Tumor microenvironment-activated theranostic nanozymes for trimodal imaging-guided combined therapy.

Synergistic therapy is expected to be a promising strategy for highly effective cancer treatment. However, the rational design of a simple and multifunctional nanoplatform still remains a grand challenge. Considering the nature of weak acidic, hypoxic, and H2O2 abundant tumor microenvironment, we constructed an indocyanine green (ICG) modified platinum nanoclusters (Pt NCs) decorated gold nanobipyramids (Au NBPs) to form the multifunctional nanocomposites (Au NBPs@Pt NCs-ICG) for multimodal imaging mediated phototherapy and chemodynamic cancer therapy. The photosensitizer ICG was covalently linked to Au NBPs@Pt NCs by bridging molecules of SH-PEG-NH2 for both photodynamic therapy (PDT) and fluorescence imaging. Besides, Au NBPs@Pt NCs-ICG nanocomposites exhibited catalase- and peroxidase-like activities to generate O2 and ·OH, which relieved the tumor hypoxia and upregulated antitumoral ROS level. Moreover, the combination of Au NBPs and ICG endowed the Au NBPs@Pt NCs-ICG with super photothermal conversion for effective photothermal imaging and therapy. In addition, the Au NBPs@Pt NCs-ICG nanoplatform displayed excellent X-ray computed tomography (CT) imaging ability due to the presence of high-Z elements (Au and Pt). Overall, our results demonstrated that Au NBPs@Pt NCs-ICG nanoplatform exhibited a multimodal imaging guided synergistic PTT/PDT/CDT therapeutic manners and held great potential as an efficient treatment for breast cancer.

A meta-analysis of the Zilongjin tablets for non-small cell lung cancer and its network pharmacology of action against NSCLC and COVID-19.

Objective: To objectively evaluate the efficacy of the Zilongjin tablets in non-small cell lung cancer (NSCLC) and to explore its potential mechanism of action against NSCLC and COVID-19 based on network pharmacology. Methods: The database was searched for randomized controlled trials (RCTs) of the Zilongjin tablets for NSCLC published up to 22 August 2022. The quality of included trials was assessed using Cochrane standard guidelines, and a meta-analysis was performed using Rev Man 5.3. Gene targets for intersections of NSCLC and COVID-19 (the NC) and drugs were obtained from the TCMSP database, HERB database, GeneCards database, and the NCBI database for network pharmacology research. Results: Meta-analysis included 14 articles with 2,430 patients. The meta-analysis showed that the Zilongjin tablets combined with conventional chemotherapy were significantly more effective than chemotherapy alone in the treatment of NSCLC. A total of 29 drug-disease intersecting targets were identified in the network pharmacology. The "ingredient-target-pathway" diagram component-target-pathway network contained 119 nodes and 429 edges, with the majority of targets associated with inflammatory responses. Conclusion: The efficacy and quality of life of the Zilongjin tablets combined conventional chemotherapy for NSCLC were significantly better than chemotherapy alone, alleviating various adverse effects. At the same time, the Zilongjin tablets may modulate the inflammatory response to alleviate NSCLC and COVID-19.

Biocompatible Mesoporous Silica-Polydopamine Nanocomplexes as MR/Fluorescence Imaging Agent for Light-Activated Photothermal-Photodynamic Cancer Therapy In Vivo.

Conventional cancer phototherapy with single modality suffers from low therapeutic efficacy and undesired posttreatment damage for adjacent normal tissues. Therefore, the lower NIR laser irradiation power is vital to the reduction or preclusion of risk of scalds and burns in normal tissues. Herein, we rationally proposed a novel multifunctional nanocomplex, which enabled good magnetic resonance (MR) imaging contrast effect and promising photothermal conversion efficacy. The prepared core/shell nanocomplexes [MSN-Ce6@PDA (Mn)] were composed of chlorin e6-embedded mesoporous silica/nanoparticle composites as the cores, and then polydopamine and manganese ions were conjugated on the cores to form protective shells. The MSN-Ce6@PDA (Mn) nanocomplexes revealed superior properties in colloidal stability, photothermal conversion, reaction oxygen species generation, magnetic resonance imaging, etc. Under the guidance of MR and fluorescence imaging, these MSN-Ce6@PDA (Mn) nanocomplexes were found to be primarily accumulated in the MDA-MB-231 tumor area. Furthermore, the combined photodynamic and photothermal therapy exhibited strong inhibition to the growth of MDA-MB-231 tumor in vitro and in vivo. Besides, the MSN-Ce6@PDA (Mn) nanocomplexes also exhibited excellent biocompatibility and low damage to the healthy animals. Hence, the results demonstrated that the prepared MSN-Ce6@PDA (Mn) nanocomplex would be a promising potential for multimodal imaging-guided phototherapy.

Preparation of doxorubicin-loaded porous iron Oxide@ polydopamine nanocomposites for MR imaging and synergistic photothermal-chemotherapy of cancer.

Recently, the development of biosafe nanocomposites with integrated diagnosis and therapeutic modality is received great attention in anti-cancer drug delivery. In this sturdy, we developed a multifunctional PION@PDA-PEG nanocomposite that combines the functions of magnetic resonance (MR) imaging, photothermal therapy (PTT) and chemotherapy into one single nanoprobe. The spherical and uniform-sized porous iron oxide nanoparticles (PION) were synthesized via a simple solvothermal method. Subsequently, a near-infrared light (NIR) sensitive polydopamine (PDA) shell was directly coated on the surface of PIONs to form monodisperse and biosafe core-shell nanocomposites, Thereafter, the surface of nanocomposites was further modified with polyethylene glycol (PEG) to prolong their blood circulation lifetime. The prepared PION@PDA-PEG showed excellent biocompatibility and promising MR imaging contrast agent capability. Furthermore, the porous structure of PION and the abundant functional groups of PDA shell permitted the remarkable drug loading capacity of more than 24.1 wt%. In addition, the synergistic photothermal- chemotherapy exhibited obvious enhanced anti-tumor effect in in-vitro cell experiment. These results suggest that the developed PION@PDA-PEG nanocomposite can be utilized as an efficient drug nanocarrier for biomedical applications including MR imaging and photothermal-chemotherapy.

Cerium-Promoted Ginsenosides Accumulation by Regulating Endogenous Methyl Jasmonate Biosynthesis in Hairy Roots of Panax ginseng.

Among rare earth elements, cerium has the unique ability of regulating the growth of plant cells and the biosynthesis of metabolites at different stages of plant development. The signal pathways of Ce3+-mediated ginsenosides biosynthesis in ginseng hairy roots were investigated. At a low concentration, Ce3+ improved the elongation and biomass of hairy roots. The Ce3+-induced accumulation of ginsenosides showed a high correlation with the reactive oxygen species (ROS), as well as the biosynthesis of endogenous methyl jasmonate (MeJA) and ginsenoside key enzyme genes (PgSS, PgSE and PgDDS). At a Ce3+ concentration of 20 mg L-1, the total ginsenoside content was 1.7-fold, and the total ginsenosides yield was 2.7-fold that of the control. Malondialdehyde (MDA) content and the ROS production rate were significantly higher than those of the control. The activity of superoxide dismutase (SOD) was significantly activated within the Ce3+ concentration range of 10 to 30 mg L-1. The activity of catalase (CAT) and peroxidase (POD) strengthened with the increasing concentration of Ce3+ in the range of 20-40 mg L-1. The Ce3+ exposure induced transient production of superoxide anion (O2•-) and hydrogen peroxide (H2O2). Together with the increase in the intracellular MeJA level and enzyme activity for lipoxygenase (LOX), there was an increase in the gene expression level of MeJA biosynthesis including PgLOX, PgAOS and PgJMT. Our results also revealed that Ce3+ did not directly influence PgSS, PgSE and PgDDS activity. We speculated that Ce3+-induced ROS production could enhance the accumulation of ginsenosides in ginseng hairy roots via the direct stimulation of enzyme genes for MeJA biosynthesis. This study demonstrates a potential approach for understanding and improving ginsenoside biosynthesis that is regulated by Ce3+-mediated signal transduction.

A Novel 5-HT1B Receptor Agonist of Herbal Compounds and One of the Therapeutic Uses for Alzheimer's Disease.

The serotonin receptor 5-HT1B is widely expressed in the central nervous system and has been considered a drug target in a variety of cognitive and psychiatric disorders. The anti-inflammatory effects of 5-HT1B agonists may present a promising approach for Alzheimer's disease (AD) treatment. Herbal antidepressants used in the treatment of AD have shown functional overlap between the active compounds and 5-HT1B receptor stimulation. Therefore, compounds in these medicinal plants that target and stimulate 5-HT1B deserve careful study. Molecular docking, drug affinity responsive target stability, cellular thermal shift assay, fluorescence resonance energy transfer (FRET), and extracellular regulated protein kinases (ERK) 1/2 phosphorylation tests were used to identify emodin-8-O-ß-d-glucopyranoside (EG), a compound from Chinese medicinal plants with cognitive deficit attenuating and antidepressant effects, as an agonist of 5-HT1B. EG selectively targeted 5-HT1B and activated the 5-HT1B-induced signaling pathway. The activated 5-HT1B pathway suppressed tumor necrosis factor (TNF)-α levels, thereby protecting neural cells against beta-amyloid (Aß)-induced death. Moreover, the agonist activity of EG towards 5-HT1B receptor, in FRET and ERK1/2 phosphorylation, was antagonized by SB 224289, a 5-HT1B antagonist. In addition, EG relieved AD symptoms in transgenic worm models. These results suggested that 5-HT1B receptor activation by EG positively affected Aß-related inflammatory process regulation and neural death resistance, which were reversed by antagonist SB 224289. The active compounds such as EG might act as potential therapeutic agents through targeting and stimulating 5-HT1B receptor for AD and other serotonin-related disorders. This study describes methods for identification of 5-HT1B agonists from herbal compounds and for evaluating agonists with biological functions, providing preliminary information on medicinal herbal pharmacology.

Palladium nanosheet-knotted injectable hydrogels formed via palladium-sulfur bonding for synergistic chemo-photothermal therapy.

Nanoparticle (NP)-based hydrogels that can introduce synergistic advantages to the novel three-dimensional scaffold have garnered much attention recently. However, the application of NP-crosslinked hydrogels still remains challenging due to the complicated synthesis and/or modification of the NPs and the changed properties of the NPs after gelation. Herein, a novel palladium nanosheet (Pd NS)-based hydrogel (Pd Gel) with Pd NSs as crosslinkers was obtained by simply mixing Pd NSs with thiol-terminated four-arm polyethylene glycol (4arm-PEG-thiol). It was found that the formed Pd Gel was injectable, possibly due to the dynamic Pd-S bonds formed between Pd NSs and 4arm-PEG-thiol. In addition, compared with free Pd NSs, the Pd NSs within the hydrogel exhibited a significantly higher stability. We have further demonstrated that the formed hydrogel could encapsulate the commonly used anticancer drug doxorubicin (DOX) to form DOX@Pd Gel for combined chemo-photothermal therapy. Particularly, Pd NSs with a high absorption in the near-infrared (NIR) region could convert the energy of NIR laser into heat with a high efficiency, which is beneficial for photothermal therapy. Moreover, DOX@Pd Gel could maintain a sustainable release of DOX and the NIR laser irradiation could accelerate this drug release process. Then, the explosively released DOX and the hyperthermia generated from Pd NSs under NIR laser irradiation acted in a synergistic way to realize the combined therapeutic effect of the chemo-photothermal treatment. Finally, the in vivo anticancer effect and safety of the combined therapy were also verified by the tumor-bearing mouse model. Taken together, this work constructs a NP-crosslinked, NIR laser-activatable and injectable photothermal hydrogel via dynamic Pd-S bonding, and demonstrates that the hydrogel allows us to release DOX more precisely, eliminate tumor more effectively and inhibit tumor metastasis more persistently, which will advance the development of novel anticancer strategies.

Optimal dietary alcoholic extract of lotus leaf improved growth performance and health status of grass carp (Ctenopharyngodon idellus).

Grass carp (Ctenopharyngodon idellus) is one of the most important aquaculture fish in China. This study tried to explore the effects of dietary alcoholic extract of lotus leaf (AELL) addition on the growth performance and health status of grass carp by feeding juvenile fish (average weight: 34 ±â€¯1 g) with four different experimental diets: control, AELL7, AELL14 and AELL21 for 8 weeks. At the end of the growth trial, the highest values of final body weight (FBW), weight gain rate (WGR), specific growth rate (SGR) and feed intake (FI) all occurred in group AELL14 (P < 0.05). Compared to control, the crude lipid content of whole-body and the serum malondialdehyde (MDA) in the three experimental groups decreased, while the serum superoxide dismutase (SOD), glutathione peroxidase (GSH) and total antioxidant capacity (T-AOC) values almost all increased in the three experimental groups. The highest serum immunoglobulin M (IgM) concentration occurred in AELL14 group (P < 0.05). In AELL14 and AELL21 groups, both the serum complement 3 (C3) concentration and lysozyme (LYS) activity were significantly higher, whereas the final cumulative mortality in challenge test was significantly lower, when compared to those in control group (P < 0.05). The AELL exerted dose-dependent beneficial effects on grass carp health through up-regulating related gene expressions and enzyme activity. In conclusion, the optimal dietary AELL level is 0.14% for juvenile grass carp.

Characterization and expression analysis of FGF6 (fibroblast growth factor 6) genes of grass carp (Ctenopharyngodon idellus) reveal their regulation on muscle growth.

The present study was conducted to investigate the regulative function of FGF6 in the muscle growth of grass carp (Ctenopharyngodon idellus) by the bioinformatics analysis and expression pattern analyses of FGF6 genes in different developmental stages and tissues, as well as the correlation analysis between muscle growth and FGF6 expression after fish were fed with different levels of dietary lotus leaf flavonoids (LLF) (0, 0.03%, 0.06%, 0.09%). Results showed that the FGF6a and FGF6b genes are two homologs of the FGF6 family, encoding 205 and 209 amino acids, respectively. Alignment of amino acid sequences and phylogenetic analysis demonstrated that FGF6a and FGF6b are highly conserved with other vertebrates. Quantitative RT-PCR analysis showed both FGF6a and FGF6b expressions were high in brain and muscle but low in other examined tissues. During embryonic development, FGF6a and FGF6b mRNA expressions could be detected as early as at fertilized egg stage and displayed the highest value at cleavage stage. Dietary LLF affected the gene expression of FGF6 in white muscle. The relative expression of FGF6a of 0.06% LLF group was significantly higher than that of 0.09% LLF group, while FGF6b expression of 0.06% LLF group was higher than those of other groups (P < 0.05). The muscle fiber diameter was significantly higher in 0.06% LLF group in comparison with other groups, while the fiber density in this group was lower (P < 0.05). Both FGF6a and FGF6b expressions were positively correlated with fiber diameter but negatively correlated with fiber density. These results collectively suggest that FGF6a and FGF6b play an important role in muscle growth regulation in grass carp.