Prenatal Inflammatory Exposure Predisposes Offspring to Chronic Kidney Diseases Via the Activation of the eIF2α-ATF4 Pathway.

It has recently become more recognized that renal diseases in adults can originate from adverse intrauterine (maternal) environmental exposures. Previously, we found that prenatal lipopolysaccharide (LPS) exposure can result in chronic renal inflammation, which leads to renal damage in older offspring rats. To test whether prenatal inflammatory exposure predisposes offspring to renal damage, a mouse model of oral adenine consumption-induced chronic kidney disease (CKD) was applied to offspring from prenatal LPS-treated mothers (offspring-pLPS) and age-matched control offspring of prenatal saline-treated mothers (offspring-pSaline). We found that offspring-pLPS mice presented with more severe renal collagen deposition and renal dysfunction after 4 weeks of adenine consumption than sex- and treatment-matched offspring-pSaline controls. To illustrate the underlying molecular mechanism, we subjected offspring-pLPS and offspring-pSaline kidneys to genome-wide transcriptomic analysis. Bioinformatic analysis of the sequencing data, together with further experimental confirmation, revealed a strong activation of the PERK-eIF2α-ATF4-mediated unfolded protein response (UPR) in offspring-pLPS kidneys, which likely contributed to the CKD predisposition seen in offspring-pLPS mice. More importantly, the specific eIF2α-ATF4 signaling inhibitor ISIRB was able to prevent adenine-induced CKD in the offspring-pLPS mice. Our findings suggest that the eIF2α-ATF4-mediated UPR, but not PERK, is likely the major disease-causing pathway in prenatal inflammatory exposure-induced CKD predisposition. Our study also suggests that targeting this signaling pathway is a potentially promising approach for CKD treatment.

Targeting S100A9 Prevents ß-Adrenergic Activation-Induced Cardiac Injury.

Altered cardiac innate immunity is highly associated with the progression of cardiac disease states and heart failure. S100A8/A9 is an important component of damage-associated molecular patterns (DAMPs) that is critically involved in the pathogenesis of heart failure, thus considered a promising target for pharmacological intervention. In the current study, initially, we validated the role of S100A8/A9 in contributing to cardiac injury and heart failure via the overactivation of the ß-adrenergic pathway and tested the potential use of paquinimod as a pharmacological intervention of S100A8/A9 activation in preventing cardiac dysfunction, collagen deposition, inflammation, and immune cell infiltration in ß-adrenergic overactivation-mediated heart failure. This finding was further confirmed by the cardiomyocyte-specific silencing of S100A9 via the use of the adeno-associated virus (AAV) 9-mediated short hairpin RNA (shRNA) gene silencing system. Most importantly, in the assessment of the underlying cellular mechanism by which activated S100A8/A9 cause aggravated progression of cardiac fibrosis and heart failure, we discovered that the activated S100A8/A9 can promote fibroblast-macrophage interaction, independent of inflammation, which is likely a key mechanism leading to the enhanced collagen production. Our results revealed that targeting S100A9 provides dual beneficial effects, which is not only a strategy to counteract cardiac inflammation but also preclude cardiac fibroblast-macrophage interactions. The findings of this study also indicate that targeting S100A9 could be a promising strategy for addressing cardiac fibrosis, potentially leading to future drug development.

Circ_0082182 promotes oncogenesis and metastasis of colorectal cancer in vitro and in vivo by sponging miR-411 and miR-1205 to activate the Wnt/ß-catenin pathway.

BACKGROUND: Circular RNAs (circRNAs) are a class of endogenous single-strand RNA transcripts with crucial regulation in human cancers. The objective of this study is to investigate the role of circ_0082182 in CRC and its specific functional mechanism. METHODS: The quantitative real-time polymerase chain reaction (qRT-PCR) was performed to measure the levels of circ_0082182, microRNA-411 (miR-411) and microRNA-1205 (miR-1205). Cell proliferation was detected by Cell counting Kit-8 (CCK-8) and colony formation assays. Flow cytometry was used for determining cell cycle and cell apoptosis. Cell apoptosis was also assessed by caspase3 and caspase9 activities. Cell migration and invasion were examined using scratch assay and transwell assay. The interaction between circ_0082182 and miRNA was validated by the dual-luciferase reporter and biotinylated RNA pull-down assays. Wnt/ß-catenin pathway and epithelial-mesenchymal transition (EMT)-associated proteins were quantified by Western blot. Xenograft model was established for the research of circ_0082182 in vivo. RESULTS: Circ_0082182 was upregulated in CRC and could predict the poor prognosis of CRC patients. Functionally, circ_0082182 promoted CRC cell proliferation, cell cycle progression, and metastasis while inhibited apoptosis. Subsequently, circ_0082182 was shown to act as the sponges of miR-411 and miR-1205. MiR-411 and miR-1205 were identified as tumor inhibitors in CRC. Furthermore, circ_0082182 promoted the CRC progression via sponging miR-411 and miR-1205. Moreover, circ_0082182 facilitated the Wnt/ß-catenin pathway and EMT process by targeting miR-411 and miR-1205. In vivo, circ_0082182 accelerated the CRC tumorigenesis and EMT process by activating the Wnt/ß-catenin pathway by downregulating the expression of miR-411 or miR-1205. CONCLUSION: This study showed that circ_0082182 functioned as an oncogene in the developing process of CRC by sponging miR-411 or miR-1205 to activate the Wnt/ß-catenin pathway. Circ_0082182 might be a molecular target in the diagnosis and treatment of CRC.

The double-edged sword effect of macrophage targeting delivery system in different macrophage subsets related diseases.

BACKGROUND: Monocyte/macrophage-targeting delivery systems (MTDSs) have been focused upon as an emerging routine for delivering drugs to treat various macrophage-related diseases. However, the ability of MTDSs to distinguish different macrophage-related diseases and their impact on macrophage function and disease progression have not been systematically revealed, which is important for actively targeted therapeutic or diagnostic strategies. RESULTS: Herein, we used dextran-modified polystyrene nanoparticles (DEX-PS) to demonstrate that modification of nanoparticles by dextran can specifically enhance their recognition by M2 macrophages in vitro, but it is obstructed by monocytes in peripheral blood according to in vivo assays. DEX-PS not only targeted and became distributed in tumors, an M2 macrophage-related disease, but was also highly distributed in an M1 macrophage-related disease, namely acute peritonitis. Thus, DEX-PS acts as a double-edged sword in these two different diseases by reeducating macrophages to a pro-inflammatory phenotype. CONCLUSIONS: Our results suggest that MTDSs, even those designed based on differential expression of receptors on specific macrophage subtypes, lack the ability to distinguish different macrophage subtype-related diseases in vivo. In addition to the potential impact of these carrier materials on macrophage function, studies of MTDSs should pay greater attention to the distribution of nanoparticles in non-target macrophage-infiltrated disease sites and their impact on disease processes.

Prevention of Obesity Related Diseases through Laminarin-induced targeted delivery of Bindarit.

Rationale: The developement of oral targeted therapeutics for obesity and obesity-related diseases is challenging, as these diseases involve multiple lesions distributed throughout the whole body. Herein, we report a successful stragety for targeted oral delivery of bindarit to multiple obesity-related lesions including inflamed adipose tissue, fatty liver and atherosclerotic plaques. Methods: The computer simulation from atomstic to mesoscale was first applied for designing bindarit-loaded nanoparticles (pBIN) and laminarin-modified bindarit-loaded nanoparticles (LApBIN). Then pBIN were suceesfully prepared using a dialysis procedure, and LApBIN were prepared though the interaction bewtween laminarin and pBIN. The physiochemical properties, in vitro and in vivo pharmacokinetics, oral targeting capability and in vivo efficacy of LApBIN in various obesity-related diseases were examined. Results: LApBIN were sucessfully designed and prepared. Following oral administration of LApBIN, the nanoparticles could be sucessully orally adsorbed and translocated to monocytes. Contributed by the recruitment of monocytes to multiple obesity-related lesions, LApBIN successfully delivered bindarit to these lesions, and effectively suppressed inflammation there, which exerted successful preventive effects on high-fat-diet-induced obesity, insulin resistance, fatty liver and atherosclerosis. Conclusions:This strategy could represent a promising approach to develop effective oral treatments for obesity and other metabolic diseases.

Biomimetic oral targeted delivery of bindarit for immunotherapy of atherosclerosis.

Monocyte chemoattractant protein-1 (MCP-1) plays an important role in the development of atherosclerosis. However, the application of bindarit (a specific synthetic inhibitor of MCP-1) in atherosclerosis has not been confirmed due to the non-specific distribution profile in vivo. Herein, based on the recruitment of monocytes into atherosclerotic plaques, we successfully delivered bindarit into the interior of atherosclerotic plaques through a yeast-derived microcapsule (YC) mediated biomimetic approach. In this biomimetic approach, bindarit was firstly assembled with polyethyleneimine to form the positively charged nanoparticles (BIN/PEI NPs) via multiple intermolecular forces, and then the obtained BIN/PEI NPs were packed into YCs by electrostatic force-mediated spontaneous deposition. Through an oral adsorption routine similar to yeasts, bindarit loaded YCs (BIN/YCs) were distributed into peripheral blood monocytes after oral administration, and then their targeted delivery to atherosclerotic plaques was successfully performed through monocyte transportation. Correspondingly, oral delivery of bindarit loaded YCs afforded notably potentiated efficacies for inhibiting the MCP-1 and further reducing the recruitment of monocytes into atherosclerotic plaques, and thus presented a good efficacy in preventing the formation of atherosclerotic plaques. These results demonstrated that a 'Trojan horse'-like YC mediated nanomedicine delivery strategy is expected to realize the application of certain potential anti-inflammatory drugs in the treatment of atherosclerosis and is of great significance for the development of novel strategies for atherosclerosis treatment.

Facile Engineering of Indomethacin-Induced Paclitaxel Nanocrystal Aggregates as Carrier-Free Nanomedicine with Improved Synergetic Antitumor Activity.

Carrier-free nanomedicines mainly composed of drug nanocrystals are considered as promising candidates for next-generation nanodrug formulations. However, such nanomedicines still need to be stabilized by additive surfactants, synthetic polymers, or biologically based macromolecules. Based on the strong intermolecular interactions between indomethacin (IDM, a COX-2 inhibitor) and paclitaxel (PTX, a chemotherapy drug), we herein successfully engineered a novel kind of carrier-free nanomedicines that organized as IDM-induced PTX nanocrystal aggregates via one-pot self-assembly without any nonactive excipients. In the assemblies of IDM and PTX (IDM/PTX assemblies), PTX nanocrystals were casted with amorphous IDM molecules, like a "brick-cement" architecture. In serum, these nanoassemblies could rapidly collapse into a great number of smaller nanoparticles, thus targeting the tumor site through the EPR effect. Under the assistance of IDM on immunotherapy, the IDM/PTX assemblies showed obviously improved synergetic antitumor effects of immunotherapy and chemotherapy. The self-assembly of two synergistic active substances into nanomedicines without any nonactive excipients might open an alternative avenue and give inspiration to fabricate novel carrier-free nanomedicines in many fields.

Cytotoxic triterpenoid glycosides from the roots of Camellia oleifera.

Eight new triterpenoid saponins, oleiferosides A-H (1-8), were isolated from the EtOH extract of the roots of Camellia oleifera. Their structures were elucidated by a combination of 1D and 2D NMR techniques, mass spectrometry, and chemical methods. All were characterized to be oleanane-type saponins with sugar moieties linked to C-3 of the aglycone. Cytotoxic activities of these saponins were evaluated against four human tumor cell lines (A549, B16, BEL-7402, and MCF-7) by using the MTT in vitro assay. Compound 3 exhibited potent cytotoxic activitiy against all the tested cell lines with IC50 values < 10 µM. Compounds 1, 2, 4, and 5 showed moderate cytotoxic activities toward the tested cell lines.