Nebivolol, an antihypertensive agent, has new application in inhibiting melanoma.

Repurposing existing drugs for cancer therapy has become an important strategy because of its advantages, such as cost reduction, effect and safety. The present study was designed to investigate the antimelanoma effect and possible mechanisms of action of nebivolol, which is an approved and widely prescribed antihypertensive agent. In this study, we explored the effect of nebivolol on cell proliferation and cell activity in melanoma in vitro and the potential antimelanoma mechanism of nebivolol through a series of experiments, including the analysis of the effects with regard to cell apoptosis and metastasis. Furthermore, we evaluated the antimelanoma effect on xenograft tumor models and inspected the antimelanoma mechanism of nebivolol in vivo using immunohistochemical and immunofluorescence staining assays. As results in this work, in vitro, nebivolol possessed a strong activity for suppression proliferation and cell cycle arrest on melanoma. Moreover, nebivolol significantly induced cell apoptosis in melanoma through a mitochondrial-mediated endogenous apoptosis pathway. Additionally, nebivolol inhibited melanoma cell metastasis. More importantly, nebivolol exhibited significantly effective melanoma xenograft models in vivo, which related to the mechanism of apoptosis induction, proliferation inhibition, metastasis blocking and angiogenesis arrest. Overall, the data of the present study recommend that nebivolol holds great potential in application as a novel agent for the treatment of melanoma.

Structural characterization and immunomodulatory activity of a water-soluble polysaccharide from Poria cocos.

In order to investigate the structural characteristics and immunomodulatory effects of Poria cocos polysaccharides, a water-soluble homogeneous polysaccharide (PCP-2) was isolated by water extraction and alcohol precipitation and further purified by Cellulose DEAE-52 and Sephacryl S-100HR column chromatography. PCP-2 is a heteropolysaccharide composed of glucose, galactose, mannose, and fucose in a molar ratio of 42.0: 35.0: 13.9: 9.1. It exhibits a narrow molecular weight distribution at 2.35 kDa with a branching degree of 37.1 %. The main chain types of PCP-2 include 1,3-ß-D-Glc and 1,6-ß-D-Glc as the backbone glucans and 1,6-α-D-Gal as the backbone heterogalactan. In vitro experiments demonstrate that PCP-2 directly stimulate RAW264.7 cell proliferation and secretion of inflammatory factors such as NO and TNF-α. In cyclophosphamide (CTX)-induced mice, it promotes the development of thymus and spleen immune organs, elevates the blood levels of IgG, IgA, IgM and CD3+CD4+ T cells, increases the intestinal villus height/ crypt depth ratio and improves gut barrier dysfunctions. These findings suggest that PCP-2 is a natural fungal polysaccharide with broad spectrum of immunoenhancing effects, which can significantly ameliorate the immunocompromised state.

Repurposing of Antidiarrheal Loperamide for Treating Melanoma by Inducing Cell Apoptosis and Cell Metastasis Suppression In Vitro and In Vivo.

BACKGROUND: Melanoma is the most common skin tumor worldwide and still lacks effective therapeutic agents in clinical practice. Repurposing of existing drugs for clinical tumor treatment is an attractive and effective strategy. Loperamide is a commonly used anti-diarrheal drug with excellent safety profiles. However, the affection and mechanism of loperamide in melanoma remain unknown. Herein, the potential anti-melanoma effects and mechanism of loperamide were investigated in vitro and in vivo. METHODS: In the present study, we demonstrated that loperamide possessed a strong inhibition in cell viability and proliferation in melanoma using MTT, colony formation and EUD incorporation assays. Meanwhile, xenograft tumor models were established to investigate the anti-melanoma activity of loperamide in vivo. Moreover, the effects of loperamide on apoptosis in melanoma cells and potential mechanisms were explored by Annexin V-FITC apoptosis detection, cell cycle, mitochondrial membrane potential assay, reactive oxygen species level detection, and apoptosis-correlation proteins analysis. Furthermore, loperamide-suppressed melanoma metastasis was studied by migration and invasion assays. What's more, immunohistochemical and immunofluorescence staining assays were applied to demonstrate the mechanism of loperamide against melanoma in vivo. Finally, we performed the analysis of routine blood and blood biochemical, as well as hematoxylin-eosin (H&E) staining, in order to investigate the safety properties of loperamide. RESULTS: Loperamide could observably inhibit melanoma cell proliferation in vitro and in vivo. Meanwhile, loperamide induced melanoma cell apoptosis by accumulation of the sub-G1 cells population, enhancement of reactive oxygen species level, depletion of mitochondrial membrane potential, and apoptosis-related protein activation in vitro. Of note, apoptosis-inducing effects were also observed in vivo. Subsequently, loperamide markedly restrained melanoma cell migration and invasion in vitro and in vivo. Ultimately, loperamide was witnessed to have an amicable safety profile. CONCLUSION: These findings suggested that repurposing of loperamide might have great potential as a novel and safe alternative strategy to cure melanoma via inhibiting proliferation, inducing apoptosis and cell cycle arrest, and suppressing migration and invasion.

Advances in the Study of Plant-Derived Vesicle-Like Nanoparticles in Inflammatory Diseases.

All humans are universally affected by inflammatory diseases, and there is an urgent need to identify new anti-inflammatory drugs with good therapeutic benefits and minimal side effects to the organism. Recently, it has been found that plant-derived vesicle-like nanoparticles (PDVLNs) have good biocompatibility, with their active ingredients exhibiting good therapeutic effects on inflammation. They can also be used as drug carriers for targeted delivery of anti-inflammatory drugs. Therefore, PDVLNs represent a popular research area for novel anti-inflammatory drugs. This paper details the origin, biological functions, isolation and purification, and identification of PDVLNs, as well as the therapeutic effects of their intrinsic bioactive components on inflammatory diseases. It also introduces their targets as drug carriers to facilitate the development and application of PDVLNs anti-inflammatory drugs.

Study on Optimal Extraction and Hypoglycemic Effect of Quercetin.

Quercetin was extracted from Portulaca oleracea L. through biphasic acid hydrolysis to investigate its potential as a suppressor of dipeptidyl peptidase IV (DPP-IV) and its hypoglycemic effect in type 2 diabetic mice. The extraction procedure was optimized utilizing the response surface method (RSM) in a single-factor experimental setting. An extraction efficiency of 0.675% was achieved using the following optimized parameters: 0.064 mol/L vitriol, 1 : 109.155 solid-liquid ratio, and 21.408 min ultrasonication. Overall, findings indicate the effectiveness of quercetin extraction. A mouse model for type 2 diabetes was established to receive oral treatment with various quercetin concentrations for 8 weeks. Fasting blood glucose (FBG) and the DPP-IV activity in the serum were significantly reduced. The weight and insulin levels of the mice in the quercetin group were raised compared to those in the model group (P < 0.01). Quercetin dose-dependently inhibited postprandial blood glucose excursions, as demonstrated by the oral glucose tolerance test. These results confirmed that quercetin has hypoglycemic effects and considerably improves insulin sensitivity via DPP-IV targeting.

Functional plasticity of neutrophils after low- or high-dose irradiation in cancer treatment - A mini review.

Over the last several decades, radiotherapy has been considered the primary treatment option for a broad range of cancer types, aimed at prolonging patients' survival and slowing down tumor regression. However, therapeutic outcomes of radiotherapy remain limited, and patients suffer from relapse shortly after radiation. Neutrophils can initiate an immune response to infection by releasing cytokines and chemokines to actively combat pathogens. In tumor immune microenvironment, tumor-derived signals reprogram neutrophils and induce their heterogeneity and functional versatility to promote or inhibit tumor growth. In this review, we present an overview of the typical phenotypes of neutrophils that emerge after exposure to low- and high-dose radiation. These phenotypes hold potential for developing synergistic therapeutic strategies to inhibit immunosuppressive activity and improve the antitumor effects of neutrophils to render radiation therapy as a more effective strategy for cancer patients, through tumor microenvironment modulation.

Effects of wearable physical activity tracking for breast cancer survivors: A systematic review and meta-analysis.

PURPOSE: Breast cancer is the most common cancer type worldwide, with its survivors often experiencing physical and psychosocial health problems. Wearable device use is an innovative and effective way to promote physical activity and improve health-related outcomes in breast cancer survivors; however, the current evidence is unclear. We aimed to determine the effects of wearable devices on physical activity and health-related outcomes in breast cancer survivors. METHODS: PubMed, Embase, Web of Science, and Cochrane Library databases were searched to identify eligible studies from inception to September 2022. Additional relevant studies were obtained from the reference lists of the identified studies. Two reviewers independently screened the eligible studies, appraised the risk of bias, and extracted the data. Meta-analysis was conducted using Review Manager version 5.3. FINDINGS: Sixteen randomized controlled trials were included. Physical activity tracking and pedometer-based interventions improved moderate-intensity physical activity (standardized mean difference [SMD] = 0.32, 95% confidence interval [CI]: 0.17-0.46, p < 0.0001), moderate-to-vigorous physical activity (SMD = 0.85, 95%CI: 0.38-1.32, p = 0.0004), total physical activity (SMD = 0.51, 95%CI: 0.12-0.90, p = 0.01), quality of life (SMD = 0.17, 95%CI: 0.03-0.31, p = 0.01), physical function (SMD = 0.21, 95%CI: 0.04-0.38, p = 0.02), and mood state profiles (SMD = -0.58, 95%CI: -1.13 to 0.02, p = 0.04) in breast cancer survivors. However, the effects of low-intensity physical activity, vigorous-intensity physical activity, fatigue, anxiety, depression, and sleep quality could not be ascertained. CONCLUSIONS: Physical activity tracking and pedometer-based interventions were effective in increasing physical activity and improving health-related outcomes in breast cancer survivors. IMPLICATIONS FOR NURSING PRACTICE: This review offers availability of credible evidence supporting the potential usefulness and effectiveness of wearable physical activity trackers on physical activity and health-related outcomes in breast cancer survivors.

Drug Value of Drynariae Rhizoma Root-Derived Extracellular Vesicles for Neurodegenerative Diseases Based on Proteomics and Bioinformatics.

Extracellular vesicles (EVs) are nano-sized membrane vesicles released by various cell types. Mammalian EVs have been studied in-depth, but the role of plant EVs has rarely been explored. For the first time, EVs from Drynariae Rhizoma roots were isolated and identified using transmission electron microscopy and a flow nano analyzer. Proteomics and bioinformatics were applied to determine the protein composition and complete the functional analysis of the EVs. Seventy-seven proteins were identified from Drynariae Rhizoma root-derived EVs, with enzymes accounting for 47% of the proteins. All of the enzymes were involved in important biological processes in plants. Most of them, including NAD(P)H-quinone oxidoreductase, were enriched in the oxidative phosphorylation pathway in plants and humans, and Alzheimer's disease, Huntington's disease, and Parkinson's disease, which are associated with oxidative stress in humans. These findings suggested that EVs from Drynariae Rhizoma roots could alleviate such neurological diseases and that enzymes, especially NAD(P)H-quinone oxidoreductase, might play an important role in the process.

Endoscopic- versus x-ray-guidance for placement of nasojejunal tubes in critically ill patients: a systematic review and meta-analysis of randomized controlled trials.

Nasojejunal tubes (NJTs) are increasingly used in critically ill patients. NJT insertion with endoscopic- or x-ray-guidance can be achieved with success rates above 90%. This systematic review and meta-analysis of randomized controlled trials (RCTs) compares the efficiency and safety of these two methods in critically ill patients. We searched Chinese and English databases for RCTs comparing endoscopy- and x-ray-guided NJT placement published up to July 5, 2021. Meta-analyses were performed using RevMan5 software to compute mean differences (MDs) and odds ratios (ORs). Eleven RCTs (n=676) were included. The endoscopic group had a higher procedure success rate (OR=2.14, 95% CI [1.19, 3.85], Z=2.52, P=0.01) and shorter insertion time (MD=-3.70 min, 95% CI [-6.90, -0.50], Z=2.27, P=0.02) than the x-ray group. NJT indwelling time and post-insertion complications were similar between groups. The x-ray group had fewer complications during placement (OR=8.08, 95% CI [3.58, 18.22], Z=5.03, P<0.00001]; on subgroup analysis, only gastrointestinal non-bleeding adverse events differed significantly between groups (OR=2.78, 95% CI [1.43, 5.39], Z=3.03, P=0.002). Visual analog scale discomfort scores were better in the x-ray group (MD=4.10, 95% CI [3.57, 4.63], Z=15.07, P<0.00001). Compared with x-ray-guided NJT placement, endoscopy-guided placement was faster, had a higher success rate, and was associated with fewer gastrointestinal non-bleeding adverse events and less discomfort during insertion. Endoscopic guidance is recommended for NJT placement in critically ill patients to improve placement efficiency. X-ray guidance is a good alternative, depending on the hospital setting, as it is convenient, economical, and potentially safer.

Gene expression patterns associated with tumor-infiltrating CD4+ and CD8+ T cells in invasive breast carcinomas.

BACKGROUND: Breast carcinoma is one of the most common tumors in women. The immune microenvironment, especially T cell infiltration, is related to the occurrence and prognosis of breast carcinoma. OBJECTIVE: This study investigated the gene expression patterns associated with tumor-infiltrating CD4+ and CD8+ T cells in invasive breast carcinomas. METHODS: The gene expression data and corresponding clinical phenotype data from the Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) were downloaded. The stromal and immune score were calculated using ESTIMATE. The differentially expressed genes (DEGs) with a high vs. low stromal score and a high vs. low immune score were screened and then functionally enriched. The tumor-infiltrating immune cells were investigated using the Cibersort algorithm, and the CD4+ and CD8+ T cell-related genes were identified using a Spearman correlation test of infiltrating abundance with the DEGs. Moreover, the miRNA-mRNA pairs and lncRNA-miRNA pairs were predicted to construct the competing endogenous RNAs (ceRNA) network. Kaplan-Meier (K-M) survival curves were also plotted. RESULTS: In total, 478 DEGs with a high vs. low stromal score and 796 DEGs with a high vs. low immune score were identified. In addition, 39 CD4+ T cell-related genes and 78 CD8+ T cell-related genes were identified; of these, 14 genes were significantly associated with the prognosis of BRCA patients. Moreover, for CD4+ T cell-related genes, the chr22-38_28785274-29006793.1-miR-34a/c-5p-CAPN6 axis was identified from the ceRNA network, whereas the chr22-38_28785274-29006793.1-miR-494-3p-SLC9A7 axis was identified for CD8+ T cell-related genes. CONCLUSIONS: The chr22-38_28785274-29006793.1-miR-34a/c-5p-CAPN6 axis and the chr22-38_28785274-29006793.1-miR-494-3p-SLC9A7 axis might regulate cellular activities associated with CD4+ and CD8+ T cell infiltration, respectively, in BRCA.

Recent progress in the use of mitochondrial membrane permeability transition pore in mitochondrial dysfunction-related disease therapies.

Mitochondria have various cellular functions, including ATP synthesis, calcium homeostasis, cell senescence, and death. Mitochondrial dysfunction has been identified in a variety of disorders correlated with human health. Among the many underlying mechanisms of mitochondrial dysfunction, the opening up of the mitochondrial permeability transition pore (mPTP) is one that has drawn increasing interest in recent years. It plays an important role in apoptosis and necrosis; however, the molecular structure and function of the mPTP have still not been fully elucidated. In recent years, the abnormal opening up of the mPTP has been implicated in the development and pathogenesis of diverse diseases including ischemia/reperfusion injury (IRI), neurodegenerative disorders, tumors, and chronic obstructive pulmonary disease (COPD). This review provides a systematic introduction to the possible molecular makeup of the mPTP and summarizes the mitochondrial dysfunction-correlated diseases and highlights possible underlying mechanisms. Since the mPTP is an important target in mitochondrial dysfunction, this review also summarizes potential treatments, which may be used to inhibit pore opening up via the molecules composing mPTP complexes, thus suppressing the progression of mitochondrial dysfunction-related diseases.

Single-Cell Analysis Reveals Characterization of Infiltrating T Cells in Moderately Differentiated Colorectal Cancer.

Objective: This study aimed to characterize the tumor-infiltrating T cells in moderately differentiated colorectal cancer. Methods: Using single-cell RNA sequencing data of isolated 1632 T cells from tumor tissue and 1252 T cells from the peripheral blood of CRC patients, unsupervised clustering analysis was performed to identify functionally distinct T cell populations, followed by correlations and ligand-receptor interactions across cell types. Finally, differential analysis of the tumor-infiltrating T cells between colon cancer and rectal cancer were carried out. Results: A total of eight distinct T cell populations were identified from tumor tissue. Tumor-Treg showed a strong correlation with Th17 cells. CD8+TRM was positively correlated with CD8+IEL. Seven distinct T cell populations were identified from peripheral blood. There was a strong correlation between CD4+TN and CD4+blood-TCM. Colon cancer and rectal cancer showed differences in the composition of tumor-infiltrating T cell populations. Tumor-infiltrating CD8+IEL cells were found in rectal cancer but not in colon cancer, while CD8+ TN cells were found in the peripheral blood of colon cancer but not in that of rectal cancer. A larger number of tumor-infiltrating CD8+ Tex (88.94%) cells were found in the colon cancer than in the rectal cancer (11.06%). The T cells of the colon and rectal cancers showed changes in gene expression pattern. Conclusions: We characterized the T cell populations in the CRC tumor tissue and peripheral blood.

Ultrasonication-promoted synthesis of luminescent sulfur nano-dots for cellular imaging applications.

An ultrasonication-promoted strategy was proposed to synthesize luminescent S-dots, which reduced the synthesis time from the commonly used 5 days to several hours. The as-synthesized S-dots show a high photostability and low cytotoxicity, and are then successfully applied for cellular imaging.

Lattice Dynamics and Thermal Stability of Cubic-Phase CsPbI3 Quantum Dots.

Cubic-phase CsPbI3 quantum dots (QDs) have been recently synthesized with merits of excellent optoelectronic performance. However, vital properties of cubic CsPbI3 including lattice dynamics and stability at high temperature remain poorly explored. We fabricate cubic CsPbI3 QDs and study their lattice dynamic and thermal stability to 700 K. We obtain Raman modes of cubic CsPbI3 QDs from 300 to 500 K at ultra-low-frequency range down to 15 cm-1, consistent with first-principles calculations. Above 550 K, the modification of Raman features suggests sample degradation. Consistently, temperature-dependent photoluminescence measurements indicate the absence of other luminescence phases up to 700 K. With increasing temperature, the CsPbI3 QD photoluminescence peak has a blue shift with exponentially decreasing intensity, showing faster electronic degradation than structural degradation. Our work provides detailed investigation of CsPbI3 QD lattice dynamics, band gap, and their high-temperature behavior, potentially useful for their emerging optoelectronic applications.

Fluid Retention Caused by Rosiglitazone Is Related to Increases in AQP2 and αENaC Membrane Expression.

Peroxisome proliferator activated receptor-γ (PPARγ) is a ligand-activated transcription factor of the nuclear hormone receptor superfamily. The decreased phosphorylation of PPARγ due to rosiglitazone (ROS) is the main reason for the increased insulin sensitivity caused by this antidiabetic drug. However, there is no clear evidence whether the nuclear translocation of p-PPARγ stimulated by ROS is related to fluid retention. It is also unclear whether the translocation of p-PPARγ is associated with the change of aquaporin-2 (AQP2) and epithelial sodium channel α subunit (αENaC) in membranes, cytoplasm, and nucleus. Our experiments indicate that ROS significantly downregulates nuclear p-PPARγ and increases membrane AQP2 and αENaC; however, SR1664 (a nonagonist PPARγ ligand) reduces p-PPARγ and has no effect on AQP2 and αENaC. Therefore, we conclude that in vitro the fluid retention caused by ROS is associated with the increases in membrane αENaC and AQP2 but has little relevance to the phosphorylation of PPARγ.

[GC-MS analysis of chemical constituents of volatile oil from flowers of Rhododendron mucronatum].

OBJECTIVE: To analyze the chemical constituents of volatile oil from flowers of Rhododendron mucronatum. METHODS: The volatile oil was extracted by water-steam distillation and analyzed by GC-MS. RESULTS: Forty-nine compounds, which occupied 79.55% of total constituents, were identified. The major constituents were linalool, beta-eudesmene, phytol, benzyl benzoate, benzyl salicylate and nonyl aldehyde. CONCLUSION: The chemical constituents of volatile oil, which contain many bioactive constituents, are mainly composed of terpenes, esters, and alkanes.