The molecular mechanisms of cuproptosis and its relevance to cardiovascular disease.

Recently, cuproptosis has been demonstrated to be a new non-apototic cell death mode that is characterized by copper dependence and the regulation of mitochondrial respiration. Cuproptosis is distinct from known cell death modes such as apoptosis, necrosis, pyroptosis, or ferroptosis. Excessive copper induces cuproptosis by promoting protein toxic stress reactions via copper-dependent anomalous oligomerization of lipoylation proteins in the tricarboxylic acid (TCA) cycle and reducing iron-sulfur cluster protein levels. Ferredoxin1 (FDX1) promotes dihydrolipoyl transacetylase (DLAT) lipoacylation and abates iron-sulfur cluster proteins by reducing Cu2+ to Cu+, inducing cell death. Copper homeostasis depends on the copper transporter, and disturbances to this homeostasis cause cuproptosis. Recent evidence has shown that cuproptosis plays a significant role in the occurrence and development of many cardiovascular diseases, such as myocardial ischemia/reperfusion (I/R) injury, heart failure, atherosclerosis, and arrhythmias. Copper chelators, such as ammonium tetrathiomolybdate(VI) and DL-Penicillamine, may ease the above cardiovascular diseases by inhibiting the cuproptosis pathway. Oxidative phosphorylation inhibitors may inhibit cuproptosis by inhibiting protein stress response. In conclusion, cuproptosis plays an essential role in cardiovascular disease pathogenesis. Inhibition of cardiovascular cuproptosis is expected to become a potential treatment. Here, we will thoroughly review the molecular mechanisms involved in cuproptosis and its significance in cardiovascular disease.

Tigliane-and daphnane-type diterpenoids from the buds of Daphne genkwa with their cytotoxic activities.

Two new tigliane- and daphnane-type diterpenoids, given the trivial names daphnegens A-B (1-2) were isolated from the buds of Daphne genkwa. Their structures were assigned on the basis of extensive spectroscopic. The absolute configurations of both compounds were determined by comparison of their calculated and experimental CD curves. In addition, compounds 1-2 were tested for their cytotoxic activities against MCF-7 and HepG-2 human cancer cell lines, and compound 2 showed remarkable cytotoxic activity against HepG-2 cell line with the IC50 value of 11.5 µM.

The psychological status of 8817 hospital workers during COVID-19 Epidemic: A cross-sectional study in Chongqing.

BACKGROUND: There was an outbreak of COVID-19 towards the end of 2019 in China, which spread all over the world rapidly. The Chinese healthcare system is facing a big challenge where hospital workers are experiencing enormous psychological pressure. This study aimed to (1) investigate the psychological status of hospital workers and (2) provide references for psychological crisis intervention in the future. METHOD: An online survey was conducted to collect sociodemographic features, epidemic-related factors, results of PHQ-9, GAD-7, PHQ-15, suicidal and self-harm ideation (SSI), and the score of stress and support scales. Chi-square test, t-test, non-parametric, and logistic regression analysis were used to detect the risk factors to psychological effect and SSI. RESULTS: 8817 hospital workers participated in this online survey. The prevalence of depression, anxiety, somatic symptoms, and SSI were 30.2%, 20.7%, 46.2%, and 6.5%, respectively. Logistic regression analysis showed that female, single, Tujia minority, educational background of junior or below, designated or county hospital, need for psychological assistance before or during the epidemic, unconfident about defeating COVID-19, ignorance about the epidemic, willingness of attending parties, and poor self-rated health condition were independent factors associated with high-level depression, somatic symptom, and SSI among hospital workers (P<0.05). LIMITATIONS: This cross-sectional study cannot reveal the causality, and voluntary participation could be prone to selection bias. A modified epidemic-related stress and support scale without standardization was used. The number of hospital workers in each hospital was unavailable. CONCLUSION: There were a high level of psychological impact and SSI among hospital workers, which needed to be addressed. County hospital workers were more severe and easier to be neglected. More studies on cognitive and behavioral subsequence after a public health disaster among hospital workers are needed.

Application of Paclitaxel-loaded EGFR Peptide-conjugated Magnetic Polymeric Liposomes for Liver Cancer Therapy.

Developing the methodologies that allow for safe and effective delivery of therapeutic drugs to target sites is a very important research area in cancer therapy. In this study, polyethylene glycol (PEG)-coated magnetic polymeric liposome (MPL) nanoparticles (NPs) assembled from octadecyl quaternized carboxymethyl chitosan (OQC), PEGylated OQC, cholesterol, and magnetic NPs, and functionalized with epithelial growth factor receptor (EGFR) peptide, were successfully prepared for in-vivo liver targeting. The two-step liver targeting strategy, based on both magnetic force and EGFR peptide conjugation, was evaluated in a subcutaneous hepatocellular carcinoma model of nude mouse. The results showed that EGFR-conjugated MPLs not only accumulated in the liver by magnetic force, but could also diffuse into tumor cells as a result of EGFR targeting. In addition, paclitaxel (PTX) was incorporated into small EGFR-conjugated MPLs (102.0±0.7 nm), resulting in spherical particles with high drug encapsulation efficiency (>90%). The use of the magnetic targeting for enhancing the transport of PTX-loaded EGFR-conjugated MPLs to the tumor site was further confirmed by detecting PTX levels. In conclusion, PTX-loaded EGFR-conjugated MPLs could potentially be used as an effective drug delivery system for targeted liver cancer therapy.

Over-the-scope-clip applications for perforated peptic ulcer.

AIM: To investigate the effectiveness of over-the-scope-clip (OTSC)-based endoscopic closure in patients with perforated peptic ulcer (PPU). METHODS: One hundred six patients diagnosed with PPU were treated with either OTSC (n = 26) or conservative treatments (n = 80), respectively. The outcome assessments included technical success rate, clinical success rate, post-treatment complications after 1 month, mortality rate, time to resume oral feeding, length of hospital stay, and the administration of antibiotics. RESULTS: In the OTSC group, technical and clinical success was achieved in 100% of patients without any complications, including death, incomplete closure, duodenal obstruction, and gastrointestinal bleeding, with a median operation time of 10 min. All patients in the OTSC group were discharged, while the mortality rate in the control group was 13.8%. Subsequent surgeries were required in 30% of patients in the control group. The median times to resume oral feeding were 3.5 (interquartile range [IQR] 2.0-5.25) days in the OTSC group and 7.0 (IQR 5.0-9.0) days in the control group (p < 0.001). One month post-procedure, 30% (24/80) of patients in the control group and 0 (0/26) in the OTSC group required additional operations (p < 0.001). No significant difference was found in the length of the hospital stay and the administration of antibiotics between the two groups (p > 0.05). CONCLUSIONS: OTSC-based endoscopic technique, with a high clinical success rate and a shorter time to resume oral feeding, was effective in achieving closure of PPU with a diameter < 15 mm.

Noninvasive evaluation of corneal viscoelasticity based on displacement in response to acoustic radiation force.

Noninvasive assessment of corneal mechanical properties in vivo will help to the understanding of the pathogenesis and early diagnosis of ectatic corneal disorders. This study presented a noninvasive method that assesses the corneal biomechanical properties by exciting the cornea with acoustic radiation force and monitoring its displacement using a dual-frequency confocal transducer. A 3.85-MHz pushing element was used to induce localized tissue displacement, and the displacement was detected by the 12.8-MHz detecting elements using pulse-echo methods. Under constant acoustic radiation force, 0the tissue displacement are directly correlated with tissue biomechanical properties, a set of parameters were extracted from local displacement waveform, including relaxation time constant (τ), relative elasticity (RE) and relative viscosity (RV). In order to obtain corneal samples with different mechanical properties, the fresh bovine eyes were performed by collagen cross-linking (CXL). The result indicated that the estimated τ in untreated corneas were statistically significantly different (p<;0.05) from those of treated corneas and the estimation of τ varied significantly with different degrees of CXL. It is possible to develop a non-invasive, effective and efficient method with high spatial resolution.

Neuropeptide Y stimulates osteoblastic differentiation and VEGF expression of bone marrow mesenchymal stem cells related to canonical Wnt signaling activating in vitro.

Neuropeptide Y (NPY) is a neuropeptide secreted by sensory nerve fibers distributed in the marrow and vascular canals of bone tissue. However, the effect of NPY on the osteogenic ability of bone marrow mesenchymal stem cells (BMSCs) remains controversial and has not been thoroughly investigated. To explore the osteogenic activity and the migration and VEGF expression capabilities of BMSCs affected by NPY, as well as the underlying mechanisms, we investigated the potential relationships among NPY, osteoblastic differentiation, angiogenesis and canonical Wnt signaling in BMSCs. NPY was observed to regulate osteoblastic differentiation at concentrations ranging from 10(-8) to 10(-12)mol/L, and the effects of NPY on the levels of Wnt signaling proteins were detected using Western blotting. To unravel the underlying mechanism, BMSCs were treated with NPY after pretreatment with the NPY-1R antagonist PD160170 or the Wnt pathway antagonist DKK1, and gene expression levels of Wnt signaling molecules and osteoblastic markers were determined by qPCR. Our results indicated that NPY significantly promoted osteoblastic differentiation of BMSCs in a concentration-dependent manner and up-regulated the expression levels of proteins including ß-catenin and p-GSK-3ß and the mRNA level of ß-catenin. Moreover, NPY promoted the translocation of ß-catenin into nucleus. The effects of NPY were inhibited by PD160170 or DKK1. Additionally, NPY enhanced the ability of BMSCs to migrate and promoted the expression of vascular endothelial growth factor (VEGF) as measured by immunocytochemical staining, qPCR and Western blot. These results suggested that NPY may stimulate osteoblastic differentiation via activating canonical Wnt signaling and enhance the angiogenic capacity of BMSCs.

RETRACTED: Effect of transplantation of BMMSCs on pathological change of gastric precancerous lesions of rats.

OBJECTIVE: To build the rat model of gastric precancerous lesions and discuss the effect of transplantation of mesenchymal stem cells (BMMSCs) on the pathological change. METHODS: The rat model of gastric precancerous lesions was built using N-methyl-N'-nitro-N'-nitrosoguanidine. After the intravenous transplantation of BMMSCs, the migration and colonization location was then observed, as well as its effect on the related factors of gastric precancerous lesions, including VEGF, IL-10 and IFN-γ. RESULTS: BMMSCs were mainly colonized in the gastric body and gastric antrum, which could be differentiated into the epithelial and interstitial cells. The expression of VEGF in the transplantation group and non-transplantation group was significantly higher than that in the control group (P < 0.05); while the expression of VEGF in the transplantation group was significantly higher than that in the non-transplantation group (t = 3.88, P < 0.001). The expression of serum IL-10 and IFN-γ in the transplantation group and non-transplantation group was significantly higher than that in the control group (P < 0.05), while the expression of IL-10 and IFN-γ in the transplantation group was significantly lower than that in the non-transplantation group (t = 3.03, P = 0.004; t = 3.80, P < 0.001). CONCLUSIONS: BMMSCs can be directionally differentiated into the epithelial and interstitial cells and can also regulate the related growth factors and inflammatory factors to reduce the injury of inflammation, relieve or reverse the process of gastric precancerous lesions.

Protective Effect of Neuropeptide Substance P on Bone Marrow Mesenchymal Stem Cells against Apoptosis Induced by Serum Deprivation.

Substance P (SP) contributes to bone formation by stimulating the proliferation and differentiation of bone marrow stromal cells (BMSCs); however, the possible involved effect of SP on apoptosis induced by serum deprivation (SD) in BMSCs is unclear. To explore the potential protective effect of SP and its mechanism, we investigated the relationships among SP, apoptosis induced by SD, and Wnt signaling in BMSCs. SP exhibited a protective effect, as indicated by a reduction in the apoptotic rate, nuclear condensation, caspase-3 and caspase-9 activation, and the ratio of Bax/Bcl-2 that was observed after 24 h of SD. This protective effect was blocked by the inhibition of Wnt signaling or antagonism of the NK-1 receptor. Moreover, SP promoted the mRNA and protein expression of Wnt signaling molecules such as ß-catenin, p-GSK-3ß, c-myc, and cyclin D1 in addition to the nuclear translocation of ß-catenin, indicating that active Wnt signaling is involved in SP inhibition of apoptosis. Our results revealed that mediated by the NK-1 receptor, SP exerts an inhibitory effect on serum deprivation induced apoptosis in BMSCs that is related to the activation of canonical Wnt signaling.

Neuropeptide substance P improves osteoblastic and angiogenic differentiation capacity of bone marrow stem cells in vitro.

Our previous work showed that implanting a sensory nerve or vascular bundle when constructing vascularized and neurotized bone could promote bone osteogenesis in tissue engineering. This phenomenon could be explained by the regulatory function of neuropeptides. Neuropeptide substance P (SP) has been demonstrated to contribute to bone growth by stimulating the proliferation and differentiation of bone marrow stem cells (BMSCs). However, there have been no prior studies on the association between Wnt signaling and the mechanism of SP in the context of BMSC differentiation. Our results have shown that SP could enhance the differentiation of BMSCs by activating gene and protein expression via the Wnt pathway and by translocating ß-catenin, which can be inhibited by Wnt signaling blocker treatment or by the NK-1 antagonist. SP could also increase the growth factor level of bone morphogenetic protein-2 (BMP-2). Additionally, SP could enhance the migration ability of BMSCs, and the promotion of vascular endothelial growth factor (VEGF) expression by SP has been studied. In conclusion, SP could induce osteoblastic differentiation via the Wnt pathway and promote the angiogenic ability of BMSCs. These results indicate that a vascularized and neurotized tissue-engineered construct could be feasible for use in bone tissue engineering strategies.

Ultra-short plasmonic splitters and waveguide cross-over based on coupled surface plasmon slot waveguides.

Composite metal-dielectric-metal (MDM) surface plasmon polariton (SPP) structures are first proposed to realize the ultra-short optical splitters with simplified designs. The operation mechanism is based on the contra-directional coupling achieved in composite plasmonic slot waveguides. In certain cases, the switching function can also be realized. It is further shown that based on the same physical mechanism multi-dielectric-core composite MDM structures could serve as a novel plasmonic waveguide crossover component with low cross talk and high throughput.

Fabrication of centimeter-sized single-domain two-dimensional colloidal crystals in a wedge-shaped cell under capillary forces.

Self-assembly of colloidal spheres confined within cells of different shapes formed with two slides under capillary forces are studied. It is found that by controlling the shape of the cell the curvature of the drying front can result in a significant effect on the self-organization process. A curved drying front formed within parallel slides is always associated with growth of colloidal crystal structures with a high density of disorder. We demonstrate that single-domain two-dimensional colloidal crystals with centimeter size can be grown under capillary forces under a straight drying front formed in a wedge-shaped cell. These findings are demonstrated by laser diffraction, microscopy imaging methods and off-normal optical transmission measurements. The present growth method should be of importance in expanding colloidal crystal applications in angle-resolved nanosphere lithography, as well as in preparation of high-quality quasi-three-dimensional plasmonic crystals.