Hybrid-Driven Origami Gripper with Variable Stiffness and Finger Length.

Soft grippers due to their highly compliant material and self-adaptive structures attract more attention to safe and versatile grasping tasks compared to traditional rigid grippers. However, those flexible characteristics limit the strength and the manipulation capacity of soft grippers. In this paper, we introduce a hybrid-driven gripper design utilizing origami finger structures, to offer adjustable finger stiffness and variable grasping range. This gripper is actuated via pneumatic and cables, which allows the origami structure to be controlled precisely for contraction and extension, thus achieving different finger lengths and stiffness by adjusting the cable lengths and the input pressure. A kinematic model of the origami finger is further developed, enabling precise control of its bending angle for effective grasping of diverse objects and facilitating in-hand manipulation. Our proposed design method enriches the field of soft grippers, offering a simple yet effective approach to achieve safe, powerful, and highly adaptive grasping and in-hand manipulation capabilities.

Ameliorative Effect of Coenzyme Q10 on Phenotypic Transformation in Human Smooth Muscle Cells with FBN1 Knockdown.

Mutations of the FBN1 gene lead to Marfan syndrome (MFS), which is an autosomal dominant connective tissue disorder featured by thoracic aortic aneurysm risk. There is currently no effective treatment for MFS. Here, we studied the role of mitochondrial dysfunction in the phenotypic transformation of human smooth muscle cells (SMCs) and whether a mitochondrial boosting strategy can be a potential treatment. We knocked down FBN1 in SMCs to create an MFS cell model and used rotenone to induce mitochondrial dysfunction. Furthermore, we incubated the shFBN1 SMCs with Coenzyme Q10 (CoQ10) to assess whether restoring mitochondrial function can reverse the phenotypic transformation. The results showed that shFBN1 SMCs had decreased TFAM (mitochondrial transcription factor A), mtDNA levels and mitochondrial mass, lost their contractile capacity and had increased synthetic phenotype markers. Inhibiting the mitochondrial function of SMCs can decrease the expression of contractile markers and increase the expression of synthetic genes. Imposing mitochondrial stress causes a double-hit effect on the TFAM level, oxidative phosphorylation and phenotypic transformation of FBN1-knockdown SMCs while restoring mitochondrial metabolism with CoQ10 can rapidly reverse the synthetic phenotype. Our results suggest that mitochondria function is a potential therapeutic target for the phenotypic transformation of SMCs in MFS.

CircTBC1D22A inhibits the progression of colorectal cancer through autophagy regulated via miR-1825/ATG14 axis.

Distant metastasis is the main cause of death in patients with colorectal cancer (CRC). A better understanding of the mechanisms of metastasis can greatly improve the outcome of patients with CRC. Accumulating evidence suggests that circRNA plays pivotal roles in cancer progression and metastasis, especially acting as a miRNA sponge to regulate the expression of the target gene. A public database bioinformatics analysis found that miR-1825 was highly expressed in CRC tissues. In this study, miR-1825 was highly expressed in CRC tissues, which was positively correlated with lymph node metastasis and distant metastasis. In vitro and in vivo experiments confirmed that miR-1825 was positively correlated with the proliferation and migration of CRC cells. This event can be inhibited by circTBC1D22A. CircTBC1D22A can directly interact with miR-1825 and subsequently act as a miRNA sponge to regulate the expression of the target gene ATG14, which collectively advances the autophagy-mediated progression and metastasis of CRC.

Antioxidant Minerals Modified the Association between Iron and Type 2 Diabetes in a Chinese Population.

Inconsistent findings exist regarding the relationship between heme iron intake and type 2 diabetes (T2D) among Western and Eastern populations. Easterners tend to consume a plant-based diet which is abundant in antioxidant minerals. To examine the hypothesis that antioxidant mineral may modify the relationship between iron and T2D, we performed a case-control study by measuring the serum mineral levels in 2198 Chinese subjects. A total of 2113 T2D patients and 2458 controls were invited; 502 T2D patients and 1696 controls were finally analyzed. In the total population, high serum iron showed a positive association with T2D odds (odds ratio [OR] = 1.27 [1.04, 1.55]); high magnesium (OR = 0.18 [0.14, 0.22]), copper (OR = 0.27 [0.21, 0.33]), zinc (OR = 0.37 [0.30, 0.46]), chromium (OR = 0.61 [0.50, 0.74]), or selenium concentrations (OR = 0.39 [0.31, 0.48]) were inversely associated with T2D odds. In contrast, in individuals with higher magnesium (>2673.2 µg/dL), zinc (>136.7 µg/dL), copper (>132.1 µg/dL), chromium (>14.0 µg/dL), or selenium concentrations (>16.8 µg/dL), serum iron displayed no association with T2D (p > 0.05). Serum copper and magnesium were significant modifiers of the association between iron and T2D in individuals with different physiological status (p < 0.05). Our findings support the idea that consuming a diet rich in antioxidant minerals is an effective approach for preventing T2D.

Integrated Bioinformatics Analysis to Identify a Novel Four-Gene Prognostic Model of Breast Cancer and Reveal Its Association with Immune Infiltration.

Liquid-liquid phase separation (LLPS) impact immune signaling in cancer and related genes have shown prognostic value in breast cancer (BRCA). However, the crosstalk between LLPS and immune infiltration in BRCA remain unclear. Therefore, we aimed to develop a novel prognostic model of BRCA related to LLPS and immune infiltration. BRCA-related, liquid-liquid phase separation (LLPS)-related genes, and differentially expressed genes (DEGs) were identified using public databases. Mutation and drug sensitivity analyses were performed using Gene Set Cancer Analysis database. Univariate cox regression and LASSO Cox regression were used for the construction and verification of prognostic model. Kaplan-Meier analysis was performed to evaluate overall survival (OS). Gene set variation analysis was conducted to analyze key pathways. CIBERSORT was used to assess immune infiltration and its correlation with prognostic genes was determined through Pearson analysis. A total of 6056 BRCA-associated genes, 3775 LLPS-associated genes, and 4049 DEGs, resulting in 314 overlapping genes. Twenty-eight prognostic genes were screened, and some of them were mutational and related to drug sensitivity Subsequently, a prognostic model comprising L1CAM, EVL, FABP7, and CST1 was built. Patients in high-risk group had shorter OS than those in low-risk group. The infiltrating levels of CD8+ T cells, macrophages M0, macrophages M2, dendritic cells activated, and mast cells resting was altered in high-risk group of breast cancer patients compared to low-risk group. L1CAM, EVL, FABP7, and CST1 were related to these infiltrating immune cells. L1CAM, EVL, FABP7, and CST1 were potential diagnostic biomarkers and therapeutic targets for BRCA.

Novel molecular insights into pyroptosis in triple-negative breast cancer prognosis and immunotherapy.

BACKGROUND: Patients with triple-negative breast cancer (TNBC) often have a poor prognostic outcome. Current treatment strategies cannot benefit all TNBC patients. Previous findings suggested pyroptosis as a novel target for suppressing cancer development, although the relationship between TNBC and pyroptosis-related genes (PRGs) was still unclear. METHODS: Gene expression data and clinical follow-up of TNBC patients were collected from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO). PRGs were screened using weighted gene co-expression network analysis. Cox regression analysis and the least absolute shrinkage and selection operator (i.e. LASSO) technique were applied to construct a pyroptosis-related prognostic risk score (PPRS) model, which was further combined with the clinicopathological characteristics of TNBC patients to develop a survival decision tree and a nomogram. The model was used to calculate the PPRS, and then the overall survival, immune infiltration, immunotherapy response and drug sensitivity of TNBC patients were analyzed based on the PPRS. RESULTS: The PPRS model was closely related to clinicopathological features and can independently and accurately predict the prognosis of TNBC. According to normalized PPRS, patients in different cohorts were divided into two groups. Compared with the high-PPRS group, the low-PPRS group had significantly higher ESTIMATE (i.e. Estimation of STromal and Immune cells in MAlignantTumours using Expression data) score, immune score and stromal score, and it also had overexpressed immune checkpoints and significantly reduced Tumor Immune Dysfunction and Exclusion (TIDE) score, as well as higher sensitivity to paclitaxel, veliparib, olaparib and talazoparib. A decision tree and nomogram based on PPRS and clinical characteristics can improve the prognosis stratification and survival prediction for TNBC patients. CONCLUSIONS: A PPRS model was developed to predict TNBC patients' immune characteristics and response to immunotherapy, chemotherapy and targeted therapy, as well as their survival outcomes.

The activator protein-1 complex governs a vascular degenerative transcriptional programme in smooth muscle cells to trigger aortic dissection and rupture.

BACKGROUND AND AIMS: Stanford type A aortic dissection (AD) is a degenerative aortic remodelling disease marked by an exceedingly high mortality without effective pharmacologic therapies. Smooth muscle cells (SMCs) lining tunica media adopt a range of states, and their transformation from contractile to synthetic phenotypes fundamentally triggers AD. However, the underlying pathomechanisms governing this population shift and subsequent AD, particularly at distinct disease temporal stages, remain elusive. METHODS: Ascending aortas from nine patients undergoing ascending aorta replacement and five individuals undergoing heart transplantation were subjected to single-cell RNA sequencing. The pathogenic targets governing the phenotypic switch of SMCs were identified by trajectory inference, functional scoring, single-cell regulatory network inference and clustering, regulon, and interactome analyses and confirmed using human ascending aortas, primary SMCs, and a ß-aminopropionitrile monofumarate-induced AD model. RESULTS: The transcriptional profiles of 93 397 cells revealed a dynamic temporal-specific phenotypic transition and marked elevation of the activator protein-1 (AP-1) complex, actively enabling synthetic SMC expansion. Mechanistically, tumour necrosis factor signalling enhanced AP-1 transcriptional activity by dampening mitochondrial oxidative phosphorylation (OXPHOS). Targeting this axis with the OXPHOS enhancer coenzyme Q10 or AP-1-specific inhibitor T-5224 impedes phenotypic transition and aortic degeneration while improving survival by 42.88% (58.3%-83.3% for coenzyme Q10 treatment), 150.15% (33.3%-83.3% for 2-week T-5224), and 175.38% (33.3%-91.7% for 3-week T-5224) in the ß-aminopropionitrile monofumarate-induced AD model. CONCLUSIONS: This cross-sectional compendium of cellular atlas of human ascending aortas during AD progression provides previously unappreciated insights into a transcriptional programme permitting aortic degeneration, highlighting a translational proof of concept for an anti-remodelling intervention as an attractive strategy to manage temporal-specific AD by modulating the tumour necrosis factor-OXPHOS-AP-1 axis.

Dandelion Polysaccharides Ameliorate High-Fat-Diet-Induced Atherosclerosis in Mice through Antioxidant and Anti-Inflammatory Capabilities.

Dandelion (Taraxacum officinale), a member of the Asteraceae (Compositae) family, is well known as the traditional medical plant. Dandelion polysaccharides, a natural active ingredient extracted from the dandelion, possess immune regulation, anti-inflammatory, antioxidant, and anti-aggregation properties. These properties suggest that dandelion polysaccharides might alleviate atherosclerosis. Using an ApoE-/- atherosclerotic mice model fed a high-fat diet, we investigated the impact and potential mechanism of dandelion polysaccharides on atherosclerosis. We observed that dandelion polysaccharides significantly reduced the levels of triglyceride, total cholesterol, and low-density lipoprotein-cholesterol in serum, while elevated the high-density lipoprotein-cholesterol level. Concomitantly, dandelion polysaccharides reduced the area of atherosclerotic lesions and necrotic core of the aortic sinus, and increased the collagen content. Mechanistic studies showed that dandelion polysaccharides were effective in reducing serum malondialdehyde levels while elevating the enzymatic activities of superoxide dismutase and glutathione peroxidase. Furthermore, dandelion polysaccharides reduced the expression of chemotactic factor Mcp-1 and pro-inflammatory cytokines (Tnf-α, Il-1ß, and Il-6) in atherosclerotic lesions. Overall, these results indicated that dandelion polysaccharides may take an important part in the attenuation of atherosclerosis via its antioxidant and anti-inflammatory properties.

The Effects of Dietary Protein and Polysaccharide Fortification on Disease.

Proteins and polysaccharides are versatile natural macromolecules that are ubiquitous in nature, and a tailored diet that is fortified with them has been developed to ameliorate a wide array of diseases [...].

Comparative efficacy on outcomes of C-CABG, OPCAB, and ONBEAT in coronary heart disease: a systematic review and network meta-analysis of randomized controlled trials.

IMPORTANCE: Coronary artery bypass grafting (CABG) remains the gold standard for the treatment of multivessel and left main coronary heart disease. However, the current evidence about the optimal surgical revascularization strategy is inconsistent and is not sufficient to allow for definite conclusions. Thus, this topic needs to be extensively discussed. OBJECTIVE: The aim of this present study was to compare the clinical outcomes of off-pump CABG (OPCAB), conventional on-pump CABG (C-CABG), and on-pump beating heart (ONBEAT) CABG via an updated systematic review and network meta-analysis of randomized controlled trials. DATA SOURCES: PubMed, Web of Science, and the Cochrane Central Registry were searched for relevant randomized controlled trials that were published in English before 1 December 2021. STUDY SELECTION: Published trials that included patients who received OPCAB, C-CABG, and ONBEAT CABG were selected. DATA EXTRACTION AND SYNTHESIS: Two authors independently screened the search results, assessed the full texts to identify eligible studies and the risk of bias of the included studies, and extracted data. All processes followed the Preferred Reporting Items for Systematic Review and Meta-analysis of Individual Participant Data. MAIN OUTCOMES AND MEASURES: The primary outcome was postoperative mortality in patients who underwent C-CABG, OPCAB, or ONBEAT CABG. The secondary outcomes were postoperative myocardial infarction, stroke, and renal impairment in the three groups. The time point for analysis of outcomes was all time periods during the postoperative follow-up. RESULTS: A total of 39 385 patients (83 496.2 person-years) in 65 studies who fulfilled the prespecified criteria were included. In the network meta-analysis, OPCAB was associated with an increase of 12% in the risk of all-cause mortality when compared with C-CABG [odds ratio (OR): 1.12; 95% CI: 1.04-1.21], a reduction of 49% in the risk of myocardial infarction when compared with ONBEAT (OR: 0.51; 95% CI: 0.26-0.99), a reduction of 16% in the risk of stroke when compared with C-CABG (OR: 0.84; 95% CI: 0.72-0.99) and a similar risk of renal impairment when compared with C-CABG and ONBEAT. CONCLUSIONS AND RELEVANCE: OPCAB was associated with higher all-cause mortality but lower postoperative stroke compared with C-CABG. OPCAB was associated with a lower postoperative myocardial infarction than that of ONBEAT. Early mortality was comparable among OPCAB, ONBEAT, and C-CABG.

Exploring perceived restoration, landscape perception, and place attachment in historical districts: insights from diverse visitors.

Improving the quality of the built environment to enhance people's mental health is gaining traction across various fields, precipitating valuable actions on the wave of "Healthy China 2030" initiative. While ample studies have confirmed the benefits of interaction with natural or green spaces, the investigation into the restorative potential in urban built settings remains notably underexplored. In this study, we focused on historical districts, conducting a questionnaire survey to evaluate the restorative experiences of individuals visiting these sites. We used Partial Least Square-Structural Equation Modelling (PLS-SEM) to analyze a conceptual model that encompasses landscape perception, place attachment, and perceived restoration, with a specific focus on detecting the mediating role of place attachment and the moderating influence of visitor groups. The results showed that landscape perception significantly influenced the perceived restoration, which contained the indirect effect pathway through place dependence and place identity, as well as the potent direct impact of landscape perception. Moreover, employing a multi-group analysis (MGA), we discerned that different visitor groups partially moderate the relationship between landscape perception, place attachment, and perceived restoration. This study validates the restorative features in historic districts and highlights the importance of cognitive-emotional bond in promoting psychological restoration.

Mitochondrial carrier 1 (MTCH1) governs ferroptosis by triggering the FoxO1-GPX4 axis-mediated retrograde signaling in cervical cancer cells.

Cervical cancer is one of the leading causes of cancer death in women. Mitochondrial-mediated ferroptosis (MMF) is a recently discovered form of cancer cell death. However, the role and the underlying mechanism of MMF in cervical cancer remain elusive. Here, using an unbiased screening for mitochondrial transmembrane candidates, we identified mitochondrial carrier 1 (MTCH1) as a central mediator of MMF in cervical cancers. MTCH1-deficiency disrupted mitochondrial oxidative phosphorylation while elevated mitochondrial reactive oxygen species (ROS) by decreasing NAD+ levels. This mitochondrial autonomous event initiated a mitochondria-to-nucleus retrograde signaling involving reduced FoxO1 nuclear translocation and subsequently downregulation of the transcription and activity of a key anti-ferroptosis enzyme glutathione peroxidase 4 (GPX4), thereby elevating ROS and ultimately triggering ferroptosis. Strikingly, targeting MTCH1 in combination with Sorafenib effectively and synergistically inhibited the growth of cervical cancer in a nude mouse xenograft model by actively inducing ferroptosis. In conclusion, these findings enriched our understanding of the mechanisms of MMF in which MTCH1 governed ferroptosis though retrograde signaling to FoxO1-GPX4 axis, and provided a potential therapeutic target for treating cervical cancer.

Food groups and urologic cancers risk: a systematic review and meta-analysis of prospective studies.

Background: To assess the association between 12 food groups intake and the risk of urologic cancers. Methods: We scanned PubMed and Web of Science databases up to April 1st, 2023, and 73 publications met the inclusion criteria in the meta-analysis. We used a random effects model to estimate the summary risk ratios (RRs) and 95% confidence intervals (95% CI). Results: In the linear dose-response meta-analysis, an inverse association was found between each additional daily 100 g of fruits [RR: 0.89, 95%CI = (0.83, 0.97)], 100 g of vegetables [RR: 0.92, 95%CI = (0.85, 0.99)], 12 g of alcohol [RR: 0.91, 95%CI = (0.88, 0.94)] and 1 cup of coffee [RR: 0.95, 95%CI = (0.83, 0.97)] intake and the risk of renal cell carcinoma. Conversely, each additional daily 100 g of red meat intake was positively associated with renal cell carcinoma [RR: 1.41, 95%CI = (1.03, 2.10)]. Inverse associations were observed between each additional daily 50 g of egg [RR: 0.73, 95%CI = (0.62, 0.87)] and each additional daily 1 cup of tea consumption and bladder cancer risk [RR: 0.97, 95%CI = (0.94, 0.99)]. There were no significant associations for nonlinear dose-response relationships between 12 food groups and urological cancers. Conclusion: Our meta-analysis strengthens the evidence that appropriate intake of specific food groups, such as fruits, vegetables, alcohol, tea, and coffee, is associated with the risk of renal cell carcinoma or bladder cancer. More studies are required to fill the knowledge gap on the links between various food groups and urologic cancers because the evidence was less credible in this meta-analysis. Systematic Review Registration: This study was registered on PROSPERO (CRD42022340336).

STC3141 improves acute lung injury through neutralizing circulating histone in rat with experimentally-induced acute respiratory distress syndrome.

Background: Acute respiratory distress syndrome (ARDS) remains a challenge because of its high morbidity and mortality. Circulation histones levels in ARDS patients were correlated to disease severity and mortality. This study examined the impact of histone neutralization in a rat model of acute lung injury (ALI) induced by a lipopolysaccharide (LPS) double-hit. Methods: Sixty-eight male Sprague-Dawley rats were randomized to sham (N = 8, received saline only) or LPS (N = 60). The LPS double-hit consisted of a 0.8 mg/kg intraperitoneal injection followed after 16 h by 5 mg/kg intra-tracheal nebulized LPS. The LPS group was then randomized into five groups: LPS only; LPS +5, 25, or 100 mg/kg intravenous STC3141 every 8 h (LPS + L, LPS + M, LPS + H, respectively); or LPS + intraperitoneal dexamethasone 2.5 mg/kg every 24 h for 56 h (LPS + D). The animals were observed for 72 h. Results: LPS animals developed ALI as suggested by lower oxygenation, lung edema formation, and histological changes compared to the sham animals. Compared to the LPS group, LPS + H and +D groups had significantly lower circulating histone levels and lung wet-to-dry ratio, and the LPS + D group also had lower BALF histone concentrations; the blood neutrophils and platelets counts in LPS + D group did not change, meanwhile, the LPS + L, +M and +H groups had significantly lower neutrophil counts and higher platelet counts in the blood; the total number of BALF WBC, platelet counts, MPO and H3 were significantly lower in the LPS + L, +M, +H and +D groups than in the LPS only group; and the degree of inflammation was significantly less in the LPS + L, +M, +H and +D groups, moreover, inflammation in the LPS + L, +M and +H animals showed a dose-dependent response; finally, the LPS + L, +M, +H and +D groups had improved oxygenation compared to the LPS group, and there were no statistical differences in PCO2 or pH among groups. All animals survived. Conclusion: Neutralization of histone using STC3141, especially at high dose, had similar therapeutic effects to dexamethasone in this LPS double-hit rat ALI model, with significantly decreased circulating histone concentration, improved acute lung injury and oxygenation.

Different Crystallization Behavior of Amorphous ITO Film by Rapid Infrared Annealing and Conventional Furnace Annealing Technology.

An amorphous indium tin oxide (ITO) film (Ar/O2 = 80:0.5) was heated to 400 °C and maintained for 1-9 min using rapid infrared annealing (RIA) technology and conventional furnace annealing (CFA) technology. The effect of holding time on the structure, optical and electrical properties, and crystallization kinetics of ITO films, and on the mechanical properties of the chemically strengthened glass substrates, were revealed. The results show that the nucleation rate of ITO films produced by RIA is higher and the grain size is smaller than for CFA. When the RIA holding time exceeds 5 min, the sheet resistance of the ITO film is basically stable (8.75 Ω/sq). The effect of holding time on the mechanical properties of chemically strengthened glass substrates annealed using RIA technology is less than that of CFA technology. The percentage of compressive-stress decline of the strengthened glass after annealing using RIA technology is only 12-15% of that using CFA technology. For improving the optical and electrical properties of the amorphous ITO thin films, and the mechanical properties of the chemically strengthened glass substrates, RIA technology is more efficient than CFA technology.

Research on Determining Elastic-Plastic Constitutive Parameters of Materials from Load Depth Curves Based on Nanoindentation Technology.

It is of great significance for structural design and engineering evaluation to obtain the elastic-plastic parameters of materials. The inverse estimation of elastic-plastic parameters of materials based on nanoindentation technology has been applied in many pieces of research, but it has proved to be difficult to determine the elastic-plastic properties of materials by only using a single indentation curve. A new optimal inversion strategy based on a spherical indentation curve was proposed to obtain the elastoplastic parameters (the Young's modulus E, yield strength σy, and hardening exponent n) of materials in this study. A high-precision finite element model of indentation with a spherical indenter (radius R = 20 µm) was established, and the relationship between the three parameters and indentation response was analyzed using the design of experiment (DOE) method. The well-posed problem of inverse estimation under different maximum indentation depths (hmax1 = 0.06 R, hmax2 = 0.1 R, hmax3 = 0.2 R, hmax4 = 0.3 R) was explored based on numerical simulations. The results show that the unique solution with high accuracy can be obtained under different maximum press-in depths (the minimum error was within 0.2% and the maximum error was up to 1.5%). Next, the load-depth curves of Q355 were obtained by a cyclic loading nanoindentation experiment, and the elastic-plastic parameters of Q355 were determined by the proposed inverse-estimation strategy based on the average indentation load-depth curve. The results showed that the optimized load-depth curve was in good agreement with the experimental curve, and the optimized stress-strain curve was slightly different from the tensile test, and the obtained parameters were basically consistent with the existing research.

Low Zinc Alleviates the Progression of Thoracic Aortic Dissection by Inhibiting Inflammation.

Vascular inflammation triggers the development of thoracic aortic dissection (TAD). Zinc deficiency could dampen tissue inflammation. However, the role of zinc as a nutritional intervention in the progression of TAD remains elusive. In this study, we employed a classical ß-aminopropionitrile monofumarate (BAPN)-induced TAD model in mice treated with low zinc and observed that the TAD progression was greatly ameliorated under low zinc conditions. Our results showed that low zinc could significantly improve aortic dissection and rupture (BAPN + low zinc vs. BAPN, 36% vs. 100%) and reduce mortality (BAPN + low zinc vs. BAPN, 22% vs. 57%). Mechanically, low zinc attenuated the infiltration of macrophages and inhibited the expression of inflammatory cytokines, suppressed the phenotype switch of vascular smooth muscle cells from contractile to synthetic types, and eventually alleviated the development of TAD. In conclusion, this study suggested that low zinc may serve as a potential nutritional intervention approach for TAD prevention.

Regulatory roles of copper metabolism and cuproptosis in human cancers.

Copper is an essential micronutrient for human body and plays a vital role in various biological processes including cellular respiration and free radical detoxification. Generally, copper metabolism in the body is in a stable state, and there are specific mechanisms to regulate copper metabolism and maintain copper homeostasis. Dysregulation of copper metabolism may have a great connection with various types of diseases, such as Wilson disease causing copper overload and Menkes disease causing copper deficiency. Cancer presents high mortality rates in the world due to the unlimited proliferation potential, apoptosis escape and immune escape properties to induce organ failure. Copper is thought to have a great connection with cancer, such as elevated levels in cancer tissue and serum. Copper also affects tumor progression by affecting angiogenesis, metastasis and other processes. Notably, cuproptosis is a novel form of cell death that may provide novel targeting strategies for developing cancer therapy. Copper chelators and copper ionophores are two copper coordinating compounds for the treatment of cancer. This review will explore the relationship between copper metabolism and cancers, and clarify copper metabolism and cuproptosis for cancer targeted therapy.

Mitochondrial Homeostasis in VSMCs as a Central Hub in Vascular Remodeling.

Vascular remodeling is a common pathological hallmark of many cardiovascular diseases. Vascular smooth muscle cells (VSMCs) are the predominant cell type lining the tunica media and play a crucial role in maintaining aortic morphology, integrity, contraction and elasticity. Their abnormal proliferation, migration, apoptosis and other activities are tightly associated with a spectrum of structural and functional alterations in blood vessels. Emerging evidence suggests that mitochondria, the energy center of VSMCs, participate in vascular remodeling through multiple mechanisms. For example, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α)-mediated mitochondrial biogenesis prevents VSMCs from proliferation and senescence. The imbalance between mitochondrial fusion and fission controls the abnormal proliferation, migration and phenotypic transformation of VSMCs. Guanosine triphosphate-hydrolyzing enzymes, including mitofusin 1 (MFN1), mitofusin 2 (MFN2), optic atrophy protein 1 (OPA1) and dynamin-related protein 1 (DRP1), are crucial for mitochondrial fusion and fission. In addition, abnormal mitophagy accelerates the senescence and apoptosis of VSMCs. PINK/Parkin and NIX/BINP3 pathways alleviate vascular remodeling by awakening mitophagy in VSMCs. Mitochondrial DNA (mtDNA) damage destroys the respiratory chain of VSMCs, resulting in excessive ROS production and decreased ATP levels, which are related to the proliferation, migration and apoptosis of VSMCs. Thus, maintaining mitochondrial homeostasis in VSMCs is a possible way to relieve pathologic vascular remodeling. This review aims to provide an overview of the role of mitochondria homeostasis in VSMCs during vascular remodeling and potential mitochondria-targeted therapies.

mTORC2: a multifaceted regulator of autophagy.

Autophagy is a multi-step catabolic process that delivers cellular components to lysosomes for degradation and recycling. The dysregulation of this precisely controlled process disrupts cellular homeostasis and leads to many pathophysiological conditions. The mechanistic target of rapamycin (mTOR) is a central nutrient sensor that integrates growth signals with anabolism to fulfil biosynthetic and bioenergetic requirements. mTOR nucleates two distinct evolutionarily conserved complexes (mTORC1 and mTORC2). However, only mTORC1 is acutely inhibited by rapamycin. Consequently, mTORC1 is a well characterized regulator of autophagy. While less is known about mTORC2, the availability of acute small molecule inhibitors and multiple genetic models has led to increased understanding about the role of mTORC2 in autophagy. Emerging evidence suggests that the regulation of mTORC2 in autophagy is mainly through its downstream effector proteins, and is variable under different conditions and cellular contexts. Here, we review recent advances that describe a role for mTORC2 in this catabolic process, and propose that mTORC2 could be a potential clinical target for the treatment of autophagy-related diseases. Video abstract.