Active Ingredients from Chinese Medicine for Combination Cancer Therapy.

Combination therapy against cancer has gained increasing attention because it can help to target multiple pathways to tackle oncologic progression and improve the limited antitumor effect of single-agent therapy. Chinese medicine has been studied extensively in cancer therapy and proven to be efficacious in many cases due to its wide spectrum of anticancer activities. In this review, we aim to summarize the recent progress of active ingredients from Chinese medicine (AIFCM) in combination with various cancer therapeutic modalities, including chemotherapy, gene therapy, radiotherapy, phototherapy and immunotherapy. In addition to highlighting the potential contribution of AIFCM in combination cancer therapy, we also elucidate the underlying mechanisms behind their synergistic effect and improved anticancer efficacy, thereby encouraging the inclusion of these AIFCM as part of effective armamentarium in fighting intractable cancers. Finally, we present the challenges and future perspectives of AIFCM combination therapy as a feasible and promising strategy for the optimization of cancer treatment and better clinical outcomes.

In Situ Transformable Nanoplatforms with Supramolecular Cross-Linking Triggered Complementary Function for Enhanced Cancer Photodynamic Therapy.

In vivo cross-linking of nanoparticles is widely used to increase accumulation of therapeutic agents at tumor site for enhanced therapy. However, the components in nanoplatforms usually only play for one role and are independent of each other, unable to amplify their biofunctions. Herein, a complementary functioning tumor microenvironment triggered, supramolecular coordination-induced nanoparticle cross-linking strategy is constructed for enhanced photodynamic therapy. Manganese oxide (MnOx ) and polyhydroxy photosensitizer hypericin (Hyp) are coated and loaded onto lanthanide-doped upconversion nanoparticles (UCNPs) to form transformable UCNP@MnOx -Hyp. In CT26 mouse colon cancer cells and xenograft tumors, UCNP@MnOx -Hyp is reduced by glutathione and H2 O2 , releasing Mn2+ and Hyp for in situ cross-linking to transform to UCNP@Mn2+ -Hyp. Compared to the simple photosensitizer-loaded UCNP@PEI-Hyp, the Mn2+ -Hyp coordination redshifts absorbance of Hyp and improves the energy transfer efficiency from UCNPs to Hyp (5.6-fold). In turn, the supramolecular coordination-induced UCNPs cross-linking exhibits enhanced luminescence recovery and increased intracellular accumulation of both UCNPs and Hyp, thus enhancing the photodynamic therapy efficacy both at cellular level (2.1-fold) and in vivo, realizing the function amplification of each component after responsive transformation and offering a new avenue for enhanced cancer therapy.

Comprehensive comparison on the anti-inflammation and GC-MS-based metabolomics discrimination between Bupleuri chinense DC. and B. scorzonerifolium Willd.

Bupleuri Radix (BR) is a traditional Chinese medicine and widely used for cold and fever, influenza, inflammation, hepatitis and menstrual diseases. Two authentic medicinal plants of Bupleuri chinense DC. (Beichaihu, BCH) and B. scorzonerifolium Willd. (Nanchiahu, NCH) are recommended by the current Chinese Pharmacopoeia for BR. In the present study, the comparative investigations on the anti-inflammatory effects and gas chromatography-mass spectrometry (GC-MS)-based metabolomics for the species discrimination of BCH and NCH were conducted and reported. The in vitro evaluations indicated that the supercritical fluid extracts (SFEs) (IC50 of 6.39 ± 0.52 and 1.32 ± 0.05 mg (herb)/mL for BCH and NCH) were determined to be more potent than those of the hydro-distillation extracts (HDEs) (IC50 of 203.90 ± 8.08 and 32.32 ± 2.27 mg (herb)/mL for BCH and NCH) against LPS-induced inflammation in RAW264.7 macrophages. The higher anti-inflammatory effects of NCH were associated to its different chemical compositions to the BCH as characterized by the GC-MS analysis. Furthermore, based on the metabolomics and deep chemometric approaches, a minimum combination containing 15 chemical markers was optimized from the identified components and successfully applied for the species discrimination of BCH and NCH. This study not only helps to comparative understand BCH and NCH both in phytochemistry and pharmacology, but also provides the potential chemical markers for improvement of methods for the quality control of BCH and NCH.

Confined Construction of Ultrasmall Molybdenum Disulfide-Loaded Porous Silica Particles for Efficient Tumor Therapy.

Recently, molybdenum sulfide (MoS2) has shown great application potential in tumor treatment because of its good photothermal properties. Unfortunately, most of the current molybdenum disulfide-based nanotherapeutic agents suffer from complex preparation processes, low photothermal conversion efficiencies, and poor structural/compositional regulation. To address these issues, in this paper, a facile "confined solvothermal" method is proposed to construct an MoS2-loaded porous silica nanosystem (designated as MoS2@P-hSiO2). The maximum photothermal efficiency of 79.5% of molybdenum-based materials reported in the literature at present was obtained due to the ultrasmall MoS2 nanoclusters and the rich porous channels. Furthermore, both in vitro and in vivo experiments showed that the cascade hybrid system (MoS2/GOD@P-hSiO2) after efficient loading of glucose oxidase (GOD) displayed a significant tumor-suppressive effect and good biosafety through the combined effects of photothermal and enzyme-mediated cascade catalytic therapy. Consequently, this hybrid porous network system combining the in situ solvothermal strategy of inorganic functional components and the efficient encapsulation of organic enzyme macromolecules can provide a new pathway to construct synergistic agents for the efficient and safe treatment of tumors.

NIR-responsive polydopamine-based calcium carbonate hybrid nanoparticles delivering artesunate for cancer chemo-photothermal therapy.

Artesunate (AS), the first-line treatment of malaria with a satisfactory safety profile, has been repurposed as a potential anticancer candidate as it mainly generates reactive oxygen species (ROS) through its intrinsic endoperoxide bridge reacting with ferrous-based catalysts to suppress cancer cell growth. However, further clinical translation of AS is hindered by the attenuated anticancer efficacy due to insufficient ROS generation. Herein, we rationally integrated hydrophobic-modified AS (hAS) with biomimetic polydopamine (PDA) and biomineral calcium carbonate to fabricate high AS-loaded nanomedicine (Ca-PDA/hAS@PEG) for cancer chemo-photothermal therapy, which exerted anticancer effects in the following ways: (1) the heat was generated when PDA was irradiated by near-infrared (NIR) light for photothermal therapy. Meanwhile, the increased temperature accelerated the production of ROS from hAS, thus enhancing the anticancer efficacy of hAS-based chemotherapy; (2) hAS-mediated chemotherapy boosted the cancer inhibition effect of photothermal therapy by arousing the intracellular ROS levels in the presence of endogenous ferrous ions and sensitizing cancer cells to thermal ablation; (3) the integration of calcium carbonate into the nanoparticle facilitated the pH-responsive drug release for precise treatment. Such hybrid nanoparticles exhibited a combinational antitumor effect of photothermal therapy and chemotherapy in vivo with no systemic toxicity. Taken together, our work presents a facile strategy to improve the anticancer efficacy of AS by combining chemical modification and photothermal therapy-assisted endoperoxide bridge cleavage, which may offer opportunities to pave the way for clinical translation of AS-based nanomedicines. STATEMENT OF SIGNIFICANCE: The clinical translation of artesunate (AS) is hindered by the attenuated anticancer efficacy due to insufficient ROS generation. Herein, we rationally integrated hydrophobic-modified AS (hAS) with biomimetic polydopamine (PDA) and biomineral calcium carbonate to fabricate high AS-loaded nanomedicine (Ca-PDA/hAS@PEG) for improved cancer chemo-photothermal therapy. The heat generated from PDA in response to near-infrared light irradiation could locally ablate tumor as well as accelerate the production of ROS by hAS, thus enhancing the anticancer efficacy of hAS-based chemotherapy. On the other hand, hAS-based chemotherapy amplified the intracellular oxidative stress, sensitizing cancer cells to thermal ablation. Our work presents a facile strategy to improve the anticancer efficacy of AS by combining chemical modification and photothermal therapy-assisted endoperoxide bridge cleavage.

Dual Drug Loaded pH-sensitive Micelles for Efficient Bacterial Infection Treatment.

PURPOSE: Methicillin-resistant Staphylococcus aureus (MRSA) infection at impaired wound is associated with high risks of developing to persistent bacterial infections since bacterial biofilm is easy to form in MRSA infected wounds. An advanced therapeutic approach to effectively penetrate and eliminate bacterial biofilm and to accelerate cell proliferation and migration at the wound is crucial. METHODS: The poly(ε-caprolactone)-monomethoxyl poly (ethylene glycol) (PCL-mPEG) micelles loaded with Quercetin and Rifampicin (QRMs) were prepared. Bacterial biofilm proliferation and elimination effect of QRMs were evaluated with confocal laser scanning microscopy. Antibacterial assay was further performed to detect antibacterial activity and mechanism. The cell scratch assay and cellular uptake were performed in HaCaT skin epithelial cells. RESULTS: Our results showed that the small sized QRMs could penetrate the interior of MRSA biofilm to disperse and eradicate biofilm. Then, antibiotics are released and accumulated in the acidic biofilm environment. QRMs could kill bacteria through increasing bacterial membrane permeability and altering membrane potential and membrane fluidity. Moreover, QRMs improved intracellular and cytoplasmic delivery efficiency of drugs to epithelial cells, and in the scratch test, presented a stronger ability to promote migration and proliferation of HaCaT cells compared with free drugs. Hemolysis test further proved good biocompatibility of QRMs. CONCLUSIONS: QRMs could potentially be used as a novel dual-functional nanotherapeutic for anti-bacterial infection by eradicating biofilm and accelerating cells proliferation at MRSA infected wound.

A light-driven dual-nanotransformer with deep tumor penetration for efficient chemo-immunotherapy.

Designing a transformable nanosystem with improved tumor accumulation and penetration by tuning multiple physicochemical properties remains a challenge. Here, a near-infrared (NIR) light-driven nanosystem with size and charge dual-transformation for deep tumor penetration is developed. Methods: The core-shell nanotransformer is realized by integrating diselenide-bridged mesoporous organosilica nanoparticles as a reactive oxygen species (ROS)-responsive core with an indocyanine green (ICG)-hybrid N-isopropyl acrylamide layer as a thermosensitive shell. After loading doxorubicin (DOX), negatively charged nanomedicine prevents DOX leakage, rendering prolonged blood circulation time and high tumor accumulation. Results: Upon NIR light irradiation, mild photothermal effects facilitate the dissociation of the thermosensitive shell to achieve negative-to-positive charge reversal. Meanwhile, ICG-generated ROS cleave the diselenide bond of the organosilica core, resulting in rapid matrix degradation that produces DOX-containing smaller fragments. Such a light-driven dual-transformable nanomedicine simultaneously promotes deep tumor penetration and implements sufficient chemotherapy, along with evoking robust immunogenic cell death effects in vitro and in vivo. With the combination of a programmed cell death protein-1 (PD-1) checkpoint blockade, the nanotransformer remarkably blocks primary tumor growth and pulmonary metastasis of breast cancer with low systemic toxicity. Conclusions: This study develops a promising strategy to realize high tumor accumulation and deep penetration of light-transformable nanomedicine for efficient and safe chemo-immunotherapy.

Glytabastan B, a coumestan isolated from Glycine tabacina, alleviated synovial inflammation, osteoclastogenesis and collagen-induced arthritis through inhibiting MAPK and PI3K/AKT pathways.

The roots of Glycine tabacina are used to treat rheumatoid arthritis (RA) and joint infection in folk medicine. Glytabastan B (GlyB), a newly reported coumestan isolated from this species, was found to significantly attenuate IL-1ß-induced inflammation in SW982 human synovial cells at 3 and 6 µM, as evidenced by the decreased levels of pro-inflammatory mediators and matrix metalloproteinases (MMPs). GlyB also suppressed RANKL-induced osteoclastogenesis, decreased the expression of osteoclastogenic markers (NFATc1, CTSK, MMP-9) and osteoclast-mediated bone resorption. Further, GlyB administration (12.5 and 25 mg/kg) significantly inhibited inflammation, osteoclast formation and disease progression in collagen-induced arthritis (CIA) mice. Integration of network pharmacology, quantitative phosphoproteomic and experimental pharmacology results revealed that these beneficial actions were closely associated with the blockade of GlyB on the activation of MAPK, PI3K/AKT and their downstream signals including NF-κB and GSK3ß/NFATc1. Drug affinity responsive target stability (DARTS) assay, cellular thermal shift (CETSA) assay and molecular docking analysis confirmed that there were direct interactions between GlyB and its target proteins ERK2, JNK1 and class Ⅰ PI3K catalytic subunit p110 (α, ß, δ and γ), which significantly contributed to the inhibition of activation of MAPK and PI3K/AKT pathways. In conclusion, these results strongly suggest GlyB is a promising multiple-target candidate for the development of agents for the prevention and treatment of RA.

Surfactant-stripped J-aggregates of azaBODIPY derivatives: All-in-one phototheranostics in the second near infrared window.

Development of multifacted phototheranostics with bright fluorescence and absorbance in the second near infrared (NIR-II) window is very appealing for precise cancer diagnosis and treatment, but still challenging nowadays. Herein, we synthesize a hydrophobic annularly fused azaBODIPY (termed as HBP) molecule with sharp NIR absorbance peaked at 878 nm and bright NIR-II fluorescence. With Pluronic F127 as the surfactant and hydrophobic paclitaxel (PTX) as the spacer, such HBP molecule would self-assemble to form surfactant-stripped HBP/PTX micelles with absorption peak red-shifted to 1012 nm and intrinsic NIR-II fluorescence negligibly disturbed. We found that such HBP/PTX micelles can be utilized as a bimodal NIR-II nano-probe to enable real-time tracking of lymph nodes and tumors under an NIR-II fluorescence imaging system, as well as clear visualization of tumor microvasculatures under an NIR-II photoacoustic imaging system. Furthermore, together with 1064 nm laser exposure, such HBP/PTX micelles would synergistically suppress the growth of tumors grown on the mice upon tumor accumulation. This work highlights the concise preparation of a type of all-in-one NIR-II phototheranostics from the newly synthesized HBP molecules, thereby enables NIR-II fluorescence/photoacoustic bimodal imaging guided synergistic cancer treatment via the NIR-II laser boosted photothermal therapy and chemotherapy.

Polysaccharide PRM3 from Rhynchosia minima root enhances immune function through TLR4-NF-κB pathway.

BACKGROUND: Polysaccharides, one of the active ingredients in herbal medicine, are proved to enhance innate immunity against infections. The aim of this study is to explore the immunoregulatory ability of polysaccharides from Rhynchosia minima root in vitro and in vivo. METHODS: Polysaccharide fractions of R. minima root were obtained by chromatographic column. The content of NO was measured by spectrophotometry. The levels of cytokines (tumor necrosis factor-α, TNF-α; interleukin-6, IL-6; and monocyte chemoattractant protein-1, MCP-1) were determined by enzyme-linked immuno-sorbent assay (ELISA) kits. The translocation of p65 into the nucleus was imaged by confocal microscopy. The mRNA expression of TNF-α, IL-6, and MCP-1 was determined by quantitative real-time PCR. T-lymphocyte subgroups of spleen from immunosuppressive mouse were evaluated by flow cytometry. RESULTS: PRM3 remarkably enhanced the phagocytic ability of macrophages and promoted the release of NO and the secretion of cytokines (TNF-α, IL-6, and MCP-1) from macrophages. Simultaneously, PRM3 potently activated NF-κB signaling pathway via Toll-like receptor 4 (TLR4). In addition, PRM3 obviously increased the levels of serum cytokines, markedly up-regulated the percentages of CD3+ and CD4+ T lymphocytes and the CD4+/CD8+ ratio of splenocytes, and effectively attenuated cyclophosphamide induced immunosuppression in mice. CONCLUSIONS: PRM3 profoundly enhanced the immune function in vitro and in vivo through TLR4-NF-κB pathway and is a promising candidate of immunopotentiator which could be applied in functional foods or drugs. GENERAL SIGNIFICANCE: This study reported a polysaccharide PRM3 from R. minima root exhibited potent immunoenhancing activity and significantly alleviated cyclophosphamide-induced immunosuppression through TLR4-NF-κB pathway.

Gold nanocage decorated pH-sensitive micelle for highly effective photothermo-chemotherapy and photoacoustic imaging.

A pH-sensitive copolymer PAsp(DIP)-b-PAsp(MEA) (PDPM) was synthesized and self-assembled to micelle loading chemotherapeutic drug doxorubicin (DOX) and introducing a gold nanocage structure for photothermo-chemotherapy and photoacoustic imaging. After further surface modification with polyethylene glycol (PEG), the DOX-loaded pH-sensitive gold nanocage (D-PGNC) around 100 nm possessed a uniform spherical structure with a pH-sensitive core of PAsp(DIP) incorporating DOX, an interlayer crosslinked via disulfide bonds and decorated with discontinuous gold shell, and a PEG corona. The release of DOX from D-PGNC was turned off in bloodstream due to the cross-linking and gold decoration of interlayer but turned on inside tumor tissue by multiple stimulations including the low pH value of tumor tissue (≈6.8), the low lysosomal pH value of cancer cells (≈5.0) and near-infrared (NIR) irradiation. The gold nanocage receiving NIR irradiation could generate hyperthermia to ablate tumor cells. Moreover, the photoacoustic (PA) imaging and analysis of DOX fluorescence inside tumor tissue demonstrated that photothermal therapy based on the gold nanocage effectively drove DOX penetration inside tumor. Owing to the rapid intratumor release and deep tissue penetration of drug favorable for killing cancer cells survived the photothermal therapy, the combined therapy based on D-PGNC via NIR irradiation exhibited a synergistic treatment effect superior to either chemotherapy or NIR-induced photothermal therapy alone. STATEMENT OF SIGNIFICANCE: The novelty of the manuscript is its multifunctional system which incorporates anticancer drug DOX in its pH-sensitive core and acts as a template to introduce a gold nanocage. This nanomedicine presents potentials of sequestrating drug molecules in blood circulation but releasing them inside tumor upon responding to the acidic microenvironment therein. Exposure to NIR laser further expedited the pH-sensitive DOX release and promoted DOX penetration into cancer tissues far away from the vasculature. Consequently, the combined photothermo-chemotherapy showed synergistic effects to inhibit tumor growth and prolong animal survival in nude mice bearing human SKOV-3 ovarian tumor. Moreover, owing to the decoration with gold nanocage, the tumor accumulation and intratumor diffusion of the micelles were easily trackable using photoacoustic imaging.

Differences in Chemical Component and Anticancer Activity of Green and Ripe Forsythiae Fructus.

Forsythiae Fructus, Lianqiao in Chinese, is one of the most fundamental herbs in Traditional Chinese Medicine. Both green Forsythia (GF) and ripe Forsythia (RF) are referred to Forsythiae Fructus in medicinal applications. In most cases, they are used without distinction. In this study, a metabolomics approach was performed to compare componential differences of two Forsythiae Fructus aqueous extracts subtypes. Principal component analysis (PCA) score plots from the UPLC-MS data showed clear separation between the two subtypes, indicating there are significant differences in the chemical components between GF and RF. Meanwhile, the anticancer activity of them was also compared. GF exhibited much stronger antitumor activity than RF against B16-F10 murine melanoma both in vitro and in vivo. 15 chemical compounds were identified as specific markers for distinguishing GF and RF. Among these marker compounds, forsythoside I, forsythoside A, forsythoside E and pinoresinol were demonstrated to be key important active compounds that account for the different anticancer efficacies of GF and RF. Our data suggest that GF and RF should be distinctively used in clinical applications, particularly in the anticancer formulas, in which GF should be preferentially prescribed.

Anticancer Properties and Pharmaceutical Applications of Plumbagin: A Review.

It has been shown that plumbagin, a bioactive naphthoquinone isolated from three major plant families viz. Plumbaginaceae, Ebenceae and Droseraceae, definitively exhibits anticancer potential in diverse cancer cells both in vitro and in vivo. Plumbagin shows antineoplastic effects via multi-channel molecular mechanisms, including the induction of apoptosis and autophagy, the disruption of the cell cycle, the inhibition of invasion and metastasis, and anti-angiogenesis. Plumbagin inhibits the growth of cancer cells mainly through the modulation of the signals of PI3K/Akt/mTOR, AMPK, Ras, and so on. The pharmaceutical applications of plumbagin combined with nanocarriers to achieve better therapeutic efficiency are discussed in this review Among them, liposomes, nanoparticles, microspheres, micelles, and nisosomes are used in cancer treatment. The anticancer study of plumbagin in vivo is also summarized in this review. On the whole, we aim to review the research progress of plumbagin both in pharmacological and pharmaceutical filed, which may provide some reference for further research of plumbagin.

Near-infrared light activation of quenched liposomal Ce6 for synergistic cancer phototherapy with effective skin protection.

Current photodynamic therapy (PDT) is suffering from limited efficacy towards hypoxia tumors and severe post-treatment photo-toxicity such as light-induced skin damages. To make PDT more effective in cancer treatment while being patient-comfortable, herein, a hexylamine conjugated chlorin e6 (hCe6) as the photosensitizer together with a lipophilic near-infrared (NIR) dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) are co-encapsulated into polyethylene glycol (PEG) shelled liposomes. In the obtained DiR-hCe6-liposome, the photosensitizing effect of hCe6 is quenched by DiR via fluorescence resonance energy transfer (FRET). Interestingly, upon irradiation with a 785-nm NIR laser to photobleach DiR, both fluorescence and photodynamic effect of hCe6 in DiR-hCe6-liposome would be activated. Meanwhile, such NIR irradiation applied on tumors of mice with intravenous injection of DiR-hCe6-liposome could result in mild photothermal heating, which in turn would promote intra-tumor blood flow and relieve tumor hypoxia, contributing to the enhanced photodynamic tumor treatment. Importantly, compared to hCe6-loaded liposomes, DiR-hCe6-liposome without being activated by the 785-nm laser shows much lower skin photo-toxicity, demonstrating its great skin protection effect. This work demonstrates a promising yet simple strategy to prepare NIR-light-activatable photodynamic theranostics for synergistic cancer phototherapy, which is featured high specificity/efficacy in tumor treatment with minimal photo-toxicity towards the skin.

Hormetic effect of panaxatriol saponins confers neuroprotection in PC12 cells and zebrafish through PI3K/AKT/mTOR and AMPK/SIRT1/FOXO3 pathways.

Hormesis is an adaptive response of living organisms to a moderate stress. However, its biomedical implication and molecular mechanisms remain to be intensively investigated. Panaxatriol saponins (PTS) is the major bioactive components extracted from Panax notoginseng, a widely used herbal medicine for cerebrovascular diseases. This study aims to examine the hormetic and neuroprotective effects of PTS in PC12 cells and zebrafish Parkinson's disease (PD) models. Our results demonstrated that PTS stimulated PC12 cell growth by about 30% at low doses, while PTS at high doses inhibited cell growth, which is a typical hormetic effect. Moreover, we found that low dose PTS pretreatment significantly attenuated 6-OHDA-induced cytotoxicity and up-regulated PI3K/AKT/mTOR cell proliferation pathway and AMPK/SIRT1/FOXO3 cell survival pathway in PC12 cells. These results strongly suggested that neuroprotective effects of PTS may be attributable to the hormetic effect induced by PTS through activating adaptive response-related signaling pathways. Notably, low dose PTS could significantly prevent the 6-OHDA-induced dopaminergic neuron loss and improve the behavior movement deficiency in zebrafish, whereas relative high dose PTS exhibited neural toxicity, further supporting the hormetic and neuroprotective effects of PTS. This study indicates that PTS may have the potential in the development of future therapeutic medicines for PD.

Recent Advances in Anticancer Activities and Drug Delivery Systems of Tannins.

Tannins, polyphenols in medicinal plants, have been divided into two groups of hydrolysable and condensed tannins, including gallotannins, ellagitannins, and (-)-epigallocatechin-3-gallate (EGCG). Potent anticancer activities have been observed in tannins (especially EGCG) with multiple mechanisms, such as apoptosis, cell cycle arrest, and inhibition of invasion and metastases. Furthermore, the combinational effects of tannins and anticancer drugs have been demonstrated in this review, including chemoprotective, chemosensitive, and antagonizing effects accompanying with anticancer effect. However, the applications of tannins have been hindered due to their poor liposolubility, low bioavailability, off-taste, and shorter half-life time in human body, such as EGCG, gallic acid, and ellagic acid. To tackle these obstacles, novel drug delivery systems have been employed to deliver tannins with the aim of improving their applications, such as gelatin nanoparticles, micelles, nanogold, liposomes, and so on. In this review, the chemical characteristics, anticancer properties, and drug delivery systems of tannins were discussed with an attempt to provide a systemic reference to promote the development of tannins as anticancer agents.

Anti-melanoma activity of Forsythiae Fructus aqueous extract in mice involves regulation of glycerophospholipid metabolisms by UPLC/Q-TOF MS-based metabolomics study.

Metabolomics is a comprehensive assessment of endogenous metabolites of a biological system in a holistic context. In this study, we evaluated the in vivo anti-melanoma activity of aqueous extract of Forsythiae Fructus (FAE) and globally explored the serum metabolome characteristics of B16-F10 melanoma-bearing mice. UPLC/Q-TOF MS combined with pattern recognition approaches were employed to examine the comprehensive metabolic signatures and differentiating metabolites. The results demonstrated that FAE exhibited remarkable antitumor activity against B16-F10 melanoma in C57BL/6 mice and restored the disturbed metabolic profile by tumor insult. We identified 17 metabolites which were correlated with the antitumor effect of FAE. Most of these metabolites are involved in glycerophospholipid metabolisms. Notably, several lysophosphatidylcholines (LysoPCs) significantly decreased in tumor model group, while FAE treatment restored the changes of these phospholipids to about normal condition. Moreover, we found that lysophosphatidylcholine acyltransferase 1 (LPCAT1) and autotaxin (ATX) were highly expressed in melanoma, and FAE markedly down-regulated their expression. These findings indicated that modulation of glycerophospholipid metabolisms may play a pivotal role in the growth of melanoma and the antitumor activity of FAE. Besides, our results suggested that serum LysoPCs could be potential biomarkers for the diagnosis and prognosis of melanoma and other malignant tumors.

Endogenous n-3 Fatty Acids Alleviate Carbon-Tetrachloride-Induced Acute Liver Injury in Fat-1 Transgenic Mice.

n-3 polyunsaturated fatty acids (PUFAs) are beneficial for numerous models of liver diseases. The probable protective effects of n-3 PUFA against carbon-tetrachloride- (CCl4-) induced acute liver injury were evaluated in a fat-1 transgenic mouse that synthesizes endogenous n-3 from n-6 PUFA. Fat-1 mice and their WT littermates were fed a modified AIN93 diet containing 10% corn oil and were injected intraperitoneally with a single dose of CCl4 or vehicle. CCl4 challenge caused severe liver injury in WT mice, as indicated by serum parameters and histopathological changes, which were remarkably ameliorated in fat-1 mice. Endogenous n-3 PUFA decreased the elevation of oxidative stress induced by CCl4 challenge, which might be attributed to the activation of Nrf2/keap1 pathway. Additionally, endogenous n-3 PUFA reduces hepatocyte apoptosis via suppressing MAPK pathway. These findings indicate that n-3 PUFA has potent protective effects against acute liver injury induced by CCl4 in mice, suggesting that n-3 PUFA can be used for the prevention and treatment of liver injury.

Gold-Nanorods-Based Gene Carriers with the Capability of Photoacoustic Imaging and Photothermal Therapy.

Multifunctional nanoparticles with high gene transfection activity, low cytotoxicity, photoacoustic imaging ability, and photothermal therapeutic properties were prepared by conjugating low-molecular-weight polyethylenimine onto the surfaces of gold nanorods through the formation of stable S-Au bonded conjugates. Results revealed that the gene transfection efficiency of the prepared polyethylenimine-modified gold nanorods (GNRs-PEI1.8k) was higher and their cytotoxicity was less than those of the commercial reagent PEI25k. GNRs-PEI1.8k could also be potentially used as a photoacoustic and photothermal reagent to evaluate the pharmacokinetics, biodistribution, and antitumor effects of gene/drug nanoparticles. Therefore, GNRs-PEI1.8k can be considered a promising candidate for the clinical diagnosis and treatment of tumors.

Forsythiae Fructus Inhibits B16 Melanoma Growth Involving MAPKs/Nrf2/HO-1 Mediated Anti-Oxidation and Anti-Inflammation.

Forsythiae Fructus, the fruits of Forsythia suspensa (Thunb.) Vahl, Lianqiao in Chinese, is one of the most fundamental herbs in traditional Chinese medicine (TCM). It is a typical heat-clearing and detoxicating herb, according to TCM theory. In this study, we investigated the antitumor effect of Forsythiae Fructus aqueous extract (FAE) on B16-F10 melanoma cells in vivo. The transplanted B16-F10 melanoma in C57BL/6 mice was established and used for the evaluation of the in vivo antitumor effect of FAE. FAE strongly inhibited the growth of B16-F10 cells in vitro and the tumor in vivo. The survival time of tumor-bearing mice was significantly prolonged by FAE. FAE inhibited cancer cell proliferation and angiogenesis in the tumor, as indicated by the decreased expressions of Ki67 and CD31. The levels of ROS, MDA, TNF-[Formula: see text] and IL-6 decreased, while GSH increased in the FAE treatment group, indicating FAE possesses strong anti-oxidative and anti-inflammatory activity. The expression of anti-oxidant proteins Nrf-2 and HO-1, tumor suppressors P53 and p-PTEN, and the MAPK pathways in tumor tissues were upregulated by FAE treatment. These data demonstrated that FAE exhibited strong antitumor activity against B16-F10 murine melanoma both in vitro and in vivo. The antitumor effect of FAE involved decreases in oxidative stress and inflammation in the tumor, which is closely related to the heat-clearing and detoxicating properties of FAE.