Therapeutic Potential of Biochanin A in Herpes Simplex Keratitis.

Herpes simplex keratitis (HSK) is a blinding eye disease that is initiated by the herpes simplex virus type 1 (HSV-1). Resistance to acyclovir (ACV) and the side effects of corticosteroid drugs have become concerning issues, so it is crucial to develop new antivirals for treating HSK. In this study, we report that biochanin A (BCA), a naturally occurring flavonoid compound, provides multifaceted protective effects with anti-viral, anti-inflammatory, anti-oxidative stress and anti-apoptotic activities to alleviate HSK. The results show that BCA significantly inhibited HSV-1 replication in vitro and further proved that BCA principally influenced the early stage of virus infection. We reveal that BCA downregulated the expression of pro-inflammatory factors triggered by HSV-1, including TNF-α, RANTES, IL-1ß and IL-6. Furthermore, BCA treatment alleviated oxidative stress and apoptotic arising from HSV-1 infection. Lastly, we induced HSK in male C57BL/6 mice and treated them with either BCA or phosphate buffer solution (PBS) eye drops. We observed the ocular surface lesions; determined the virus load in the tear fluid, corneas as well as trigeminal ganglions (TGs); and detected the levels of inflammation and apoptosis in the corneas simultaneously. These results show that BCA inhibits HSV-1 and alleviates the corneal lesion degree. Our study illustrates that BCA is a promising therapeutic approach for application in treating HSK.

An Adaptive Bandwidth Management Algorithm for Next-Generation Vehicular Networks.

The popularity of video services such as video call or video on-demand has made it impossible for people to live without them in their daily lives. It can be anticipated that the explosive growth of vehicular communication owing to the widespread use of in-vehicle video infotainment applications in the future will result in increasing fragmentation and congestion of the wireless transmission spectrum. Accordingly, effective bandwidth management algorithms are demanded to achieve efficient communication and stable scalability in next-generation vehicular networks. To the best of our current knowledge, a noticeable gap remains in the existing literature regarding the application of the latest advancements in network communication technologies. Specifically, this gap is evident in the lack of exploration regarding how cutting-edge technologies can be effectively employed to optimize bandwidth allocation, especially in the realm of video service applications within the forthcoming vehicular networks. In light of this void, this paper presents a seamless integration of cutting-edge 6G communication technologies, such as terahertz (THz) and visible light communication (VLC), with the existing 5G millimeter-wave and sub-6 GHz base stations. This integration facilitates the creation of a network environment characterized by high transmission rates and extensive coverage. Our primary aim is to ensure the uninterrupted playback of real-time video applications for vehicle users. These video applications encompass video conferencing, live video, and on-demand video services. The outcomes of our simulations convincingly indicate that the proposed strategy adeptly addresses the challenge of bandwidth competition among vehicle users. Moreover, it notably boosts the efficient utilization of bandwidth from less crowded base stations, optimizes the fulfillment of bandwidth prerequisites for various video applications, and elevates the overall video quality experienced by users. Consequently, our findings serve as a successful validation of the practicality and effectiveness of the proposed methodology.

ALKBH5 induces fibroblast-to-myofibroblast transformation during hypoxia to protect against cardiac rupture after myocardial infarction.

INTRODUCTION: N6-methyladenosine (m6A) methylation produces a marked effect on cardiovascular diseases. The m6A demethylase AlkB homolog 5 (ALKBH5), as an m6A "eraser", is responsible for decreased m6A modification. However, its role in cardiac fibroblasts during the post-myocardial infarction (MI) healing process remains elusive. OBJECTIVES: To investigate the effect of ALKBH5 in cardiac fibroblasts during infarct repair. METHODS: MI was mimicked by permanent left anterior descending artery ligation in global ALKBH5-knockout, ALKBH5-knockin, and fibroblast-specific ALKBH5-knockout mice to study the function of ALKBH5 during post-MI collagen repair. Methylated RNA immunoprecipitation sequencing was performed to explore potential ALKBH5 targets. RESULTS: Dramatic alterations in ALKBH5 expression were observed during the early stages post-MI and in hypoxic fibroblasts. Global ALKBH5 knockin reduced infarct size and ameliorated cardiac function after MI. The global and fibroblast-specific ALKBH5-knockout mice both exhibited low survival rates along with poor collagen repair, impaired cardiac function, and cardiac rupture. Both in vivo and in vitro ALKBH5 loss resulted in impaired fibroblast activation and decreased collagen deposition. Additionally, hypoxia, but not TGF-ß1 or Ang II, upregulated ALKBH5 expression in myofibroblasts by HIF-1α-dependent transcriptional regulation. Mechanistically, ALKBH5 promoted the stability of ErbB4 mRNA and the degradation of ST14 mRNA via m6A demethylation. Fibroblast-specific ErbB4 overexpression ameliorated the impaired fibroblast-to-myofibroblast transformation and poor post-MI repair due to ALKBH5 knockout. CONCLUSION: Fibroblast ALKBH5 positively regulates post-MI healing by stabilization of ErbB4 mRNA in an m6A-dependent manner. ALKBH5/ErbB4 might be potential therapeutic targets for post-MI cardiac rupture.

Transcriptome sequencing and metabolome analysis reveal the metabolic reprogramming of partial hepatectomy and extended hepatectomy.

Surgical resection remains a critical treatment option for many patients with primary and secondary hepatic neoplasms. Extended hepatectomy (eHx) may be required for some patients with large tumors, which may cause liver failure and death. Partial hepatectomy (pHx) and eHx mouse models were constructed, liver tissues were sampled at 18, 36, and 72 h posthepatectomy. Transcriptome and metabolome analyses were employed to explore the different potential mechanisms in regeneration and injury between pHx and eHx. The results showed that eHx was associated with more severe liver injury and lower survival rates than pHx. Transcriptomics data showed there were 1842, 2129, and 1277 differentially expressed genes (DEGs) in eHx and 962, 1305, and 732 DEGs in pHx at 18, 36, and 72 h posthepatectomy, respectively, compared with the those in the sham groups. Compared with pHx, the number of DEGs in the eHx group reached a maximum of 230 at 18 h after surgery and decreased sequentially to 87 and 43 at 36 and 72 h. Metabolomics analysis identified a total of 1399 metabolites, and 48 significant differentially produced metabolites (DPMs) were screened between eHx and pHx. Combined analysis of DEGs and DPMs indicated that cholesterol metabolism and insulin resistance may be two important pathways for liver regeneration and mouse survival postextended hepatectomy. Our results showed the global influence of pHx and eHx on the transcriptome and metabolome in mouse liver, and revealed cholesterol metabolism and insulin resistance pathways might be involved in regeneration post-pHx and -eHx.

Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC.

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6hi and KRT17hi cells post-CTX was significantly associated with poor survival after mFOLFIRINOX (mFFX), but not gemcitabine (GEM), treatment. Analysis of organoid models derived from chemo-naive and post-CTX samples demonstrated that CYP3A expression is a predictor of chemotherapy response and that CYP3A-expressing drug detoxification pathways can metabolize the prodrug irinotecan, a constituent of mFFX. These findings identify CYP3A-expressing drug-tolerant cell phenotypes in residual disease that may ultimately inform adjuvant treatment selection.

Mitochondrial transplantation ameliorates doxorubicin-induced cardiac dysfunction via activating glutamine metabolism.

Doxorubicin is a wildly used effective anticancer agent. However, doxorubicin use is also related to cardiotoxic side effect in some patients. Mitochondrial damage has been shown to be one of the pathogeneses of doxorubicin-induced myocardial injury. In this study, we demonstrated that mitochondrial transplantation could inhibit doxorubicin-induced cardiotoxicity by directly supplying functional mitochondria. Mitochondrial transplantation improved contractile function and respiratory capacity, reduced cellular apoptosis and oxidative stress in cardiomyocytes. Mitochondria isolated from various sources, including mouse hearts, mouse and human arterial blood, and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all exerted similar cardioprotective effects. Mechanically, mitochondrial transplantation activates glutamine metabolism in doxorubicin-treated mice heart and blocking glutamine metabolism attenuated the cardioprotective effects of mitochondrial transplantation. Overall, our study demonstrates that mitochondria isolated from arterial blood could be used for mitochondrial transplantation, which might serve as a feasible promising therapeutic option for patients with doxorubicin-induced cardiotoxicity.

Rural-Urban Disparities in Multimorbidity Associated With Climate Change and Air Pollution: A Longitudinal Analysis Among Chinese Adults Aged 45.

Background and Objectives: Chronic conditions and multimorbidity are increasing worldwide. Yet, understanding the relationship between climate change, air pollution, and longitudinal changes in multimorbidity is limited. Here, we examined the effects of sociodemographic and environmental risk factors in multimorbidity among adults aged 45+ and compared the rural-urban disparities in multimorbidity. Research Design and Methods: Data on the number of chronic conditions (up to 14), sociodemographic, and environmental factors were collected in 4 waves of the China Health and Retirement Longitudinal Study (2011-2018), linked with the full-coverage particulate matter 2.5 (PM2.5) concentration data set (2000-2018) and temperature records (2000-2018). Air pollution was assessed by the moving average of PM2.5 concentrations in 1, 2, 3, 4, and 5 years; temperature was measured by 1-, 2-, 3-, 4-, and 5-year moving average and their corresponding coefficients of variation. We used the growth curve modeling approach to examine the relationship between climate change, air pollution, and multimorbidity, and conducted a set of stratified analyses to study the rural-urban disparities in multimorbidity related to temperature and PM2.5 exposure. Results: We found the higher PM2.5 concentrations and rising temperature were associated with higher multimorbidity, especially in the longer period. Stratified analyses further show the rural-urban disparity in multimorbidity: Rural respondents have a higher prevalence of multimorbidity related to rising temperature, whereas PM2.5-related multimorbidity is more severe among urban ones. We also found temperature is more harmful to multimorbidity than PM2.5 exposure, but PM2.5 exposure or temperature is not associated with the rate of multimorbidity increase with age. Discussion and Implications: Our findings indicate that there is a significant relationship between climate change, air pollution, and multimorbidity, but this relationship is not equally distributed in the rural-urban settings in China. The findings highlight the importance of planning interventions and policies to deal with rising temperature and air pollution, especially for rural individuals.

Activation of GPR81 aggravated intestinal ischemia/reperfusion injury-induced acute lung injury via HMGB1-mediated neutrophil extracellular traps formation.

INTRODUCTION: Intestinal ischemia/reperfusion (II/R) injury is a life-threatening situation accompanied by severe organ injury, especially acute lung injury (ALI). A great body of evidence indicates that II/R injury is usually associated with hyperlactatemia. G-protein-coupled receptor 81 (GPR81), a receptor of lactate, has been recognized as a regulatory factor in inflammation, but whether it was involved in II/R injury-induced ALI is still unknown. METHODS: To establish the II/R injury model, the superior mesenteric artery of the mice was occluded gently by a microvascular clamp for 45 min to elicit intestinal ischemia and then a 90-min reperfusion was performed. Broncho-alveolar lavage fluid (BALF) and lung tissues were obtained to evaluate the lung injury after II/R. The pulmonary histopathological alteration was evaluated by H&E staining. The concentration of proteins, the number of infiltrated cells, and the level of IL-6 were measured in BALF. The formation of neutrophil extracellular traps (NETs) was evaluated by the level of double-stranded DNA (dsDNA) and myeloperoxidase- double-stranded DNA (MPO-dsDNA) complex in BALF, and the content of citrullinated histone H3 (Cit-H3) in lung tissue. The level of HMGB1 in the BALF and plasma was measured by enzyme linked immunosorbent assay (ELISA). RESULTS: Administration of the GPR81 agonist 3,5-dihydroxybenzoic acid (DHBA) aggravated II/R injury-induced lung histological abnormalities, upregulated the concentration of proteins, the number of infiltrated cells, and the level of IL-6 in BALF. In addition, DHBA treatment increased the level of dsDNA and MPO-dsDNA complex in BALF, and promoted the elevation of Cit-H3 in lung tissue and the release of HMGB1 in BALF and plasma. CONCLUSION: After induction of ALI by II/R, the administration of DHBA aggravated ALI through NETs formation in the lung.

Effects and mechanisms of tanshinone IIA on PTSD-like symptoms.

BACKGROUND: In recent years, Salvia miltiorrhiza and its active substances have remarkably progressed in treating central neurological disorders. Tanshinone IIA (TSA) is an active ingredient derived from the rhizome of Salvia miltiorrhiza that has been found to alleviate the symptoms of several psychiatric illnesses. Post-traumatic stress disorder (PTSD) is a mental disorder that results after experiencing a serious physical or psychological injury. The currently used drugs are not satisfactory for the treatment of PTSD. However, it has been reported that TSA can improve PTSD-like symptoms like learning and memory, cognitive disorder, and depression through multi-target regulation. PURPOSE: This paper discusses the ameliorative effects of TSA on PTSD-like symptoms and the possible mechanisms of action in terms of inhibition of neuronal apoptosis, anti-neuroinflammation, and anti-oxidative stress. Based on the pathological changes and clinical observations of PTSD, we hope to provide some reference for the clinical transformation of Chinese medicine in treating PTSD. METHODS: A large number of literatures on tanshinone in the treatment of neurological diseases and PTSD were retrieved from online electronic PubMed and Web of Science databases. CONCLUSION: TSA is a widely studied natural active ingredient against mental illness. This review will contribute to the future development of TSA as a new clinical candidate drug for improving PTSD-like symptoms.

Digital Recombinase Polymerase Amplification, Digital Loop-Mediated Isothermal Amplification, and Digital CRISPR-Cas Assisted Assay: Current Status, Challenges, and Perspectives.

Digital nucleic acid detection based on microfluidics technology can quantify the initial amount of nucleic acid in the sample with low equipment requirements and simple operations, which can be widely used in clinical and in vitro diagnosis. Recently, isothermal amplification technologies such as recombinase polymerase amplification (RPA), loop-mediated isothermal amplification (LAMP), and clustered regularly interspaced short palindromic repeats-CRISPR associated proteins (CRISPR-Cas) assisted technologies have become a hot spot of attention and state-of-the-art digital nucleic acid chips have provided a powerful tool for these technologies. Herein, isothermal amplification technologies including RPA, LAMP, and CRISPR-Cas assisted methods, based on digital nucleic acid microfluidics chips recently, have been reviewed. Moreover, the challenges of digital isothermal amplification and possible strategies to address them are discussed. Finally, future directions of digital isothermal amplification technology, such as microfluidic chip and device manufacturing, multiplex detection, and one-pot detection, are outlined.

Clinical outcomes by serum potassium levels for patients hospitalized for heart failure: Secondary analysis of data from the China National Heart Failure Registry.

BACKGROUND: Dyskalemia is a mortality risk factor in patients with heart failure (HF). HYPOTHESIS: We described the prevalence of dyskalemia, and clinical outcomes by serum potassium (sK) levels, in Chinese patients hospitalized for HF. METHODS: In this secondary analysis of the prospective China National Heart Failure Registry, adult patients hospitalized between January 1, 2013 and June 30, 2015 who had at least one baseline sK measurement were followed for up to 3 years after discharge. The use of renin-angiotensin-aldosterone system inhibitors at baseline and clinical outcomes during follow-up were compared among sK groups. RESULTS: Among 6950 patients, 5529 (79.6%) had normokalemia (sK >3.5-5.0 mmol/L), 1113 (16.0%) had hypokalemia (sK 0-3.5 mmol/L), and 308 (4.4%) had hyperkalemia (sK >5.0 mmol/L). Baseline characteristics that were most common in patients with hyperkalemia than those with hypo- and normokalemia included older age, HF with reduced ejection fraction, New York Heart Association Class III/IV status, hypertension, and chronic kidney disease. Use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) differed across sK groups (p = .0001); reported in 64.1%, 63.4%, and 54.5% of patients with hypo-, normo-, and hyperkalemia, respectively. Overall, 26.6%, 28.6%, and 36.0% of patients with hypo-, normo-, and hyperkalemia had rehospitalization for worsened HF, or cardiovascular mortality; p = .0057 for between-group comparison. CONCLUSIONS: Patients with hyperkalemia received ACEIs or ARBs for HF treatment at baseline less frequently than those with hypo- or normokalemia, and had worse prognoses. This warrants further investigation into effective hyperkalemia management in HF.

Eschar dissolution and the immunoregulator effect of keratinase on burn wounds.

At present, enzyme debridement preparation has shown a good curative effect on eschar removal of burn wounds. Keratinase has shown great potential in enzymatic debridement because of its good fibrin-degrading ability. In this study, the debridement of keratinase was examined by using a third degree burn wound model in rats. We observed the wound, and keratinase shortened the time of eschar dissolution after debridement. Histopathology and immunofluorescence staining showed that the eschar in the keratinase group became thinner, inflammatory cell infiltration in the wound increased, the fluorescence intensity of the macrophage surface marker CD68 increased, and the CD163/CD86 ratio increased. In bone marrow-derived macrophages (BMDMs), there was no significant difference in the activity of CCK-8 in cells in the keratinase group compared with the control group. The fluorescence intensity of the keratinase group was higher than that of the control group. At 12 h, the cell scratches were obviously closed. The number of migrated Transwell cells increased. Flow cytometry and immunofluorescence analysis showed increased expression of CD206 and Arg-1 and decreased expression of CD86 and iNOS. The gene expression of the Arg-1, iNOS and IL-10 was increased, as shown by qPCR. The secretion of IL-10 was increased and TNF-α was decreased, as shown by ELISA. We concluded that keratinase dissolution of eschar not only has a hydrolytic effect on eschar but may also affect immune regulation to enhance the migration and phagocytosis of macrophages, promote the polarization of macrophages, and further enhance the effect of eschar dissolution. Therefore, keratinase may have good prospects for the debridement of burn wounds.

Identification of basement membrane-related biomarkers associated with the diagnosis of osteoarthritis based on machine learning.

BACKGROUND: Osteoarthritis is a very common clinical disease in middle-aged and elderly individuals, and with the advent of ageing, the incidence of this disease is gradually increasing. There are few studies on the role of basement membrane (BM)-related genes in OA. METHOD: We used bioinformatics and machine learning methods to identify important genes related to BMs in OA patients and performed immune infiltration analysis, lncRNA‒miRNA-mRNA network prediction, ROC analysis, and qRT‒PCR. RESULT: Based on the results of machine learning, we determined that LAMA2 and NID2 were the key diagnostic genes of OA, which were confirmed by ROC and qRT‒PCR analyses. Immune analysis showed that LAMA2 and NID2 were closely related to resting memory CD4 T cells, mast cells and plasma cells. Two lncRNAs, XIST and TTTY15, were simultaneously identified, and lncRNA‒miRNA‒mRNA network prediction was performed. CONCLUSION: LAMA2 and NID2 are important potential targets for the diagnosis and treatment of OA.

Diverse long-term potentiation and depression based on multilevel LiSiOxmemristor for neuromorphic computing.

Memristor-based neuromorphic computing is expected to overcome the bottleneck of von Neumann architecture. An artificial synaptic device with continuous conductance variation is essential for implementing bioinspired neuromorphic systems. In this work, a memristor based on Pt/LiSiOx/TiN structure is developed to emulate an artificial synapse, which shows non-volatile multilevel resistance state memory behavior. Moreover, the high nonlinearity caused by abrupt changes in the set process is optimized by adjusting the initial resistance. 100 levels of continuously modulated conductance states are achieved and the nonlinearity factors are reduced to 1.31. The significant improvement is attributed to the decrease in the Schottky barrier height and the evolution of the conductive filaments. Finally, due to the improved linearity of the long-term potentiation/long-term depression behaviors in LiSiOxmemristor, a robust recognition rate (∼94.58%) is achieved for pattern recognition with the modified National Institute of Standards and Technology handwriting database. The Pt/LiSiOx/TiN memristor shows significant potential in high-performance multilevel data storage and neuromorphic computing systems.

[Analysis on Cellular Immune Function Recovery after HLA Mismatched Allogeneic Hematopoietic Stem Cell Micro-Transp- lantation in Elderly AML Patients].

OBJECTIVE: To investigate the recovery of cellular immunity in elderly patients with acute myeloid leukemia (AML) after micro-transplantation (MST) and the changes of cellular immunity during relapse, as well as their clinical significance. METHODS: A total of 41 elderly AML patients who received MST treatment in a single center and 25 healthy elderly people were included. Immune function among different age groups in normal population was compared. Furthermore, immune fuction was compared between elderly AML patients of different age groups who achieved continuous complete remission (CR) after MST treatment and normal controls, between high risk group and medium-low risk group, as well as among before diagnosis, after CR, and relapse. Peripheral blood of patients and normal controls was collected, and the percentage of lymphocyte subsets was detected by multi-color flow cytometry. RESULTS: Thirty-five patients achieved CR after MST treatment while six patients did not. After MST treatment, CD3+ T cells, CD8+T cells and activated T cells in all age groups were higher than normal. Significant recovery of CD3+ and CD8+T cells was observed in both high risk and medium-low risk groups, and the overall recovery of immune cells in medium-low risk group was better. It was also observed that B lymphocytes and NK cells could not return to normal levels within 1 year after MST treatment. The proportion of CD3+ T cells, CD4+ T cells, and CD4/CD8 ratio were significantly decreased during relapse compared with continuous CR after MST (P<0.05). CONCLUSION: MST treatment can promote the recovery of CD3+T cells, CD8+T cells and other killer cells, so as to improve the cellular immune function of elderly patients, which provides a new immune cell therapy for elderly AML.

Adaptive filtering and smoothing algorithm based on variable structure interactive multiple model.

For maneuvering target tracking, a novel adaptive variable structure interactive multiple model filtering and smoothing (AVSIMMFS) algorithm is proposed in this paper. Firstly, an accurate model of the variable structure interactive multiple model algorithm is established. Secondly, by constructing a new model subset based on the original model subsets, the matching accuracy between the model subset and the actual maneuvering mode of the target is improved. Then, the AVSIMMFS algorithm is obtained by smoothing the filtered data of the new model subset. Because of the combination of forward filtering and backward smoothing, the target tracking accuracy is further improved. Finally, in order to verify the effectiveness of the algorithm, the simulation is carried out on two cases. The simulation results show that the tracking performance of AVSIMMFS algorithm is better than other methods and has lower calculation cost.

Correction to "Carboxymethyl Chitosan Oligosaccharide Holds Promise for Treatment of Stenosis Crohn's Disease".

[This corrects the article DOI: 10.1021/acsptsci.2c00035.].

Radioprotective efficacy of Astilbin in mitigating radiation-induced lung injury through inhibition of p53 acetylation.

Radiation-induced lung injury (RILI) is a common side effect in thoracic tumor patients undergoing radiotherapy. At present, there is no ideal radio-protective agent which is widely used in RILI treatment. Astilbin (AST), a bioactive flavonoid, exhibits various biological effects, including anti-inflammatory, antioxidant, and anti-fibrotic activities, which partly result from reducing oxidative stress and inflammation in various pathogenic conditions. However, the protective efficacy of AST to ameliorate RILI has not been reported. In this study, we employed network pharmacology, RNA sequencing, and experimental evaluation to reveal the effects and pharmacological mechanism of AST to treat RILI in vivo and in vitro. We observed that AST reduced radiation-induced apoptosis, DNA damage, inflammatory reactions, and the reactive oxygen species (ROS) level in human normal lung epithelial cells BEAS-2B. Further study showed that AST treatment significantly ameliorated RILI by reducing the radiation-induced pathology changes and inflammatory reaction of lung tissue in C57BL/6J mice. Mechanistically, the expression of epithelial-mesenchymal transition (EMT) markers and radiation-triggered acetylation of the p53 protein were alleviated by AST treatment. Furthermore, AST alleviated the acetylation of p53 after intervention of Trichostatin A (TSA). Our data indicate that AST can alleviate RILI by inhibiting inflammatory reactions and the EMT process through decreasing the expression of p53 acetylation. In conclusion, our study suggests that AST has great potential to be a new protective and therapeutic compound for RILI.

An ischemic area-targeting, peroxynitrite-responsive, biomimetic carbon monoxide nanogenerator for preventing myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion (MI/R) injury is common in patients who undergo revascularization therapy for myocardial infarction, often leading to cardiac dysfunction. Carbon monoxide (CO) has emerged as a therapeutic molecule due to its beneficial properties such as anti-inflammatory, anti-apoptotic, and mitochondrial biogenesis-promoting properties. However, its clinical application is limited due to uncontrolled release, potential toxicity, and poor targeting efficiency. To address these limitations, a peroxynitrite (ONOO-)-triggered CO donor (PCOD585) is utilized to generate a poly (lactic-co-glycolic acid) (PLGA)-based, biomimetic CO nanogenerator (M/PCOD@PLGA) that is coated with the macrophage membrane, which could target to the ischemic area and neutralize proinflammatory cytokines. In the ischemic area, local produced ONOO- triggers the continuous release of CO from M/PCOD@PLGA, which efficiently ameliorates MI/R injury by clearing harmful ONOO-, attenuating the inflammatory response, inhibiting cardiomyocyte apoptosis, and promoting mitochondrial biogenesis. This study provides a novel insight into the safe therapeutic use of CO for MI/R injury by utilizing a novel CO donor combined with biomimetic technology. The M/PCOD@PLGA nanogenerator offers targeted delivery of CO to the ischemic area, minimizing potential toxicity and enhancing therapeutic efficacy.