Multifunctional Nanomaterials for Advancing Neural Interfaces: Recording, Stimulation, and Beyond.

ConspectusNeurotechnology has seen dramatic improvements in the last three decades. The major focus in the field has been to design electrical communication platforms with high spatial resolution, stability, and translatability for understanding and affecting neural pathways. The deployment of nanomaterials in bioelectronics has enhanced the capabilities of conventional approaches employing microelectrode arrays (MEAs) for electrical interfaces, allowing the construction of miniaturized, high-performance neuroelectronics (Garg, R.; et al. ACS Appl. Nano Mater. 2023, 6, 8495). While these advancements in the electrical neuronal interface have revolutionized neurotechnology both in scale and breadth, an in-depth understanding of neurons' interactions is challenging due to the complexity of the environments where the cells and tissues are laid. The activity of large, three-dimensional neuronal systems has proven difficult to accurately monitor and modulate, and chemical cell-cell communication is often completely neglected. Recent breakthroughs in nanotechnology have provided opportunities to use new nonelectric modes of communication with neurons and to significantly enhance electrical signal interface capabilities. The enhanced electrochemical activity and optical activity of nanomaterials owing to their nonbulk electronic properties and surface nanostructuring have seen extensive utilization. Nanomaterials' enhanced optical activity enables remote neural state modulation, whereas the defect-rich surfaces provide an enormous number of available electrocatalytic sites for neurochemical detection and electrochemical modulation of cell microenvironments through Faradaic processes. Such unique properties can allow multimodal neural interrogation toward generating closed-loop interfaces with access to more complete neural state descriptors. In this Account, we will review recent advances and our efforts spearheaded toward utilizing nanostructured electrodes for enhanced bidirectional interfaces with neurons, the application of unique hybrid nanomaterials for remote nongenetic optical stimulation of neurons, tunable nanomaterials for highly sensitive and selective neurotransmitter detection, and the utilization of nanomaterials as electrocatalysts toward electrochemically modulating cellular activity. We highlight applications of these technologies across cell types through nanomaterial engineering with a focus on multifunctional graphene nanostructures applied though several modes of neural modulation but also an exploration of broad material classes for maximizing the potency of closed-loop bioelectronics.

DNA damage to bone marrow stromal cells by antileukemia drugs induces chemoresistance in acute myeloid leukemia via paracrine FGF10-FGFR2 signaling.

Chemoresistance remains a major challenge in the current treatment of acute myeloid leukemia (AML). The bone marrow microenvironment (BMM) plays a complex role in protecting leukemia cells from chemotherapeutics, and the mechanisms involved are not fully understood. Antileukemia drugs kill AML cells directly but also damage the BMM. Here, we determined antileukemia drugs induce DNA damage in bone marrow stromal cells (BMSCs), resulting in resistance of AML cell lines to adriamycin and idarubicin killing. Damaged BMSCs induced an inflammatory microenvironment through NF-κB; suppressing NF-κB with small molecule inhibitor Bay11-7082 attenuated the prosurvival effects of BMSCs on AML cell lines. Furthermore, we used an ex vivo functional screen of 507 chemokines and cytokines to identify 44 proteins secreted from damaged BMSCs. Fibroblast growth factor-10 (FGF10) was most strongly associated with chemoresistance in AML cell lines. Additionally, expression of FGF10 and its receptors, FGFR1 and FGFR2, was increased in AML patients after chemotherapy. FGFR1 and FGFR2 were also widely expressed by AML cell lines. FGF10-induced FGFR2 activation in AML cell lines operates by increasing P38 MAPK, AKT, ERK1/2, and STAT3 phosphorylation. FGFR2 inhibition with small molecules or gene silencing of FGFR2 inhibited proliferation and reverses drug resistance of AML cells by inhibiting P38 MAPK, AKT, and ERK1/2 signaling pathways. Finally, release of FGF10 was mediated by ß-catenin signaling in damaged BMSCs. Our data indicate FGF10-FGFR2 signaling acts as an effector of damaged BMSC-mediated chemoresistance in AML cells, and FGFR2 inhibition can reverse stromal protection and AML cell chemoresistance in the BMM.

Exosome-derived circUPF2 enhances resistance to targeted therapy by redeploying ferroptosis sensitivity in hepatocellular carcinoma.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) can be treated with sorafenib, which is the primary choice for targeted therapy. Nevertheless, the effectiveness of sorafenib is greatly restricted due to resistance. Research has shown that exosomes and circular RNAs play a vital role in the cancer's malignant advancement. However, the significance of exosomal circular RNAs in the development of resistance to sorafenib in HCC remains uncertain. METHODS: Ultracentrifugation was utilized to isolate exosomes (Exo-SR) from the sorafenib-resistant HCC cells' culture medium. Transcriptome sequencing and differential expression gene analysis were used to identify the targets of Exo-SR action in HCC cells. To identify the targets of Exo-SR action in HCC cells, transcriptome sequencing and analysis of differential expression genes were employed. To evaluate the impact of exosomal circUPF2 on resistance to sorafenib in HCC, experiments involving gain-of-function and loss-of-function were conducted. RNA pull-down assays and mass spectrometry analysis were performed to identify the RNA-binding proteins interacting with circUPF2. RNA immunoprecipitation (RIP), RNA pull-down, electrophoretic mobility shift assay (EMSA), immunofluorescence (IF) -fluorescence in situ hybridization (FISH), and rescue assays were used to validate the interactions among circUPF2, IGF2BP2 and SLC7A11. Finally, a tumor xenograft assay was used to examine the biological functions and underlying mechanisms of Exo-SR and circUPF2 in vivo. RESULTS: A novel exosomal circRNA, circUPF2, was identified and revealed to be significantly enriched in Exo-SR. Exosomes with enriched circUPF2 enhanced sorafenib resistance by promoting SLC7A11 expression and suppressing ferroptosis in HCC cells. Mechanistically, circUPF2 acts as a framework to enhance the creation of the circUPF2-IGF2BP2-SLC7A11 ternary complex contributing to the stabilization of SLC7A11 mRNA. Consequently, exosomal circUPF2 promotes SLC7A11 expression and enhances the function of system Xc- in HCC cells, leading to decreased sensitivity to ferroptosis and resistance to sorafenib. CONCLUSIONS: The resistance to sorafenib in HCC is facilitated by the exosomal circUPF2, which promotes the formation of the circUPF2-IGF2BP2-SLC7A11 ternary complex and increases the stability of SLC7A11 mRNA. Focusing on exosomal circUPF2 could potentially be an innovative approach for HCC treatment.

The development of a novel zeolite-based assay for efficient and deep plasma proteomic profiling.

Plasma proteins are considered the most informative source of biomarkers for disease diagnosis and monitoring. Mass spectrometry (MS)-based proteomics has been applied to identify biomarkers in plasma, but the complexity of the plasma proteome and the extremely large dynamic range of protein abundances in plasma make the clinical application of plasma proteomics highly challenging. We designed and synthesized zeolite-based nanoparticles to deplete high-abundance plasma proteins. The resulting novel plasma proteomic assay can measure approximately 3000 plasma proteins in a 45 min chromatographic gradient. Compared to those in neat and depleted plasma, the plasma proteins identified by our assay exhibited distinct biological profiles, as validated in several public datasets. A pilot investigation of the proteomic profile of a hepatocellular carcinoma (HCC) cohort identified 15 promising protein features, highlighting the diagnostic value of the plasma proteome in distinguishing individuals with and without HCC. Furthermore, this assay can be easily integrated with all current downstream protein profiling methods and potentially extended to other biofluids. In conclusion, we established a robust and efficient plasma proteomic assay with unprecedented identification depth, paving the way for the translation of plasma proteomics into clinical applications.

Fermented Ophiocordyceps sinensis mycelium products for preventing contrast-associated acute kidney injury: a systematic review of randomized controlled trials.

BACKGROUND: To evaluate the efficacy, effectiveness and safety of fermented Ophiocordyceps sinensis mycelium (FOSM) products for preventing contrast-associated acute kidney injury (CA-AKI). METHODS: Randomized controlled trials were searched from four Chinese and four English electronic databases and three clinical trial registries up to July 2023. Methodological quality was assessed by using the Cochrane risk-of-bias tool 2.0. Risk difference (RD) or risk ratio (RR) and mean difference (MD) were calculated along with the 95% confidence intervals (CIs). RESULTS: Fourteen trials testing three types of FOSM products (Bailing, Zhiling, and Jinshuibao capsules) involving 1271 participants injected contrast agents were included. For the risk of bias, all trials were rated as some concerns. Compared with routine preventive procedure (RPP) (saline hydration and alprostadil), FOSM products plus RPP showed beneficial effects in reducing the incidence of CA-AKI (14.62% and 5.35%, respectively; RD -0.06, 95% CI -0.09 to -0.03). Subgroup analysis showed that Bailing/Jinshuibao plus RPP demonstrated lower incidence of CA-AKI compared to RPP. However, there was no statistically significant difference between Zhiling with RPP and RPP in the incidence of CA-AKI. Additionally, only when FOSM products were taken before injection of the contrast, it was superior to RPP in reducing the incidence of CA-AKI. There was no statistical difference in adverse events between these two groups. CONCLUSIONS: Low certainty evidence suggests that preventive oral use of FOSM products as an adjuvant agent was safe and might decrease the incidence of CA-AKI. However, high-quality placebo-controlled trials are needed to confirm its benefit.

COMMD10 inhibits HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma.

BACKGROUND & AIMS: Copper (Cu) is an essential trace element whose serum levels have been reported to act as an effective indicator of the efficacy of radiotherapy. However, little is known about the role of Cu in radiotherapy. In this study we aimed to determine this role and investigate the precise mechanism by which Cu or Cu-related proteins regulate the radiosensitivity of hepatocellular carcinoma (HCC). METHODS: The expression and function of Cu and copper metabolism MURR1 domain 10 (COMMD10) were assessed via a Cu detection assay, immunostaining, real-time PCR, western blot, a radiation clonogenic assay and a 5-ethynyl-2'-deoxyuridine assay. Ferroptosis was determined by detecting glutathione, lipid peroxidation, malondialdehyde and ferrous ion (Fe) levels. The in vivo effects of Cu and COMMD10 were examined with Cu/Cu chelator treatment or lentivirus modification of COMMD10 expression in radiated mouse models. RESULTS: We identified a novel role of Cu in promoting the radioresistance of HCC cells. Ionizing radiation (IR) induced a reduction of COMMD10, which increased intracellular Cu and led to radioresistance of HCC. COMMD10 enhanced ferroptosis and radiosensitivity in vitro and in vivo. Mechanistically, low expression of COMMD10 induced by IR inhibited the ubiquitin degradation of HIF1α (by inducing Cu accumulation) and simultaneously impaired its combination with HIF1α, promoting HIF1α nuclear translocation and the transcription of ceruloplasmin (CP) and SLC7A11, which jointly inhibited ferroptosis in HCC cells. In addition, elevated CP promoted HIF1α expression by reducing Fe, forming a positive feedback loop. CONCLUSIONS: COMMD10 inhibits the HIF1α/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe homeostasis in HCC. This work provides new targets and treatment strategies for overcoming radioresistance in HCC. LAY SUMMARY: Radiotherapy benefits patients with unresectable or advanced hepatocellular carcinoma (HCC), but its effectiveness is hampered by radioresistance. Herein, we uncovered a novel role for copper in promoting the radioresistance of HCCs. This work has revealed new targets and potential treatment strategies that could be used to sensitize HCC to radiotherapy.

Synergistic Effect of High-Frequency Ultrasound with Cupric Oxide Catalyst Resulting in a Selectivity Switch in Glucose Oxidation under Argon.

We report here, and rationalize, a synergistic effect between a non-noble metal oxide catalyst (CuO) and high-frequency ultrasound (HFUS) on glucose oxidation. While CuO and HFUS are able to independently oxidize glucose to gluconic acid, the combination of CuO with HFUS led to a dramatic change of the reaction selectivity, with glucuronic acid being formed as the major product. By means of density functional theory (DFT) calculations, we show that, under ultrasonic irradiation of water at 550 kHz, the surface lattice oxygen of a CuO catalyst traps H· radicals stemming from the sonolysis of water, making the ring-opening of glucose energetically unfavorable and leaving a high coverage of ·OH radical on the CuO surface, which selectively oxidizes glucose to glucuronic acid. This work also points toward a path to optimize the size of the catalyst particle for an ultrasonic frequency that minimizes the damage to the catalyst, resulting in its successful reuse.

Copper and Copper Complexes in Tumor Therapy.

Copper (Cu), a crucial trace element in physiological processes, has garnered significant interest for its involvement in cancer progression and potential therapeutic applications. The regulation of cellular copper levels is essential for maintaining copper homeostasis, as imbalances can lead to toxicity and cell death. The development of drugs that target copper homeostasis has emerged as a promising strategy for anticancer treatment, with a particular focus on copper chelators, copper ionophores, and novel copper complexes. Recent research has also investigated the potential of copper complexes in cancer therapy.

The level of life space mobility among community-dwelling elderly: A systematic review and meta-analysis.

BACKGROUND: Multiple countries have conducted surveys on the level of life space mobility for community-dwelling elderly through the Life-Space Assessment, the results vary greatly, from 41.7 to 88.6. However, there is no meta-analysis on the current situation of community-dwelling elderly life space mobility. OBJECTIVE: To systematically assess the global level of life space mobility for community-dwelling elderly, to identify potential covariates such as geographical regions, survey years, gender, and age that contribute to the heterogeneity between the studies, and to identify the dynamic trend based on survey years. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Two reviewers searched the following 8 electronic bibliographic databases from inception until May 28, 2023: PubMed, The Cochrane Library, Web of Science, Embase, Chinese Biomedical Database, China Knowledge Resource Integrated Database, WanFang, and Weipu Database. REVIEW METHODS: This review was conducted using the Stata 14.1 and R 4.3.1. The Cochrane's Q statistical and I2 index were used to test for heterogenicity and assess the degree of heterogenicity, respectively. Studies were appraised using the Agency for Healthcare Research and Quality tool, the Newcastle-Ottawa Scale for the quality of cross-sectional studies, cohort studies, respectively. RESULTS: A total of 29 studies were selected from databases and reference lists. The pooled score of Life-Space Assessment was 66.84 (95% CI: 63.30-70.39) and the prevalence of restricted life space was 42% (95% CI: 0.27-0.57). The geographical regions, survey years, gender were found to be a significant covariate of the pooled score of life space mobility estimate in the subgroup analysis. The mean score of Life-Space Assessment gradually achieved stability after 2017. CONCLUSIONS: The life space mobility of community-dwelling elderly in the global is at a moderate level, with 42% of them experiencing restricted life space. South America, females and earlier survey years have a lower level of life space mobility. In the future, the government should identify vulnerable groups for targeted intervention to promote the level of LSM in the community-dwelling elderly. REGISTRATION: PROSPERO [CRD42023443054].

Using PRECIS-2 in Chinese herbal medicine randomized controlled trials for irritable bowel syndrome: A methodological exploration based on literature.

Background: The pragmatism levels of randomized controlled trials (RCTs) mean how similar the interventions delivered in the trial setting match those in the setting where the results will be applied. We aimed to investigate the association between the consistency of pragmatism among the characteristics of RCT design and its effect size of results in Chinese herbal medicine (CHM) for irritable bowel syndrome (IBS). Methods: Eight English and Chinese language databases were searched for RCTs on CHM for IBS. Six reviewers independently assessed the pragmatism of trials using the pragmatic-explanatory continuum indicator summary 2 (PRECIS-2) tool. The consistency of pragmatism levels among the characteristics of RCT design was calculated using the coefficient of variation. Linear regression models were adopted to explore influence factors of the pragmatism of RCTs. Results: 78 RCTs were included. The level of consistency in the pragmatism for RCT's design was significantly correlated with the effect size of the results (binary outcome, r = -0.413; P = 0.005; continuous outcome, r = -0.779, P < 0.001). PRECIS-2 score was higher in trials with individualized interventions than fixed interventions (3.29 [0.32] vs 2.90 [0.32]; Cohen's d relative effect size, 0.52; P < 0.001) and in standard or usual-treatment-controlled trials than placebo-controlled (3.05 [0.37] vs 2.83 [0.28]; Cohen's d relative effect size, 0.32; P = 0.048). Conclusion: The consistency of pragmatism level across the 9 domains of the PRECIS-2 tool in CHM IBS RCTs was positively correlated with the effect size of the results.