Iris lactea var. chinensis plant drought tolerance depends on the response of proline metabolism, transcription factors, transporters and the ROS-scavenging system.

BACKGROUND: Iris lactea var. chinensis, a perennial herbaceous species, is widely distributed and has good drought tolerance traits. However, there is little information in public databases concerning this herb, so it is difficult to understand the mechanism underlying its drought tolerance. RESULTS: In this study, we used Illumina sequencing technology to conduct an RNA sequencing (RNA-seq) analysis of I. lactea var. chinensis plants under water-stressed conditions and rehydration to explore the potential mechanisms involved in plant drought tolerance. The resulting de novo assembled transcriptome revealed 126,979 unigenes, of which 44,247 were successfully annotated. Among these, 1187 differentially expressed genes (DEGs) were identified from a comparison of the water-stressed treatment and the control (CK) treatment (T/CK); there were 481 upregulated genes and 706 downregulated genes. Additionally, 275 DEGs were identified in the comparison of the rehydration treatment and the water-stressed treatment (R/T). Based on Quantitative Real-time Polymerase Chain Reaction (qRT-PCR) analysis, the expression levels of eight randomly selected unigenes were consistent with the transcriptomic data under water-stressed and rehydration treatment, as well as in the CK. According to Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, proline metabolism-related DEGs, including those involved in the 'proline catabolic process', the 'proline metabolic process', and 'arginine and proline metabolism', may play important roles in plant drought tolerance. Additionally, these DEGs encoded 43 transcription factors (TFs), 46 transporters, and 22 reactive oxygen species (ROS)-scavenging system-related proteins. Biochemical analysis and histochemical detection showed that proline and ROS were accumulated under water-stressed conditions, which is consistent with the result of the transcriptomic analysis. CONCLUSIONS: In summary, our transcriptomic data revealed that the drought tolerance of I. lactea var. chinensis depends on proline metabolism, the action of TFs and transporters, and a strong ROS-scavenging system. The related genes found in this study could help us understand the mechanisms underlying the drought tolerance of I. lactea var. chinensis.

An Enzymatic Antibiotic Adjuvant Modulates the Infectious Microenvironment to Overcome Antimicrobial Resistance of Pathogens.

The emergence and evolution of antimicrobial resistance (AMR) pose a significant challenge to the current arsenal to fight infection. Antibiotic adjuvants represent an appealing tactic for tackling the AMR of pathogens, however, their practical applications are greatly constrained by the harsh infectious microenvironment. Herein, it is found that silver nanoclusters (Ag NCs) can possess tunable enzymatic activities to modulate infectious microenvironments. Based on this finding, an enzymatic nanoadjuvant (EnzNA) self-assembled from Ag NCs, which is inert under neutral physiological conditions but can readily disassemble into isolated Ag NCs exhibiting biofilm destructive oxidase-mimetic activity in the acidic biofilm microenvironment, is developed. Once internalized into the neutral cytoplasm of bacteria, Ag NCs switch to reveal the thiol oxidase-mimetic activity to suppress ribosomal biogenesis for AMR reversal and evolution inhibition of pathogens. Consequently, EnzNAs revitalize various existing antibiotics against methicillin-resistant Staphylococcus aureus, and potentiate the antibiotic efficacy against biofilm-mediated skin infection and lethal lung infection in mice. These findings highlight the capability of enzyme-mimetic nanomaterials to modulate the infectious microenvironment and potentiate antibiotics, providing a paradigm shift for anti-infection therapy.

CRISPR/Cas9 and Agrobacterium tumefaciens virulence proteins synergistically increase efficiency of precise genome editing via homology directed repair in plants.

CRISPR/Cas9 genome editing and Agrobacterium tumefaciens-mediated genetic transformation are widely-used plant biotechnology tools derived from bacterial immunity-related systems, each involving DNA modification. The Cas9 endonuclease introduces DNA double-strand breaks (DSBs), and the A. tumefaciens T-DNA is released by the VirD2 endonuclease assisted by VirDl and attached by VirE2, transferred to the plant nucleus and integrated into the genome. Here, we explored the potential for synergy between the two systems and found that Cas9 and three virulence (Vir) proteins achieve precise genome editing via the homology directed repair (HDR) pathway in tobacco and rice plants. Compared with Cas9T (Cas9, VirD1, VirE2) and CvD (Cas9-VirD2) systems, the HDR frequencies of a foreign GFPm gene in the CvDT system (Cas9-VirD2, VirD1, VirE2) increased 52-fold and 22-fold, respectively. Further optimization of the CvDT process with a donor linker (CvDTL) achieved a remarkable increase in the efficiency of HDR-mediated genome editing. Additionally, the HDR efficiency of the three rice endogenous genes ACETOLACTATE SYNTHASE (ALS), PHYTOENE DESATURASE (PDS), and NITROGEN TRANSPORTER 1.1 B (NRT1.1B) increased 24-, 32- and 16-fold, respectively, in the CvDTL system, compared with corresponding Cas9TL (Cas9T process with a donor linker). Our results suggest that collaboration between CRISPR/Cas9 and Agrobacterium-mediated genetic transformation can make great progress towards highly efficient and precise genome editing via the HDR pathway.

Advanced Therapies for Traumatic Central Nervous System Injury: Delivery Strategy Reinforced Efficient Microglial Manipulation.

Traumatic central nervous system (CNS) injuries, including spinal cord injury and traumatic brain injury, are challenging enemies of human health. Microglia, the main component of the innate immune system in CNS, can be activated postinjury and are key participants in the pathological procedure and development of CNS trauma. Activated microglia can be typically classified into pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Reducing M1 polarization while promoting M2 polarization is thought to be promising for CNS injury treatment. However, obstacles such as the low permeability of the blood-brain barrier and short retention time in circulation limit the therapeutic outcomes of administrated drugs, and rational delivery strategies are necessary for efficient microglial regulation. To this end, proper administration methods and delivery systems like nano/microcarriers and scaffolds are investigated to augment the therapeutic effects of drugs, while some of these delivery systems have self-efficacies in microglial manipulation. Besides, systems based on cell and cell-derived exosomes also show impressive effects, and some underlying targeting mechanisms of these delivery systems have been discovered. In this review, we introduce the roles of microglia play in traumatic CNS injuries, discuss the potential targets for the polarization regulation of microglial phenotype, and summarize recent studies and clinical trials about delivery strategies on enhancing the effect of microglial regulation and therapeutic outcome, as well as targeting mechanisms post CNS trauma.

An antioxidative sophora exosome-encapsulated hydrogel promotes spinal cord repair by regulating oxidative stress microenvironment.

Spinal cord injury (SCI) is a severe traumatic disease because of its complications and multi-organ dysfunction. After the injury, the disruption of microenvironment homeostasis in the lesion demolishes the surrounding healthy tissues via various pathways. The microenvironment regulation is beneficial for neural and functional recovery. Sustained release, cellular uptake, and long-term retention of therapeutic molecules at the impaired sites are important for continuous microenvironment improvement. In our study, a local-implantation system was constructed for SCI treatment by encapsulating exosomes derived from Flos Sophorae Immaturus (so-exos) in a polydopamine-modified hydrogel (pDA-Gel). So-exos are used as nanoscale natural vehicles of rutin, a flavonoid phytochemical that is effective in microenvironment improvement and nerve regeneration. Our study showed that the pDA-Gel-encapsulated so-exos allowed rapid improvement of the impaired motor function and alleviation of urination dysfunction by modulating the spinal inflammatory and oxidative conditions, thus illustrating a potential SCI treatment through a combinational delivery of so-exos.

A novel hypoxia-associated gene signature for prognosis prediction in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the most common malignant tumor of head and neck, which seriously threatens human life and health. However, the mechanism of hypoxia-associated genes (HAGs) in HNSCC remains unelucidated. This study aims to establish a hypoxia-associated gene signature and the nomogram for predicting the prognosis of patients with HNSCC. METHODS: Previous literature reports provided a list of HAGs. The TCGA database provided genetic and clinical information on HNSCC patients. First, a hypoxia-associated gene risk model was constructed for predicting overall survival (OS) in HNSCC patients and externally validated in four GEO datasets (GSE27020, GSE41613, GSE42743, and GSE117973). Then, immune status and metabolic pathways were analyzed. A nomogram was constructed and assessed the predictive value. Finally, experimental validation of the core genes was performed by qRT-PCR. RESULTS: A HNSCC prognostic model was constructed based on 8 HAGs. This risk model was validated in four external datasets and exhibited high predictive value in various clinical subgroups. Significant differences in immune cell infiltration levels and metabolic pathways were found between high and low risk subgroups. The nomogram was highly accurate for predicting OS in HNSCC patients. CONCLUSIONS: The 8 hypoxia-associated gene signature can serve as novel independent prognostic indicators in HNSCC patients. The nomogram combining the risk score and clinical stage enhanced predictive performance in predicting OS compared to the risk model and clinical characteristics alone.

The Cotton Apoplastic Protein CRR1 Stabilizes Chitinase 28 to Facilitate Defense against the Fungal Pathogen Verticillium dahliae.

The apoplast serves as the first battlefield between the plant hosts and invading microbes; therefore, work on plant-pathogen interactions has increasingly focused on apoplastic immunity. In this study, we identified three proteins in the apoplast of cotton (Gossypium sp) root cells during interaction of the plant with the fungal pathogen Verticillium dahliae Among these proteins, cotton host cells secrete chitinase 28 (Chi28) and the Cys-rich repeat protein 1 (CRR1), while the pathogen releases the protease VdSSEP1. Biochemical analysis demonstrated that VdSSEP1 hydrolyzed Chi28, but CRR1 protected Chi28 from cleavage by Verticillium dahliae secretory Ser protease 1 (VdSSEP1). In accordance with the in vitro results, CRR1 interacted with Chi28 in yeast and plant cells and attenuated the observed decrease in Chi28 level that occurred in the apoplast of plant cells upon pathogen attack. Knockdown of CRR1 or Chi28 in cotton plants resulted in higher susceptibility to V. dahliae infection, and overexpression of CRR1 increased plant resistance to V dahliae, the fungus Botrytis cinerea, and the oomycete Phytophthora parasitica var nicotianae By contrast, knockout of VdSSEP1 in V. dahliae destroyed the pathogenicity of this fungus. Together, our results provide compelling evidence for a multilayered interplay of factors in cotton apoplastic immunity.

Stimuli-Responsive Drug Delivery Systems for the Diagnosis and Therapy of Lung Cancer.

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer death worldwide. Numerous drugs have been developed to treat lung cancer patients in recent years, whereas most of these drugs have undesirable adverse effects due to nonspecific distribution in the body. To address this problem, stimuli-responsive drug delivery systems are imparted with unique characteristics and specifically deliver loaded drugs at lung cancer tissues on the basis of internal tumor microenvironment or external stimuli. This review summarized recent studies focusing on the smart carriers that could respond to light, ultrasound, pH, or enzyme, and provided a promising strategy for lung cancer therapy.

Sandbur Drought Tolerance Reflects Phenotypic Plasticity Based on the Accumulation of Sugars, Lipids, and Flavonoid Intermediates and the Scavenging of Reactive Oxygen Species in the Root.

The perennial grass Cenchrus spinifex (common sandbur) is an invasive species that grows in arid and semi-arid regions due to its remarkable phenotypic plasticity, which confers the ability to withstand drought and other forms of abiotic stress. Exploring the molecular mechanisms of drought tolerance in common sandbur could lead to the development of new strategies for the protection of natural and agricultural environments from this weed. To determine the molecular basis of drought tolerance in C. spinifex, we used isobaric tags for relative and absolute quantitation (iTRAQ) to identify proteins differing in abundance between roots growing in normal soil and roots subjected to moderate or severe drought stress. The analysis of these proteins revealed that drought tolerance in C. spinifex primarily reflects the modulation of core physiological activities such as protein synthesis, transport and energy utilization as well as the accumulation of flavonoid intermediates and the scavenging of reactive oxygen species. Accordingly, plants subjected to drought stress accumulated sucrose, fatty acids, and ascorbate, shifted their redox potential (as determined by the NADH/NAD ratio), accumulated flavonoid intermediates at the expense of anthocyanins and lignin, and produced less actin, indicating fundamental reorganization of the cytoskeleton. Our results show that C. spinifex responds to drought stress by coordinating multiple metabolic pathways along with other adaptations. It is likely that the underlying metabolic plasticity of this species plays a key role in its invasive success, particularly in semi-arid and arid environments.

The Cotton miR477-CBP60A Module Participates in Plant Defense Against Verticillium dahlia.

Previous reports have shown that, when Verticillium dahliae localizes at the root surface, many microRNAs (miRNAs) were identified at the early induction stage. Here, we constructed two groups from two timepoints of small RNA (sRNA) in cotton root responses to V. dahliae at the later induction stage, pathogen localizing in the interior of root tissue. We identified 71 known and 378 novel miRNAs from six libraries of the pathogen-induced and the control sRNAs. Combined with degradome and sRNA sequencing, 178 corresponding miRNA target genes were identified, in which 40 target genes from differentially expressed miRNAs were primarily associated with oxidation-reduction and stress responses. More importantly, we characterized the cotton miR477-CBP60A module in the later response of the plant to V. dahliae infection. A ß-glucuronidase fusion reporter and cleavage site analysis showed that ghr-miR477 directly cleaved the messenger RNA of GhCBP60A in the posttranscriptional process. The ghr-miR477-silencing decreased plant resistance to this fungus, while the knockdown of GhCBP60A increased plant resistance, which regulated GhICS1 expression to determine salicylic acid level. Our data documented that numerous later-inducible miRNAs in the plant response to V. dahliae, suggesting that these miRNAs play important roles in plant resistance to vascular disease.

Renal-Clearable Hollow Bismuth Subcarbonate Nanotubes for Tumor Targeted Computed Tomography Imaging and Chemoradiotherapy.

Although metallic nanomaterials with high X-ray attenuation coefficients have been widely used as X-ray computed tomography (CT) contrast agents, their intrinsically poor biodegradability requires them to be cleared from the body to avoid any potential toxicity. On the other hand, extremely small-sized nanomaterials with outstanding renal clearance properties are not much effective for tumor targeting because of their too rapid clearance in vivo. To overcome this dilemma, here we report on the hollow bismuth subcarbonate nanotubes (BNTs) assembled from renal-clearable ultrasmall bismuth subcarbonate nanoclusters for tumor-targeted imaging and chemoradiotherapy. The BNTs could be targeted to tumors with high efficiency and exhibit a high CT contrast effect. Moreover, simultaneous radio- and chemotherapy using drug-loaded BNTs could significantly suppress tumor volumes, highlighting their potential application in CT imaging-guided therapy. Importantly, the elongated nanotubes could be disassembled into isolated small nanoclusters in the acidic tumor microenvironment, accelerating the payload release and kidney excretion. Such body clearable CT contrast agent with high imaging performance and multiple therapeutic functions shall have a substantial potential for biomedical applications.

iTRAQ Protein Profile Differential Analysis of Dormant and Germinated Grassbur Twin Seeds Reveals that Ribosomal Synthesis and Carbohydrate Metabolism Promote Germination Possibly Through the PI3K Pathway.

Grassbur is a destructive and invasive weed in pastures, and its burs can cause gastric damage to animals. The strong adaptability and reproductive potential of grassbur are partly due to a unique germination mechanism whereby twin seeds develop in a single bur: one seed germinates, but the other remains dormant. To investigate the molecular mechanism of seed germination in twin seeds, we used isobaric tags for relative and absolute quantitation (iTRAQ) to perform a dynamic proteomic analysis of germination and dormancy. A total of 1,984 proteins were identified, 161 of which were considered to be differentially accumulated. The differentially accumulated proteins comprised 102 up-regulated and 59 down-regulated proteins. These proteins were grouped into seven functional categories, ribosomal proteins being the predominant group. The authenticity and accuracy of the results were confirmed by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time reverse transcription-PCR (qPCR). A dynamic proteomic analysis revealed that ribosome synthesis and carbohydrate metabolism affect seed germination possibly through the phosphoinositide 3-kinase (PI3K) pathway. As the PI3K pathway is generally activated by insulin, analyses of seeds treated with exogenous insulin by qPCR, ELISA and iTRAQ confirmed that the PI3K pathway can be activated, which suppresses dormancy and promotes germination in twin grassbur seeds. Together, these results show that the PI3K pathway may play roles in stimulating seed germination in grassbur by modulating ribosomal synthesis and carbohydrate metabolism.

The cotton MYB108 forms a positive feedback regulation loop with CML11 and participates in the defense response against Verticillium dahliae infection.

Accumulating evidence indicates that plant MYB transcription factors participate in defense against pathogen attack, but their regulatory targets and related signaling processes remain largely unknown. Here, we identified a defense-related MYB gene (GhMYB108) from upland cotton (Gossypium hirsutum) and characterized its functional mechanism. Expression of GhMYB108 in cotton plants was induced by Verticillium dahliae infection and responded to the application of defense signaling molecules, including salicylic acid, jasmonic acid, and ethylene. Knockdown of GhMYB108 expression led to increased susceptibility of cotton plants to V. dahliae, while ecotopic overexpression of GhMYB108 in Arabidopsis thaliana conferred enhanced tolerance to the pathogen. Further analysis demonstrated that GhMYB108 interacted with the calmodulin-like protein GhCML11, and the two proteins form a positive feedback loop to enhance the transcription of GhCML11 in a calcium-dependent manner. Verticillium dahliae infection stimulated Ca(2+) influx into the cytosol in cotton root cells, but this response was disrupted in both GhCML11-silenced plants and GhMYB108-silenced plants in which expression of several calcium signaling-related genes was down-regulated. Taken together, these results indicate that GhMYB108 acts as a positive regulator in defense against V. dahliae infection by interacting with GhCML11. Furthermore, the data also revealed the important roles and synergetic regulation of MYB transcription factor, Ca(2+), and calmodulin in plant immune responses.

Functional Characterization of a Dihydroflavanol 4-Reductase from the Fiber of Upland Cotton (Gossypium hirsutum).

Dihydroflavanol 4-reductase (DFR) is a key later enzyme involved in two polyphenols' (anthocyanins and proanthocyanidins (PAs)) biosynthesis, however it is not characterized in cotton yet. In present reports, a DFR cDNA homolog (designated as GhDFR1) was cloned from developing fibers of upland cotton. Silencing GhDFR1 in cotton by virus-induced gene silencing led to significant decrease in accumulation of anthocyanins and PAs. More interestingly, based on LC-MS analysis, two PA monomers, (-)-epicatachin and (-)-epigallocatachin, remarkably decreased in content in fibers of GhDFR1-silenced plants, but two new monomers, (-)-catachin and (-)-gallocatachin were present compared to the control plants infected with empty vector. The ectopic expression of GhDFR1 in an Arabidopsis TT3 mutant allowed for reconstruction of PAs biosynthesis pathway and led to accumulation of PAs in seed coat. Taken together, these data demonstrate that GhDFR1 contributes to the biosynthesis of anthocyanins and PAs in cotton.

iTRAQ protein profile differential analysis between somatic globular and cotyledonary embryos reveals stress, hormone, and respiration involved in increasing plantlet regeneration of Gossypium hirsutum L.

Somatic embryo development (SED) in upland cotton shows low frequencies of embryo maturation and plantlet regeneration. Progress in increasing the regeneration rate has been limited. Here a global analysis of proteome dynamics between globular and cotyledonary embryos was performed using isobaric tags for relative and absolute quantitation to explore mechanisms underlying SED. Of 6318 proteins identified by a mass spectrometric analysis, 102 proteins were significantly up-regulated and 107 were significantly down-regulated in cotyledonary embryos. The differentially expressed proteins were classified into seven functional categories: stress responses, hormone synthesis and signal transduction, carbohydrate and energy metabolism, protein metabolism, cell wall metabolism, cell transport, and lipid metabolism. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis showed that stress response, hormone homeostasis, and respiration and photosynthesis were involved in SED. Quantitative real-time PCR analysis confirmed the authenticity and accuracy of the proteomic analysis. Treatment of exogenous hormones showed that abscisic acid and jasmonic acid facilitate SED, whereas gibberellic acid inhibits SED and increases abnormal embryo frequency. Thus, global analysis of proteome dynamics reveals that stress response, hormone homeostasis, and respiration and photosynthesis determined cotton SED. The findings of this research improve the understanding of molecular processes, especially environmental stress response, involved in cotton SED.

OsLOL1, a C2C2-type zinc finger protein, interacts with OsbZIP58 to promote seed germination through the modulation of gibberellin biosynthesis in Oryza sativa.

Seed germination is a key developmental process in the plant life cycle that is influenced by various environmental cues and phytohormones through gene expression and a series of metabolism pathways. In the present study, we investigated a C2C2-type finger protein, OsLOL1, which promotes gibberellin (GA) biosynthesis and affects seed germination in Oryza sativa (rice). We used OsLOL1 antisense and sense transgenic lines to explore OsLOL1 functions. Seed germination timing in antisense plants was restored to wild type when exogenous GA3 was applied. The reduced expression of the GA biosynthesis gene OsKO2 and the accumulation of ent-kaurene were observed during germination in antisense plants. Based on yeast two-hybrid and firefly luciferase complementation analyses, OsLOL1 interacted with the basic leucine zipper protein OsbZIP58. The results from electrophoretic mobility shift and dual-luciferase reporter assays showed that OsbZIP58 binds the G-box cis-element of the OsKO2 promoter and activates LUC reporter gene expression, and that interaction between OsLOL1 and OsbZIP58 activates OsKO2 gene expression. In addition, OsLOL1 decreased SOD1 gene expression and accelerated programmed cell death (PCD) in the aleurone layer of rice grains. These findings demonstrate that the interaction between OsLOL1 and OsbZIP58 influences GA biosynthesis through the activation of OsKO2 via OsbZIP58, thereby stimulating aleurone PCD and seed germination.

Functional characterization of an anthocyanidin reductase gene from the fibers of upland cotton (Gossypium hirsutum).

MAIN CONCLUSION: Metabolic profiling, gene cloning, enzymatic analysis, ectopic expression, and gene silencing experiments demonstrate that the anthocyanidin reductase (ANR) pathway is involved in the biosynthesis of proanthocyanidins in upland cotton. Proanthocyanidins (PAs) are oligomeric or polymeric flavan-3-ols, however, the biosynthetic pathway of PAs in cotton remains to be elucidated. Here, we report on an anthocyanidin reductase (ANR) gene from cotton fibers and the ANR pathway of PAs. Phytochemical analysis demonstrated that leaves, stems, roots, and early developing fibers produced PAs and their monomers, including (-)-epicatechin, (-)-catechin, (-)-epigallocatechin, and (-)-gallocatechin. Crude PA extractions from different tissues were boiled in Butanol:HCl. Cyanidin, delphinidin, and pelargonidin were produced, indicating that cotton PAs include diverse extension unit structures. An ANR cDNA homolog (named GhANR1) was cloned from developing fibers. The open reading frame, composed of 1,011 bp nucleotides, was expressed in E. coli to obtain a recombinant protein. In the presence of NADPH, the recombinant enzyme catalyzed cyanidin, delphinidin, and pelargonidin to (-)-epicatechin and (-)-catechin, (-)-epigallocatechin and (-)-gallocatechin, and (-)-epiafzelechin and (-)-afzelechin, respectively. The ectopic expression of GhANR11 in an Arabidopsis ban mutant allowed for the reconstruction of the ANR pathway and PA biosynthesis in the seed coat. Virus-induced gene silencing (VIGS) of GhANR11 led to a significant increase in anthocyanins and a decrease in the PAs, (-)-epicatechin, and (-)-catechin in the stems and leaves of VIGS-infected plants. Taken together, these data demonstrate that the ANR pathway contributes to the biosynthesis of flavan-3-ols and PAs in cotton.

Transcriptomic analysis reveals the lipid metabolism-related gene regulatory characteristics and potential therapeutic agents for myocardial ischemia-reperfusion injury.

Background: Impaired energy balance caused by lipid metabolism dysregulation is an essential mechanism of myocardial ischemia-reperfusion injury (MI/RI). This study aims to explore the lipid metabolism-related gene (LMRG) expression patterns in MI/RI and to find potential therapeutic agents. Methods: Differential expression analysis was performed to screen the differentially expressed genes (DEGs) and LMRGs in the MI/RI-related dataset GSE61592. Enrichment and protein-protein interaction (PPI) analyses were performed to identify the key signaling pathways and genes. The expression trends of key LMRGs were validated by external datasets GSE160516 and GSE4105. The corresponding online databases predicted miRNAs, transcription factors (TFs), and potential therapeutic agents targeting key LMRGs. Finally, the identified LMRGs were confirmed in the H9C2 cell hypoxia-reoxygenation (H/R) model and the mouse MI/RI model. Results: Enrichment analysis suggested that the "lipid metabolic process" was one of the critical pathways in MI/RI. Further differential expression analysis and PPI analysis identified 120 differentially expressed LMRGs and 15 key LMRGs. 126 miRNAs, 55 TFs, and 51 therapeutic agents were identified targeting these key LMRGs. Lastly, the expression trends of Acadm, Acadvl, and Suclg1 were confirmed by the external datasets, the H/R model and the MI/RI model. Conclusion: Acadm, Acadvl, and Suclg1 may be the key genes involved in the MI/RI-related lipid metabolism dysregulation; and acting upon these factors may serve as a potential therapeutic strategy.

Identification of the communal pathogenesis and immune landscape between viral myocarditis and dilated cardiomyopathy.

AIMS: Studies have confirmed that viral myocarditis (VMC) is one of the risk factors for dilated cardiomyopathy (DCM). The molecular mechanisms underlying the progression from VMC to DCM remain unclear and require further investigation. METHODS AND RESULTS: The mRNA microarray datasets GSE57338 (DCM) and GSE1145 (VMC) were obtained from the Gene Expression Omnibus database. The candidate key genes were further screened using weighted correlation network analysis (WGCNA), protein-protein interaction and external dataset validation, and the correlation between the candidate key genes and immune cells and the signalling pathways of the candidate key genes were observed by enrichment analysis and immune infiltration analysis. The expression of key genes was validated in the external dataset GSE35182. The crosstalk genes between DCM and VMC were mainly enriched in 'transcriptional misregulation in cancer', 'FoxO signalling pathway', 'AGE-RAGE signalling pathway in diabetic complications', 'thyroid hormone signalling pathway', 'AMPK signalling pathway', and other signalling pathways. The immune infiltration analysis indicated that VMC was mainly associated with resting dendritic cells and M0 macrophages, while DCM was mainly associated with monocytes, M0 macrophages, CD8+ T cells, resting CD4 memory T cells, naive CD4+ T cells, and resting mast cells. In DCM-related dataset GSE57338 and VMC-related dataset GSE1145, a total of 18 candidate key genes were differentially expressed. BLC6, FOXO1, and UBE2M were identified as the key genes that lead to the progression from VMC to DCM by GSE35182. CONCLUSIONS: Three key genes (BLC6, FOXO1, and UBE2M) were identified and provided new insights into the diagnosis and treatment of VMC with DCM.

A Pluripotential Neutrophil-Mimic Nanovehicle Modulates Immune Microenvironment with Targeted Drug Delivery for Augmented Antitumor Chemotherapy.

The limited therapeutic outcomes and severe systemic toxicity of chemotherapy remain major challenges to the current clinical antitumor therapeutic regimen. Tumor-targeted drug delivery that diminishes the undifferentiated systemic distribution is a practical solution to ameliorating systemic toxicity. However, the tumor adaptive immune microenvironment still poses a great threat that compromises the therapeutic efficacy of chemotherapy by promoting the tolerance of the tumor cells. Herein, a pluripotential neutrophil-mimic nanovehicle (Neutrosome(L)) composed of an activated neutrophil membrane-incorporated liposome is proposed to modulate the immune microenvironment and synergize antitumor chemotherapy. The prominent tumor targeting capability inherited from activated neutrophils and the improved tumor penetration ability of Neutrosome(L) enable considerable drug accumulation in tumor tissues (more than sixfold that of free drug). Importantly, Neutrosome(L) can modulate the immune microenvironment by restricting neutrophil infiltration in tumor tissue, which may be attributed to the neutralization of inflammatory cytokines, thus potentiating antitumor chemotherapy. As a consequence, the treatment of cisplatin-loaded Neutrosome(L) performs prominent tumor suppression effects, reduces systemic drug toxicity, and prolongs the survival period of tumor-bearing mice. The pluripotential neutrophil-mimic nanovehicle proposed in this study can not only enhance the tumor accumulation of chemotherapeutics but also modulate the immune microenvironment, providing a compendious strategy for augmented antitumor chemotherapy.