Blocking Metallothionein-2 Expression by Copper-Doped Carbon Dots Induces Cellular Antioxidant System Collapse for Antitumor Therapy.

The insufficient antioxidant reserves in tumor cells play a critical role in reactive oxygen species (ROS)-mediated therapeutics. Metallothionein-2 (MT-2), an intracellular cysteine-rich protein renowned for its potent antioxidant properties, is intricately involved in tumor development and correlates with a poor prognosis. Consequently, MT-2 emerges as a promising target for tumor therapy. Herein, we present the development of copper-doped carbon dots (Cu-CDs) to target MT-2 to compromise the delicate antioxidant reserves in tumor cells. These Cu-CDs with high tumor accumulation and prolonged body retention can effectively suppress tumor growth by inducing oxidative stress. Transcriptome sequencing unveils a significant decrease in MT-2 expression within the in vivo tumor samples. Further mechanical investigations demonstrate that the antitumor effect of Cu-CDs is intricately linked to apolipoprotein E (ApoE)-mediated downregulation of MT-2 expression and the collapse of the antioxidant system. The robust antitumor efficacy of Cu-CDs provides invaluable insights into developing MT-2-targeted nanomedicine for cancer therapies.

Carbon Dots as Potential Therapeutic Agents for Treating Non-Alcoholic Fatty Liver Disease and Associated Inflammatory Bone Loss.

Nonalcoholic fatty liver disease (NAFLD) has emerged as one of the most significant metabolic diseases worldwide and is associated with heightened systemic inflammation, which has been shown to foster the development of extrahepatic complications. So far, there is no definitive, effective, and safe treatment for NAFLD. Although antidiabetic agents show potential for treating NAFLD, their efficacy is significantly limited by inadequate liver accumulation at safe doses and unwanted side effects. Herein, we demonstrate that pharmacologically active carbon dots (MCDs) derived from metformin can selectively accumulate in the liver and ameliorate NAFLD by activating hepatic PPARα expression while maintaining an excellent biosafety. Interestingly, MCDs can also improve the function of extrahepatic organs and tissues, such as alleviating alveolar inflammatory bone loss, in the process of treating NAFLD. This study proposes a feasible and safe strategy for designing pharmacologically active MCDs to target the liver, which regulates lipid metabolism and systemic inflammation, thereby treating NAFLD and its related extrahepatic complications.

Fe-doped carbon dots: a novel biocompatible nanoplatform for multi-level cancer therapy.

BACKGROUND: Tumor treatment still remains a clinical challenge, requiring the development of biocompatible and efficient anti-tumor nanodrugs. Carbon dots (CDs) has become promising nanomedicines for cancer therapy due to its low cytotoxicity and easy customization. RESULTS: Herein, we introduced a novel type of "green" nanodrug for multi-level cancer therapy utilizing Fe-doped carbon dots (Fe-CDs) derived from iron nutrient supplement. With no requirement for target moieties or external stimuli, the sole intravenous administration of Fe-CDs demonstrated unexpected anti-tumor activity, completely suppressing tumor growth in mice. Continuous administration of Fe-CDs for several weeks showed no toxic effects in vivo, highlighting its exceptional biocompatibility. The as-synthesized Fe-CDs could selectively induce tumor cells apoptosis by BAX/Caspase 9/Caspase 3/PARP signal pathways and activate antitumoral macrophages by inhibiting the IL-10/Arg-1 axis, contributing to its significant tumor immunotherapy effect. Additionally, the epithelial-mesenchymal transition (EMT) process was inhibited under the treatment of Fe-CDs by MAPK/Snail pathways, indicating the capacity of Fe-CDs to inhibit tumor recurrence and metastasis. CONCLUSIONS: A three-level tumor treatment strategy from direct killing to activating immunity to inhibiting metastasis was achieved based on "green" Fe-CDs. Our findings reveal the broad clinical potential of Fe-CDs as a novel candidate for anti-tumor nanodrugs and nanoplatform.

Strontium-Incorporated Carbon Nitride Nanosheets Modulate Intracellular Tension for Reinforced Bone Regeneration.

Strontium-containing agents have been demonstrated to elicit both bone anabolic and antiosteoporotic effects, showing great potential for the treatment of bone loss. However, an increased incidence of strontium-induced side effects restricts their clinical applications. Herein, oxidized carbon nitride nanosheets (CN) are delicately used to incorporate Sr2+ for the first time to achieve high osteogenic efficacy. The lamellar structure and enriched nitrogen species of CN provide them with a high surface area-to-volume ratio and abundant anchoring sites for Sr2+ incorporation. Importantly, Sr2+-incorporated CN (CNS) could synergistically promote osteoblast differentiation and bone regeneration at a single, very low Sr2+ dose. Mechanically, CNS could activate the FAK/RhoA signaling pathway to modulate the intracellular tension that stimulates osteoblasts differentiation. The present study will provide a new paradigm to enhance the efficacy of osteogenic metal ions by using lamellar nanocarriers.

Reinforced Blood-Derived Protein Hydrogels Enable Dual-Level Regulation of Bio-Physiochemical Microenvironments for Personalized Bone Regeneration with Remarkable Enhanced Efficacy.

Physiological microenvironment engineering has shown great promise in combating a variety of diseases. Herein, we present the rational design of reinforced and injectable blood-derived protein hydrogels (PDA@SiO2-PRF) composed of platelet-rich fibrin (PRF), polydopamine (PDA), and SiO2 nanofibers that can act as dual-level regulators to engineer the microenvironment for personalized bone regeneration with high efficacy. From the biophysical level, PDA@SiO2-PRF with high stiffness can withstand the external loading and maintaining the space for bone regeneration in bone defects. Particularly, the reinforced structure of PDA@SiO2-PRF provides bone extracellular matrix (ECM)-like functions to stimulate osteoblast differentiation via Yes-associated protein (YAP) signaling pathway. From the biochemical level, the PDA component in PDA@SiO2-PRF hinders the fast degradation of PRF to release autologous growth factors in a sustained manner, providing sustained osteogenesis capacity. Overall, the present study offers a dual-level strategy for personalized bone regeneration by engineering the biophysiochemical microenvironment to realize enhanced osteogenesis efficacy.

Accuracy of the Euro CTO(CASTLE) score obtained on coronary computed tomography angiography for Predicting 30-minute wire crossing in chronic total occlusions.

BACKGROUND: To investigate the feasibility and accuracy of the Euro CTO (CASTLE)CTA score obtained on coronary computed tomography angiography (CCTA) for predicting the success of percutaneous coronary intervention (PCI) and the 30-min wire crossing in chronic total occlusions (CTO). METHOD: One hundred and fifty patients (154 CTO cases; median age, 61 (interquartile range [IQR], 54-68) years; 75.3% male) received CCTA at the People's Hospital of Liaoning Provincce within 1 month before the procedure. The Euro CTO (CASTLE) score obtained on CCTA(CASTLECTA) was calculated and compared with the Euro CTO (CASTLE) score obtained based on coronary angiography (CASTLECAG) for the predictive value of 30-min wire crossing and CTO procedural success. RESULTS: In our study, the CTO-PCI success rate was 89.0%, with guidewires of 65 cases (42.2%) crossing within 30 min. There were no significant differences in the median CASTLECTA and CASTLECAG scores in the procedure success group (3 [IQR, 2-4] vs 3 (IQR, 2-3]; p = 0.126). However, the median CASTLECTA score was significantly higher than the median CASTLECAG score in the procedure failure group (4 [IQR, 3-5.5] vs 4 [IQR, 2.5-5.5]; p = 0.021). There was no significant difference between the median CASTLECTA score and the median CASTLECAG score in the 30-min wire crossing failure group (3 [IQR, 3-4] vs 3 [IQR, 2-4]; p = 0.254). However, the median CASTLECTA score was significantly higher than the median CASTLECAG score in the 30-min wire crossing group (3 [IQR, 2-3] vs 2 [IQR, 2-3]; p < 0.001). The CASTLECTA score described higher levels of calcification than the CASTLECAG score (48.1% vs 33.8%; p = 0.015). There was no significant difference between the CASTLECTA score (area under the curve [AUC], 0.643; 95% confidence interval [CI], 0.561-0.718) and the CASTLECAG score (AUC, 0.685; 95% CI, 0.606-0.758) for predicting procedural success (p = 0.488). The CASTLECTA score (AUC, 0.744; 95% CI, 0.667-0.811) was significantly better than the CASTLECAG score (AUC, 0.681; 95% CI, 0.601-0.754; p = 0.046) for predicting 30-min wire crossing with the best cut-off value being CASTLECTA ≤ 3. The sensitivity, specificity, positive predictive value, and negative predictive value were 90.8%, 55.2%, 54.6%, and 87.0%, respectively. CONCLUSION: The CASTLECTA scores obtained from noninvasive CCTA perform better for the prediction of the 30-min wire crossing than the CASTLECAG score.

Associations between pulmonary function and cognitive decline in the middle-aged and older adults: evidence from the China Health and Retirement Longitudinal Study.

BACKGROUND: Studies observing the relationship between pulmonary function and the risk of cognitive impairment in middle-aged and older adults was increasing, but the results were inconsistent. To date, evidence from longitudinal data is scarce and further research is urgently needed. METHODS: We used data from the China Health and Retirement Longitudinal Study. Participants were enrolled in 2011/2013 and followed up in 2013, 2015 and 2018. Pulmonary function was assessed via peak expiratory flow (PEF). Cognitive function, measured by episodic memory and mental status, was assessed through a face-to-face interview in each survey. RESULTS: A total of 8,274 participants (52.86% males; mean age, 56.44 years) were included. The scores of global cognition (12.46 versus 11.51, P < 0.001) of men were significantly higher than women at baseline, with a total of 5096 participants (61.59%) declining during the follow-up. Higher baseline PEF was associated with lower absolute decline in global cognition (OR per 1-SD difference 0.921; P = 0.031) and mental status (OR per 1-SD difference 0.9889; P = 0.002) during follow-up in men, and significant associations between higher baseline PEF and a lower absolute decline in the episodic memory were both found in men (OR per 1-SD difference 0.907; P = 0.006) and women (OR per 1-SD difference 0.915; P = 0.022). Second analysis showed that the significant associations between positive PEF variation and a lower rate of 4-year decline in global cognition, mental status and episodic memory were all only found in men. In subgroup analyses, higher PEF at baseline was significantly associated with a lower absolute decline of global cognition among male individuals >60 years. Significant associations between higher PEF at baseline and lower absolute decline in global cognition and episodic memory during follow-up were only found in never-smokers, while higher PEF was related to lower absolute decline in mental status among non-smoking and smoking males. CONCLUSIONS: Pulmonary function correlates with cognitive functions in middle-aged and older people, especially males. Additional studies characterizing early and long-term PEF changes are needed.

An alternative splicing signature in human Crohn's disease.

BACKGROUND: Although hundreds of risk loci for Crohn's disease (CD) have been identified, the underlying pathogenesis of CD remains unclear. Recently, evidence has shown that aberrant gene expression in colon tissues of CD patients is associated with the progression of CD. We reasoned that post-transcriptional regulation, especially alternative splicing (AS), may also play important roles in the pathogenesis of CD. METHODS: We re-analyzed public mRNA-seq data from the NCBI GEO dataset (GSE66207) and identified approximately 3000 unique AS events in CD patients compared to healthy controls. RESULTS: "Lysine degradation" and "Sphingolipid metabolism" were the two most enriched AS events in CD patients. In a validation study, we also sequenced eight subjects and demonstrated that key genes that were previously linked to CD, such as IRF1 and STAT3, also had significant AS events in CD. CONCLUSION: Our study provided a landscape of AS events in CD, especially as the first study focused on a Chinese cohort. Our data suggest that dysregulation of AS may be a new mechanism that contributes to the pathogenesis of CD.

Dysregulation of alternative splicing is associated with the pathogenesis of ulcerative colitis.

BACKGROUND: Although numerous risk loci for ulcerative colitis (UC) have been identified in the human genome, the pathogenesis of UC remains unclear. Recently, multiple transcriptomic analyses have shown that aberrant gene expression in the colon tissues of UC patients is associated with disease progression. A pioneering study also demonstrated that altered post-transcriptional regulation is involved in the progression of UC. Here, we provide a genome-wide analysis of alternative splicing (AS) signatures in UC patients. We analyzed three datasets containing 74 tissue samples from UC patients and identified over 2000 significant AS events. RESULTS: Skipped exon and alternative first exon were the two most significantly altered AS events in UC patients. The immune response-related pathways were remarkably enriched in the UC-related AS events. Genes with significant AS events were more likely to be dysregulated at the expression level. CONCLUSIONS: We present a genomic landscape of AS events in UC patients based on a combined analysis of two cohorts. Our results indicate that dysregulation of AS may have a pivotal role in determining the pathogenesis of UC. In addition, our study uncovers genes with potential therapeutic implications for UC treatment.

Magnetic resonance elastography in staging liver fibrosis in non-alcoholic fatty liver disease: a pooled analysis of the diagnostic accuracy.

BACKGROUND: This study was performed to systematically evaluate the accuracy of magnetic resonance elastography (MRE) in staging of liver fibrosis in non-alcoholic fatty liver disease (NAFLD). METHODS: PUBMED, EMBASE, Web of Science, CNKI, Cochrane Library database were searched from January 2008 to December 2018 for studies related to MRE in the diagnosis of NAFLD liver fibrosis. The quality of the included literature was assessed by Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The pooled sensitivity, the pooled specificity, and area under the receiver operating characteristic curve (AUROC) value was performed by STATA 14.0 software. RESULTS: A total of 12 studies were included, involving 910 patients. The pooled sensitivity and specificity of each group were 0.77 (95%CI 0.69-0.83) and 0.90 (95%CI 0.83-0.94) for F ≥ 1 (mild liver fibrosis), 0.87 (95%CI 0.74-0.94) and 0.86 (95%CI 0.71-0.94) for F ≥ 2 (significant liver fibrosis), 0.89 (95%CI 0.81-0.94) and 0.84 (95%CI 0.63-0.94) for F ≥ 3(severe liver fibrosis), 0.94 (95%CI 0.85-0.98) and 0.75 (95%CI 0.35-0.94) for F ≥ 4 (early cirrhosis), respectively. The area under the summary receiver operating characteristic (SROC) curve was 0.89, 0.93, 0.93, and 0.95, respectively. CONCLUSIONS: MRE has high accuracy in the diagnosis of hepatic fibrosis staging in patients with NAFLD.