Pharmacological upregulation of macrophage-derived itaconic acid by pubescenoside C attenuated myocardial ischemia-reperfusion injury.

INTRODUCTION: Myocardial ischemia-reperfusion injury (MIRI) remains a prevalent clinical challenge globally, lacking an ideal therapeutic strategy. Macrophages play a pivotal role in MIRI pathophysiology, exhibiting dynamic inflammatory and resolutive functions. Macrophage polarization and metabolism are intricately linked to MIRI, presenting potential therapeutic targets. Pubescenoside C (PBC) from Ilex pubescens showed significantly anti-inflammatory effects, however, the effect of PBC on MIRI is unknown. OBJECTIVES: This study aimed to assess the cardioprotective effects of PBC against MIRI and elucidate the underlying mechanisms. METHODS: Sprague-Dawley rats, H9c2 and RAW264.7 macrophages were used to establish the in vitro and in vivo models of MIRI. TTC/Evans blue staining, immunohistochemical staining, metabonomics analysis, chemical probe, surface plasmon resonance (SPR), co-immunoprecipitation (CO-IP) assays were used for pharmacodynamic and mechanism study. RESULTS: PBC administration effectively reduced myocardial infarct size, decreased ST-segment elevation, and lowered CK-MB levels, concurrently promoting macrophage M2 polarization in MIRI. Furthermore, PBC-treated macrophages and their conditioned culture medium attenuated the apoptosis of H9c2 cells induced by oxygen-glucose deprivation/reoxygenation (OGD/R). Metabonomics analysis revealed that PBC increased the production of itaconic acid (ITA) and malic acid (MA) in macrophages, which conferred protection against OGD/R injury in H9c2 cells. Mechanistic investigations indicated that ITA exerted its effects by covalently modifying pyruvate kinase M2 (PKM2) at Cys474, Cys424, and Lys151, thereby facilitating PKM2's mitochondrial translocation and enhancing the PKM2/Bcl2 interaction, subsequently leading to decreased degradation of Bcl2. SPR assays further revealed that PBC bound to HSP90, facilitating the interaction between HSP90 and GSK3ß and resulting in the inactivation of GSK3ß activity and upregulation of key metabolic enzymes for ITA and MA production (Acod1 and Mdh2). CONCLUSION: PBC alleviates MIRI-induced cardiomyocyte apoptosis by modulating the HSP90/ITA/PKM2 axis. Furthermore, pharmacological upregulation of ITA emerges as a promising therapeutic approach for MIRI, hinting at PBC's potential as a candidate drug for MIRI therapy.

Neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for initially unresectable locally advanced colon cancer: short-term outcomes of an open-label, single-centre, randomised, controlled, phase 3 trial.

Background: Neoadjuvant chemotherapy (NACT) is commonly used to downstage the tumor in locally advanced colon cancer (LACC) and improve the R0 resection rate. Neoadjuvant chemoradiotherapy (NACRT) is the standard treatment for locally advanced rectal and esophageal cancers, but its benefits in LACC remain poorly understood. This study aimed to compare the effects and safety of NACRT and NACT on R0 resection and survival rates in initially unresectable LACC. Methods: This was an open-label, single-center, randomized, controlled trial conducted between May 11, 2019 and May 30, 2022. Forty-five patients with initially unresectable LACC were randomly allocated to the NACT (control, n = 20) or NACRT (research, n = 25) group. The NACT group received XELOX (oxaliplatin 100-130 mg/m2, qd, d1, every 3 weeks; and capecitabine 1000 mg/m2, bid, d1-d14, every 3 weeks) for 4 cycles. The NACRT group, in addition to chemotherapy, received daily irradiation (GTV 45-50 Gy/25 F; CTV 42.5-45 Gy/25 F). Surgery was scheduled 6-12 weeks after neoadjuvant treatment and adjuvant chemotherapy was administered if the patient developed resectable LACC. The primary endpoint was the 5-year overall survival (OS) rate. The secondary outcomes included the 3-year progression-free survival (PFS) and R0 resection rates. This study was registered with ClinicalTrials.gov (NCT03970694). Findings: In short-term outcome analysis, NACRT significantly improved the R0 resection rate (80% for NACRT vs. 20% for NACT, P < 0.001). The NACRT and NACT groups had a 3-year OS of 87.6% and 75% (P = 0.037) and a 3-year PFS of 76% and 45% (P = 0.049), respectively. The 5-year OS was not reached. In the NACRT group, no local or regional recurrence was observed in patients who underwent surgery during the follow-up period, compared to two patients in the NACT group. Both NACT and NACRT were well tolerated, with no significant differences in severe adverse events. The most commonly observed grade 3-4 AE was myelosuppression (39% for NACRT and 47% for NACT, P = 0.609). No grade 5 AEs were observed between the two groups. Interpretation: Adding radiation to NACT increased the R0 resection rate, prolonged the PFS, and potentially improved OS in selected patients with initially unresectable LACC. The trial findings indicate that this approach is safe, feasible, and may confer a survival benefit. Funding: This study was supported by grants from the National Natural Science Foundation of China (82373213 to Dr Gao, 82202952 to Dr Wang); and the Natural Science Foundation of Guangdong Province (2023A1515010290 to Dr Chang). Funding sources were not involved in the study design, data collection, analysis and interpretation, writing of the report, or decision to submit the article for publication.

Progression of mesenchymal stem cell regulation on imbalanced microenvironment after spinal cord injury.

Spinal cord injury (SCI) results in significant neural damage and inhibition of axonal regeneration due to an imbalanced microenvironment. Extensive evidence supports the efficacy of mesenchymal stem cell (MSC) transplantation as a therapeutic approach for SCI. This review aims to present an overview of MSC regulation on the imbalanced microenvironment following SCI, specifically focusing on inflammation, neurotrophy and axonal regeneration. The application, limitations and future prospects of MSC transplantation are discussed as well. Generally, a comprehensive perspective is provided for the clinical translation of MSC transplantation for SCI.

Construction and validation of a risk prediction model for extrauterine growth restriction in preterm infants born at gestational age less than 34 weeks.

Objective: This study aimed to develop and validate a model for predicting extrauterine growth restriction (EUGR) in preterm infants born ≤34 weeks gestation. Methods: Preterm infants from Guangxi Maternal and Child Health Hospital (2019-2021) were randomly divided into training (80%) and testing (20%) sets. Collinear clinical variables were excluded using Pearson correlation coefficients. Predictive factors were identified using Lasso regression. Random forest (RF), support vector machine (SVM), and logistic regression (LR) models were then built and evaluated using the confusion matrix, area under the curve (AUC), and the F1 score. Additionally, calibration curves and decision curve analysis (DCA) were plotted to assess the performance and practical utility of the models. Results: The study included 387 infants, with no significant baseline differences between training (n = 310) and testing (n = 77) sets. LR identified gestational age, birth weight, premature rupture of membranes, patent ductus arteriosus, cholestasis, and neonatal sepsis as key EUGR predictors. The RF model (19 variables) demonstrated an accuracy of greater than 90% during training, and superior AUC (0.62), F1 score (0.80), and accuracy (0.72) in testing compared to other models. Conclusions: Gestational age, birth weight, premature rupture of membranes, patent ductus arteriosus, cholestasis, and neonatal sepsis are significant EUGR predictors in preterm infants ≤34 weeks. The model shows promise for early EUGR prediction in clinical practice, potentially enhancing screening efficiency and accuracy, thus saving medical resources.

Collinear Spin Current Induced by Artificial Modulation of Interfacial Symmetry.

Current induced spin-orbit torque (SOT) manipulation of magnetization is pivotal in spintronic devices. However, its application for perpendicular magnetic anisotropy magnets, crucial for high-density storage and memory devices, remains nondeterministic and inefficient. Here, a highly efficient approach is demonstrated to generate collinear spin currents by artificial modulation of interfacial symmetry, achieving 100% current-induced field-free SOT switching in CoFeB multilayers with perpendicular magnetization on stepped Al2O3 substrates. This field-free switching is primarily driven by the out-of-plane anti-damping SOT generated by the planar spin Hall effect (PSHE), resulting from reduced interface symmetry due to orientation-determined steps. Microscopic theoretical analysis confirms the presence and significance of PSHE in this process. Notably, this method for generating out-of-plane spin polarization along the collinear direction of the spin-current with artificial modulation of interfacial symmetry, overcomes inherent material symmetry constraints. These findings provide a promising avenue for universal control of spin-orbit torque, addressing challenges associated with low crystal symmetry and highlighting its great potential to advance the development of energy-efficient spintronic devices technology.

Highly sensitive biosensors for real-time monitoring of histamine at acupoint PC6 in rats based on graphene-modified acupuncture needles.

Acupoints are the local initial response sites of acupuncture therapeutic effects. As a biomarker, histamine is released into the acupoint region and plays its role concurrently as acupuncture needles are inserted into acupoints. Hence, real-time monitoring of histamine at acupoints is important to elucidate the effectiveness of the acupoint-activation process in acupuncture. Therefore, we developed highly sensitive acupuncture/Au particles/graphene biosensors by electrodeposition, brushing, and annealing methods based on bare acupuncture needles. We achieved a histamine detection limit of approximately 4.352 (±3.419) × 10-12 mol L-1 and good sensitivity of approximately 6.296 (±3.873) µA µM-1, with satisfactory specificity, repeatability, and stability in vitro, rendering them more competitive and suitable for real-time monitoring in vivo without causing additional damage. Subsequently, we conducted real-time histamine monitoring at non-acupoint and acupoint PC6 in rats, respectively. Our results showed minimal changes at the non-acupoint, whereas a trend of initial increase followed by a decrease was observed at acupoint PC6. The change in histamine concentration at acupoint PC6 reflected its involvement in the acupoint-activation procedure. Moreover, its peak position at ∼18 min could provide guidance for optimizing needle retaining time for maximum therapeutic effect. This work presents the first real-time in vivo monitoring of histamine at acupoints with high sensitivity and underscores the specificity of histamine release between non-acupoint and acupoint PC6, demonstrating great potential for elucidating the acupoint-activation mechanisms in acupuncture. Additionally, this work expands the application of nanomaterials in the integration of medicine and engineering, which is an important aspect of the future development of materials science.

Elevated concentrations of amyloid-ß oligomers and their proapoptotic effects on age-related cataract.

Recently, amyloid-ß oligomers (AßOs) have been studied as the primary pathogenic substances in Alzheimer's disease (AD). Our previous study revealed that the Aß expression level is closely related to ARC progression. Here, we demonstrated that the accumulation of AßOs in the lens epithelium of age-related cataract (ARC) patients increased during ARC progression and that this alteration was consistent with the changes in mitochondrial function, oxidative stress, and cellular apoptosis. In vitro, human lens epithelial cells (HLECs) treated with AßOs exhibited Ca2+ dyshomeostasis, impaired mitochondrial function, elevated oxidative stress levels, and increased apoptosis. Moreover, the proapoptotic effect of AßOs was alleviated after the uptake of mitochondrial Ca2+ was inhibited. These results establish that AßOs may promote HLEC apoptosis by inducing mitochondrial Ca2+ overload, thus preliminarily revealing the possible association between the accumulation of AßOs and other pathological processes in ARC.

Interactions between fibroblasts and monocyte-derived cells in chronic lung injuries induced by real-ambient particulate matter exposure.

Long-term exposure to fine particulate matter (PM2.5) can lead to chronic lung injury, including inflammation, idiopathic pulmonary fibrosis, and cancer. Mesenchymal cells, such as fibroblasts, myeloid-derived suppressor cells (MDSCs), and interstitial macrophages (IMs), contribute to immune regulation in lung, yet their diversity and functions upon long-term exposure to particulate matter (PM) remain inadequately characterized. In this study, we conducted a 16-week real-ambient PM exposure experiment on C57BL/6 J male mice in Shijiazhuang, China. We used single-cell RNA sequencing to analyze the cellular and molecular changes in lung tissues. Notably, we revealed a significant increase in specific fibroblast (ATX+, Col5a1+Meg3+, universal fibroblasts) and monocyte-derived cell subpopulations (monocytic-MDSCs (M-MDSCs), Lyve1loMHC-Ⅱhi IMs, Lyve1hiMHC-Ⅱlo IMs) that exhibited pro-inflammatory and pro-fibrotic functions. These cell subpopulations engaged in immunosuppressive signaling pathways and interactions with various cytokines, shaping a pulmonary microenvironment similar to those associated with cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). This altered immune environment may promote the development of pulmonary fibrosis caused by PM exposure, underscoring the intricate roles of mesenchymal cells in chronic lung injury and highlighting the cancer-causing potential of PM2.5 exposure.

A fungal effector suppresses plant immunity by manipulating DAHPS-mediated metabolic flux in chloroplasts.

Plant secondary metabolism represents an important and ancient form of defense against pathogens. Phytopathogens secrete effectors to suppress plant defenses and promote infection. However, it is largely unknown, how fungal effectors directly manipulate plant secondary metabolism. Here, we characterized a fungal defense-suppressing effector CfEC28 from Colletotrichum fructicola. Gene deletion assays showed that ∆CfEC28-mutants differentiated appressoria normally on plant surface but were almost nonpathogenic due to increased number of plant papilla accumulation at attempted penetration sites. CfEC28 interacted with a family of chloroplast-localized 3-deoxy-d-arabinose-heptulonic acid-7-phosphate synthases (DAHPSs) in apple. CfEC28 inhibited the enzymatic activity of an apple DAHPS (MdDAHPS1) and suppressed DAHPS-mediated secondary metabolite accumulation through blocking the manganese ion binding region of DAHPS. Dramatically, transgene analysis revealed that overexpression of MdDAHPS1 provided apple with a complete resistance to C. fructicola. We showed that a novel effector CfEC28 can be delivered into plant chloroplasts and contributes to the full virulence of C. fructicola by targeting the DAHPS to disrupt the pathway linking the metabolism of primary carbohydrates with the biosynthesis of aromatic defense compounds. Our study provides important insights for understanding plant-microbe interactions and a valuable gene for improving plant disease resistance.

Dysfunction of Endothelial Cell-Mediated Intercellular Communication and Metabolic Pathways in Age-Related Macular Degeneration.

PURPOSE: Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, but the therapies are not satisfactory. This study aimed to find AMD specific features through the analysis of high-throughput sequencing. METHODS: In this study, we integrated six projects containing single-cell RNA sequencing (scRNA-seq) data to perform a comprehensive analysis for AMD samples in the tissues of retina and retinal pigment epithelium/choroid, and in the positions of macula and periphery. Differentially expressed genes (DEGs) were analyzed and crucial signaling pathways were identified across cell types and between the macula and periphery. The intercellular signaling transduction among cell types were inferred by "CellChat" to build cell-cell communication network under normal and AMD conditions, and verified at the transcriptional level. The CD31+ endothelial cells were obtained to evaluate the enrichment of KEGG pathways in atrophic and neovascular AMD, and GSVA was adopted to discover differential metabolic signals in each AMD type. RESULTS: Thirteen major cell types were identified in the integrated scRNA-seq data. Although no disease-specific cell type or differential cell proportion was found, DEGs and enriched pathways were shown in cell-type- and position-dependent manners. Severe impairment of endothelial cell-mediated cell interactions was found in the signaling transduction network of the macula, and compromised cell interactions were observed in the periphery. Furthermore, distinct signaling pathways and metabolic states were uncovered in atrophic and neovascular AMD. Striking reduction in energy metabolism, lipid metabolism, and oxidative stress was indicated in the atrophic AMD. CONCLUSION: Conclusively, we discover aberrant signals and metabolic pathways in AMD samples, providing insight into mechanisms and potential therapeutic targets for the AMD treatment.