Design, Synthesis, and Antitumor Activities of Isomers of Artemisinin Dimer Derivatives.

In recent years, numerous studies have reported on the anti-tumor properties of artemisinin and its derivatives. However, the relationship between their artemisinin chirality and activity remains unknown. In this study, we synthesized a series of artemisinin dimer derivatives with three different chiral structures and tested their antiproliferative activity in MCF-7 and HepG2 cells using the CCK-8 assay. Interestingly, we discovered that artemisinin dimer derivatives with ß, ß and α, ß conformations at C-10 exhibited stronger anti-tumor activity than those with an α, α configuration in MCF-7 and HepG2 cells. Notably, compound 4 showed an activity of 0.06 µM in MCF-7 cells. This study demonstrates the relationship between the conformation and activity of artemisinin dimer derivatives, and these derivatives have the potential to be developed into anti-cancer drugs.

Spatial-Drug-Laden Protease-Activatable M1 Macrophage System Targets Lung Metastasis and Potentiates Antitumor Immunity.

Lung metastasis is a critical cause of cancer mortality and its therapy is largely challenged by the limited drug delivery efficiency and robust immunosuppression in metastatic tumors. Herein, we designed a spatial-drug-laden M1 macrophage system with liposomal R848 inside and fibroblast activation protein protease (FAP)-sensitive phospholipid-DM4 conjugate on the membrane of M1 macrophage (RDM). RDM could preferentially accumulate at the metastatic lesions in lungs and responsively release the therapeutic agents as free drug molecules or drug-loaded nanovesicles. RDM treatment notably enhanced the infiltration of CD3+CD8+ T cells to lung metastasis and, respectively, caused an 8.54-, 12.87- and 2.85-fold improvement of the granzyme-B-, interferon-γ-, and Ki67-positive subtypes versus negative control. Moreover, RDM treatment produced a 90.99% inhibition of lung metastasis in 4T1 models and significant prolongation of survival in three murine lung metastatic models. Therefore, the drug-laden FAP-sensitive M1 macrophage system represents a feasible strategy to target lung metastasis and boost antitumor immunity for antimetastasis therapy.

Synthesis and characterization of single-phase Tb3+/Eu3+ doped metal-organic framework phosphors for warm light WLED applications.

A novel single-phase luminescent material, Ln@bio-MOF-1 (Ln: Tb3+ and Eu3+), was synthesized by a facile hydrothermal method. The structural and luminescence characteristics of the MOF materials were studied in detail. The chromaticity of the as-prepared samples might be easily modulated using molar amounts of Tb3+ and Eu3+. Sample Tb/Eu@bio-MOF-1 (1) demonstrates a white emission (CIE coordinates: 0.328, 0.338), which is very close to the standard white light (0.333, 0.333). Tb/Eu@bio-MOF-1 (1) has a quantum yield of 52.9%, which is higher than those in most reported works. The corresponding LED devices were prepared to further explore the possible applications of Ln@bio-MOF-1 in WLEDs. The achieved LED device has a high color rendering index (CRI) of 86.2 and a low correlated color temperature (CCT) of 4725 K, which indicates that Tb/Eu@bio-MOF-1 (1) might be a feasible luminescent material for WLED applications.

Macrophage Membrane-Coated Nano-Gemcitabine Promotes Lymphocyte Infiltration and Synergizes AntiPD-L1 to Restore the Tumoricidal Function.

The limited lymphocyte infiltration and exhaustion of tumoricidal functions in solid tumors remain a formidable obstacle to cancer immunotherapy. Herein, we designed a macrophage membrane-coated nano-gemcitabine system (MNGs) to promote lymphocyte infiltration and then synergized anti-programmed death ligand 1 (antiPD-L1) to reinvigorate the exhausted lymphocytes. MNGs exhibited effective intratumor-permeating and responsive drug-releasing capacity, produced notable elimination of versatile immunosuppressive cells, and promoted lymphocyte infiltration into cancer cell regions in tumors, but over 50% of these infiltrated lymphocytes were in the exhausted state. Compared with MNG monotherapy, the MNGs+antiPD-L1 combination produced 31.77% and 30.63% reduction of exhausted CD3+CD8+ T cells and natural killer (NK) cells and 2.83- and 3.17-fold increases of interferon-γ (IFN-γ)-positive subtypes, respectively, thereby resulting in considerable therapeutic benefits in several tumor models. Thus, MNGs provide an encouraging strategy to promote lymphocyte infiltration and synergize antiPD-L1 to restore their tumoricidal function for cancer immunotherapy.

ROS-Responsive Nanocomplex of aPD-L1 and Cabazitaxel Improves Intratumor Delivery and Potentiates Radiation-Mediated Antitumor Immunity.

Despite the promising benefits of immune checkpoint inhibitors (ICIs) in clinical cancer treatments, the therapeutic efficacy is largely restricted by low antitumor immunity and limited intratumor delivery in solid tumors. Herein, we designed a reactive oxygen species (ROS)-responsive albumin nanocomplex of antiprogrammed cell death receptor ligand 1 (aPD-L1) and cabazitaxel (RAN-PC), which exhibited prominent tumor accumulation and intratumor permeation in 4T1 tumors. Compared with the negative control, the RAN-PC + radiation treatment (RAN-PC+X) produced a 3.61- and 5.10-fold enhancement in CD3+CD8+ T cells and the interferon (IFN)-γ-expressing subtype, respectively, and notably reduced versatile immunosuppressive cells. Moreover, RAN-PC+X treatment resulted in notable retardation of tumor growth, with a 78.97% inhibition in a 4T1 breast tumor model and a 90.30% suppression in a CT-26 colon tumor model. Therefore, the ROS-responsive albumin nanocomplex offers an encouraging platform for ICIs with prominent intratumor delivery capacity for cancer immunotherapy.

Strategies of engineering nanomedicines for tumor retention.

The retention of therapeutic agents in solid tumors at sufficient concentration and duration is crucial for their antitumor effects. Given the important contribution of nanomedicines to oncology, we herein summarized two major strategies of nanomedicines for tumor retention, such as transformation- and interactions-mediated strategies. The transformation-mediated retention strategy was achieved by enlarging particle size of nanomedicines or modulating the morphology into fibrous structures, while the interactions-mediated retention strategy was accomplished by modulating nanomedicines to promote their interactions with versatile cells or components in tumors. Moreover, we provide some considerations and perspectives of tumor-retaining nanomedicines for effective cancer therapy.

Nanomedicine Strategies to Circumvent Intratumor Extracellular Matrix Barriers for Cancer Therapy.

The dense and heterogeneous physical network of the extracellular matrix (ECM) in tumors represents a formidable barrier that limits intratumor drug delivery and the therapeutic efficacy of many anticancer therapies. Here, the two major nanomedicine strategies to circumvent intratumor ECM barriers: regulating the physiochemical properties of nanomedicines and remodeling the components and structure of the ECM are summarized. Nanomedicines can be rationally regulated by optimizing physiochemical properties or designed with biomimetic features to promote ECM permeation capability. Meanwhile, they can also be designed to remodel the ECM by modulating signaling pathways or destroying the components and architecture of the ECM via chemical, biological, or physical treatments. These efforts produce profound improvements in intratumor drug delivery and anticancer efficacy. Moreover, to aid in their anticancer efficacy, feasible approaches for improving ECM-circumventing nanomedicines are proposed.

M2 macrophage microvesicle-inspired nanovehicles improve accessibility to cancer cells and cancer stem cells in tumors.

Cancer cells and cancer stem cells (CSCs) are the major players of cancer malignancy and metastasis, but they are extremely difficult to access. Inspired by the vital role of macrophages and microvesicle-mediated cell-cell communication in tumors, we herein designed M2 macrophage microvesicle-inspired nanovehicle of cabazitaxel (M-CFN) to promote accessibility to cancer cells and CSCs in tumors. In the 4T1 tumor model, M-CFN flexibly permeated the tumor mass, accessed cancer cells and CD90-positive cells, and significantly promoted their entry into CSC fractions in tumors. Moreover, M-CFN treatment profoundly eliminated aldehyde dehydrogenase (ALDH)-expressing CSCs in 4T1 and MCF-7 tumors, produced notable depression of tumor growth and caused 93.86% suppression of lung metastasis in 4T1 models. Therefore, the M2 macrophage microvesicle-inspired nanovehicle provides an encouraging strategy to penetrate the tumor tissues and access these insult cells in tumors for effective cancer therapy.

Tumor-permeated bioinspired theranostic nanovehicle remodels tumor immunosuppression for cancer therapy.

The robust immunosuppressive microenvironment in tumor represents a key challenge of cancer treatment, and their modulations by versatile therapeutic agents are critically hampered by the limited intratumoral delivery. Herein, we report a bioinspired tumor-responsive theranostic nanovehicle (BTN) with striking tumor-penetrating capability to relieve the profound immunosuppression in tumor for effective cancer therapy. BTN is designed by loading tumor-activated melittin pro-peptide, theranostic photochlor and reactive oxygen species (ROS)-responsive prodrug of chemo-immunomodulator gemcitabine into a bioinspired lipoprotein-based nanovehicle, which display prominent tumor accumulation and flexible intratumoral permeation. Notably, the BTN-mediated combinational treatment caused drastic elimination of multiple immunosuppressive cells and remarkable infiltration of cytotoxic lymphocytes in tumor, thereby essentially relieving the tumor immunosuppression and strikingly depressing the tumor growth. Therefore, this design provides an encouraging delivery nanoplatform with distinguished immunosuppression-relieving capacity for effective cancer therapy.

Nanoparticles-mediated reoxygenation strategy relieves tumor hypoxia for enhanced cancer therapy.

Tumor hypoxia is a characteristic hallmark of malignant solid tumors, which remains an essential impediment to many current treatments like chemotherapy, radiotherapy, photodynamic therapy and immunotherapy, thereby leading to poor clinical prognosis after therapy. Rationally, modulating tumor hypoxia can be of great interest to augment the therapeutic efficacy of these treatments. In this review, we focus our discussion on current advances in nanoparticles-mediated tumor reoxygenation strategy for relieving tumor hypoxia to improve the therapeutic efficacy of versatile therapies. These nanoparticles can improve tumor oxygen levels via nanoparticles-mediated oxygen-carrying or oxygen-generating tactics to synergize the effectiveness of many current therapeutic modalities. Based on these considerable summaries and analyses, we propose some feasible perspectives on nanoparticles-based tumor reoxygenations to ameliorate the therapeutic outcomes.

The enhancement mechanism of wine-processed Radix Scutellaria on NTG-induced migraine rats.

To elucidate the increasing dissolution and enhancement mechanism of wine-processed Radix Scutellaria (RS) by fractal theory in nitroglycerin (NTG)-induced migraine rats. We prepared three RS from the process with 10% (S1), 15% (S2), 20% (S3) (v/m) rice wine. Mercury intrusion porosimetry and scanning electron microscope were employed to explore the internal structure of RS and the components dissolution of RS was analyzed by HPLC. Rats were randomly allocated into following groups and orally given different solutions for 10days: normal group (NOR, normal saline), model group (MOD, normal saline), Tianshu capsule group (TSC, 0.425mg/kg), ibuprofen group (IBU, 0.0821mg/kg), crude RS group (CRU, 1.04mg/kg) and wine-processed RS group (WP, 1.04mg/kg) followed by bolus subcutaneously injection of NTG (10mg/kg) to induce migraine model except NOR. Biochemical indexes (nitric oxide-NO, calcitonin-gene-related peptide-CGRP, and endothelin-ET) and c-fos positive cells were measured with commercial kits and immunohistochemical method, separately. Total surface area significantly increased in wine-processed RS (p<0.05) while fractal dimension markedly decreased (p<0.05) compared with crude RS. Additionally, S3 owned the highest increase of dissolution including the percentage increase of total extract, total flavonoids and main compounds (all p<0.05 vs S1 and S2). Pharmacodynamic data showed c-fos positive cells significantly decreased (p<0.05) in WP compared with MOD and the level of NO, CGRP, ET in WP was better than that of CRU. Wine-processed RS could be a promising candidate medicine for migraine treatment due to its increased component dissolution.

Monocyclic monoterpenes as penetration enhancers of ligustrazine hydrochloride for dermal delivery.

The purpose of this study was to explore the enhancing effects and the mechanism of monocyclic monoterpene penetration enhancers (menthol and menthone) on the transdermal absorption of ligustrazine hydrochloride (LH). Franz-type diffusion cells were used to determine percutaneous parameters of LH in vitro and surface changes of porcine skin were studied by a scanning electron microscope (SEM). The effects of promoters on the biophysical natures of stratum corneum (SC) were researched by Fourier transform-infrared (FT-IR). Penetration parameters of menthol (p < 0.01) and menthone groups (p < 0.05) were greater than those of the control; morphological changes of skin monitored by SEM demonstrated that the menthone group had the most disruption and desquamation of SC flakes, which resulted from extracted lipids. FT-IR measurements showed menthone had the greatest changes in peak shift and peak area, which resulted from C-H stretching vibrations of SC lipids. The results suggest that the penetration mechanism might include disturbing and extracting SC lipids and the hydrogen bond connection.

Hypocholesterolemic effect of emodin by simultaneous determination of in vitro and in vivo bile salts binding.

Emodin is an active anthraquinone derivative from Rheum palmatum and some other Chinese herbs and it is traditionally used for treating a variety of diseases. In this study, we investigated the hypocholesterolemic effects and mechanism of emodin on hypercholesterolemia rats. In vitro, capability of emodin binding to sodium deoxycholate which is one kind of bile salts (BAs) was evaluated by detection of surplus content of sodium deoxycholate. In vivo, hypocholesterolemic effects were assessed by determining total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) level of serum and TC, TG level of the liver. Oil red O staining was employed to determine lipid droplet of the liver. The mechanism was explored by BAs in feces, the liver and small intestine. Furthermore, cholesterol 7α-hydroxylase (CYP7A1) activity was measured to evaluate cholesterol's transforming to BAs. The results indicated that TC level of emodin group apparently decreased comparing with model group (p<0.05). Emodin could bind to BAs both in vivo (p<0.05) and in vitro. CYP7A1 activity in emodin group apparently increased comparing with model group (p<0.05). Data suggested that emodin had the potential value for treatment of hypercholesterolemia. The underlying mechanism is probably associated with binding capability to BAs and subsequent increasing expression of CYP7A1.

Antitumor Activity of Total Flavonoids from Daphne genkwa in Colorectal Cancer.

Daphne genkwa Sieb.et Zucc. is a well-known medicinal plant. This study was designed to investigate the anticancer effects of total flavonoids in D. genkwa (TFDG) in vitro and in vivo. HT-29 and SW-480 human colorectal cancer cells were cultured to investigate the anticancer activity of TFDG. In addition, the Apc(Min/+) mouse model was applied in the in vivo experiment. Results of the cell experiment revealed that TFDG possessed significant inhibitory effects on HT-29 and SW-480 human colorectal cancer cells (both p < 0.01). Furthermore, our in vivo data showed that after treatment with TFDG, there was a significant increase in life span (both p < 0.01) and tumor numbers were reduced in the colon (both p < 0.01), which was supported by the data of tumor distribution, body weight changes and organ index. Our results also indicated that expressions of interleukin (IL)-1α, IL-1ß, IL-6, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in gut tissue were downregulated by treatments of TFDG, and immunity cytokine secretions in the serum were regulated after oral administration of TFDG. Taken together, these findings suggested that TFDG has a potential clinical utility in colorectal cancer therapeutics, and TFDG's action is likely linked to its ability to regulate immune function and inhibit the production of inflammatory cytokines.

Novel Application of Natural Anisole Compounds as Enhancers for Transdermal Delivery of Ligustrazine.

To improve the transdermal delivery of ligustrazine, Foeniculum vulgare food origin anisole compounds were employed as promoters. Transdermal fluxes of ligustrazine were determined by Franz-type diffusion cells. Fourier transform-infrared (FT-IR) spectra were used to detect the biophysical changes of the stratum corneum and to explore the mechanism of permeation enhancement. A scanning electron microscope (SEM) was used to monitor the morphological changes of the skin. Among the three anisoles, anisic acid increased the penetration flux of ligustrazine significantly. The ligustrazine flux with anisic acid (11.9 µg/cm(2)/h) was higher than that any other group (p < 0.05). Spectra observations revealed that these anisole enhancers were able to disturb and extract the stratum corneum lipids. In addition, apparent density was used to describe the desquamation extent of the scutella. Multiple mechanisms are involved in the permeation enhancement of ligustrazine, including disturbing and extracting stratum corneum lipid, forming a competitive hydrogen bond. All data suggested that anisole compounds could be a group of safe and active penetration enhancers for transdermal delivery of ligustrazine.

Antioxidative Activity of Flavonoids from Abrus cantoniensis against Ethanol-Induced Gastric Ulcer in Mice.

The present study investigated the flavonoids from Abrus cantoniensis against ethanol-induced gastric ulcers in mice. The flavonoids from A. cantoniensis were extracted with ethanol and purified by macroporous resin and polyamide. The 2,2-diphenyl-1-picrylhydrazyl assay was used to measure the antioxidative activities in vitro. The ethanol-induced ulcer mouse model was used to evaluate the gastroprotective activities of the flavonoids from A. cantoniensis. In addition, a method was established to ensure accuracy for animal ulcer evaluation. The flavonoids from A. cantoniensis showed a strong free radical scavenging capacity with an IC50 of 43.83 µg/mL in the 2,2-diphenyl-1-picrylhydrazyl assay. At doses between 28.16-112.67 mg/kg, the flavonoids conspicuously reduced the ulcer index in ethanol-induced mice (p<0.001). Significant differences were found in the levels of superoxide dismutase, catalase, glutathione, and myeloperoxidase in the stomach tissues between the flavonoids from the A. cantoniensis groups and the ethanol control group. The gastroprotective effect of the flavonoids from A. cantoniensis could be due to its antioxidative activity of the defensive mechanism. The data revealed that the flavonoids from A. cantoniensis could be a potential therapeutic agent for gastric ulcer prevention and treatment.

Effects of jianpi herbal suppository on hemorheology and CD62p in patients with ulcerative colitis.

OBJECTIVE: To compare the effects of a Chinese herbal suppository (Jianpi suppository) and Western Medicine (mesalazine) on hemorheology and CD62p in patients with ulcerative colitis (UC). METHODS: In a randomized trial, 120 mild to moderate UC patients were randomly divided into two equal groups. The Jianpi suppository group used Chinese herbal suppository rectally, while the mesalazine group was treated with mesalazine tablets orally. Two 15-day courses of treatment were carried out in both groups. Changes in the hemorheology and CD62p indices in patients were observed. RESULTS: The hemorheology and CD62p indices in the Jianpi suppository group decreased significantly more than those of the mesalazine group. CONCLUSION: Jianpi suppository is effective in improving the hypercoagulability of UC patients, and therefore may be worth using in clinical practice.

How to achieve deep remission in treatment of inflammatory bowel disease.

OBJECTIVE: This article investigates the methods of achieving deep remission of inflammatory bowel disease (IBD). METHODS: Increasing recognition of the concept of quality of care is contributing to the evolution of treatment goals in patients with IBD from clinical response and remission (symptom control) toward deep remission. A change in the treatment goal requires a change in the treatment strategy. Optimization of conventional therapy, early treatment, use of the Lemann score, performance of double-balloon endoscopy, treatment using Traditional Chinese Medicine, and good communication between physicians and patients are needed to attain deep remission. RESULTS: The above-mentioned methods can help to achieve deep remission. CONCLUSION: Using the avoeve methods, it will be possible to improve the prognoses of patients with IBD by minimizing complications and bowel damage and thereby changing the course of the disease.