Manipulating the Host-Guest Chemistry of Cucurbituril to Propel Highly Reversible Zinc Metal Anodes.

Rechargeable aqueous zinc-ion batteries are practically plagued by the short lifespan and low Coulombic efficiency (CE) of Zn anodes resulting from random dendrite deposition and parasitic reactions. Herein, the host-guest chemistry of cucurbituril additive with Zn2+ to achieve longstanding Zn anodes is manipulated. The macrocyclic molecule of cucurbit[5]uril (CB[5]) is delicately designed to reconstruct both the CB[5]-adsorbed electric-double layer (EDL) structure at the Zn interface and the hydrated sheath of Zn2+ ions. Especially benefiting from the desirable carbonyl rims and suitable hydrophobic cavities, the CB[5] has a strong host-guest interaction with Zn2+ ions, which exclusively permits rapid Zn2+ flux across the EDL interface but retards the H2O radicals and SO4 2-. Accordingly, such a unique particle redistributor warrants long-lasting dendrite-free deposition by homogenizing Zn nucleation/growth and significantly improved CE by inhibiting side reactions. The Zn anode can deliver superior reversibility in CB[5]-containing electrolyte with a ninefold increase of cycle lifetime and an elevated CE of 99.7% under harsh test conditions (10 mA cm-2/10 mA h cm-2). The work opens a new avenue from the perspective of host-guest chemistry to propel the development of rechargeable Zn metal batteries and beyond.

Surface Engineering of MoS2 Quantum Dots via Cyclodextrin-Based Host-Guest Chemistry as Versatile Platforms for Enhanced Cell Imaging Application.

Transition metal chalcogenide quantum dots (QDs), especially MoS2 QDs, are an emerging class of novel optical probes for versatile bioanalytical applications owing to their distinct physicochemical properties. However, the reasonable use of these QDs for biological imaging has been largely restricted due to the challenge of controllable surface functionalization. In this work, we report a new strategy to engineer the surface of MoS2 QDs by taking advantage of cyclodextrin (CD)-based host-guest chemistry. The prepared ß-CD-modified QDs (ß-CD-MoS2 QDs) exhibit enhanced fluorescence properties, excellent biocompatibility, and good stability, making them promising as novel optical probes for bioimaging. Cellular imaging experiments revealed that these ß-CD-MoS2 QDs can enter living cells through multiple internalization pathways, which differs significantly from pristine QDs. Particularly, we observed that the intracellular accumulation of MoS2 QDs in lipid droplets was enhanced owing to the specific binding of ß-CD to cholesterol, which was then harnessed for monitoring the lipid metabolism in living cells via fluorescence imaging. Furthermore, we also demonstrated the potential use of ß-CD-MoS2 QDs for targeted cell imaging and microplate-based cell recognition, which can be easily achieved via bioconjugation with functional motifs (e.g., folate acid) through host-guest chemistry. Altogether, these results illustrate the great potential of engineering the surface of MoS2 QDs and other analogous materials via CD-based host-guest chemistry for advancing their cell imaging applications.

Efficient Delivery of GSDMD-N mRNA by Engineered Extracellular Vesicles Induces Pyroptosis for Enhanced Immunotherapy.

Pyroptosis is a newly discovered inflammatory form of programmed cell death, which promotes systemic immune response in cancer immunotherapy. GSDMD is one of the key molecules executing pyroptosis, while therapeutical delivery of GSDMD to tumor cells is of great challenge. In this study, an extracellular vesicles-based GSDMD-N mRNA delivery system (namely EVTx ) is developed for enhanced cancer immunotherapy, with GSDMD-N mRNA encapsulated inside, Ce6 (Chlorin e6 (Ce6), a hydrophilic sensitizer) incorporated into extracellular vesicular membrane, and HER2 antibody displayed onto the surface. Briefly, GSDMD-N mRNA is translationally repressed in donor cells by optimized puromycin, ensuring the cell viability and facilitating the mRNA encapsulation into extracellular vesicles. When targeted and delivered into HER2+ breast cancer cells by the engineered extracellular vesicles, the translational repression is unleashed in the recipient cells as the puromycin is diluted and additionally inactivated by sonodynamic treatment as the extracellular vesicles are armed with Ce6, allowing GSDMD-N translation and pyroptosis induction. In addition, sonodynamic treatment also induces cell death in the recipient cells. In the SKBR3- and HER2 transfected 4T1- inoculated breast tumor mouse models, the engineered EVTx efficiently induces a powerful tumor immune response and suppressed tumor growth, providing a nanoplatform for cancer immunotherapy.

PRMT5 regulates RNA m6A demethylation for doxorubicin sensitivity in breast cancer.

Cancer cells respond to various stressful conditions through the dynamic regulation of RNA m6A modification. Doxorubicin is a widely used chemotherapeutic drug that induces DNA damage. It is interesting to know whether cancer cells regulate the DNA damage response and doxorubicin sensitivity through RNA m6A modification. Here, we found that doxorubicin treatment significantly induced RNA m6A methylation in breast cancer cells in both a dose- and a time-dependent manner. However, protein arginine methyltransferase 5 (PRMT5) inhibited RNA m6A modification under doxorubicin treatment by enhancing the nuclear translocation of the RNA demethylase AlkB homolog 5 (ALKBH5), which was previously believed to be exclusively localized in the nucleus. Then, ALKBH5 removed the m6A methylation of BRCA1 for mRNA stabilization and further enhanced DNA repair competency to decrease doxorubicin efficacy in breast cancer cells. Importantly, we identified the approved drug tadalafil as a novel PRMT5 inhibitor that could decrease RNA m6A methylation and increase doxorubicin sensitivity in breast cancer. The strategy of targeting PRMT5 with tadalafil is a promising approach to promote breast cancer sensitivity to doxorubicin through RNA methylation regulation.

Hydrogel armed with Bmp2 mRNA-enriched exosomes enhances bone regeneration.

BACKGROUND: Sustained release of bioactive BMP2 (bone morphogenetic protein-2) is important for bone regeneration, while the intrinsic short half-life of BMP2 at protein level cannot meet the clinical need. In this study, we aimed to design Bmp2 mRNA-enriched engineered exosomes, which were then loaded into specific hydrogel to achieve sustained release for more efficient and safe bone regeneration. RESULTS: Bmp2 mRNA was enriched into exosomes by selective inhibition of translation in donor cells, in which NoBody (non-annotated P-body dissociating polypeptide, a protein that inhibits mRNA translation) and modified engineered BMP2 plasmids were co-transfected. The derived exosomes were named ExoBMP2+NoBody. In vitro experiments confirmed that ExoBMP2+NoBody had higher abundance of Bmp2 mRNA and thus stronger osteogenic induction capacity. When loaded into GelMA hydrogel via ally-L-glycine modified CP05 linker, the exosomes could be slowly released and thus ensure prolonged effect of BMP2 when endocytosed by the recipient cells. In the in vivo calvarial defect model, ExoBMP2+NoBody-loaded GelMA displayed great capacity in promoting bone regeneration. CONCLUSIONS: Together, the proposed ExoBMP2+NoBody-loaded GelMA can provide an efficient and innovative strategy for bone regeneration.

ROS triggered local delivery of stealth exosomes to tumors for enhanced chemo/photodynamic therapy.

BACKGROUND: Exosomes are recognized as effective platforms for targeted delivery for their high physicochemical stability and biocompatibility. However, most of the exosomes are inevitably and rapidly cleared by mononuclear phagocytic system (MPS) during cancer therapy. How to engineer exosome to enhance the delivery efficiency is being intensively explored. In this study, we have constructed mPEG2000-TK-CP05 decorated exosomes as effective delivery platforms to achieve enhanced photodynamic/chemical cancer therapy. RESULTS: Exosomes were coated with CP05-TK-mPEG2000, in which CP05 is a peptide with high affinity to exosomal CD63 and TK could be cleaved by ROS. The resulted exosomes, namely stealth Exo, were electroporated to load RB (photosensitizer Rose Bengal) and Dox (Doxorubicin). We verified that the Stealth Exo@RB (Stealth Exo additionally loaded with RB) could escape MPS while accumulate in the tumor region efficiently in the xenograft model when laser irradiation conducted locally. Additionally, we revealed that the Stealth Exo serves as an efficient platform for Dox delivery. Dox, together with the RB mediated photodynamic therapy induce tumor cell damage synergistically in the tumor region. Moreover, the proposed switchable stealth exosomes minimized the dose of toxic Dox and thus allowed robust tumor immune response. CONCLUSIONS: Our results indicated that the proposed Stealth Exo greatly improves both the accessibility and efficiency of drug delivery, with minimal chemical or genetic engineering. The proposed Stealth Exo serve as a promising and powerful drug delivery nanoplatform in cancer treatment.

An optimized exosome production strategy for enhanced yield while without sacrificing cargo loading efficiency.

BACKGROUND: Exosome mediated mRNA delivery is a promising strategy for the treatment of multiple diseases. However, the low yield of exosomes is a bottleneck for clinical translation. In this study, we boosted exosome production via simultaneously reducing the expression of genes inhibiting exosome biogenesis and supplementing the culture medium with red cell membrane components. RESULTS: Among the candidate genes, knocking down of Rab4 was identified to have the highest efficacy in promoting exosome biogenesis while without any obvious cytotoxicity. Additionally, supplementing red cell membrane particles (RCMPs) in the culture medium further promoted exosome production. Combination of Rab4 knockdown and RCMP supplement increased exosome yield up to 14-fold. As a proof-of-concept study, low-density lipoprotein receptor (Ldlr) mRNA was forced expressed in the exosome donor cells and passively encapsulated into the exosomes during biogenesis with this strategy. Though exosome production per cell increased, the booster strategy didn't alter the loading efficiency of therapeutic Ldlr mRNA per exosome. Consistently, the therapeutic exosomes derived by the strategy alleviated liver steatosis and atherosclerosis in Ldlr-/- mice, similar as the exosomes produced by routine methods. CONCLUSIONS: Together, the proposed exosome booster strategy conquers the low yield bottleneck to some extent and would certainly facilitate the clinical translation of exosomes.

Selective Encapsulation of Therapeutic mRNA in Engineered Extracellular Vesicles by DNA Aptamer.

Extracellular vesicles (EV)-based delivery of therapeutic mRNAs is challenged by the low loading efficiency. In this study, we designed a DNA aptamer consisting of two parts: the single strand part recognized the AUG region of target mRNA, preventing mRNA from translation and ribosome assembly; and the double strand part containing the elements recognized by the CD9-ZF (zinc finger) motifs, sorting DNA aptamer-mRNA complex into CD9-ZF engineered EVs. In vitro and in vivo studies revealed that the system could efficiently load functional mRNAs to the EVs. Furthermore, adipose specific delivery of loaded Pgc1α mRNA via the strategy could efficiently induce white adipocyte browning. Similarly, delivery of interleukin-10 (Il-10) mRNA via the strategy had potent anti-inflammatory effect in inflammatory bowel disease (IBD) mouse model. Together, our study has proposed an efficient strategy to load therapeutic mRNAs of interest into EVs, which could be used as a promising strategy for gene therapy.

Ultrasound triggered topical delivery of Bmp7 mRNA for white fat browning induction via engineered smart exosomes.

BACKGROUND: Efficient and topical delivery of drugs is essential for maximized efficacy and minimized toxicity. In this study, we aimed to design an exosome-based drug delivery platform endowed with the ability of escaping from phagocytosis at non-target organs and controllably releasing drugs at targeted location. RESULTS: The swtichable stealth coat CP05-TK-mPEG was synthesized and anchored onto exosomes through the interaction between peptide CP05 and exosomal surface marker CD63. Chlorin e6 (Ce6) was loaded into exosomes by direct incubation. Controllable removal of PEG could be achieved by breaking thioketal (TK) through reactive oxygen species (ROS), which was produced by Ce6 under ultrasound irradiation. The whole platform was called SmartExo. The stealth effects were analyzed in RAW264.7 cells and C57BL/6 mice via tracing the exosomes. To confirm the efficacy of the engineered smart exosomes, Bone morphogenetic protein 7 (Bmp7) mRNA was encapsulated into exosomes by transfection of overexpressing plasmid, followed by stealth coating, with the exosomes designated as SmartExo@Bmp7. Therapeutic advantages of SmartExo@Bmp7 were proved by targeted delivering Bmp7 mRNA to omental adipose tissue (OAT) of obese C57BL/6 mice for browning induction. SmartExo platform was successfully constructed without changing the basic characteristics of exosomes. The engineered exosomes effectively escaped from the phagocytosis by RAW264.7 and non-target organs. In addition, the SmartExo could be uptaken locally on-demand by ultrasound mediated removal of the stealth coat. Compared with control exosomes, SmartExo@Bmp7 effectively delivered Bmp7 mRNA into OAT upon ultrasound irradiation, and induced OAT browning, as evidenced by the histology of OAT and increased expression of uncoupling protein 1 (Ucp1). CONCLUSIONS: The proposed SmartExo-based delivery platform, which minimizes side effects and maximizing drug efficacy, offers a novel safe and efficient approach for targeted drug delivery. As a proof, the SmartExo@Bmp7 induced local white adipose tissue browning, and it would be a promising strategy for anti-obesity therapy.

In Vitro and in Vivo RNA Inhibition by CD9-HuR Functionalized Exosomes Encapsulated with miRNA or CRISPR/dCas9.

In vitro and in vivo delivery of RNAs of interest holds promise for gene therapy. Recently, exosomes are considered as a kind of rational vehicle for RNA delivery, especially miRNA and/or siRNA, while the loading efficiency is limited. In this study, we engineered the exosomes for RNA loading by constructing a fusion protein in which the exosomal membrane protein CD9 was fused with RNA binding protein, while the RNA of interest either natively harbors or is engineered to have the elements for the binding. By proof-of-principle experiments, we here fused CD9 with HuR, an RNA binding protein interacting with miR-155 with a relatively high affinity. In the exosome packaging cells, the fused CD9-HuR successfully enriched miR-155 into exosomes when miR-155 was excessively expressed. Moreover, miR-155 encapsulated in the exosomes in turn could be efficiently delivered into the recipient cells and recognized the endogenous targets. In addition, we also revealed that the CD9-HuR exosomes could enrich the functional miRNA inhibitor or CRISPR/dCas9 when the RNAs were engineered to have the AU rich elements. Taken together, we here have established a novel strategy for enhanced RNA cargo encapsulation into engineered exosomes, which in turn functions in the recipient cells.

Chronic myeloid leukemia-derived exosomes attenuate adipogenesis of adipose derived mesenchymal stem cells via transporting miR-92a-3p.

Cancer-associated cachexia (CAC) has tremendous effects on the patient's tolerance to chemotherapy and the quality of life, especially in the advanced stages, such as the acute and terminal stages of chronic myeloid leukemia (CML). However, the underlying mechanisms and mediators remain unclear. Here, we showed that mice injected with CML-derived exosomes had significant weight loss and great drop of body fat rate. In the meanwhile, we found that CML-derived exosomes could be taken up by adipose tissue, and, in turn, suppressed the adipogenic ability of adipose-derived mesenchymal stem cells (ADSCs). By RNA sequencing, miR-92a-3p was found highly expressed in both CML cells and the derivative exosomes. Mechanistically, miR-92a-3p inhibited adipogenesis of ADSCs via posttranscriptionally decreasing C/EBPα expression when transferred into the ADSCs with the exosomes, and encapsulating miR-92a-3p inhibitor into CML exosomes blocked the antiadipogenic effects of CML exosomes. In addition, we also found that miR-92a-3p was highly expressed in exosomes from some other types of cancers that cause cachexia. These results demonstrate that adipogenesis inhibition by tumor-derived exosomes, mainly exosomal microRNAs like miR-92a-3p, are the main mediators for CAC.

Construction and validation of the CRISPR/dCas9-EZH2 system for targeted H3K27Me3 modification.

Cell phenotypes are closely related to the epigenome, which could be precisely regulated by the targeted manipulation of epigenetic marks. Here, we have successfully produced a targeted histone methylation system, which consists of nuclease-null dCas9 protein, the sgRNA fused with PP7 RNA aptamers and the Enhancer of Zeste Homolog 2 (EZH2) fused to PP7 coat protein (PCP). Guided by the dCas9/sgRNA-PP7, the PCP-EZH2 can specifically target gene loci to catalyze 3 methylation of histone H3 lysine 27, resulting in the inhibition of gene expression. This kind of gene inhibition system is supposed to be highly effective, specific and flexible. As a proof-of-concept study, sgRNA targeting C/ebpα promoter region was designed. In the cells co-infected with the dCas9, sgRNA/C/ebpα-PP7 and PCP-EZH2, the expression of C/ebpα gene was significantly reduced via induction of trimethylation to H3K27 on C/ebpα promoter, with the results epigenetically inherited in the daughter cells. In conclusion, our results successfully established a gene modification system consisting of dCas9/sgRNA-PP7 and PCP-EZH2, providing a robust tool for targeted manipulation of gene epigenetic modification and expression.

Targeted blocking of miR328 lysosomal degradation with alkalized exosomes sensitizes the chronic leukemia cells to imatinib.

Imatinib resistance remains the biggest hurdle for the treatment of chronic myeloid leukemia (CML), with the underlying mechanisms not fully understood. In this study, we found that miR328 significantly and strikingly decreased among other miRNA candidates during the induction of imatinib resistance. Overexpression of miR328 sensitized resistant cells to imatinib via post-transcriptionally decreasing ABCG2 expression, while miR328 knockdown conferred imatinib resistance in parental K562 cells. Moreover, miR328 was found selectively degraded in the lysosomes of K562R cells, as inhibition of lysosome with chloroquine restored miR328 expression and increased sensitivity to imatinib. Moreover, delivery of alkalized exosomes increased endogenous miR328 expression. Compared with the corresponding controls, the alkalized exosomes with or without miR328 sensitized the chronic leukemia cells to imatinib. Taken together, our study has revealed that lysosomal clearance of miR328 in imatinib-resistant cells at least partially contributes to the drug resistance, while delivery of alkalized exosomes would sensitize the chromic leukemia cells to imatinib.

Systematically Characterize the Anti-Alzheimer's Disease Mechanism of Lignans from S. chinensis based on In-Vivo Ingredient Analysis and Target-Network Pharmacology Strategy by UHPLC⁻Q-TOF-MS.

Lignans from Schisandra chinensis (Turcz.) Baill can ameliorate cognitive impairment in animals with Alzheimer's disease (AD). However, the metabolism of absorbed ingredients and the potential targets of the lignans from S. chinensis in animals with AD have not been systematically investigated. Therefore, for the first time, we performed an in-vivo ingredient analysis and implemented a target-network pharmacology strategy to assess the effects of lignans from S. chinensis in rats with AD. Ten absorbed prototype constituents and 39 metabolites were identified or tentatively characterized in the plasma of dosed rats with AD using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Based on the results of analysis of the effective constituents in vivo, the potential therapeutic mechanism of the effective constituents in the rats with AD was investigated using a target-network pharmacology approach and independent experimental validation. The results showed that the treatment effects of lignans from S. chinensis on cognitive impairment might involve the regulation of amyloid precursor protein metabolism, neurofibrillary tangles, neurotransmitter metabolism, inflammatory response, and antioxidant system. Overall, we identified the effective components of lignans in S. chinensis that can improve the cognitive impairment induced by AD and proposed potential therapeutic metabolic pathways. The results might serve as the basis for a fundamental strategy to explore effective therapeutic drugs to treat AD.

Maternal exosomes in diabetes contribute to the cardiac development deficiency.

Maternal diabetes mellitus induces an increased risk of congenital heart defects (CHD), however, the exact mechanisms are still not fully illustrated. In this study, diabetic pregnant C57BL/6 mice were induced by injection of streptozotocin before mating. Compared with the control normal mice, diabetic pregnant mice displayed significant changes of the exosomal miRNA contents in the blood, as revealed by RNA-seq analysis. Multiple of these miRNAs were found involved in cardiac development regulation. Moreover, fluorescence labeled exosomes and gold nanoparticles could cross the placenta barrier and infiltrated into the embryonic organs/tissues, including the heart, during embryonic development. Injection of diabetic maternal exosomes strikingly increased the risk of CHD in the normal recipient pregnant mice. Taken together, we could draw the conclusion that maternal exosomes in diabetes could cross the maternal-fetal barrier and contribute to the cardiac development deficiency possibly via miRNAs, providing new insights in CHD prevention and treatment.

Simultaneous encryption and compression of medical images based on optimized tensor compressed sensing with 3D Lorenz.

BACKGROUND: The existing techniques for simultaneous encryption and compression of images refer lossy compression. Their reconstruction performances did not meet the accuracy of medical images because most of them have not been applicable to three-dimensional (3D) medical image volumes intrinsically represented by tensors. METHODS: We propose a tensor-based algorithm using tensor compressive sensing (TCS) to address these issues. Alternating least squares is further used to optimize the TCS with measurement matrices encrypted by discrete 3D Lorenz. RESULTS: The proposed method preserves the intrinsic structure of tensor-based 3D images and achieves a better balance of compression ratio, decryption accuracy, and security. Furthermore, the characteristic of the tensor product can be used as additional keys to make unauthorized decryption harder. CONCLUSIONS: Numerical simulation results verify the validity and the reliability of this scheme.

GSK3: A potential target and pending issues for treatment of Alzheimer's disease.

Glycogen synthase kinase-3 (GSK3), consisting of GSK3α and GSK3ß subtypes, is a complex protein kinase that regulates numerous substrates. Research has observed increased GSK3 expression in the brains of Alzheimer's disease (AD) patients and models. AD is a neurodegenerative disorder with diverse pathogenesis and notable cognitive impairments, characterized by Aß aggregation and excessive tau phosphorylation. This article provides an overview of GSK3's structure and regulation, extensively analyzing its relationship with AD factors. GSK3 overactivation disrupts neural growth, development, and function. It directly promotes tau phosphorylation, regulates amyloid precursor protein (APP) cleavage, leading to Aß formation, and directly or indirectly triggers neuroinflammation and oxidative damage. We also summarize preclinical research highlighting the inhibition of GSK3 activity as a primary therapeutic approach for AD. Finally, pending issues like the lack of highly specific and affinity-driven GSK3 inhibitors, are raised and expected to be addressed in future research. In conclusion, GSK3 represents a target in AD treatment, filled with hope, challenges, opportunities, and obstacles.

MIIP downregulation drives colorectal cancer progression through inducing peri-cancerous adipose tissue browning.

BACKGROUND: The enrichment of peri-cancerous adipose tissue is a distinctive feature of colorectal cancer (CRC), accelerating disease progression and worsening prognosis. The communication between tumor cells and adjacent adipocytes plays a crucial role in CRC advancement. However, the precise regulatory mechanisms are largely unknown. This study aims to explore the mechanism of migration and invasion inhibitory protein (MIIP) downregulation in the remodeling of tumor cell-adipocyte communication and its role in promoting CRC. RESULTS: MIIP expression was found to be decreased in CRC tissues and closely associated with adjacent adipocyte browning. In an in vitro co-culture model, adipocytes treated with MIIP-downregulated tumor supernatant exhibited aggravated browning and lipolysis. This finding was further confirmed in subcutaneously allografted mice co-injected with adipocytes and MIIP-downregulated murine CRC cells. Mechanistically, MIIP interacted with the critical lipid mobilization factor AZGP1 and regulated AZGP1's glycosylation status by interfering with its association with STT3A. MIIP downregulation promoted N-glycosylation and over-secretion of AZGP1 in tumor cells. Subsequently, AZGP1 induced adipocyte browning and lipolysis through the cAMP-PKA pathway, releasing free fatty acids (FFAs) into the microenvironment. These FFAs served as the primary energy source, promoting CRC cell proliferation, invasion, and apoptosis resistance, accompanied by metabolic reprogramming. In a tumor-bearing mouse model, inhibition of ß-adrenergic receptor or FFA uptake, combined with oxaliplatin, significantly improved therapeutic efficacy in CRC with abnormal MIIP expression. CONCLUSIONS: Our data demonstrate that MIIP plays a regulatory role in the communication between CRC and neighboring adipose tissue by regulating AZGP1 N-glycosylation and secretion. MIIP reduction leads to AZGP1 oversecretion, resulting in adipose browning-induced CRC rapid progression and poor prognosis. Inhibition of ß-adrenergic receptor or FFA uptake, combined with oxaliplatin, may represent a promising therapeutic strategy for CRC with aberrant MIIP expression.

Profibrogenic macrophage-targeted delivery of mitochondrial protector via exosome formula for alleviating pulmonary fibrosis.

Pulmonary fibrosis (PF) is a devastating lung disease with limited treatment options. During this pathological process, the profibrogenic macrophage subpopulation plays a crucial role, making the characterization of this subpopulation fundamentally important. The present study revealed a positive correlation between pulmonary macrophages with higher mitochondrial mass (Mømitohigh) and fibrosis. Among the Mømitohigh subpopulation of CD206+ M2, characterized by higher expression of dynamin 1-like (Drp1), as determined by flow cytometry and RNA-seq analysis, a therapeutic intervention was developed using an exosome-based formula composed of pathfinder and therapeutics. A pathfinder exosome called "exosomeMMP19 (ExoMMP19)", was constructed to display matrix metalloproteinase-19 (MMP19) on the surface to locally break down the excessive extracellular matrix (ECM) in the fibrotic lung. A therapeutic exosome called "exosome therapeutics (ExoTx)", was engineered to display D-mannose on the surface while encapsulating siDrp1 inside. Prior delivery of ExoMMP19 degraded excessive ECM and thus paved the way for ExoTx to be delivered into Mømitohigh, where ExoTx inhibited mitochondrial fission and alleviated PF. This study has not only identified Mømitohigh as profibrotic macrophages but it has also provided a potent strategy to reverse PF via a combination of formulated exosomes.

Effects of donepezil treatment on plasma and urine metabolites in amyloid beta-induced Alzheimer's disease rats.

Accumulated clinical and biomedical evidence suggests that abnormalities in systemic metabolic processes such as fatty acid and amino acid metabolism can affect the brain function and behavior of various central nervous system diseases such as Alzheimer's disease (AD). In this study, metabolic profiling was used to investigate changes in plasma and urine metabolites following stereotactic injection of amyloid ß (Aß) and treatment with donepezil in rats. Aß causes cognitive impairment, while donepezil treatment successfully improves memory impairment. Donepezil improves Aß-induced plasma fatty acid and bile acid metabolism disorders, as well as Aß-induced urine phenylalanine and tryptophan metabolism disorders in rats. More specifically, the plasma fatty acids improved by donepezil include alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, arachidonic acid, oleic acid, and palmitic acid, among others. Additionally, donepezil significantly restored the downregulation of bile acids such as ursodeoxycholic acid, cholic acid, and glycocholic acid caused by Aß. As for urine metabolites, phenylacetylglycine, epinephrine, and other phenylalanine metabolites, as well as kynurenic acid, xanthurenic acid, and other tryptophan metabolites, were worsened by Aß and improved by donepezil. These findings suggest that the cognitive impairment induced by Aß and the improvement by donepezil are associated with changes in metabolic disorders in rats. This study provides basic data for the effects of Aß and donepezil on plasma and urine metabolites in Aß-induced AD rat models.