Extracellular RNA Sensing Mediates Inflammation and Organ Injury in a Murine Model of Polytrauma.

Severe traumatic injury leads to marked systemic inflammation and multiorgan injury. Endogenous drivers such as extracellular nucleic acid may play a role in mediating innate immune response and the downstream pathogenesis. Here, we explored the role of plasma extracellular RNA (exRNA) and its sensing mechanism in inflammation and organ injury in a murine model of polytrauma. We found that severe polytrauma-bone fracture, muscle crush injury, and bowel ischemia-induced a marked increase in plasma exRNA, systemic inflammation, and multiorgan injury in mice. Plasma RNA profiling with RNA sequencing in mice and humans revealed a dominant presence of miRNAs and marked differential expression of numerous miRNAs after severe trauma. Plasma exRNA isolated from trauma mice induced a dose-dependent cytokine production in macrophages, which was almost abolished in TLR7-deficient cells but unchanged in TLR3-deficient cells. Moreover, RNase or specific miRNA inhibitors against the selected proinflammatory miRNAs (i.e., miR-7a-5p, miR-142, let-7j, miR-802, and miR-146a-5p) abolished or attenuated trauma plasma exRNA-induced cytokine production, respectively. Bioinformatic analyses of a group of miRNAs based on cytokine readouts revealed that high uridine abundance (>40%) is a reliable predictor in miRNA mimic-induced cytokine and complement production. Finally, compared with the wild-type, TLR7-knockout mice had attenuated plasma cytokine storm and reduced lung and hepatic injury after polytrauma. These data suggest that endogenous plasma exRNA of severely injured mice and ex-miRNAs with high uridine abundance prove to be highly proinflammatory. TLR7 sensing of plasma exRNA and ex-miRNAs activates innate immune responses and plays a role in inflammation and organ injury after trauma.

Three-Dimensional Covalent Organic Frameworks: From Synthesis to Applications.

Three-dimensional covalent organic frameworks (3D COFs) with spatially periodic networks demonstrate significant advantages over their 2D counterparts, including enhanced specific surface areas, interconnected channels, and more sufficiently exposed active sites. Nevertheless, research on these materials has met an impasse due to serious problems in crystallization and stability, which must be solved for practical applications. In this Minireview, we first summarize some strategies for preparing functional 3D COFs, including crystallization techniques and functionalization methods. Hereafter, applications of these functional materials are presented, covering adsorption, separation, catalysis, fluorescence, sensing, and batteries. Finally, the future challenges and perspectives for the development of 3D COFs are discussed.

Piezochromism in Dynamic Three-Dimensional Covalent Organic Frameworks.

Piezochromic materials with pressure-dependent photoluminescence tuning properties are important in many fields, such as mechanical sensors, security papers, and storage devices. Covalent organic frameworks (COFs), as an emerging class of crystalline porous materials (CPMs) with structural dynamics and tunable photophysical properties, are suitable for designing piezochromic materials, but there are few related studies. Herein, we report two dynamic three-dimensional COFs based on aggregation-induced emission (AIE) or aggregation-caused quenching (ACQ) chromophores, termed JUC-635 and JUC-636 (JUC=Jilin University China), and for the first time, study their piezochromic behavior by diamond anvil cell technique. Due to the various luminescent groups, JUC-635 has completely different solvatochromism and molecular aggregation behavior in the solvents. More importantly, JUC-635 with AIE effect exhibits a sustained fluorescence upon pressure increase (≈3 GPa), and reversible sensitivity with high-contrast emission differences (Δλem =187 nm) up to 12 GPa, superior to other CPMs reported so far. Therefore, this study will open a new gate to expand the potential applications of COFs as exceptional piezochromic materials in pressure sensing, barcoding, and signal switching.

Brain innate immune response via miRNA-TLR7 sensing in polymicrobial sepsis.

Sepsis-associated encephalopathy (SAE) occurs in sepsis survivors and is associated with breakdown of the blood-brain barrier (BBB), brain inflammation, and neurological dysfunction. We have previously identified a group of extracellular microRNAs (ex-miRNAs), such as miR-146a-5p, that were upregulated in the plasma of septic mice and human, and capable of inducing potent pro-inflammatory cytokines and complements. Here, we established a clinically relevant mouse model of SAE and investigated the role of extracellular miRNAs and their sensor Toll-like receptor 7 (TLR7) in brain inflammation and neurological dysfunction. We observed BBB disruption and a profound neuroinflammatory responses in the brain for up to 14 days post-sepsis; these included increased pro-inflammatory cytokines production, microglial expansion, and peripheral leukocyte accumulation in the CNS. In a battery of neurobehavioral tests, septic mice displayed impairment of motor coordination and neurological function. Sepsis significantly increased plasma RNA and miRNA levels for up to 7 days, such as miR-146a-5p. Exogenously added miR-146a-5p induces innate immune responses in both cultured microglia/astrocytes and the intact brain via a TLR7-dependent manner. Moreover, mice genetically deficient of miR-146a showed reduced accumulation of monocytes and neutrophils in the brain compared to WT after sepsis. Finally, ablation of TLR7 in the TLR7-/- mice preserved BBB integrity, reduced microglial expansion and leukocyte accumulation, and attenuated GSK3ß signaling in the brain, but did not improve neurobehavioral recovery following sepsis. Taken together, these data establish an important role of extracellular miRNA and TLR7 sensing in sepsis-induced brain inflammation.

Uncovering the cellular capacity for intensive and specific feedback self-control of the argonautes and MicroRNA targeting activity.

The miRNA pathway has three segments-biogenesis, targeting and downstream regulatory effectors. We aimed to better understand their cellular control by exploring the miRNA-mRNA-targeting relationships. We first used human evolutionarily conserved sites. Strikingly, AGOs 1-3 are all among the top 14 mRNAs with the highest miRNA site counts, along with ANKRD52, the phosphatase regulatory subunit of the recently identified AGO phosphorylation cycle; and the AGO phosphorylation cycle mRNAs share much more than expected miRNA sites. The mRNAs for TNRC6, which acts with AGOs to channel miRNA-mediated regulatory actions onto specific mRNAs, are also heavily miRNA-targeted. In contrast, upstream miRNA biogenesis mRNAs are not, and neither are downstream regulatory effectors. In short, binding site enrichment in miRNA targeting machinery mRNAs, but neither upstream biogenesis nor downstream effector mRNAs, was observed, endowing a cellular capacity for intensive and specific feedback control of the targeting activity. The pattern was confirmed with experimentally determined miRNA-mRNA target relationships. Moreover, genetic experiments demonstrated cellular utilization of this capacity. Thus, we uncovered a capacity for intensive, and specific, feedback-regulation of miRNA targeting activity directly by miRNAs themselves, i.e. segment-specific feedback auto-regulation of miRNA pathway, complementing miRNAs pairing with transcription factors to form hybrid feedback-loop.

Three-Dimensional Triptycene-Based Covalent Organic Frameworks with ceq or acs Topology.

The growth of three-dimensional covalent organic frameworks (3D COFs) with new topologies is still considered as a great challenge due to limited availability of high-connectivity building units. Here we report the design and synthesis of 3D triptycene-based COFs, termed JUC-568 and JUC-569, following the deliberate symmetry-guided design principle. By combining a triangular prism (6-connected) node with a planar triangle (3-connected) or another triangular prism node, the targeted COFs adopt non-interpenetrated ceq or acs topology, respectively. Both materials show permanent porosity and impressive performance in the adsorption of CO2 (∼98 cm3/g at 273 K and 1 bar), CH4 (∼48 cm3/g at 273 K and 1 bar), and especially H2 (up to 274 cm3/g or 2.45 wt % at 77 K and 1 bar), which is highest among porous organic materials reported to date. This research thus provides a promising strategy for diversifying 3D COFs based on complex building blocks and promotes their potential applications in energy storage and environment-related fields.

3D Hydrazone-Functionalized Covalent Organic Frameworks as pH-Triggered Rotary Switches.

The property expansion of 3D functionalized covalent organic frameworks (COFs) is important for developing their potential applications. Herein, the first case of 3D hydrazone-decorated COFs as pH-triggered molecular switches is reported, and their application in the stimuli-responsive drug delivery system is explored. These functionalized COFs with hydrazone groups on the channel walls are obtained via a multi-component bottom-up synthesis strategy. They exhibit a reversible E/Z isomerization at various pH values, confirmed by UV-vis absorption spectroscopy and proton conduction. Remarkably, after loading cytarabine (Ara-C) as a model drug molecule, these pH-responsive COFs show an excellent and intelligent sustained-release effect with an almost fourfold increase in the Ara-C release at pH = 4.8 than at pH = 7.4, which will effectively improve drug-targeting. Thus, these results open a way toward designing 3D stimuli-responsive functionalized COF materials and promote their potential application as drug carriers in the field of disease treatment.

Design and applications of three dimensional covalent organic frameworks.

Covalent organic frameworks (COFs), as an emerging class of crystalline porous polymers connected by dynamic covalent bonds, have been well studied over the past decade. Recently, three dimensional (3D) COFs have attracted extensive interest for the synthesis and applications of novel COFs. The principal reason for this rising trend is based on their unique porous features and excellent performances compared to previously reported two dimensional (2D) frameworks with the layered AA-stacking mode. This critical review describes the current state-of-the-art development of 3D COFs in the design principles, synthetic methods, functionalization strategies, and potential applications. Some major challenges associated with future perspectives are further discussed, inspiring the development of 3D COFs.

Three-Dimensional Radical Covalent Organic Frameworks as Highly Efficient and Stable Catalysts for Selective Oxidation of Alcohols.

With excellent designability, large accessible inner surface, and high chemical stability, covalent organic frameworks (COFs) are promising candidates as metal-free heterogeneous catalysts. Here, we report two 3D radical-based COFs (JUC-565 and JUC-566) in which radical moieties (TEMPO) are uniformly decorated on the channel walls via a bottom-up approach. Based on grafted functional groups and suitable regular channels, these materials open up the application of COFs as highly efficient and selective metal-free redox catalysts in aerobic oxidation of alcohols to relevant aldehydes or ketones with outstanding turn over frequency (TOF) up to 132 h-1 , which has exceeded other TEMPO-modified catalytic materials tested under similar conditions. These stable COF-based catalysts could be easily recovered and reused for multiple runs. This study promotes potential applications of 3D functional COFs anchored with stable radicals in organic synthesis and material science.

Three-Dimensional Large-Pore Covalent Organic Framework with stp Topology.

Three-dimensional (3D) covalent organic frameworks (COFs) are excellent crystalline porous polymers for numerous potential applications, but their building units and topological nets have been limited. Herein we report the design and synthesis of the first 3D large-pore COF with the stp topology constructed from a 6-connected triptycene-based monomer. The new COF (termed JUC-564) has a high specific surface area (up to 3300 m2 g-1), the largest pore size among 3D COFs (43 Å), and record-breaking low density among crystalline materials reported to date (0.108 g cm-3). The large pore size of JUC-564 was confirmed by the incorporation of a protein. This study expands the structural varieties of 3D COFs based on the deliberate symmetry-guided design principle as well as their applications for adsorption and separation of large biological molecules.

Reversal of paclitaxel resistance in human ovarian cancer cells with redox-responsive micelles consisting of α-tocopheryl succinate-based polyphosphoester copolymers.

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle in achieving the therapeutic benefits of paclitaxel (PTX) in the treatment of human ovarian carcinoma. This study is aimed to develop an efficient PTX drug delivery approach to overcome MDR. Redox-responsive micelles consisting of amphiphilic polymers containing disulfide linkages, ie, poly (phosphate ester)-SS-D-α-tocopheryl succinate (POPEA-SS-TOS, PSST) were prepared. PTX-loaded PSST micelles (PTX/PSST-M) designed to display synergistic functions, including reversible inhibition of P-gp, intracellular redox-sensitive release and potent anticancer activities. The average size of PTX/PSST-M was 68.1±4.9 nm. The encapsulated PTX was released quickly through redox-triggered dissociation of micelles. The inhibition of P-gp activity and enhanced cellular accumulation of the PSST micelles were validated. PTX/PSST-M showed significantly increased cytotoxicity against PTX-resistant human ovarian cancer A2780/PTX cells: when the cells were treated with PTX/PSST-M for 48 h, the equivalent IC50 value of PTX was reduced from 61.51 to 0.49 µmol/L. The enhanced cytotoxic effects of PTX/PSST-M against A2780/PTX cells were attributed to their synergistic effects on reducing the mitochondrial transmembrane potential, ATP depletion, ROS production, and activation of apoptotic pathways. Furthermore, PTX/PSST-M significantly increased cell apoptosis/necrosis and cell cycle arrest at the G2/M phase in A2780/PTX cells. These results demonstrate that the redox-responsive PSST micelles inhibit P-gp activity and have a good potential to effectively reverse PTX resistance in human ovarian carcinoma cells by activating intrinsic apoptotic pathways.

Three-dimensional covalent organic frameworks with nia nets for efficient separation of benzene/cyclohexane mixtures.

The synthesis of three-dimensional covalent organic frameworks with highly connected building blocks presents a significant challenge. In this study, we report two 3D COFs with the nia topology, named JUC-641 and JUC-642, by introducing planar hexagonal and triangular prism nodes. Notably, our adsorption studies and breakthrough experiments reveal that both COFs exhibit exceptional separation capabilities, surpassing previously reported 3D COFs and most porous organic polymers, with a separation factor of up to 2.02 for benzene and cyclohexane. Additionally, dispersion-corrected density functional theory analysis suggests that the good performance of these 3D COFs can be attributed to the incorporation of highly aromatic building blocks and the presence of extensive pore structures. Consequently, this research not only expands the diversity of COFs but also highlights the potential of functional COF materials as promising candidates for environmentally-friendly separation applications.

Corrigendum: Targeting innate immunity in breast cancer therapy: a narrative review.

[This corrects the article DOI: 10.3389/fimmu.2021.771201.].

Demystifying phytoconstituent-derived nanomedicines in their immunoregulatory and therapeutic roles in inflammatory diseases.

In the past decades, phytoconstituents have appeared as critical mediators for immune regulations among various diseases, both in eukaryotes and prokaryotes. These bioactive molecules, showing a broad range of biological functions, would hold tremendous promise for developing new therapeutics. The discovery of phytoconstituents' capability of functionally regulating immune cells and associating cytokines, suppressing systemic inflammation, and remodeling immunity have rapidly promoted the idea of their employment as anti-inflammatory agents. In this review, we discuss various roles of phyto-derived medicines in the field of inflammatory diseases, including chronic inflammation, autoimmune diseases, and acute inflammatory disease such as COVID-19. Nevertheless, traditional phyto-derived medicines often concurred with their clinical administration limitations, such as their lack of cell specificity, inefficient cytoplasmic delivery, and rapid clearance by the immune system. As alternatives, phyto-derived nano-approaches may provide significant benefits. Both unmodified and engineered nanocarriers present the potential to serve as phytoconstituent delivery systems to improve therapeutic physio-chemical properties and pharmacokinetic profiles. Thus, the development of phytoconstituents' nano-delivery designs, their new and perspective approaches for therapeutical applications are elaborated herein.

Nucleic acid strategies for infectious disease treatments: The nanoparticle-based oral delivery route.

Therapies based on orally administrated nucleic acids have significant potential for the treatment of infectious diseases, including chronic inflammatory diseases such as inflammatory bowel disease (IBD)-associated with the gastrointestinal (GI) tract, and infectious and acute contagious diseases like coronavirus disease 2019 (COVID-19). This is because nucleic acids could precisely regulate susceptibility genes in regulating the pro- and anti-inflammatory cytokines expression related to the infections. Unfortunately, gene delivery remains a major hurdle due to multiple intracellular and extracellular barriers. This review thoroughly discusses the challenges of nanoparticle-based nucleic acid gene deliveries and strategies for overcoming delivery barriers to the inflammatory sites. Oral nucleic acid delivery case studies were also present as vital examples of applications in infectious diseases such as IBD and COVID-19.

Pyruvate-Driven Oxidative Phosphorylation is Downregulated in Sepsis-Induced Cardiomyopathy: A Study of Mitochondrial Proteome.

BACKGROUND: Sepsis-induced cardiomyopathy (SIC) is a major contributing factor for morbidity and mortality in sepsis. Accumulative evidence has suggested that cardiac mitochondrial oxidative phosphorylation is attenuated in sepsis, but the underlying molecular mechanisms remain incompletely understood. METHODS: Adult male mice of 9 to 12 weeks old were subjected to sham or cecal ligation and puncture procedure. Echocardiography in vivo and Langendorff-perfused hearts were used to assess cardiac function 24 h after the procedures. Unbiased proteomics analysis was performed to profile mitochondrial proteins in the hearts of both sham and SIC mice. Seahorse respirator technology was used to evaluate oxygen consumption in purified mitochondria. RESULTS: Of the 665 mitochondrial proteins identified in the proteomics assay, 35 were altered in septic mice. The mitochondrial remodeling involved various energy metabolism pathways including subunits of the electron transport chain, fatty acid catabolism, and carbohydrate oxidative metabolism. We also identified a significant increase of pyruvate dehydrogenase (PDH) kinase 4 (PDK4) and inhibition of PDH activity in septic hearts. Furthermore, compared to sham mice, mitochondrial oxygen consumption of septic mice was significantly reduced when pyruvate was provided as a substrate. However, it was unchanged when PDH was bypassed by directly supplying the Complex I substrate NADH, or by using the Complex II substrate succinate, or using Complex IV substrate, or by providing the beta-oxidation substrate palmitoylcarnitine, neither of which require PDH for mitochondrial oxygen consumption. CONCLUSIONS: These data demonstrate a broad mitochondrial protein remodeling, PDH inactivation and impaired pyruvate-fueled oxidative phosphorylation during SIC, and provide a molecular framework for further exploration.

Anti-Tumor Effects of Chinese Medicine Compounds by Regulating Immune Cells in Microenvironment.

As the main cause of death in the world, cancer is one of the major health threats for humans. In recent years, traditional Chinese medicine has gained great attention in oncology due to the features of multi-targets, multi-pathways, and slight side effects. Moreover, lots of traditional Chinese medicine can exert immunomodulatory effects in vivo. In the tumor microenvironment, tumor cells, immune cells as well as other stromal cells often coexist. With the development of cancer, tumor cells proliferate uncontrollably, metastasize aggressively, and modulate the proportion and status of immune cells to debilitate the antitumor immunity. Reversal of immunosuppressive tumor microenvironment plays an essential role in cancer prevention and therapy. Immunotherapy has become the most promising strategy for cancer therapy. Chinese medicine compounds can stimulate the activation and function of immune cells, such as promoting the maturation of dendritic cells and inducing the differentiation of myeloid-derived suppressor cells to dendritic cells and macrophages. In the present review, we summarize and discuss the effects of Chinese medicine compounds on immune cells in the tumor microenvironment, including innate immune cells (dendritic cells, natural killer cells, macrophages, and myeloid-derived suppressor cells) and adaptive immune cells (CD4+/CD8+ T lymphocytes and regulatory T cells), and the various immunomodulatory roles of Chinese medicine compounds in cancer therapy such as improving tumor-derived inflammation, enhancing the immunity after surgery or chemotherapy, blocking the immune checkpoints, et al., aiming to provide more thoughts for the anti-tumor mechanisms and applications of Chinese medicine compounds in terms of tumor immunity.

Current Strategies and Potential Prospects of Nanomedicine-Mediated Therapy in Inflammatory Bowel Disease.

Inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis are highly debilitating. IBDs are associated with the imbalance of inflammatory mediators within the inflamed bowel. Conventional drugs for IBD treatment include anti-inflammatory medications and immune suppressants. However, they suffer from a lack of bioavailability and high dose-induced systemic side effects. Nanoparticle (NP)-derived therapy improves therapeutic efficacy and increases targeting specificity. Recent studies have shown that nanomedicines, based on bowel disease's pathophysiology, are a fast-growing field. NPs can prolong the circulation period and reduce side effects by improving drug encapsulation and targeted delivery. Here, this review summarizes various IBD therapies with a focus on NP-derived applications, whereas their challenges and future perspectives have also been discussed.

Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials.

Significance: Sepsis is a critical clinical syndrome with life-threatening organ dysfunction induced by a dysregulated host response to infection. Despite decades of intensive research, sepsis remains a leading cause of in-hospital mortality with few specific treatments. Recent Advances: Toll-like receptors (TLRs) are a part of the innate immune system and play an important role in host defense against invading pathogens such as bacteria, virus, and fungi. Using a combination of genetically modified animal models and pharmacological agents, numerous preclinical studies during the past two decades have demonstrated that dysregulated TLR signaling may contribute to sepsis pathogenesis. However, many clinical trials targeting inflammation and innate immunity such as TLR4 have yielded mixed results. Critical Issues: Here we review various TLRs and the specific molecules these TLRs sense-both the pathogen-associated and host-derived stress molecules, and their converging signaling pathways. We critically analyze preclinical investigations into the role of TLRs in animal sepsis, the complexity of targeting TLRs for sepsis intervention, and the disappointing clinical trials of the TLR4 antagonist eritoran. Future Directions: Future sepsis treatments will depend on better understanding the complex biological mechanisms of sepsis pathogenesis, the high heterogeneity of septic humans as defined by clinical presentations and unique immunological biomarkers, and improved stratifications for targeted interventions.

Targeting Innate Immunity in Breast Cancer Therapy: A Narrative Review.

Although breast cancer has been previously considered "cold" tumors, numerous studies are currently conducted to explore the great potentials of immunotherapies in improving breast cancer patient outcomes. In addition to the focus on stimulating adaptive immunity for antitumor responses, growing evidence showed the importance of triggering host innate immunity to eradicate established tumors and/or control tumor metastasis of breast cancer. In this review, we first briefly introduce the breast tumor immune microenvironment. We also discuss innate immune targets and pathways and mechanisms of their synergy with the adaptive antitumor response and other treatment strategies. Lastly, we review clinical trials targeting innate immune pathways for breast cancer therapies.