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.

Effectiveness of metagenomic next-generation sequencing in the diagnosis of infectious diseases: A systematic review and meta-analysis.

OBJECTIVES: Early diagnosis of infectious diseases remains a challenge. This study assessed the diagnostic value of mNGS in infections and explored the effect of various factors on the accuracy of mNGS. METHODS: An electronic article search of PubMed, Cochrane Library, and Embase was performed. A total of 85 papers were eligible for inclusion and analysis. Stata 12.0 was used for statistical calculation to evaluate the efficacy of mNGS for the diagnosis of infectious diseases. RESULTS: The AUC of 85 studies was 0.88 (95%CI, 0.85-0.90). The AUC of the clinical comprehensive diagnosis and conventional test groups was 0.92 (95%CI, 0.89-0.94) and 0.82 (95%CI, 0.78-0.85), respectively. The results of subgroup analysis indicated that the PLR and NLR were 12.67 (95%CI, 6.01-26.70) and 0.05 (95%CI, 0.03-0.10), respectively, in arthrosis infections. The PLR was 24.41 (95%CI, 5.70-104.58) in central system infections and the NLR of immunocompromised patients was 0.08 (95%CI, 0.01-0.62). CONCLUSION: mNGS demonstrated satisfactory diagnostic performance for infections, especially for bone and joint infections and central system infections. Moreover, mNGS also has a high value in the exclusion of infection in immunocompromised patients.

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.

A PD-L1 Antibody-Conjugated PAMAM Dendrimer Nanosystem for Simultaneously Inhibiting Glycolysis and Promoting Immune Response in Fighting Breast Cancer.

Breast cancer is the most frequent malignancy affecting women, yet current therapeutic strategies remain ineffective for patients with late-stage or metastatic disease. Here an effective strategy is reported for treating metastatic breast cancer. Specifically, a self-assembling dendrimer nanosystem decorated with an antibody against programmed cell death ligand 1 (PD-L1) is established for delivering a small interfering RNA (siRNA) to target 3-phosphoinositide-dependent protein kinase-1 (PDK1), a kinase involved in cancer metabolism and metastasis. This nanosystem, named PPD, is designed to target PD-L1 for cancer-specific delivery of the siRNA to inhibit PDK1 and modulate cancer metabolism while promoting programmed cell death 1 (PD-1)/PD-L1 pathway-based immunotherapy. Indeed, PPD effectively generates simultaneous inhibition of PDK1-induced glycolysis and the PD-1/PD-L1 pathway-related immune response, leading to potent inhibition of tumor growth and metastasis without any notable toxicity in tumor-bearing mouse models. Collectively, these results highlight the potential use of PPD as an effective and safe tumor-targeting therapy for breast cancer. This study constitutes a successful proof of principle exploiting the intrinsic features of the tumor microenvironment and metabolism alongside a unique self-assembling dendrimer platform to achieve specific tumor targeting and siRNA-based gene silencing in combined and precision cancer therapy.

Integrated Osteoinductive Factors─Exosome@MicroRNA-26a Hydrogel Enhances Bone Regeneration.

MicroRNAs (miRNAs) are a new therapeutic tool that can target multiple genes by inducing translation repression and target mRNA degradation. Although miRNAs have gained significant attention in oncology and in work on genetic disorders and autoimmune diseases, their application in tissue regeneration remains hindered by several challenges, such as miRNA degradation. Here, we reported Exosome@MicroRNA-26a (Exo@miR-26a), an osteoinductive factor that can be substituted for routinely used growth factors, which was constructed using bone marrow stem cell (BMSC)-derived exosomes and microRNA-26a (miR-26a). Exo@miR-26a-integrated hydrogels significantly promoted bone regeneration when implanted into defect sites; as the exosome stimulated angiogenesis, miR-26a promoted osteogenesis while the hydrogel enabled a site-directed release. Moreover, BMSC-derived exosomes further facilitated healthy bone regeneration by repressing osteoclast differentiation-related genes rather than damaging osteoclasts. Taken together, our findings demonstrate the promising potential of Exo@miR-26a for bone regeneration and provide a new strategy for the application of miRNA therapy in tissue engineering.

Natural products targeting glycolytic signaling pathways-an updated review on anti-cancer therapy.

Glycolysis is a complex metabolic process that occurs to convert glucose into pyruvate to produce energy for living cells. Normal cells oxidized pyruvate into adenosine triphosphate and carbon dioxide in the presence of oxygen in mitochondria while cancer cells preferentially metabolize pyruvate to lactate even in the presence of oxygen in order to maintain a slightly acidic micro-environment of PH 6.5 and 6.9, which is beneficial for cancer cell growth and metastasis. Therefore targeting glycolytic signaling pathways provided new strategy for anti-cancer therapy. Natural products are important sources for the treatment of diseases with a variety of pharmacologic activities. Accumulated studies suggested that natural products exhibited remarkable anti-cancer properties both in vitro and in vivo. Plenty of studies suggested natural products like flavonoids, terpenoids and quinones played anti-cancer properties via inhibiting glucose metabolism targets in glycolytic pathways. This study provided an updated overview of natural products controlling glycolytic pathways, which also provide insight into druggable mediators discovery targeting cancer glucose metabolism.

Evaluation of teaching effect of first-aid comprehensive simulation-based education in clinical medical students.

Background: Although students mastered the composition skills, they lack of the ability to effectively integrate these composition skills in real clinical situations. To address the problem, we set up different levels of situational simulation training for medical students in grades 2-4, and evaluate the teaching effect of first-aid situation comprehensive simulation-based education (SBE) on clinical medical students. Methods: The medical students in Grade 2, 3, and 4 received different situational SBE, respectively. The 2nd-year medical students received a single skill module which included cardiopulmonary resuscitation, endotracheal intubation, and electric defibrillation training. The 3rd-year medical students received a single subject module which included cardiovascular and respiratory system training. The 4th-year medical students received the integrated multidisciplinary module which combined first-aid skills, clinical thinking, and teamwork training. The primary outcome was the expert evaluation and peer evaluation. The secondary outcome was students' satisfaction questionnaire response. In our training, we arranged an adequate teaching staff for intensive training and timely feedback (the student-teacher ratio of 5:1), adequate time for repetitive practice (Each SBE was carried out within 4 h), curriculum design, and integration from real cases by clinicians, realistic computer-driven mannequins to ensure simulation fidelity, providing a different difficult level of SBE to different grades of students, and pre- and post-tests for outcome measurement. Results: In all of the single skill module, single subject module or comprehensive disciplines module, the scores in the expert evaluation and peer assessment after the training were significantly higher than before the training, and the differences were statistically significant (p < 0.05). The integrated subject training, although having the lowest pre-and post-test marks, had the largest increase in score. Conclusion: The first aid comprehensive simulation-based education in grade 2-4 clinical medical students, basing on timely feedback, repetitive practice, curriculum integration, simulation fidelity, and outcome measurement are effective in improving the students' proficiency in managing the real emergencies.

Efficacy of anti-fungal agents for invasive fungal infection prophylaxis in liver transplant recipients: A network meta-analysis.

At present, there is still a lack of effective invasive fungal prophylaxis therapy in liver transplant recipients (LTRs). This study aimed to analysis the latest evidence on efficacy of current prophylactic anti-fungal therapy, and systematically compare between anti-fungal agents and placebo by a fixed-effects meta-analysis in all randomised controlled trials. A network meta-analysis was performed for invasive fungal infection (IFI) among different agents in 14 randomised controlled trials, in which 10 anti-fungal approaches were identified. Overall, anti-fungal prophylaxis reduced the rate of IFI (RR 0.30, 95% CI 0.18-0.52) and proven IFI (RR 0.27, 95% CI 0.14-0.53) when compared to placebo. In the network meta-analysis, an equivalent reduction in the rate of IFI was observed in fluconazole (OR 4.70, 95% CI 1.22-18.10), itraconazole (OR 5.82, 95% CI 1.10-30.71) and Liposomal amphotericin B (LAmB, OR 5.74, 95% CI 1.29-25.58) groups when compared with placebo. Anidulafungin might be the most effective agents in IFI prevention; however, this superiority did not meet statistically significance. Our study indicated that fluconazole, echinocandins and LAmB are equivalent in efficacy. Of which, fluconazole is recommended for the prevention of IFI in LTRs due to its efficacy, economics and compliance.

Octreotide-based therapies effectively protect mice from acute and chronic gastritis.

Gastritis is a common inflammation of stomach with multiple pathogenesis. This study was designed to investigate the protective effects of oral octreotide (OCT) against ethanol-induced acute gastric injury and H. pylori-induced chronic gastritis via promoting gastric mucosa restoration, reducing gastric acid secretion and inflammation. Male C57BL/6J mice were randomly divided and treated with three doses of OCT (0.5, 2.5, 10 mg/kg) alone or combined respectively with 10 mg/kg omeprazole (OME), 0.2 g/L metronidazole (MTZ)/0.1 g/L clarithromycin (CLR) in drinking water. Oxidative stress analysis, bacterial load analysis, qPCR, gastric histopathology examinations were performed in our study. Ethanol-induced acute gastric ulcer was restored by OCT alone at doses of 2.5 mg/kg, or combined with OME as indicated by markedly reducing Gastrin, Il-6 and Il1b expression through induction of Muc5ac and Occludin, significantly improving hyperacidity and gastric bleeding. As well, OCT combined with MTZ/CLR restored the integrity of gastric mucosa damaged by H. pylori via elevating the expression of Muc5ac and somatostatin receptor 2, decreasing inflammation and increasing the number of chorionic or glands. Besides, OCT is more suitable for long-term medication in the treatment of chronic gastritis than OME. In conclusion, our results proved that the newly developed oral OCT-based therapies were more effective to reverse gastric mucosa damage and inflammation in ethanol and H. pylori infection-induced gastric injury, it is of great significance for supplementing new clinical regimens for the treatment of acute and chronic gastritis.

Cost-Effectiveness Analysis of Adding Daratumumab to Bortezomib, Melphalan, and Prednisone for Untreated Multiple Myeloma.

Background: To evaluate the cost-effectiveness of adding daratumumab to bortezomib, melphalan, and prednisone for transplant-ineligible newly diagnosed multiple myeloma patients. Methods: A three-state Markov model was developed from the perspective of US payers to simulate the disease development of patient's life time for daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) and bortezomib, melphalan, and prednisone (VMP) regimens. The primary outputs were total costs, expected life-years (LYs), quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). Results: The base case results showed that adding daratumumab to VMP provided an additional 3.00 Lys or 2.03 QALYs, at a cost of $262,526 per LY or $388,364 per QALY. Sensitivity analysis indicated that the results were most sensitive to utility of progression disease of D-VMP regimens, but no matter how these parameters changed, ICERs remained higher than $150,000 per QALY. Conclusion: In the case that the upper limit of willingness to pay threshold was $150,000 per QALY from the perspective of US payers, D-VMP was not a cost-effective regimen compared to VMP.

miR-218 contributes to drug resistance in multiple myeloma via targeting LRRC28.

Multiple myeloma (MM) is a malignant neoplasm featured by obvious drug resistance and poor prognosis. MicroRNAs (miRNAs) are a class of small noncoding RNAs with crucial roles in many biological processes including cancer initiation and progression. The current study aims to investigate the pathogenic role and molecular mechanism of miRNAs in MM drug resistance. In the present study, The expression profile of miRNAs in MM samples was analyzed by microarray and real-time polymerase chain reaction. Protein expressions were detected by Western blot analysis. Cell apoptosis was detected by the Annexin V staining assay. The interaction between miRNA and the targeting mRNA was assessed using Dual luciferase reporter assay. Herein, we show that expression profile of miRNAs is deregulated in MM. miR-218, one of the most aberrational miRNAs in MM, is significantly decreased in MM cells compared to peripheral blood mononuclear cell (PBMC). Genetic manipulation reveals miR-218 control the response of MM cells to anticancer drug bortezomib (BTZ). Overexpression of miR-218 causes a significant aberrant genes expression including leucine rich repeat containing 28 (LRRC28). Mechanistic study shows that miR-218 control the drug response through mediating the expression of LRRC28 in MM cells. Overexpression of LRRC28 significantly reserves miR-218-mediated cell response to BTZ. Taken together, miR-218 is decreased in MM that contributes to BTZ resistance via targeting LRRC28, which might be used as a novel therapeutic target for multiple myeloma.

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.

Rational Design of a High-Performance Quinoxalinone-Based AIE Photosensitizer for Image-Guided Photodynamic Therapy.

Because light exhibits excellent spatiotemporal resolution, photodynamic therapy (PDT) is becoming a promising method for cancer treatment. However, in a single photosensitizer (PS), it remains a big challenge to achieve all key properties including effective singlet oxygen (1O2) production under long-wavelength laser and bright near-infrared (NIR) emission without toxicity in the dark. In addition, clinically used traditional PSs encounter quenched fluorescence and decreased 1O2 production because of molecular aggregation in aqueous solution. To solve the aforementioned issues, quinoxalinone CN (QCN) with effective 1O2 generation under long-wavelength (530 nm) laser irradiation and aggregation-induced NIR emission is rationally designed by precise optimization of the quinoxalinone scaffold. After being encapsulated by an amphiphilic polymer (DSPE-PEG), the yielded nanoparticles exhibit highly efficient 1O2 production and stable NIR fluorescence located at 800 nm without obvious toxicity under the dark. Both in vitro and in vivo evaluation identify that QCN would be a promising PS for image-guided PDT of tumors.

Recent progress in nanotechnology based ferroptotic therapies for clinical applications.

Ferroptosis is a new iron and reactive oxygen species dependent programmed cell death process which is different from apoptosis, necrosis, and autophagy. It is closely related to a number of disease progression including cancers, neurodegenerative disease, cerebral hemorrhage, liver disease, and renal failure. The development of different ferroptotic inducers has been proved as an efficient therapeutic strategy for a variety of chemoradiotherapy-resistant cancer cells and cancer stem cells. In addition, the development of ferroptotic inhibitors is also becoming an emerging research hotspot for the treatment of many non-cancerous diseases. Furthermore, the combination of nanotechnology with ferroptotic therapies has exhibited additional advantages such as enhanced targeting and/or stimuli-responsive ability to tumor microenvironment, ameliorated drug solubility, ease of preparation and the integration of multifunctional theranostic platforms to develop synergetic combined therapies of great clinical importance. This paper reviews the latest advances of using tailored ferroptotic nanoparticles and ferroptotic molecular probes to be relevant for the accurate diagnosis and treatment of different diseases. Finally, the opportunities and challenges of this burgeoning field were spotlighted to promote the rational design of nano-ferroptotic drugs or theranostic probes in the near future.

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.