Anticancer Mechanisms and Potential Anticancer Applications of Antimicrobial Peptides and Their Nano Agents.

Traditional chemotherapy is one of the main methods of cancer treatment, which is largely limited by severe side effects and frequent development of multi-drug resistance by cancer cells. Antimicrobial peptides (AMPs) with high efficiency and low toxicity, as one of the most promising new drugs to replace chemoradiotherapy, have become a current research hotspot, attracting the attention of worldwide researchers. AMPs are natural-source small peptides from the innate immune system, and certain AMPs can selectively kill a broad spectrum of cancer cells while exhibiting less damage to normal cells. Although it involves intracellular mechanisms, AMPs exert their anti-cancer effects mainly through membrane destruction effect; thus, AMPs also hold unique advantages in fighting drug-resistant cancer cells. However, the poor stability and hemolytic toxicity of peptides limit their clinical application. Fortunately, functionalized nanoparticles have many possibilities in overcoming the shortcomings of AMPs, which provides a huge prospect for better application of AMPs. In this paper, we briefly introduce the characteristics and different sources of AMPs, review and summarize the mechanisms of action and the research status of AMPs used as an anticancer therapy, and finally focus on the further use of AMPs nano agents in the anti-cancer direction.

MMP-2 Responsive Peptide Hydrogel-Based Nanoplatform for Multimodal Tumor Therapy.

Introduction: Responsive drug delivery systems hold great promise for tumor treatment as they focus on therapeutic agents directly, thus minimizing systemic toxicities and drug leakage. In this study, we covalently bound a matrix metalloproteinases-2 (MMP-2) enzyme-sensitive peptide to a tissue-penetrating peptide to rationally design a MMP-2 responsive multifunctional peptide hydrogel platform (aP/IR@FMKB) for cancer photothermal-chemo-immunotherapy. The constructed aP/IR@FMKB with bufalin (BF) loaded in trimethyl chitosan nanoparticles (TB NPs), photothermal agent IR820, and immune checkpoint inhibitor aPD-L1 by self-assembly could be dissociated in the presence of MMP-2 enzyme, triggering content release. Methods: TB NPs, IR820, and aPD-L1 were encapsulated by intermolecular self-assembly and enzyme-sensitive nanogels (aP/IR@FMKB) were constructed. The in vitro cytotoxicity of the blank gels and their ability to induce immunogenic cell death (ICD) in aP/IR@FMKB were evaluated using 4T1 cells. The promotion of deep tumor penetration and enzyme responsiveness was analyzed using a 3D cell model. The retention and antitumor activity at the tumor sites were examined using the primary tumor model. To assess the antitumor effect of aP/IR@FMKB induced by the immune response and its mechanism of action, recurrent tumor and distal tumor models were constructed. Results: This hydrogel system demonstrated exceptional photothermal performance and displayed prolonged local retention. Furthermore, the induction of ICD through IR820 and TB NPs sensitized the PD-L1 blockade, resulting in a remarkable 3.5-fold and 5.2-fold increase in the frequency of intratumor-infiltrating CD8+ T-cells in the primary tumor and distal tumor, respectively. Additionally, this system demonstrated remarkable efficacy in suppressing primary, distal, and recurrent tumors, underscoring its potential as a highly potent therapeutic strategy. Conclusion: This innovative design of the responsive hydrogel can effectively modulate the tumor immune microenvironment while also demonstrating sensitivity to the PD-1/PD-L1 blockade. This significant finding highlights the promising potential of this hydrogel in the field of multimodal tumor therapy.

Stimulus-responsive nano lipidosome for enhancing the anti-tumour effect of a novel peptide Dermaseptin-PP.

OBJECTIVE: Dermaseptin-PP is a newly discovered anticancer peptide with a unique antitumour mechanism and remarkable effect. However, this α-helix anticancer peptide risks haemolysis when used at high doses, which limits its further application. This study aims to prepare a pH-responsive liposome, Der-loaded-pHSL, using nanotechnology to avoid the haemolysis risk of Dermaseptin-PP and increase its accumulation in tumour sites to enhance efficacy and reduce toxicity. METHODS: The characterisation of Der-loaded-pHSL was carried out employing preparation. The effect of haemolysis and tumour inhibition were investigated by in vitro haemolysis assay and cytotoxicity assay. The cell uptake under different pH conditions was investigated by flow cytometry, and the effect of pH on tumour cell selectivity was evaluated. In order to evaluate the in vivo targeting and antitumour effect of Der-loaded-pHSL, the in vivo distribution experiment and the pharmacodynamic experiment were performed using the nude mouse tumour model. RESULTS: The preparation method of the Der-loaded-pHSL is simple, and the liposome has good nanoparticle characteristics. When Dermaseptin-PP was prepared as liposome, haemolysis was significantly decreased, and tumour cell inhibition was significantly enhanced. Compared with ordinary liposomes, this change was more significant in Der-loaded-pHSL. The uptake of pH-sensitive liposomes was higher in the simulated acidic tumour microenvironment, and the uptake showed a specific acid dependence. In vivo experiments showed that Der-loaded-pHSL had a significant tumour-targeting effect and could significantly enhance the antitumour effect of Dermaseptin-PP. CONCLUSION: Der-loaded-pHSL designed in this study is a liposome with a quick, simple, effective preparation method, which can significantly reduce the haemolytic toxicity of Dermaseptin-PP and enhance its antitumour effect by increasing the tumour accumulation and cell intake. It provides a new idea for applying Dermaseptin-PP and other anticancer peptides with α-helical structure.

A paclitaxel prodrug nanoparticles with glutathion/reactive oxygen species dual-responsive and CD206 targeting to improve the anti-tumour effect.

As a first-line anticancer drug, paclitaxel has shortcomings, such as poor solubility and lack of tumour cell selectivity, which limit its further applications in clinical practice. Therefore, the authors aimed to utilise the characteristics of prodrug and nanotechnology to prepare a reactive oxygen species (ROS) and GSH dual-responsive targeted tumour prodrug nanoparticle Man-PEG-SS-PLGA/ProPTX to improve the clinical application status of paclitaxel limitation. The characterisation of Man-PEG-SS-PLGA/ProPTX was carried out through preparation. The cytotoxicity of nanoparticles on tumour cells and the effect on apoptosis of tumour cells were investigated by cytotoxicity assay and flow cytometry analysis. The ROS responsiveness of nanoparticles was investigated by detecting the ROS level of tumour cells. The tumour cell selectivity of the nanoparticles was further investigated by receptor affinity assay and cell uptake assay. The particle size of Man-PEG-SS-PLGA/ProPTX was (132.90 ± 1.81) nm, the dispersion coefficient Polymer dispersity index was 0.13 ± 0.03, and the Zeta potential was (-8.65 ± 0.50) mV. The encapsulation rate was 95.46 ± 2.31% and the drug load was 13.65 ± 2.31%. The nanoparticles could significantly inhibit the proliferation and promote apoptosis of MCF-7, HepG2, and MDA-MB-231 tumour cells. It has good ROS response characteristics and targeting. The targeted uptake mechanism is energy-dependent and endocytosis is mediated by non-clathrin, non-caveolin, lipid raft/caveolin, and cyclooxygenase (COX)/caveolin with a certain concentration dependence and time dependence. Man-PEG-SS-PLGA/ProPTX is a tumour microenvironment-responsive nanoparticle that can actively target tumour cells. It restricts the release of PTX in normal tissues, enhances its selectivity to tumour cells, and has significant antitumour activity, which is expected to solve the current limitations of PTX use.

Interaction between travel restriction policies and the spread of COVID-19.

To investigate the interaction between travel restriction policies and the spread of COVID-19, we collected data on human mobility trends, population density, Gross Domestic Product (GDP) per capita, daily new confirmed cases (or deaths), and the total confirmed cases (or deaths), as well as governmental travel restriction policies from 33 countries. The data collection period was from April 2020 to February 2022, resulting in 24,090 data points. We then developed a structural causal model to describe the causal relationship between these variables. Using the Dowhy method to solve the developed model, we found several significant results that passed the refutation test. Specifically, travel restriction policies played an important role in slowing the spread of COVID-19 until May 2021. International travel controls and school closures had an impact on reducing the spread of the pandemic beyond the impact of travel restrictions. Additionally, May 2021 marked a turning point in the spread of COVID-19 as it became more infectious, but the mortality rate gradually decreased. The impact of travel restriction policies on human mobility and the pandemic diminished over time. Overall, the cancellation of public events and restrictions on public gatherings were more effective than other travel restriction policies. Our findings provide insights into the effects of travel restriction policies and travel behavioral changes on the spread of COVID-19, while controlling for informational and other confounding variables. This experience can be applied in the future to respond to emergent infectious diseases.

Combined Thermosensitive Gel Co-Loaded with Dermaseptin-PP and PTX Liposomes for Effective Local Chemotherapy.

Introduction: Chemotherapeutic drugs are often ineffective due to the delivery. Local chemotherapy, which has high drug concentration, low systemic toxicity, and long duration, has shown excellent potential. Cationic antimicrobial peptides have been proved to enhance the tumor cells' uptake of chemotherapeutic drugs through the membrane-breaking effect. In this study, we designed and developed a thermosensitive gel co-loaded with Dermaseptin-PP and paclitaxel liposomes to increase local chemotherapy. Methods: The paclitaxel liposomes were prepared. Then, it was co-loaded with Dermaseptin-PP in a poloxamer-based thermosensitive gel to obtain Dermaseptin-PP/paclitaxel liposomes gel. The thermosensitivity of gels was investigated by test tube inversion method. The rheology was tested by rheometer. The in vitro cytotoxicity and the permeation in tumor of gels were examined by H157 cells and the 3D cell model, respectively. The retention in tumor and antitumor activity of gels were evaluated by H157 tumor-bearing nude mice. Results: The particle size of paclitaxel liposomes was 148.97 ± 0.21 nm. The encapsulation rate was 86.1%, and the drug loading capacity was 19.4%. The gels had slow-release and temperature-sensitive properties. The porous 3D network structure of the gels could ensure that the drug was fixed into the tumor. In vitro and in vivo distribution studies showed that Dermaseptin-PP promoted the permeation of the gels in H157 multicellular tumor spheres and achieved longer retention in tumor. In vitro and in vivo antitumor studies demonstrated that Dermaseptin-PP/paclitaxel liposomes gel significantly inhibited the growth of tumors for local chemotherapy with good biosafety. Conclusion: This study provided a promising nanomedicine platform for combining antimicrobial peptides and chemotherapeutic drugs for local chemotherapy.

Novel image features of optical coherence tomography for pathological classification of lung cancer: Results from a prospective clinical trial.

Background: This study aimed to explore the characteristics of optical coherence tomography (OCT) imaging for differentiating between benign and malignant lesions and different pathological types of lung cancer in bronchial lesions and to preliminarily evaluate the clinical value of OCT. Methods: Patients who underwent bronchoscopy biopsy and OCT between February 2019 and December 2019 at the Chinese PLA General Hospital were enrolled in this study. White-light bronchoscopy (WLB), auto-fluorescence bronchoscopy (AFB), and OCT were performed at the lesion location. The main characteristics of OCT imaging for the differentiation between benign and malignant lesions and the prediction of the pathological classification of lung cancer in bronchial lesions were identified, and their clinical value was evaluated. Results: A total of 135 patients were included in this study. The accuracy of OCT imaging for differentiating between benign and malignant bronchial lesions was 94.1%, which was significantly higher than that of AFB (67.4%). For the OCT imaging of SCC, adenocarcinoma, and small-cell lung cancer, the accuracies were 95.6, 94.3, and 92%, respectively. The accuracy, sensitivity, and specificity of OCT were higher than those of WLB. In addition, these main OCT image characteristics are independent influencing factors for predicting the corresponding diseases through logistic regression analysis between the main OCT image characteristics in the study and the general clinical features of patients (p<0.05). Conclusion: As a non-biopsy technique, OCT can be used to improve the diagnosis rate of lung cancer and promote the development of non-invasive histological biopsy.

Network pharmacology-based prediction and verification of the active ingredients and potential targets of Huagan Decoction for reflux esophagitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Huagan Decoction (HGD), a famous traditional Chinese medicine (TCM) formula, has been widely used in the treatment of reflux esophagitis (RE). However, its effective compounds, potential targets and molecular mechanism remain unclear. AIM OF THE STUDY: To investigate effective compounds, potential targets and molecular mechanism of HGD against RE by using network pharmacology combined with in vitro validation, with the aims of observing the action of HGD and exploring new therapeutic strategies for RE treatment. MATERIALS AND METHODS: Effective compounds and potential targets of HGD, as well as related genes of RE, were collected from public databases. Pharmacological clustering and Gene Ontology (GO) enrichment analysis were applied to find targets that involving in the anti-inflammatory module. The pathways were drawn using Cytoscape 3.8.0. Important ingredients, potential targets, and signaling pathways were determined through the construction of protein-protein interaction (PPI), GO and Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, cell experiments were carried out. RESULTS: A total of 54 active ingredients and 240 RE-related gene targets of HGD were identified. The active compound-target network was visualized and pharmacological clustering further sorted 53 proteins that involve in the regulation of inflammatory responses. GO analysis confirmed the classification was statistically significant. Analysis of compound-target network revealed that quercetin and geniposide may be key ingredients for the anti-inflammatory effect of HGD against RE. The potential targets regulated by HGD are IL-6, IL-1ß, PTGS2, AKT1, TNF-α, MAPK1, IL-8, IL-10, CCL2 and MAPK3. In vitro experiment showed that quercetin and geniposide could inhibit the inflammatory response of HET-1A cells through p38MAPK/NF-κB signaling pathway, which was consistent with the prediction by the network pharmacology approach. CONCLUSIONS: Geniposide and quercetin could be effective therapeutic ingredients for the HGD against RE. They play anti-inflammatory effects via down-regulating the pro-inflammatory cytokines and the conduction of p38MAPK/NF-κB signal. This research provides a comprehensive study on the active components, potential targets, and molecular mechanisms of HGD against RE. Moreover, the study supplies a feasible approach to reveal the mechanisms of TCM formula.

The effects of Wuhan highway lockdown measures on the spread of COVID-19 in China.

To verify the effects of Wuhan highway lockdown measures on the spread of COVID-19 across China cities, we extracted the vehicle outflow from Wuhan to 245 cities from the Chinese highway toll system. A dynamic exponential risk model that considered the vehicle outflow, city gross domestic product, city population, and distance between two cities was established to characterize the spread of pandemics and quantify the blocking effects. Results showed that an early highway lockdown measure could indeed reduce the confirmed cases and vehicles with 1-9 seats played a leading role. The confirmed cases in Guangxi, Henan, and Shanxi could be reduced by more than 50%, as well as Hubei by 20% if the highway was closed 3 days in advance. The blocking effects on Fujian, Jiangxi, Guangdong, Hunan, and Shandong were not obvious, where the number of confirmed cases only decreased by a small proportion (below 10%). The findings could be used to help each provincial government to adjust policies properly and improve the effectiveness of epidemic control and prevention. Moreover, the proposed method could also be applied to various countries or regions affected by COVID-19, as well as other similar pandemics.

MicroRNA-889-3p restrains the proliferation and epithelial-mesenchymal transformation of lung cancer cells via down-regulation of Homeodomain-interacting protein kinase 1.

Dysregulated microRNAs (miRNAs) are common in human cancers and are involved in the proliferation, promotion, and metastasis of tumor cells. Therefore, the aim of this study was to evaluate the expression and biological function of miR-889-3p in lung cancer (LC). MiR-889-3p and Homeodomain-interacting protein kinase 1 (HIPK1) expression was detected in human LC tissues and cells. The correlation of miR-889-3p with the clinicopathology of LC patients was observed. After the transfection of miR-889-3p and HIPK1-related plasmids in human LC cell line A549, several studies were employed for detection of cell growth. In addition, the targeting of miR-889-3p with HIPK1 was verified. The results clarified miR-889-3p was down-regulated, while HIPK1 was up-regulated in LC tissues. Elevated miR-889-3p or repressed HIPK1 weakened the viability, epithelial-mesenchymal transition (EMT), invasion, migration of LC cells, whereas strengthened apoptosis. MiR-889-3p targeted HIPK1; MiR-889-3p mediated HIPK1 to affect the proliferation and EMT of LC cells. Therefore, it is concluded that miR-889-3p repressing HIPK1 restrains the proliferation and EMT of LC cells, providing a novel target for LC therapy.

Recent strategies for nano-based PTT combined with immunotherapy: from a biomaterial point of view.

Cancer has been a great threat to humans for decades. Due to the limitations of monotherapy, combinational therapies such as photothermal therapy (PTT) and immunotherapy have gained increasing attention with expectation to overcome the shortfalls of each other and obtain satisfactory therapeutic outcomes. PTT can inhibit primary tumors by thermal ablation but usually fails to achieve complete eradication and cannot prevent metastasis and recurrence. Meanwhile, the efficacy of immunotherapy is usually attenuated by the weak immunogenicity of tumor and the immunosuppressive tumor microenvironment (ITM). Therefore, many recent studies have attempted to synergize PTT with immunotherapy in order to enhance the therapeutic efficacy. In this review, we aim to summarize the cutting-edge strategies in combining nano-based PTT with immunotherapy for cancer treatment. Herein, the combination strategies were mainly classified into four categories, including 1) nano-based PTT combined with antigens to induce host immune responses; 2) nano-based PTT in combination with immune adjuvants acting as in situ vaccines; 3) nano-based PTT synergized with immune checkpoint blockade or other regulators to relieve the ITM; 4) nano-based PTT combined with CAR-T therapy or cytokine therapy for tumor treatment. The characteristics of various photothermal agents and nanoplatforms as well as the immunological mechanisms for the synergism were also introduced in detail. Finally, we discussed the existing challenges and future prospects in combined PTT and immunotherapy.

Epidemiology and microbiology of Gram-negative bloodstream infections in a tertiary-care hospital in Beijing, China: a 9-year retrospective study.

Background: Gram-negative bacterial bloodstream infections (BSIs) are associated with high morbidity and mortality. The present study examines the incidence, clinical characteristics, microbiological features, drug resistance and mortality associated with Gram-negative bacterial BSIs at a tertiary-care hospital in Beijing, China.Methods: This retrospective cohort study of patients with Gram-negative bacterial BSIs was performed between 1 January 2010 and 31 December 2018 at the Chinese People,s Liberation Army General Hospital.Results: A total of 6867 episodes of Gram-negative bacterial BSIs occurred among 3199 patients over 9 years. The overall incidence of Gram-negative bacterial BSIs fluctuated from 2.30 to 2.55 episodes per 1000 admissions over 9 years. Escherichia coli was the major pathogen (34.3%). The antibiotic resistance of ESBLs-producing E. coli was higher than non-ESBLs producing E. coli including the majority of antibiotics, but to carbapenems (0.7% VS 5.1%). Between 2010 and 2018, the overall mortality of Gram-negative bacterial BSIs decreased from 11.41% to 9.05% (X2 = 6.95, P = 0.434).Conclusions: Cephalosporins and carbapenem antibiotics were considered as the optimal treatment for patients with Gram-negative bacterial BSIs except for A. baumannii, which was treated according to the drug sensitivity or multidrug combination.