Network Pharmacology with Experimental Investigation of the Mechanisms of Rhizoma Polygonati against Prostate Cancer with Additional Herbzymatic Activity.

A combination therapy of Rhizoma Polygonati (RP) with goji (Lycium chinense) has earned a long history in the prescriptions to promote male health. However, the mechanisms at both molecular and nanoscale quantum levels are unclear. Here, we found that processed RP extract induces apoptosis and cell cycle arrest in cancer cells, thereby inhibiting prostate cancer cell proliferation enhanced by processed goji extract associated with an augment of the nanoscale herbzyme of phosphatase. For network pharmacology analysis, RP-induced PI3K-AKT pathways are essential for both benign prostatic hyperplasia and prostate cancer, and the RP/goji combination induces potent pathways which include androgen and estrogen response, kinase regulation, apoptosis, and prostate cancer singling. In addition, the experimental investigation showed that the prostate cancer cells are sensitive to RP extract for inhibiting colony formation. Finally, the natural compound baicalein found in RP ingredients showed a linked activity of top-ranked signaling targets of kinases including MAPK, AKT, and EGFR by the database of cMAP and HERB. Thus, both the nanozyme and ingredients might contribute to the RP in anti-prostate cancer which can be enhanced by goji extract. The proposed nanoscale RP extract might be of significance in developing novel anti-prostate cancer agents by combining goji compositions and targeted therapy compounds.

Macrophage Polarization in Cardiac Tissue Repair Following Myocardial Infarction.

Cardiovascular disease is the leading cause of mortality and morbidity around the globe, creating a substantial socio-economic burden as a result. Myocardial infarction is a significant contributor to the detrimental impact of cardiovascular disease. The death of cardiomyocytes following myocardial infarction causes an immune response which leads to further destruction of tissue, and subsequently, results in the formation of non-contractile scar tissue. Macrophages have been recognized as important regulators and participants of inflammation and fibrosis following myocardial infarction. Macrophages are generally classified into two distinct groups, namely, classically activated, or M1 macrophages, and alternatively activated, or M2 macrophages. The phenotypic profile of cardiac macrophages, however, is much more diverse and should not be reduced to these two subsets. In this review, we describe the phenotypes and functions of macrophages which are present in the healthy, as well as the infarcted heart, and analyze them with respect to M1 and M2 polarization states. Furthermore, we discuss therapeutic strategies which utilize macrophage polarization towards an anti-inflammatory or reparative phenotype for the treatment of myocardial infarction.

Generation of particle assemblies mimicking enzymatic activity by processing of herbal food: the case of rhizoma polygonati and other natural ingredients in traditional Chinese medicine.

Processed herbs have been widely used in eastern and western medicine; however, the mechanism of their medicinal effects has not yet been revealed. It is commonly believed that a central role is played by chemically active molecules produced by the herbs' metabolism. In this work, processed rhizoma polygonati (RP) and other herbal foods are shown to exhibit intrinsic phosphatase-like (PL) activity bounded with the formation of nano-size flower-shaped assembly. Via quantum mechanical calculations, an enzymatic mechanism is proposed. The enzymatic activity may be induced by the interaction between the sugar molecules distributed on the surface of the nanoassemblies and the phosphatase substrate via either a hydroxyl group or the deprotonated hydroxyl group. Meanwhile, the investigation was further extended by processing some fresh herbs and herbal food through a similar protocol, wherein other enzymatic activities (such as protease, and amylase) were observed. The PL activity exhibited by the processed natural herbs was found to be able to effectively inhibit cancer cell growth via phosphatase signaling, possibly by crosstalk with kinase signaling or DNA damage by either directly binding or unwinding of DNA, as evidenced by high-resolution atomic-force microscopy (HR-AFM). In this work, the neologism herbzyme (herb + enzyme) is proposed. This study represents the first case of scientific literature introducing this new term. Besides the well-known pharmacological properties of the natural molecules contained in herbs and herbal food, there exists an enzymatic/co-enzymatic activity attributed to the nanosized assemblies.

Preconditioned and Genetically Modified Stem Cells for Myocardial Infarction Treatment.

Ischemic heart disease and myocardial infarction remain leading causes of mortality worldwide. Existing myocardial infarction treatments are incapable of fully repairing and regenerating the infarcted myocardium. Stem cell transplantation therapy has demonstrated promising results in improving heart function following myocardial infarction. However, poor cell survival and low engraftment at the harsh and hostile environment at the site of infarction limit the regeneration potential of stem cells. Preconditioning with various physical and chemical factors, as well as genetic modification and cellular reprogramming, are strategies that could potentially optimize stem cell transplantation therapy for clinical application. In this review, we discuss the most up-to-date findings related to utilizing preconditioned stem cells for myocardial infarction treatment, focusing mainly on preconditioning with hypoxia, growth factors, drugs, and biological agents. Furthermore, genetic manipulations on stem cells, such as the overexpression of specific proteins, regulation of microRNAs, and cellular reprogramming to improve their efficiency in myocardial infarction treatment, are discussed as well.

Biomaterials Loaded with Growth Factors/Cytokines and Stem Cells for Cardiac Tissue Regeneration.

Myocardial infarction causes cardiac tissue damage and the release of damage-associated molecular patterns leads to activation of the immune system, production of inflammatory mediators, and migration of various cells to the site of infarction. This complex response further aggravates tissue damage by generating oxidative stress, but it eventually heals the infarction site with the formation of fibrotic tissue and left ventricle remodeling. However, the limited self-renewal capability of cardiomyocytes cannot support sufficient cardiac tissue regeneration after extensive myocardial injury, thus, leading to an irreversible decline in heart function. Approaches to improve cardiac tissue regeneration include transplantation of stem cells and delivery of inflammation modulatory and wound healing factors. Nevertheless, the harsh environment at the site of infarction, which consists of, but is not limited to, oxidative stress, hypoxia, and deficiency of nutrients, is detrimental to stem cell survival and the bioactivity of the delivered factors. The use of biomaterials represents a unique and innovative approach for protecting the loaded factors from degradation, decreasing side effects by reducing the used dosage, and increasing the retention and survival rate of the loaded cells. Biomaterials with loaded stem cells and immunomodulating and tissue-regenerating factors can be used to ameliorate inflammation, improve angiogenesis, reduce fibrosis, and generate functional cardiac tissue. In this review, we discuss recent findings in the utilization of biomaterials to enhance cytokine/growth factor and stem cell therapy for cardiac tissue regeneration in small animals with myocardial infarction.

Recent Advances in the Controlled Release of Growth Factors and Cytokines for Improving Cutaneous Wound Healing.

Bioengineered materials are widely utilized due to their biocompatibility and degradability, as well as their moisturizing and antibacterial properties. One field of their application in medicine is to treat wounds by promoting tissue regeneration and improving wound healing. In addition to creating a physical and chemical barrier against primary infection, the mechanical stability of the porous structure of biomaterials provides an extracellular matrix (ECM)-like niche for cells. Growth factors (GFs) and cytokines, which are secreted by the cells, are essential parts of the complex process of tissue regeneration and wound healing. There are several clinically approved GFs for topical administration and direct injections. However, the limited time of bioactivity at the wound site often requires repeated drug administration that increases cost and may cause adverse side effects. The tissue regeneration promoting factors incorporated into the materials have significantly enhanced wound healing in comparison to bolus drug treatment. Biomaterials protect the cargos from protease degradation and provide sustainable drug delivery for an extended period of time. This prolonged drug bioactivity lowered the dosage, eliminated the need for repeated administration, and decreased the potential of undesirable side effects. In the following mini-review, recent advances in the field of single and combinatorial delivery of GFs and cytokines for treating cutaneous wound healing will be discussed.

Sequential Delivery of Cryogel Released Growth Factors and Cytokines Accelerates Wound Healing and Improves Tissue Regeneration.

Growth factors and cytokines that are secreted by cells play a crucial role in the complex physiological reaction to tissue injury. The ability to spatially and temporally control their actions to maximize regenerative benefits and minimize side effects will help accelerate wound healing and improve tissue regeneration. In this study, the sequential targeted delivery of growth factor/cytokine combinations with regulatory functions on inflammation and tissue regeneration was examined using an internal splint wound healing model. Four examined growth factors and cytokines were effectively incorporated into a novel chitosan-based cryogel, which offered a controlled and sustained release of all factors while maintaining their biological activities. The cryogels incorporated with inflammation modulatory factors (IL-10 and TGF-ß) and with wound healing factors (VEGF and FGF) were placed on the wound surface on day 0 and day 3, respectively, after wound initiation. Although wound area gradually decreased in all groups over time, the area in the cryogel group with growth factor/cytokine combinations was significantly reduced starting on day 7 and reached about 10% on day 10, as compared to 60-65% in the control groups. Sequential delivery of inflammation modulatory and wound healing factors enhanced granulation tissue formation, as well as functional neovascularization, leading to regenerative epithelialization. Collectively, the chitosan-based cryogel can serve as a controlled release system for sequential delivery of several growth factors and cytokines to accelerate tissue repair and regeneration.

Date Pit Carbon Dots Induce Acidic Inhibition of Peroxidase and Disrupt DNA Repair in Antibacteria Resistance.

Carbon nanodots (C-dots) are emerging as a new type of promising agent in anticancer, imaging, and new energy. Reports as well as the previous research indicate that certain C-dots can enhance targeted cancer therapy. However, in-depth mechanisms for such anticancer effect remain unclear. In this work, treatment provided by the date pit-derived C-dots, exhibits significant DNA damage; Annexin V/7-AAD-mediated apoptosis, and G2/M cell cycle arrest in prostate cancer cells. The application of C-dots to the cell generally leads to acidulation of the cell medium, cooperated with membrane compact. The date pit-derived C-dots are observed inhibiting the horseradish peroxidase. Moreover, the C-dots disrupt likely through nucleotide excision DNA repair at low dose during DNA ligation step suggesting the antimicrobial effect and targeting Pim-1, EGFR, mTOR, and DNA damage pathways in cancer cells. For the first time the detailed and novel mechanisms underlying the C-dots, derived from the date-pit, as an efficient, low-cost, and green nanomaterial are reveled for cancer therapy and anti-infection.

Systematic analysis of NLMP suggests nuclear localization of RTK/MET kinases resemble cancer cell clearance.

BACKGROUND: Some membrane proteins can translocate into the nucleus, defined as nuclear localized membrane proteins (NLMPs), including receptor tyrosine kinases (RTKs). We previously showed that nuclear MET (nMET), a member of RTKs, mediates cancer stem-like cells self-renewal to promote cancer recurrence. However, it is unknown that nMET or mMET, which is the ancestor in the evolution of cancer cell survival and clearance. Here, we aim to study the NLMP functions in cell death, differentiation and survival. METHOD: We applied the systematic reanalysis of functional NLMP and clinical investigations of nMET from databases. In addition, we used soft agar assay, immunoblotting, flow cytometry, and immunofluorescence confocal microscopy for examinations of nMET functions including stem-like cell formation, cell signaling, cell cycle regulation, and co-localization with regulators of cell signaling. ShRNA, antibody of recognizing surface membrane MET based treatment were used to downregulate endogenous nMET to uncover its function. RESULTS: We predicted and demonstrated that nMET and nEGFR are most likely not ancestors. nMET overexpression induces both cell death and survival with drug resistance and stem cell-like characters. Moreover, the paradoxical function of nMET in both cell death and cell survival is explained by the fact that nMET induces stem cell-like cell growth, DNA damage repair, to evade the drug sensitization for survival of single cells while non-stem cell-like nMET expressing single cells may undergo clearance by cell death through cell cycle arrest induced by p21. CONCLUSION: Taken together, our data suggest a link between nuclear RTK and cancer cell evolutionary clearance via cell death, and drug resistance for survival through stemness selection. Targeting evolved nuclear RTKs in cancer stem cells would be a novel avenue for precision cancer therapy.

Nuclear MET requires ARF and is inhibited by carbon nanodots through binding to phospho-tyrosine in prostate cancer.

Nuclear receptor tyrosine kinases (nRTKs) are aberrantly upregulated in many types of cancers, but the regulation of nRTK remains unclear. We previously showed androgen deprivation therapy (ADT) induces nMET in castration-resistant prostate cancer (CRPC) specimens. Through gene expression microarray profiles reanalysis, we identified that nMET signaling requires ARF for CRPC growth in Pten/Trp53 conditional knockout mouse model. Accordingly, aberrant MET/nMET elevation correlates with ARF in human prostate cancer (PCa) specimens. Mechanistically, ARF elevates nMET through binding to MET cytoplasmic domain to stabilize MET. Furthermore, carbon nanodots resensitize cancer cells to MET inhibitors through DNA damage response. The inhibition of phosphorylation by carbon nanodots was identified through binding to phosphate group of phospho-tyrosine via computational calculation and experimental assay. Thus, nMET is essential to precision therapy of MET inhibitor. Our findings reveal for the first time that targeting nMET axis by carbon nanodots can be a novel avenue for overcoming drug resistance in cancers especially prostate cancer.

Dysregulation of YAP by ARF Stimulated with Tea-derived Carbon Nanodots.

YAP is a downstream nuclear transcription factor of Hippo pathway which plays an essential role in development, cell growth, organ size and homeostasis. It was previously identified that elevation of YAP in genomics of genetic engineered mouse (GEM) model of prostate cancer is associated with Pten/Trp53 inactivation and ARF elevation hypothesizing the essential crosstalk of AKT/mTOR/YAP with ARF in prostate cancer. However, the detailed function and trafficking of YAP in cancer cells remains unclear. Using GEM microarray model, we found ARF dysregulates Hippo and Wnt pathways. In particular, ARF knockdown reduced non-nuclear localization of YAP which led to an increase in F-actin. Mechanistically, ARF knockdown suppressed protein turnover of ß-catenin/YAP, and therefore enhanced the activity of AKT and phosphorylation of YAP. Moreover, we found tea-derived carbon dots can interact with ARF in nucleus that may further lead to the non-nuclear localization of YAP. Thus, we reported a novel crosstalk of ARF/ß-catenin dysregulated YAP in Hippo pathway and a new approach to stimulate ARF-mediated signaling to inhibit nuclear YAP using nanomaterials implicating an innovative avenue for treatment of cancer.