Near-Infrared Light-Triggered Thermoresponsive Pyroptosis System for Synergistic Tumor Immunotherapy.

Pyroptosis, as an inflammatory cell death, has been widely applied in tumor therapy, but its systemic adverse reactions caused by nonspecific activation still seriously hinder its application. Herein, a near-infrared (NIR) light-triggered thermoresponsive pyroptosis strategy is designed for on-demand initiation of pyroptosis and synergistic tumor immunotherapy. Specifically, glucose oxidase (GOx) loaded and heat-sensitive material p(OEOMA-co-MEMA) (PCM) modified mesoporous Pt nanoparticles (abbreviated as PCM Pt/GOx) are prepared as the mild-temperature triggered pyroptosis inducer. Pt nanoparticles can not only serve as nanozyme with catalase-like activity to promote GOx catalytic reaction, but also act as photothermal agent to achieve mild-temperature photothermal therapy (PTT) and thermoresponsive GOx release on-demand under the irradiation of NIR light, thereby activating and promoting pyroptosis. In vitro and in vivo experiments prove that NIR light-triggered thermoresponsive pyroptosis system exhibits excellent antitumor immunity activity as well as significantly inhibits tumor growth. The precise control of pyroptosis by NIR light as well as pyroptosis cooperated with mild-temperature PTT for synergistically attenuated tumor immunotherapy are reported for the first time. This work provides a new method to initiate pyroptosis on demand, which is of great significance for spatiotemporally controllable pyroptosis and immunotherapy.

A novel aptamer-based small RNA delivery platform and its application to cancer therapy.

Major challenges such as nuclease degradation, rapid renal clearance, non-specific delivery, poor cellular uptake and inflammatory response have limited the clinical application of small RNA-mediated gene silencing. To overcome these challenges, we designed a novel targeting small RNA delivery platform comprising of three oligonucleotides: (1) a guide RNA sequence, (2) part of a passenger sequence linked to a DNA aptamer via a PEG linker, and (3) another passenger sequence conjugated to cholesterol, which assemble through complementary base pair annealing. Remarkably, in the presence of magnesium, this molecule self-assembled into a nanoparticle with a hydrophobic cholesterol core, hydrophilic RNA oligonucleotide shell and PEG-linked DNA aptamer flare. The nanoparticles conferred protection to the RNA oligonucleotides against nuclease degradation, which increased bioavailability, and reduced systemic inflammatory responses. The aptamer allowed targeted delivery of RNA therapeutics through cell-specific surface markers, and once inside the cell, the nanoparticles induced lysosomal leakage that released the RNA oligonucleotides into the cytosol to achieve gene silencing. We created a c-Kit-targeting miR-26a delivery particle that specifically accumulated in c-Kit+ breast cancer, significantly increased T cell recruitment, and inhibited tumor growth. Regression of large established tumors were achieved when the nanoparticle was used in combination with anti-CTLA-4 monoclonal antibody.

Usnea Acid-Incorporated Ca2+ /Mn2+ Ions Reservoirs for Elevated Ion-Interference Therapy through Synergetic Biocatalysis and Osmolarity Imbalance.

Ion-interference therapy (IIT) utilizes ions to disturb intracellular biological processes and has been received increasing attention in tumor treatments recently. However, the low therapeutic efficiency still hinders its further biological applications. Herein, via a simple and one-pot gas diffusion process, polyethylene glycol (PEG)-modified Mn2+ ions and usnic acid (UA)-incorporated CaCO3 nanomaterials (PEG CaMnUA) as Ca2+ /Mn2+ ions reservoirs are prepared for magnetic resonance imaging (MRI)-guided UA-elevated IIT. Among PEG CaMnUA, UA not only increases cytoplasmic Ca2+ ions to amplify Ca2+ overload caused by CaCO3 decomposition, but also enhances Mn2+ ions-participated Fenton-like biocatalysis by intracellular H2 O2 generation and glutathione consumption. Then increasing the intracellular oxidative stress and decreasing the triphosadenine supply induce apoptosis together, resulting in UA-boosted IIT. The simple and efficient design of the dual ions reservoirs will contribute to improve the antitumor activity of IIT and further development of calcium-based nanomaterials in the future.

A Noble AuPtAg-GOx Nanozyme for Synergistic Tumor Immunotherapy Induced by Starvation Therapy-Augmented Mild Photothermal Therapy.

Notwithstanding immune checkpoint blocking (ICB) therapy has made eminent clinical breakthroughs, overcoming immunologically "cold" tumors remains challenging. Here, a cascade potentiated nanomodulator AuPtAg-GOx is engineered for boosting immune responsiveness. Upon 1064 nm laser irradiation, AuPtAg-mediated mild photothermal therapy (PTT) activates cytotoxic T lymphocytes and reverses the immunogenic "cold" tumor microenvironment. Further, to amplify the thermal sensitivity of tumor cells, glucose oxidase (GOx) is introduced to suppress the production of heat shock proteins, thereby promoting mild photothermal therapy. Complementarily, AuPtAg nanozymes with catalase-like activity can ameliorate tumor hypoxia, significantly improving the GOx activity. As a result, the combination of AuPtAg-GOx with self-augmented photothermal ability and PD-L1 antibody can further escalate the antitumor efficacy. The AuPtAg-GOx-based synergistic starvation therapy, mild PTT, and immunotherapy cascade enhancement therapy strategy can be a favorable tool to effectively kill cancer cells.

[Analysis of Wumei Pills in treating chronic digestive system diseases with concept of "treating different diseases with same method" based on network pharmacology and molecular docking].

The present study explored the material basis and underlying mechanism of Wumei Pills in the treatment of ulcerative colitis(UC), diabetic enteropathy(DE), and irritable bowel syndrome(IBS) based on network pharmacology and molecular docking.The active components and targets of Wumei Pills were obtained and screened out from TCMSP, and the target names were standardized by UniProt.The related targets of UC, DE, and IBS were searched from GeneCards, DisGeNET, DrugBank, and OMIM.The Venn dia-gram was constructed using the Venny 2.1 online analysis tool to obtain the common targets of the drug and diseases.The "drug-active ingredient-target" network was constructed by Cytoscape 3.7.2.Gene Ontology(GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analyses of common targets were carried out by DAVID.The main active components and targets were docked by AutoDock.The therapeutic mechanism of Wumei Pills was presumedly related to the regulation of the cancer pathway, TNF signaling pathway, HIF-1 signaling pathway, PI3 K-Akt signaling pathway, NF-κB signaling pathway, Toll-like receptor signaling pathway, JAK-STAT signaling pathway, etc.The results of molecular docking showed that the main active components could bind to the core targets, possessing stable conformation.The therapeutic effects of Wumei Pills against three diseases involved a variety of compounds such as flavonoids, sterols, and alkaloids in the prescriptions, which acted on key targets through multiple organs and participated in multiple signaling pathways such as apoptosis and immune inflammation, thereby exerting the therapeutic action on different diseases with the same method.This study explained the underlying mechanism of Wumei Pills in "treating different diseases with same method", and is expected to provide a theoretical basis for further understanding the mechanism of Wumei Pills and exploring the new clinical application.

Hollow Aluminum Hydroxide Modified Silica Nanoadjuvants with Amplified Immunotherapy Effects through Immunogenic Cell Death Induction and Antigen Release.

In spite of the widespread application of vaccine adjuvants in various preventive vaccines at present, the existing adjuvants are still hindered by weak cellular immunity responses in therapeutic cancer vaccines. Herein, a hollow silica nanoadjuvant containing aluminum hydroxide spikes on the surface (SiAl) is synthesized for the co-loading of chemotherapeutic drug doxorubicin (Dox) and tumor fragment (TF) as tumor antigens (SiAl@Dox@TF). The obtained nanovaccines show significantly elevated anti-tumor immunity responses thanks to silica and aluminum-based composite nanoadjuvant-mediated tumor antigen release and Dox-induced immunogenic cell death (ICD). In addition, the highest frequencies of dendritic cells (DCs), CD4+ T cells, CD8+ T cells, and memory T cells as well as the best mice breast cancer (4T1) tumor growth inhibitory are also observed in SiAl@Dox@TF group, indicating favorable potential of SiAl nanoadjuvants for further applications. This work is believed to provide inspiration for the design of new-style nanoadjuvants and adjuvant-based cancer vaccines.

A Multichannel Ca2+ Nanomodulator for Multilevel Mitochondrial Destruction-Mediated Cancer Therapy.

Subcellular organelle-targeted nanoformulations for cancer theranostics are receiving increasing attention owing to their benefits of precise drug delivery, maximized therapeutic index, and reduced off-target side effects. Herein, a multichannel calcium ion (Ca2+ ) nanomodulator (CaNMCUR+CDDP ), i.e., a cisplatin (CDDP) and curcumin (CUR) co-incorporating calcium carbonate (CaCO3 ) nanoparticle, is prepared by a facile one-pot strategy in a sealed container with in situ synthesized polydopamine (PDA) as a template to enhance Ca2+ -overload-induced mitochondrial dysfunction in cancer therapy. After systemic administration, the PEGylated CaNMCUR+CDDP (PEG CaNMCUR+CDDP ) selectively accumulates in tumor tissues, enters tumor cells, and induces multilevel destruction of mitochondria by the combined effects of burst Ca2+ release, Ca2+ efflux inhibition by CUR, and chemotherapeutic CDDP, thereby observably boosting mitochondria-targeted tumor inhibition. Fluorescence imaging of CUR combined with photoacoustic imaging of PDA facilitates the visualization of the nanomodulator. The facile and practical design of this multichannel Ca2+ nanomodulator will contribute to the development of multimodal bioimaging-guided organelle-targeted cancer therapy in the future.

Polydopamine-Incorporated Nanoformulations for Biomedical Applications.

Polydopamine (PDA), a pigment in natural melanin, has attracted considerable attention because of its excellent optical properties, extraordinary adhesion, and good biocompatibility, which make it a promising material for application in energy, environmental, and biomedical fields. In this review, PDA-incorporated nanoformulations are focused for biomedical applications such as drug delivery, bioimaging, and tumor therapy. First, the recent advances in PDA-incorporated nanoformulations for drug delivery are discussed. Further, their application in boimaging, such as fluorescence imaging, photothermal imaging, and photoacoustic imaging, is reviewed. Next, their therapeutic applications, including chemotherapy, photodynamic therapy, photothermal therapy, and synergistic therapy are discussed. Finally, other biomedical applications of PDA-incorporated nanoformulations such as biosensing and clinical diagnosis are briefly presented. Finally, the biomedical applications of PDA-incorporated nanoformulations along with their prospects are summarized.

Controlled clinical trials of external using of Cheezheng Qingpeng ointment on reliving analgesia and swelling for the treatment of rheumatoid arthritis / 中国骨伤

<p><b>OBJECTIVE</b>To observe the clinical efficacy on analgesia and detumescence of Cheezheng Qingpeng ointment in the treatment of rheumatoid arthritis.</p><p><b>METHODS</b>From December 2004 to May 2006, 78 patients were divided into the treatment group and the control group randomly using PROC PLAN from SAS software. There were 40 patients in the treatment group, 30 patients were male and 10 patients were female, with an average age of (48.2+/-9.7) years, who were treated with Cheezheng Qingpeng ointment external treatment. Thirty-eight patients were in the control group, 30 patients were male and 8 patients were female, with an average age of (47.7+/-13.7) years, and were treated with Diclofenac diethylamine emugel. All the patients were treated for 2 weeks. The metacarpophalangeal joint with most severe pain and swelling was observed. The indexes including joint pain, tenderness, swelling, joint motion and morning stiffness were detected and the VAS scores were compared between the two groups.</p><p><b>RESULTS</b>All the patients completed the trial, 35 patients in the treatment group and 33 patients in the control group. At the end of 2 weeks, 1 patient in the treatment group obtained an excellent result, 27 good and 7 bad; in the control group, 2 patients got an excellent result, 20 good and 11 bad. There were no statistically difference of therapeutic effects between the two groups. At the 1st week after treatment, the joint swelling score of the treatment group was (4.0+/-1.4), which was lower than the (5.5+/-1.9) in the control group.</p><p><b>CONCLUSION</b>There is no obvious difference of therapeutic effects between Cheezheng Qingpeng ointment and diclofenac diethylamine emugel for the treatment of rheumatoid arthritis, but the relieving of swelling of Cheezheng Qingpeng ointment is better than that of Diclofenac Diethylamine Emugel.</p>

Relationship between quality of life and TCM syndrome types in patients with diabetes mellitus / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To explore the relationship between the syndrome types differentiated by traditional Chinese medicine and the quality of life (QOL) in patients with diabetes mellitus (DM).</p><p><b>METHODS</b>The QOL in patients was investigated with Short Form-36 questionnaire (SF-36), and compared with that of healthy subjects for control; the TCM syndrome type was differentiated at the same time by the outcomes of symptoms acquired from the questionnaire.</p><p><b>RESULTS</b>The score of all the domains of QOL was respectively lower in the DM patients than that in the healthy subjects. The score of some domains of QOL showed correlation with different TCM syndrome types.</p><p><b>CONCLUSION</b>QOL of DM patients significantly decreased. The variation of syndrome types could significantly influence some domains of QOL.</p>

Effects of jianwei yuyang granule on inflammatory reaction and NF-kappaB expression in rat gastric mucosa of ulcer healing and recurrence / 中国中药杂志

<p><b>OBJECTIVE</b>To observe the effects of Jianwei Yuyang granule (JWYY) on inflammatory reaction and NF-kappaB expression in rat gastric mucosa of ulcer healing and recurrence.</p><p><b>METHOD</b>Gastric ulcer was induced in rat by acetic acid according Okeba's method with some modification and the recurrence model was induced by IL-1beta. Pathohistology of ulcer healing and recurrence was observed. Density of inflammatory cell infiltrating regenerative mucosa, NF-kappaB protein and mRNA expression were measured.</p><p><b>RESULT</b>JWYY had effects on improving the quality of ulcer healing, reducing the rate of ulcer recurrence, decreasing the density of inflammatory cell infiltrating regenerative mucosa and suppressing the activation and expression quantity of NF-kappaB protein and mRNA.</p><p><b>CONCLUSION</b>JWYY may promote the ulcer healing and prevent the recurrence of the gastric ulcer by suppressing the activation of NF-kappaB and the following inflammatory reaction.</p>