Reply-Letter to the editor.

In our previously published article, we focused on an increasing global health issue, the double burden of malnutrition, and conducted a single-center prospective study with 3160 patients to examine the combined effects of obesity and malnutrition on clinical outcomes in patients with ischemic stroke. Ana Patrícia da Silva Sou et al. and Jiqin Wu et al. recently commented on our finding, and we hope this Reply helps to clarify some of the important points we aimed to make in the original article.

Prognosis of patients with coexisting obesity and malnutrition after ischemic stroke: A cohort study.

BACKGROUND: The double burden of malnutrition, defined as the coexistence of obesity and malnutrition, is an increasing global health concern and is unclear in patients after ischemic stroke. The current study explored the combined impacts of obesity and malnutrition on patients with ischemic stroke. METHODS: We conducted a single-center prospective cohort study with patients with ischemic stroke enrolled in Minhang Hospital in China between January 2018 and December 2022. Patients were stratified into four categories based on their obesity (defined by body mass index) and nutritional status (classified according to the Controlling Nutritional Status score): (1) nourished nonobese, (2) malnourished nonobese, (3) nourished obese, and (4) malnourished obese. The primary end points were poor outcomes and all-cause mortality at 3 months. RESULTS: A total of 3160 participants with ischemic stroke were included in our study, of which 64.7% were male and the mean age was 69 years. Over 50% of patients were malnourished. At 3-month follow-up, the malnourished nonobese had the worst outcomes (34.4%), followed by the malnourished obese (33.2%), nourished nonobese (25.1%), and nourished obese (21.8%; P < 0.001). In multivariable analyses, with nourished nonobese group as the reference, the malnourished nonobese group displayed poorer outcomes (odds ratio [OR], 1.395 [95% CI, 1.169-1.664], P < 0.001) and higher all-cause mortality (OR, 1.541 [95% CI, 1.054-2.253], P = 0.026), but only a nonsignificant increase in poor prognosis rate (33.2% vs. 25.1%, P = 0.102) and mortality (4.2% vs. 3.6%, P = 0.902) were observed in the malnourished obese group. CONCLUSION: A high prevalence of malnutrition is observed in the large population suffering from ischemic attack, even in the obese. Malnourished patients have the worst prognosis particularly in those with severe nutritional status regardless of obesity, while the best functional outcomes and the lowest mortality are demonstrated in nourished obese participants.

NSCLC extracellular vesicles containing miR-374a-5p promote leptomeningeal metastasis by influencing blood‒brain barrier permeability.

Leptomeningeal metastasis (LM) is a devastating complication of advanced non-small cell lung cancer (NSCLC). Diagnosis and monitoring of LM can be challenging. Extracellular vesicles (EVs) microRNAs (miRNAs) have become a new noninvasive diagnostic biomarker. The purpose of this study was to examine the clinical value and role of EVs miRNAs in NSCLC-LM. According to next-generation sequencing (NGS), miRNAs with differential expression of EVs in serum of NSCLC patients with LM and non-LM were detected to find biological markers for the diagnosis of LM. Cellular and in vivo experiments were conducted to explore the pathogenesis of EVs miRNA promoting LM in NSCLC. In the present study, we first demonstrated the serum level of EV-associated miR-374a-5p in patients with LM of lung cancer was much higher than that in patients without LM and was correlated with the survival time of patients with LM. Further studies showed that EVs miR-374a-5p efficiently destroys tight junctions and the integrity of the cerebral microvascular endothelial cell barrier, resulting in increased blood-brain barrier (BBB) permeability. Mechanistically, miR-374a-5p regulates the distribution of ZO-1 and occludin in endothelial cells by targeting ADD3, increasing vascular permeability and promoting LM. Implications: These results suggest that serum NSCLC-derived EVs miR-374a-5p is involved in premetastatic niche formation by regulating the permeability of BBB to promote NSCLC-LM, and can be used as a blood biomarker for the diagnosis and prognosis of NSCLC-LM.

Prediction of poststroke cognitive impairment based on the systemic inflammatory response index.

BACKGROUND: Poststroke cognitive impairment (PSCI) is a prevalent complication among stroke survivors. Although the systemic inflammatory response index (SIRI) has been shown to be a reliable predictor of a variety of inflammatory diseases, the association between the SIRI and PSCI is still unclear. Therefore, the purpose of this study was to investigate the relationship between SIRI and PSCI, and to design a nomogram to predict the risk of PSCI in acute ischemic stroke (AIS) patients. METHODS: A total of 1342 patients with AIS were included in the study. Using the Mini-Mental State Examination scale, patients were separated into PSCI and non-PSCI groups within 2 weeks of stroke. Clinical data and SIRI values were compared between the groups. We developed the optimal nomogram for predicting PSCI using multivariate logistic regression. Finally, the nomogram was validated using the receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA). RESULTS: In total, 690 (51.4%) patients were diagnosed with PSCI. After adjusting for potential confounders, the SIRI (OR = 1.226, OR: 1.095-1.373, p < .001) was shown to be an independent risk factor for PSCI in the logistic regression analysis. The nomogram based on patient gender, age, admission National Institutes of Health Stroke Scale scores, education, diabetes mellitus, and SIRI had good discriminative ability with an area under the curve (AUC) of 0.716. The calibration curve and Hosmer-Lemeshow test revealed excellent predictive accuracy for the nomogram. Finally, the DCA showed the good clinical utility of the model. CONCLUSION: Increased SIRI on admission is correlated with PSCI, and the nomogram built with SIRI as one of the predictors can help identify PSCI early.

3D Printing of Cobalt-Incorporated Chloroapatite Bioceramic Composite Scaffolds with Antioxidative Activity for Enhanced Osteochondral Regeneration.

Osteochondral defects are often accompanied by excessive reactive oxygen species (ROS) caused by osteoarthritis or acute surgical inflammation. An inflammatory environment containing excess ROS will not only hinder tissue regeneration but also impact the quality of newly formed tissues. Therefore, there is an urgent need to develop scaffolds with both ROS scavenging and osteochondral repair functions to promote and protect osteochondral tissue regeneration. In this work, by using 3D printing technology, a composite scaffold based on cobalt-incorporated chloroapatite (Co-ClAP) bioceramics, which possesses ROS-scavenging activity and can support cell proliferation, adhesion, and differentiation, is developed. Benefiting from the catalytic activity of Co-ClAP bioceramics, the composite scaffold can protect cells from oxidative damage under ROS-excessive conditions, support their directional differentiation, and simultaneously mediate an anti-inflammatory microenvironment. In addition, it is also confirmed by using rabbit osteochondral defect model that the Co-ClAP/poly(lactic-co-glycolic acid) scaffold can effectively promote the integrated regeneration of cartilage and subchondral bone, exhibiting an ideal repair effect in vivo. This study provides a promising strategy for the treatment of defects with excess ROS and inflammatory microenvironments.

High serum lactate dehydrogenase to albumin ratio is associated with increased risk of poor prognosis after ischemic stroke.

BACKGROUND: Lactate dehydrogenase to albumin ratio (LAR) is a comprehensive biomarker for anaerobiosis, inflammation, and nutritional status, but its prognostic value for ischemic stroke has rarely been reported. We aimed to prospectively investigate whether serum LAR is associated with the prognosis of ischemic stroke patients in a large-scale cohort study. MATERIALS AND METHODS: Serum LAR levels were measured among 6634 patients with ischemic stroke admitted at Minhang hospital from January 2018 to December 2022. The primary outcome was the composite of major disability and death (modified Rankin Scale score [mRS] ≥ 3) at 3-month follow up. Secondary outcomes included death and the ordered 7-level category score of mRS. Multivariate logistic regression and restricted cubic splines were adopted to evaluate the associations between serum LAR levels and adverse clinical outcomes of ischemic stroke. RESULTS: During 3 months of follow-up period, a total of 2125 patients experienced primary outcome. After multivariate adjustment, the highest quartile of serum LAR was associated with an increased risk of primary outcome (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.27-1.83; P for trend < 0.001). Each standard deviation higher log-transformed serum LAR resulted in a 20% (95% CI, 12%-28%) increased risk of primary outcome. Furthermore, multivariable-adjusted restricted cubic spline analyses showed a linear association between the serum LAR level with primary outcome (P for linearity < 0.001). Finally, the addition of serum LAR to conventional risk factors significantly improved risk predictive abilities for the primary outcome (net reclassification improvement [NRI]: 18.35%, P < 0.001; integrated discrimination improvement [IDI]: 0.35%, P < 0.001) at 3-month follow up in patients with ischemic stroke. CONCLUSION: High serum LAR level was independently associated with an increased risk of adverse clinical outcomes among patients with ischemic stroke, indicating that serum LAR may be a valuable prognostic biomarker for ischemic stroke.

A Multifunctional Hydrogel for Simultaneous Visible H2 O2 Monitoring And Accelerating Diabetic Wound Healing.

Diabetic wound is one of the chronic wounds that is difficult to heal, and effective treatment of it still confronts a great challenge. Monitoring the variation of diabetic wound microenvironment (such as hydrogen peroxide (H2 O2 )) can understand the wound state and guide the wound management. Herein, a multifunctional hydrogel with the abilities of monitoring the H2 O2 concentration, alleviating oxidative stress and promoting wound healing is developed, which is prepared by encapsulating manganese-containing bioactive glass (MnBG) and CePO4 :Tb in biocompatible gelatin methacryloyl (GelMA) hydrogel (CPT-MnBG-Gel). On the one hand, the H2 O2 -dependent fluorescence quenching effect of the CePO4 :Tb contributes to visible monitoring of the H2 O2 concentration of wounds via smartphone imaging, and the CPT-MnBG-Gel hydrogel can effectively monitor the H2 O2 level of 10.35-200 µmol L-1 . On the other hand, MnBG can alleviate oxidative stress and promote the proliferation, migration and differentiation of fibroblasts and endothelial cells in vitro owing to the bioactive Mn and Si ions, and in vivo evaluation also demonstrates that the CPT-MnBG-Gel hydrogels can effectively accelerate wound healing. Hence, such multifunctional hydrogel is promising for diabetic wound management and accelerating wound healing.

Anti-CHAC1 exosomes for nose-to-brain delivery of miR-760-3p in cerebral ischemia/reperfusion injury mice inhibiting neuron ferroptosis.

Ferroptosis plays a critical role in ischemic stroke, and anti-ferroptosis strategies were regarded as potentially effective measures. Based on ferroptosis-related mechanisms, this study aims to design and prepare anti-ferroptosis exosomes from adipose-derived mesenchymal stem cells (ADSC-Exo) for treating ischemic brain injury via intranasal (IN) administration. According to the bioinformatic analysis, CHAC1 was a key gene in the progress of ferroptosis in ischemic stroke. miR-760-3p can inhibit the expression of CHAC1 and may be abundant in ADSC-Exo. Therefore, ADSC-Exo were successfully isolated and the immunofluorescence showed that they can be efficiently delivered to the brain via IN administration. Additionally, IN administration of ADSC-Exo can effectively improve the neurobehavior function of mice after I/R, and improve the ferroptosis-related outcomes. As the immunofluorescence showed the co-localization of NeuN with CHAC1 obviously, we further evaluated the systematic effect of ADSC-Exo in an oxygen-glucose deprivation (OGD) mouse neuroblastoma cell line N2a model. The results showed that miR-760-3p in ADSC-Exo contributed to their function in inhibiting ferroptosis by targeting CHAC1 in neurons. Collectively, the present study successfully designed and prepared anti-CHAC1 ADSC-Exo and suggested a promising exosome-based strategy for anti-ferroptosis therapy in cerebral ischemia/reperfusion injury.

Metal-Organic Frameworks-Based Nanoplatforms for the Theranostic Applications of Neurological Diseases.

Neurological diseases are the foremost cause of disability and the second leading cause of death worldwide. Owing to the special microenvironment of neural tissues and biological characteristics of neural cells, a considerable number of neurological disorders are currently incurable. In the past few years, the development of nanoplatforms based on metal-organic frameworks (MOFs) has broadened opportunities for offering sensitive diagnosis/monitoring and effective therapy of neurology-related diseases. In this article, the obstacles for neurotherapeutics, including delayed diagnosis and misdiagnosis, the existence of blood brain barrier (BBB), off-target treatment, irrepressible inflammatory storm/oxidative stress, and irreversible nerve cell death are summarized. Correspondingly, MOFs-based diagnostic/monitoring strategies such as neuroimaging and biosensors (electrochemistry, fluorometry, colorimetry, electrochemiluminescence, etc.) and MOFs-based therapeutic strategies including higher BBB permeability, targeting specific lesion sites, attenuation of neuroinflammation/oxidative stress as well as regeneration of nerve cells, are extensively highlighted for the management of neurological diseases. Finally, the challenges of the present research from perspective of clinical translation are discussed, hoping to facilitate interdisciplinary studies at the intersections between MOFs-based nanoplatforms and neurotheranostics.

Microneedle-Assisted Transdermal Delivery of 2D Bimetallic Metal-Organic Framework Nanosheet-Based Cascade Biocatalysts for Enhanced Catalytic Therapy of Melanoma.

Current conventional treatments for malignant melanoma still face limitations, especially low therapeutic efficacy and serious side effects, and more effective strategies are urgently needed to develop them. Delivering biocatalysts into tumors to efficiently trigger in situ cascade reactions has shown huge potential in producing more therapeutic species or generating stronger tumoricidal effects for augmented tumor therapy. Recently, ultrathin 2D metal-organic framework (MOF) nanosheets have acquired great interest in biocatalysis owing to their large surface areas and abundant accessible active catalytic sites. Herein, an enhanced catalytic therapeutic strategy against melanoma is developed by biocompatible microneedle (MN)-assisted transdermal delivery of a 2D bimetallic MOF nanosheet-based cascade biocatalyst (Cu-TCPP(Fe)@GOD). Profiting from the constructed dissolving MN system, the loaded Cu-TCPP(Fe)@GOD hybrid nanosheets can be accurately delivered into the melanoma sites through skin barriers, and subsequently, trigger the specific cascade catalytic reactions in response to the acidic tumor microenvironment to effectively generate highly toxic hydroxyl radical (• OH) and deplete glucose nutrient for inducing the death of melanoma cells. The ultimate results prove the high melanoma inhibition effect and biosafety of such therapeutic modality, exhibiting a new and promising strategy to conquer malignant melanoma.

Metal-Organic Framework-Based Nanoagents for Effective Tumor Therapy by Dual Dynamics-Amplified Oxidative Stress.

Overproduction of reactive oxygen species (ROS) within tumors can cause oxidative stress on tumor cells to induce death, which has motivated us to develop ROS-mediated tumor therapies, such as typical photodynamic therapy (PDT) and Fenton reaction-mediated chemodynamic therapy (CDT). However, these therapeutic modalities suffer from compromised treatment efficacy owing to their limited generation of highly reactive ROS in a tumor microenvironment (TME). In this work, a nanoscale iron-based metal-organic framework, MIL-101(Fe), is synthesized as a Fenton nanocatalyst to perform the catalytic conversion of hydroxyl radicals (·OH) from hydrogen peroxide (H2O2) under the acidic environment and as a biocompatible and biodegradable nanocarrier to deliver a 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) photosensitizer for light-activated singlet oxygen (1O2) generation. By coupling such chemodynamic/photodynamic effects, the photosensitizer-integrated nanoagents (MIL-101(Fe)@TCPP) could enable more ROS production within tumors to induce amplified oxidative damage for tumor-specific synergistic therapy. In vitro results show that MIL-101(Fe)@TCPP nanoagents achieve the acid-responsive CDT and effective PDT, and synergistic CDT/PDT provides an enhanced therapeutic effect. Ultimately, based on such synergistic therapy, MIL-101(Fe)@TCPP nanoagents cause a significant tumor growth inhibition in vivo without severe side effects, showing great potential for anti-tumor application.