Activating caspase-8/Bid/ROS signaling to promote apoptosis of breast cancer cells by folate-modified albumin baicalin-loaded nanoparticles.

Abnormal apoptosis can lead to uncontrolled cell growth, aberrant homeostasis or the accumulation of mutations. Therapeutic agents that re-establish the normal functions of apoptotic signaling pathways offer an attractive strategy for the treatment of breast cancer. Baicalin (BA) is one of the natural compounds with anti-proliferation and pro-apoptosis activities against numerous tumor cells. However, low bioavailability restricts the clinical application of BA. In order to improve its therapeutic efficacy and study the mechanism of actions, active targeting delivery systems were developed for targeting tumor environment and selective cell killing effects. It emphasized on the construction of folate-conjugated albumin nanoparticles loaded with baicalin (FA-BSANPs/BA) and mechanisms of which on the promotion of breast cancer apoptosis. The physicochemical properties and structural characteristics of FA-BSANPs/BA were investigated. Cell experiments were carried out to study the targeted anti-breast cancer effects of FA-BSANPs/BA and its mechanism. The results showed that FA-BSANPs/BA was successfully constructed with stable structural characteristics and sustained release effects. Cellular uptake and MTT showed that it increased targeted uptake efficiency and cytotoxicity. Flow cytometry and western blot confirmed that it promoted apoptosis by increasing the expression of caspase-8 and ROS, and decreasing the level of Bid. It is suggested that the pro-apoptotic mechanism of FA-BSANPs/BA is related to regulation of key proteins in extrinsic apoptotic pathway. In conclusion, FA-BSANPs/BA is a good delivery carrier and significantly inhibits the breast cancer growth compared with free BA. The mechanism of FA-BSANPs/BA promoting apoptosis of breast cancer may be due to its action on the caspase-8/Bid/ROS pathway.

Role of inflammatory microenvironment: potential implications for improved breast cancer nano-targeted therapy.

Tumor cells, inflammatory cells and chemical factors work together to mediate complex signaling networks, which forms inflammatory tumor microenvironment (TME). The development of breast cancer is closely related to the functional activities of TME. This review introduces the origins of cancer-related chronic inflammation and the main constituents of inflammatory microenvironment. Inflammatory microenvironment plays an important role in breast cancer growth, metastasis, drug resistance and angiogenesis through multifactorial mechanisms. It is suggested that inflammatory microenvironment contributes to providing possible mechanisms of drug action and modes of drug transport for anti-cancer treatment. Nano-drug delivery system (NDDS) becomes a popular topic for optimizing the design of tumor targeting drugs. It is seen that with the development of therapeutic approaches, NDDS can be used to achieve drug-targeted delivery well across the biological barriers and into cells, resulting in superior bioavailability, drug dose reduction as well as off-target side effect elimination. This paper focuses on the review of modulation mechanisms of inflammatory microenvironment and combination with nano-targeted therapeutic strategies, providing a comprehensive basis for further research on breast cancer prevention and control.

Key Factor Regulating Inflammatory Microenvironment, Metastasis, and Resistance in Breast Cancer: Interleukin-1 Signaling.

Breast cancer is one of the top-ranked cancers for incidence and mortality worldwide. The biggest challenges in breast cancer treatment are metastasis and drug resistance, for which work on molecular evaluation, mechanism studies, and screening of therapeutic targets is ongoing. Factors that lead to inflammatory infiltration and immune system suppression in the tumor microenvironment are potential therapeutic targets. Interleukin-1 is known as a proinflammatory and immunostimulatory cytokine, which plays important roles in inflammatory diseases. Recent studies have shown that interleukin-1 cytokines drive the formation and maintenance of an inflammatory/immunosuppressive microenvironment through complex intercellular signal crosstalk and tight intracellular signal transduction, which were found to be potentially involved in the mechanism of metastasis and drug resistance of breast cancer. Some preclinical and clinical treatments or interventions to block the interleukin-1/interleukin-1 receptor system and its up- and downstream signaling cascades have also been proven effective. This study provides an overview of IL-1-mediated signal communication in breast cancer and discusses the potential of IL-1 as a therapeutic target especially for metastatic breast cancer and combination therapy and current problems, aiming at enlightening new ideas in the study of inflammatory cytokines and immune networks in the tumor microenvironment.

Design and development of spirulina polysaccharide-loaded nanoemulsions with improved the antitumor effects of paclitaxel.

Aims: In this study, we prepared spirulina polysaccharides into spirulina polysaccharide-loaded nanoemulsions (SPS-NEs), and determined the antitumor effect of SPS-NEs, when combined with paclitaxel (PTX).Methods: SPS-NEs were prepared by a phase transformation method. The Characterisation and stability of SPS-NEs was measured. The antitumor effect of SPS-NEs combined with PTX was determined by S180 cells or RAW 264.7 macrophages and S180 tumour-bearing mice.Results: SPS-NEs were spherical and stable, the particle size of SPS-NEs was 84.6 ± 3.31 nm, PDI = 0.235 ± 0.02. PTX + SPS-NEs exhibited a much greater toxicity against RAW 264.7 cells than PTX. PTX + SPS-NEs increased the release of NO, IL-6 and TNF-α, and the expression of p-p65 NF-κB, p-I-κB, TLR4. In addition, PTX + SPS-NEs significantly inhibited tumour growth by 72.82% and increased the secretion of serum IL-2, TNF-α and IFN-γ.Conclusions: SPS-NEs can regulate immunity through TLR4/NF-κB signalling pathways, which enhances the anti-tumour effect of PTX.

Vitamin K1 Inhibition of Renal Crystal Formation through Matrix Gla Protein in the Kidney.

BACKGROUND AND OBJECTIVES: Vitamin K (VK) plays a major role in modifying the binding of calcium in bones and blood vessels. Understanding the effect of VK on crystal formation in the kidney would contribute to advancing the treatment and prevention of kidney stones. METHODS: Rats were treated with vitamin K1 (VK1) for 8 weeks. VK1 levels were detected and crystal formation were observed. HK2 cells were exposed to calcium oxalate monohydrate crystals. Apoptosis and cell viability were detected. Crystal deposition was analyzed using atomic absorption assay. The adenovirus vectors expressing matrix Gla protein (MGP) and siMGP were constructed to elucidate the effect and mechanism of VK1 on crystal formation. MGP expression in vivo and in vitro was analyzed by Western blot. The mRNA levels of monocyte chemoattractant protein-1 (MCP-1) and collagen I was measured by semiquantitative RT-PCR. RESULTS: The concentrations of VK1 in whole blood and kidney tissues rose under treatment with VK1. Crystal formation was inhibited from the second to the 6th week, the frequency and quality of crystal formation decreased significantly, and the location of crystal formation was limited to a greater extent in the rats treated by VK1 compared to the control group. Warfarin treatment in the crystals-exposed HK2 cells significantly increased the number of crystals adhering to cells and the number of apoptotic cells and reduced cell viability. VK1 treatment reversed warfarin's above influence. VK1 inhibited the upregulations of MCP-1 and collagen I in kidney tissues under crystal load. VK1 treatment increased MGP expression in vivo and in vitro, and MGP is necessary for VK1 to play a role in crystal deposition in cells. CONCLUSIONS: VK1 treatment can inhibit the formation of renal crystals in vivo. VK1 increases MGP expression and functions through MGP to reduce crystal deposition in cells and provide cell protection. Our findings suggest that VK1 treatment could be a potential strategy for the treatment and prevention of nephrolithiasis.

Research Advances in the Intervention of Inflammation and Cancer by Active Ingredients of Traditional Chinese Medicine.

A large body of evidence has shown that inflammation and cancer are strongly related. Thus anti-inflammatory agents have been investigated for cancer prevention and treatment in preclinical and clinical studies, including the nonsteroidal anti-inflammatory drugs (NSAIDs) and traditional Chinese medicine (TCM). In TCM, there exist a wide range of biologically active substances, such as saponins, flavonoids, alkaloids, polysaccharides, polyphenols, phenylpropanoids, and quinones. Many of these active ingredients have been reported to inhibit inflammation, activate inflammatory immune response, and/or inhibit cancer cell proliferation and tumor growth. Given the potential role of inflammation in cancer initiation and progression, the inflammatory tumor microenvironment, the cross-talks between inflammatory and cancer cells, and multitargeting activities of some TCM compounds, we summarize the current knowledge on the anti-inflammatory and anti-cancer properties of ingredients of TCM together with their underlying mechanisms in an integrated way. We hope to provide a reliable basis and useful information for the development of new treatment strategies of inflammation and cancer comprehensively using TCM and their active ingredients.

Wnt pathway in osteosarcoma, from oncogenic to therapeutic.

Osteosarcoma is the most common malignant bone tumor in children and adolescents. Although pathologic characteristics of this disease are clear and well established, much remains to be understood about this tumor, particularly at the molecular signaling level. Secreted signaling molecules of the Wnt family have been widely investigated and found to play a central role in controlling embryonic bone development, bone mass, and postnatal bone regeneration. A variety of studies also suggest that Wnt signaling pathway is closely associated with bone malignancies, including breast or prostate cancer induced bone metastasis, multiple myeloma, as well as osteosarcoma. Here, we provide an overview of the role of Wnt signaling pathway in osteosarcoma development and progression, highlighting the aberrant activation of Wnt pathway in this bone malignancy. We also discuss the potential therapeutic applications for the treatment of osteosarcoma targeting Wnt pathway.

Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple-negative breast cancer.

The conventional therapeutic treatment of triple-negative breast cancer (TNBC) is negatively influenced by the development of tumor cell drug resistant, and systemic toxicity of therapeutic agents due to off-target activity. In accordance with research findings, nanoparticles (NPs) responsive to the tumor microenvironment (TME) have been discovered for providing opportunities to selectively target tumor cells via active targeting or Enhanced Permeability and Retention (EPR) effect. The combination of the TME control and therapeutic NPs offers promising solutions for improving the prognosis of the TNBC because the TME actively participates in tumor growth, metastasis, and drug resistance. The NP-based systems leverage stimulus-responsive mechanisms, such as low pH value, hypoxic, excessive secretion enzyme, concentration of glutathione (GSH)/reactive oxygen species (ROS), and high concentration of Adenosine triphosphate (ATP) to combat TNBC progression. Concurrently, NP-based stimulus-responsive introduces a novel approach for drug dosage design, administration, and modification of the pharmacokinetics of conventional chemotherapy and immunotherapy drugs. This review provides a comprehensive examination of the strengths, limitations, applications, perspectives, and future expectations of both novel and traditional stimulus-responsive NP-based drug delivery systems for improving outcomes in the medical practice of TNBC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

EGCG attenuates the neurotoxicity of methylglyoxal via regulating MAPK and the downstream signaling pathways and inhibiting advanced glycation end products formation.

Methylglyoxal (MGO), a reactive α-oxoaldehyde formed in many foods and beverages during processing and storage, has neurotoxicity. The purpose of this study was to investigate the inhibition mechanism of (-)-epigallocatechin-3-gallate (EGCG) on MGO-induced PC12 cells damage. Cell apoptosis and reactive oxygen species (ROS) level were measured with fluorescent staining methods. Western blotting was used to detect the signal transduction mechanism. The results indicated that EGCG decreased ROS level, inhibited apoptosis and increased the expression of brain-derived neurotrophic factor. Pathways analysis revealed that the neuroprotective mechanism of EGCG might rely on regulating mitogen-activated protein kinase (MAPK) and downstream pathways. Multi-spectroscopy and molecular docking indicated that EGCG inhibited MGO-derived advanced glycation end products (AGEs) formation. Moreover, the neurotoxicity of AGEs could be alleviated by EGCG. These results suggested that EGCG could attenuate MGO-induced nerve damage via regulating MAPK and downstream pathways and inhibiting AGEs formation.

cis-Ampelopsin E, a stilbene isolated from the seeds of Paeonia suffruticosa, inhibits lipopolysaccharide-stimulated nitric oxide production in RAW 264.7 macrophages via blockade of nuclear factor-kappa B signaling pathway.

Stilbenes are a class of compounds that has been reported to inhibit a variety of pathological processes during inflammatory reactions. In this study, cis-ampelopsin E, a stilbene isolated from the seeds of Paeonia suffruticosa, was shown to dose-dependently reduce the nitric oxide (NO) production from lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. The reduction in the nitric oxide release occurred in parallel with the comparable inhibition of inducible nitric oxide synthase (iNOS) enzyme expression, which was achieved by cis-ampelopsin E's suppressive effect on nuclear factor-kappa B (NF-κB) signaling activation. By inhibiting LPS-induced inhibitor kinase (IKKα/ß) phosphorylation, cis-ampelopsin E significantly decreased LPS-induced IκBα phosphorylation, prevented IκBα degradation, and subsequently reduced the translocating of transcription factor p65 into the nucleus. As a result, the LPS-induced upregulation of NF-κB transcriptional activity was efficiently inhibited. Moreover, it is revealed that cis-ampelopsin E inhibited LPS-induced cyclooxygenase-2 (Cox-2) expression, cPLA2 activation and prostaglandin E2 (PGE2) production. These results, taken together, suggested that cis-ampelopsin E might exert potential anti-inflammatory effects via blockage of the NF-κB signaling pathway.

Triterpenes from the fungus Poria cocos and their inhibitory activity on nitric oxide production in mouse macrophages via blockade of activating protein-1 pathway.

Two new triterpenes, 29-hydroxydehydrotumulosic acid (1) and 29-hydroxydehydropachymic acid (2), together with six known compounds, dehydropachymic acid (3), dehydrotumulosic acid (4), 29-hydroxypolyporenic acid C (5), polyporenic acid C (6), tumulosic acid (7), and pachymic acid (8), were isolated from the dried sclerotia of Poria cocos. In the in vitro bioassays, these isolated compounds reduced, in a dose-dependent manner, nitric oxide (NO) production from lipopolysaccharide (LPS)-induced RAW 264.7 cells, with compounds 5 and 6, the IC(50) values of which were 16.8±2.7 and 18.2±3.3 µM, respectively, exhibiting the greatest inhibition activity. Further Western blot analysis conducted on cells pre-treated with compounds 5 and 6, and luciferase assays on activator protein 1-dependent gene expression revealed that the inhibited NO release was attributed to the reduced expression of iNOs (=inducible NO synthase) enzymes, which might be regulated via the blockade of activator protein-1 signaling pathway.

Strategies for Preparing Different Types of Lipid Polymer Hybrid Nanoparticles in Targeted Tumor Therapy.

At present, cancer is one of the most common diseases in the world, causing a large number of deaths and seriously affecting people's health. The traditional treatment of cancer is mainly surgery, radiotherapy or chemotherapy. Conventional chemotherapy is still an important treatment, but it has some shortcomings, such as poor cell selectivity, serious side effects, drug resistance and so on. Nanoparticle administration can improve drug stability, reduce toxicity, prolong drug release time, prolong system half-life, and bring broad prospects for tumor therapy. Lipid polymer hybrid nanoparticles (LPNs), which combine the advantages of polymer core and phospholipid shell to form a single platform, have become multi-functional drug delivery platforms. This review introduces the basic characteristics, structure and preparation methods of LPNs, and discusses targeting strategies of LPNs in tumor therapy in order to overcome the defects of traditional drug therapy.

Psoralen-loaded polymeric lipid nanoparticles combined with paclitaxel for the treatment of triple-negative breast cancer.

Background: Chemotherapeutic drugs are associated with toxic effects. Metastasis is the leading cause of death in breast cancer patients. Aim: To evaluate the antitumor effect of paclitaxel (PTX) combined with psoralen-loaded polymeric lipid nanoparticles (PSO-PLNs) in triple-negative breast cancer. Methods: After treatment of samples, cell viability, apoptosis, migration, invasion, expression of proteins in the IRAK1/NF-κB/FAK signal pathway, biodistribution and pathological characteristics were detected. Results: Compared with the control group, the PTX + PSO-PLNs group showed increased apoptosis and reduced migration, invasion and expression of phosphorylated IRAK1 and NF-κB, with significant inhibition of tumor growth and lung metastases and no obvious toxicity. Conclusion: Combined administration of PTX and PSO-PLNs exerted a synergistic effect and significantly inhibited the growth and metastasis of triple-negative breast cancer.

Polymeric Lipid Hybrid Nanoparticles as a Delivery System Enhance the Antitumor Effect of Emodin in Vitro and in Vivo.

This study aimed to evaluate the therapeutic efficacy of Emodin-loaded polymer lipid hybrid nanoparticles (E-PLNs) for breast cancer. The size, Zeta potential, surface morphology, encapsulation efficiency, stability, in vitro drug release of E-PLNs prepared by the nanoprecipitation method were characterized. The uptake, in-vitro cytotoxicities and apoptosis of free drug, E-PLNs were investigated against MCF-7 cells. The efficacy of E-PLNs in tumor bearing nude mice has also been studied.The average particle size of the experimentally prepared E-PLNs was (122.7±1.79) nm, and the encapsulation rate was 72.8%. Compared with free Emodin (EMO), E-PLNs showed greater toxicity to MCF-7 cells by promoting the uptake of EMO, and can promote the early apoptosis of MCF-7 cells. In addition to the morphological changes of apoptotic cells, the ratio of Bax/Bcl-2 was significantly increased, which indicated that E-PLNs can induce apoptosis in MCF-7 cells to achieve anticancer effect. Finally, E-PLNs significantly inhibited tumor growth by more than 60%, which may be related to its passive targeting effect on tumor site. Our results suggest that E-PLNs have shown good anti-breast cancer effect than free EMO. Moreover, the effect of E-PLNs on MCF-7 cells is mainly related to the induction of apoptosis.

A review of nanoparticle drug delivery systems responsive to endogenous breast cancer microenvironment.

Breast cancer, as a malignant disease that seriously threatens women's health, urgently needs to be researched to develop effective and safe therapeutic drugs. Nanoparticle drug delivery systems (NDDS), provide a powerful means for drug targeting to the breast cancer, enhancing the bioavailability and reducing the adverse effects of anticancer drug. However, the breast cancer microenvironment together with heterogeneity of cancer, impedes the tumor targeting effect of NDDS. Breast cancer microenvironment, exerts endogenous stimuli, such as hypoxia, acidosis, and aberrant protease expression, shape a natural shelter for tumor growth, invasion and migration. On the basis of the ubiquitous of endogenous stimuli in the breast cancer microenvironment, researchers exploited them to design the stimuli-responsive NDDS, which response to endogenous stimulus, targeted release drug in breast cancer microenvironment. In this review, we highlighted the effect of the breast cancer microenvironment, summarized innovative NDDS responsive to the internal stimuli in the tumor microenvironment, including the material, the targeting groups, the loading drugs, targeting position and the function of stimuli-responsive nanoparticle drug delivery system. The limitations and potential applications of the stimuli-responsive nanoparticle drug delivery systems for breast cancer treatment were discussed to further the application.

Screening of metabolites in the treatment of liver cancer xenografts HepG2/ADR by psoralen-loaded lipid nanoparticles.

OBJECTIVE: Our study aimed to find potential biomarkers for drug resistance in liver cancer cells using metabolomics and further to evaluate the potential of psoralen-loaded polymer lipid nanoparticles (PSO-PLNs) to reverse the resistance of cells to doxorubicin. METHODS: We used LC-MS-based non-targeted metabolomics, also known as global metabolite profiling, to screen in serum and urine of mice engrafted with a liver cancer cell line sensitive (HepG2/S) or resistant to doxorubicin (HepG2/ADR) for differentially regulated metabolites. We subsequently quantified the abundance of these metabolites in serum and the urine of mice. The mice were engrafted with HepG2 cells resistant against doxorubicin and were treated with I) doxorubicin, II) a combination of doxorubicin and psoralen and III) a combination of doxorubicin and psoralen packed in polymer lipid nanoparticles. RESULTS: Metabolites found to be differentially present in urine of mice engrafted with resistant HepG2 cells were: hippuric acid, hyaluronic acid, pantothenic acid, and betaine; retinoic acid and α-linolenic acid were found to be reduced in serum samples of mice with HepG2 cells resistant to doxorubicin. The targeted analysis showed that the degree of regression of metabolic markers in groups differed: treatment group 2 had stronger degree of regression than treatment group 1 and the negative control group had the smallest, which indicates that the PSO-PLNs have superior properties compared with other treatments. CONCLUSION: Psoralen reverses drug resistance of liver cancer cells and its efficacy can be increased by encapsulation in polymer lipid nanoparticles.

Two new aristolochic acid derivatives from the roots of Aristolochia fangchi and their cytotoxicities.

Phytochemical investigation of 90% ethanol extracts of the roots of Aristolochia fangchi yielded two new aristolochic acid derivatives named Aristolochic Acid F and Aristolochic Acid G, together with three known compounds. Their structures were elucidated by spectral analysis. The cytotoxicity of the isolated compounds was also determined.

Effects of immune cells and cytokines on inflammation and immunosuppression in the tumor microenvironment.

Chronic inflammation and immune responses are two core element that characterize the tumor microenvironment. A large number of immune/inflammatory cells (including tumor associated macrophages, neutrophils and myeloid derived suppressor cells) as well as cytokines (such as IL-6, IL-10, TGF-ß) are present in the tumor microenvironment, which results in both a chronic inflammatory state and immunosuppression. As a consequence tumor cell migration, invasion, metastasis and anticancer drug sensitivity are modulated. On the one hand, secreted cytokines change the function of cytotoxic T lymphocytes and antigen presenting cells, thereby inhibiting tumor specific immune responses and consequently inducing a special immunosuppressive microenvironment for tumor cells. On the other hand, tumor cells change the differentiation and function of immune/inflammatory cells in the tumor microenvironment especially via the NF-κB and STAT3 signaling pathways. This may promote proliferation of tumor cells. Here we review these double edged effects of immune/inflammatory cells and cytokines on tumor cells, and explored their interactions with inflammation, hypoxia, and immune responses in the tumor microenvironment. The tumor inflammatory or immunosuppressive reactions mediated by the high activity of NF-κB or STAT3 can occur alone or simultaneously, and there is a certain connection between them. Inhibiting the NF-κB or STAT3 signaling pathway is likely to curb the growth of tumor cells, reduce the secretion of pro-inflammatory factors, and enhance the anti-tumor immune response.

Chemokines and chemokine receptors: A new strategy for breast cancer therapy.

Chemokines and chemokine receptors not only participate in the development of tissue differentiation, hematopoiesis, inflammation, and immune regulation but also play an important role in the process of tumor development. The role of chemokines and chemokine receptors in tumors has been emphasized in recent years. More and more studies have shown that chemokines and chemokine receptors are closely related to the occurrence, angiogenesis, metastasis, drug resistance, and immunity of breast cancer. Here, we review recent progression on the roles of chemokines and chemokine receptors in breast cancer, and discuss the possible mechanism in breast cancer that might facilitate the development of new therapies by targeting chemokines as well as chemokine receptors. Chemokines and chemokine receptors play an important role in the occurrence and development of breast cancer. In-depth study of chemokines and chemokine receptors can provide intervention targets for breast cancer biotherapy. The regulation of chemokines and chemokine receptors may become a new strategy for breast cancer therapy.

Polymeric-based microneedle arrays as potential platforms in the development of drugs delivery systems.

BACKGROUND: Microscopic patches as quite promising platforms in transdermal drug delivery suffer from conventional injections. In other hand, a wide range of pharmacokinetics, ranging from fast oral administration to sustained drug delivery, can be implemented with the help of microneedle arrays (MNAs). AIM OF REVIEW: Hence, in this paper, we overviewed different kinds of MNAs such as solid/coated, hollow, porous, hydrogel/swellable, and merged-tip geometry followed by introducing different types of material (silicon, glass, ceramics, dissolving and biodegradable polymers, and hydrogel) used for fabrication of MNAs. Afterwards, some conventional and brand-new simple and customizable MN mold fabrication techniques were surveyed. Polymeric MNAs have received a great deal of attention due to their potential biocompatibility and biodegradability in comparison to other materials. Therefore, we also covered different kinds of polymers such as hydrogel/swellable, dissolving and biodegradable analogues used for the development of MNAs as potential candidates in drug delivery systems (DDSs). Finally, we discussed different challenges and future perspectives in the aspect of MNAs-based drug delivery platforms. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review may provide guidelines for the rational design of polymeric MNAs-based DDSs for promising programmable drug release and enhanced therapeutic effect.