control group, and 98, 110, and 128 proteins were altered by melatonin at the doses of 0.8, 1.6, and 2.4 mM, respectively. Proteins associated with the immune system and tricarboxylic acid cycle were increased in the three melatonin-exposed groups of cells. Specifically, the dose of 2.4 mM led to a reduction in molecules associated with protein synthesis, especially those of the ribosomal protein family. We also identified 28 potential genes shared between normal ovarian tissue and OC in all experimental groups, and melatonin was predicted to alter genes encoding ribosomal proteins. Notably, the set of proteins changed by melatonin was linked to a better prognosis for OC patients. We conclude that melatonin significantly alters the proteome of SKOV-3 cells by changing proteins involved with the immune response and mitochondrial metabolism. The concentration of 2.4 mM of melatonin promoted the largest number of protein changes. The evidence suggests that melatonin may be an effective therapeutic strategy against OC.

Novel protein kinase C phosphorylated kinase inhibitor-matrine suppresses replication of hepatitis B virus via modulating the mitogen-activated protein kinase signal.

HBV (hepatitis B virus) infection still threatens human health. Therefore, it is essential to find new effective anti-HBV compounds. Here, we identified matrine as a novel inhibitor of PKC (protein kinase C) phosphorylated kinase by screening a natural compound library. After HepG2.215 cells were treated with matrine, we carried out a phosphorylated proteomics sequence study and analyzed the prediction of related kinase expression level. In the case of HBV infection, it was found that PKC kinase mediates the activation of mitogen-activated protein kinase (MAPK) signaling pathway known as son of sevenless (SOS) activation. It was also found that PKC kinase inhibits the expression of C-X-C Motif Chemokine Ligand 8 (CXCL8) by inhibiting the activity of activating transcription factor 2/ cAMP response element binding protein (ATF2/CREB), and this effect is independent of its activated MAPK signaling pathway. Finally, Western blot was used to detect the expression of MAPK, ATF2, CREB3 phosphorylation and nonphosphorylation in matrine-treated cells and PKC-treated cells. PKC phosphorylated kinase inhibitor-matrine suppresses the replication of HBV via modulating the MAPK/ATF2 signal. Matrine is a good clinical drug to enhance the autoimmunity in the adjuvant treatment of chronic HBV infection.

Per- and polyfluoroalkyl substances (PFAS) augment adipogenesis and shift the proteome in murine 3T3-L1 adipocytes.

The Per- and polyfluoroalkyl substances (PFAS) are a wide group of fluorinated compounds, which the health effects of many of them have not been investigated. Perfluorinated sulfonates, such as perfluorooctane sulfonate (PFOS) and perfluorinated carboxylates, such as perfluorooctanoic acid (PFOA) are members of this broad group of PFAS, and previous studies have shown a correlation between the body accumulation of PFOS and PFOA and increased adipogenesis. PFOA and PFOS have been withdrawn from the market and use is limited because of their persistence, toxicity, and bioaccumulative properties. Instead, short chain PFAS have been created to replace PFOA and PFOS, but the health effects of other short chain PFAS are largely unknown. Therefore, herein we aimed to comprehensively determined the potential adipogenesis of ten different PFAS (PFBS, PFHxS, PFOS, PFBA, PFHxA, PFHA, PFOA, PFNA, PFDA, and HFPO-DA) and investigated the differences in protein expression of 3T3-L1 cells upon exposure to each PFAS. 3T3-L1 cells were differentiated with or without each PFAS for 4-days, and cellular lipid was quantified using Nile Red staining. Analysis of the adipocyte proteome was performed to identify the pathways related to adipogenesis and quantify proteins significantly affected by each PFAS. The results showed that in general, every PFAS investigated in our study has the potential to induce the 3T3-L1 differentiation to adipocytes in the presence of rosiglitazone, with the concentrations that range between 0.25 and 25 µM. Proteomics analysis revealed specific markers regarding to adipogenesis upregulated upon exposure to each of the ten PFAS.

Transcriptomic and proteomic responses of silver nanoparticles in hepatocyte-like cells derived from human induced pluripotent stem cells.

Silver nanoparticles (AgNPs) have been increasingly used in a variety of consumer products over the last decades. However, their potential adverse effects have not been fully understood. In a previous study, we characterized transcriptomic changes in human induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) in response to AgNP exposure. Here, we report findings of a follow-up proteomic study that evaluated alternations at the protein level in the same cell after being exposed to 10 µg/ml AgNPs for 24 h. In total, 6287 proteins were identified across two groups of samples (n = 3). Among these proteins, 665 were found to be differentially regulated (fold change ≥1.25, p < 0.01) between the AgNP-treated group and the untreated control group, including 264 upregulated and 401 downregulated. Bioinformatics analysis of the proteomics data, in side-by-side comparison to the transcriptomics data, confirms and substantiates previous findings on AgNP-induced alterations in metabolism, oxidative stress, inflammation, and potential association with cancer. A mechanism of action was proposed based on these results. Collectively, the findings of the current proteomic study are consistent with those of the previous transcriptomic study and further demonstrate the usefulness of iPSC-derived HLCs as an in vitro model for liver nanotoxicology.

Exposure to a combination of MWCNTs and DBP causes splenic toxicity in mice.

The large conjugated π bond in the molecular structure of carbon nanotubes (CNTs) interacts with the benzene ring structure in di (n-butyl) phthalates (DBP) through a π - π bond. Compounds of CNTs and DBP form easily, becoming another environmental pollutant of concern. We explore whether CNTs entering animals slow down the degradation of the DBP adsorbed in the CNT cavity, thereby prolonging the "hormonal activity" of DBP. In our study, male BALb/c mice were used as experimental subjects divided into four groups: the control group; the multi-walled carbon nanotubes (MWCNTs) exposure group (10mg/kg/d); the DBP exposure group (2.15 mg/kg/d); and the compound exposure group (MWCNTs + DBP). After 30 days of exposure, the mice were sacrificed and their spleens used for immunotoxicology study. The results showed that the exposure groups exhibited splenomegaly and suffered severe oxidative damage to the spleen. In the compound exposure group: levels of IgA and IgG in the serum of the mice changed, and were significantly different from levels in both the MWCNTs and DBP exposure groups (p <0.05); the pathological sections of the spleen showed that the boundary between the white pulp area (WP) and the red pulp area (RP) was blurred, that the cell arrangement was loose, and that more red blood cells were retained in the spleen. Proteomics mass spectrometry analysis showed that compared with the control group, 70 proteins were up-regulated and 27 proteins were down-regulated in the MWCNTs group, 36 proteins were up-regulated and 23 proteins were down-regulated in the DBP group, 87 proteins were up-regulated and 21 proteins were down-regulated in the compound exposure group. The results of GO enrichment analysis and KEGG enrichment analysis of the differentially expressed proteins showed that the compound exposure harmed the spleen antigen recognition, processing, and presentation, inhibited the activation and proliferation of B cells and T cells, and hindered the adaptive immune responses. Our results showed that MWCNTs and DBP compounds can damage the spleen, and impair the innate and adaptive immune functions of the body.

Mapping atopic dermatitis and anti-IL-22 response signatures to type 2-low severe neutrophilic asthma.

BACKGROUND: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases. OBJECTIVE: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma. METHODS: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort. RESULTS: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, TH2, and TH17/TH22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P < .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P < .05) and particularly in neutrophilic and mixed granulocytic sputum (P < .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with TH22/IL-22 pathways. CONCLUSIONS: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.

Proteomic Changes of Activated Hepatic Stellate Cells.

Hepatic stellate cells (HSC) are the major cellular drivers of liver fibrosis. Upon liver inflammation caused by a broad range of insults including non-alcoholic fatty liver, HSC transform from a quiescent into a proliferating, fibrotic phenotype. Although much is known about the pathophysiology of this process, exact cellular processes which occur in HSC and enable this transformation remain yet to be elucidated. In order to investigate this HSC transformation, we employed a simple, yet reliable model of HSC activation via an increase in growth medium serum concentration (serum activation). For that purpose, immortalized human LX-2 HSC were exposed to either 1% or 10% fetal bovine serum (FBS). Resulting quiescent (1% FBS) and activated (10% FBS) LX-2 cells were then subjected to in-depth mass spectrometry-based proteomics analysis as well as comprehensive phenotyping. Protein network analysis of activated LX-2 cells revealed an increase in the production of ribosomal proteins and proteins related to cell cycle control and migration, resulting in higher proliferation and faster migration phenotypes. Interestingly, we also observed a decrease in the expression of cholesterol and fatty acid biosynthesis proteins in accordance with a concomitant loss of cytosolic lipid droplets during activation. Overall, this work provides an update on HSC activation characteristics using contemporary proteomic and bioinformatic analyses and presents an accessible model for HSC activation. Data are available via ProteomeXchange with identifier PXD029121.

Maternal methylmercury exposure changes the proteomic profile of the offspring's salivary glands: Prospects on translational toxicology.

BACKGROUND: Methylmercury (MeHg) remains a public health issue since developing organisms are particularly vulnerable to this environmental contaminant. This study investigated the effect of maternal MeHg exposure on the modulation of proteomic profile of parotid (PA), submandibular (SM), and sublingual (SL) glands of offspring rats. MATERIALS AND METHODS: Pregnant Wistar rats were daily exposed to 40 µg/kg MeHg during both gestational and lactation periods. The proteomic profiles of the major salivary glands of the offspring rats were analyzed through mass spectrometry. RESULTS: The offspring rats exposed to MeHg showed significant alterations in the proteomic profiles of the PA, SM, and SL glands. Altered proteins were associated with cytoskeleton components, tissue morphogenesis, and response to stimulus and stress. CONCLUSION: This original study showed that maternal MeHg exposure significantly modulates the expression of proteins and induces alterations in the proteomic profiles of developing salivary glands.

Proteome-Informed Machine Learning Studies of Cocaine Addiction.

No anti-cocaine addiction drugs have been approved by the Food and Drug Administration despite decades of effort. The main challenge is the intricate molecular mechanisms of cocaine addiction, involving synergistic interactions among proteins upstream and downstream of the dopamine transporter. However, it is difficult to study so many proteins with traditional experiments, highlighting the need for innovative strategies in the field. We propose a proteome-informed machine learning (ML) platform for discovering nearly optimal anti-cocaine addiction lead compounds. We analyze proteomic protein-protein interaction networks for cocaine dependence to identify 141 involved drug targets and build 32 ML models for cross-target analysis of more than 60,000 drug candidates or experimental drugs for side effects and repurposing potentials. We further predict their ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties. Our platform reveals that essentially all of the existing drug candidates fail in our cross-target and ADMET screenings but identifies several nearly optimal leads for further optimization.

Artificial exosomes mediated spatiotemporal-resolved and targeted delivery of epigenetic inhibitors.

BACKGROUND: Malignant tumor is usually associated with epigenetic dysregulation, such as overexpression of histone deacetylase (HDAC), thus HDAC has emerged as a therapeutic target for cancer. Histone deacetylase inhibitor has been approved for clinical use to treat hematological cancers. However, the low solubility, short circulation lifetime, and high cytotoxicity partially limited their applications in solid tumor. METHODS: The upconversion nanoparticles (UC) modified with mesoporous silica (SUC) was used to load an HDACI, suberoylanilide hydroxamic acid (SAHA), and further camouflaged with M1 macrophage-derived exosome membranes (EMS). EMS was characterized in size and compositions. We also analyzed the epigenetic regulation induced by EMS. Furthermore, we evaluate the biodistribution and in vivo tumor inhibition after the systemic administration of EMS. RESULTS: This novel style spatiotemporal-resolved drug delivery system, EMS showed a high loading efficiency of SAHA. EMS could be taken up by lung cancer cells and lead to efficient epigenetic inhibition. We found that the integrin α4ß1 on M1-EM, was crucial for the homing of EMS to tumor tissues for the first time. In tumor-bearing mice, EMS showed spatiotemporal-resolved properties and facilitated the drug accumulation in the tumors, which induced superior anti-tumor effects. CONCLUSION: This novel style of spatiotemporal-resolved nanoparticles can be used as a theranostic platform for lung cancer therapy.