Identification of Dalbergiae Odoriferae Lignum active ingredients and potential mechanisms in the treatment of adriamycin-induced cardiotoxicity based on network pharmacology and experimental verification.

The purpose of this study is to investigate the ingredients and mechanisms through which Dalbergiae Odoriferae Lignum (DOL) reduces adriamycin-induced cardiotoxicity. DOL's ingredients and drug targets were acquired from Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), and adriamycin-induced cardiotoxicity disease targets were gathered from GeneCards and National Center for Biotechnology Information (NCBI). The therapeutic targets of DOL against adriamycin-induced cardiotoxicity were identified by intersecting drug and disease targets. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted using R. Subsequently, core targets were determined and used for molecular docking with DOL ingredients. In vitro and in vivo experiments validated DOL's primary ingredients against adriamycin-induced cardiotoxicity efficacy. Western blot and immunohistochemistry verified its impact on target protein. After intersecting 530 drug targets and 51 disease targets, 19 therapeutic targets for DOL alleviated adriamycin-induced cardiotoxicity were received. Molecular docking demonstrated that DOL primary ingredient formononetin had a robust binding affinity for nitric oxide synthase 3 (NOS3). Experimental results showed that formononetin effectively mitigated adriamycin-induced cardiotoxicity. Additionally, western blot and immunohistochemistry showed that formononetin improved NOS3 expression. The network pharmacology and experimentation suggest that the primary ingredient of DOL, formononetin, may target NOS3 to act as a therapeutic agent for adriamycin-induced cardiotoxicity.

Engineered NanoAlum from aluminum turns cold tumor hot for potentiating cancer metalloimmunotherapy.

The poor cancer immunotherapy outcome has been closely related to immunosuppressive tumor microenvironment (TME), which usually inactivates the antitumor immune cells and leads to immune tolerance. Metalloimmunotherapy by supplementing nutritional metal ions into TME has emerged as a potential strategy to activate the tumor-resident immune cells. Herein, we engineered a magnesium-contained nano-aluminum adjuvant (NanoAlum) through hydrolyzing a mixture of Mg(OH)2 and Al(OH)3, which has highly similar components to commercial Imject Alum. Peritumoral injection of NanoAlum effectively neutralized the acidic TME while releasing Mg2+ to activate the tumor-resident T cells. Meanwhile, NanoAlum also blocked the autophagy pathway in tumor cells and subsequently induced cell apoptosis. The in vivo studies showed that merely peritumoral injection of NanoAlum successfully inhibited the growth of solid tumors in mice. On this basis, NanoAlum combined with chemical drug methotrexate or immunomodulatory adjuvant CpG further induced potent antigen-specific antitumor immunity. Overall, our study first provides a rational design for engineering tumor-targeted nanomodulator from clinical adjuvants to achieve effective cancer metalloimmunotherapy against solid tumors.

Natural Herbal Medicine as a Treatment Strategy for Myocardial Infarction through the Regulation of Angiogenesis.

Methods: We conducted a literature search on the bioactive components of medicinal plants and their effects on angiogenesis after MI. We searched for articles in Web of Science, MEDLINE, PubMed, Scopus, Google Scholar, and China National Knowledge Infrastructure databases before April 2021. Results: In this article, we summarized the mechanisms by which copper ions, microRNA, Akt1, inflammation, oxidative stress, mitochondria, and pericytes are involved in angiogenesis after myocardial infarction. In addition, we reviewed the angiogenic effects of natural herbal medicines such as Salvia miltiorrhiza Bunge Bunge, Carthamus tinctorius L., Pueraria lobata, Astragalus, Panax ginseng C.A. Mey., Panax notoginseng (Burkill) F.H. Chen, Cinnamomum cassia (L.) J. Presl, Rehmannia glutinosa (Gaertn.) DC., Leonurus japonicus Houtt, Scutellaria baicalensis Georgi., and Geum macrophyllum Willd. Conclusions: Some herbs have the effect of promoting angiogenesis. In the future, natural proangiogenic drugs may become candidates for the treatment of cardiovascular diseases.

Photothermal therapy mediated by gold nanocages composed of anti-PDL1 and galunisertib for improved synergistic immunotherapy in colorectal cancer.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide. The primary treatment for CRC is surgical resection, along with chemotherapy in more advanced or inoperable cases. There is a growing interest to complement both curative and palliative treatment with immunotherapies such as the programmed cell death-1 (PD-1) and PD-ligand 1 (PDL1) checkpoint inhibitors and transforming growth factor (TGF) ß inhibitors. However, the clinical outcomes of current immunotherapeutic strategies are limited by tumor heterogeneity and drug resistance. Nanomedicine-based photothermal therapy (PTT) has shown encouraging results for solid tumor ablation. Herein, we designed and synthesized gold nanocages functionalized with primary macrophage membrane and surface anti-PDL1 antibody, and loaded with a TGFß inhibitor, galunisertib. The GNC-Gal@CMaP nanocomposites achieved low-temperature PTT and immunogenic cell death, which subsequently enhanced the anti-tumor efficacy of anti-PDL1 antibody and galunisertib via activation of antigen-presenting cells that primed tumor-specific effector T cells. This study provides experimental proof for a combination of immunotherapy and PTT against CRC. STATEMENT OF SIGNIFICANCE: The combination of photothermal therapy (PTT) with immunotherapy can achieve an inherently synergistic anti-tumor effect. Here we integrated low-temperature PTT, PDL1 antibody and TGF-ß inhibitor in hollow gold nanocage nanocomposites (GNC-Gal@CMaP) that selectively targeted colon cancer cells and accumulated in the tumor microenvironment. The GNC-Gal@CMaP nanocomposites achieved low-temperature PTT and immunogenic cell death, which subsequently enhanced the anti-tumor efficacy of anti-PDL1 antibody and galunisertib via activation of antigen-presenting cells that primed tumor-specific effector T cells. This study provides experimental proof for a combination of immunotherapy and PTT against CRC.

Genomic and Metabolomic Investigation of a Rhizosphere Isolate Streptomyces netropsis WLXQSS-4 Associated with a Traditional Chinese Medicine.

Rhizosphere microorganisms play important ecological roles in promoting herb growth and producing abundant secondary metabolites. Studies on the rhizosphere microbes of traditional Chinese medicines (TCMs) are limited, especially on the genomic and metabolic levels. In this study, we reported the isolation and characterization of a Steptomyces netropsis WLXQSS-4 strain from the rhizospheric soil of Clematis manshurica Rupr. Genomic sequencing revealed an impressive total of 40 predicted biosynthetic gene clusters (BGCs), whereas metabolomic profiling revealed 13 secondary metabolites under current laboratory conditions. Particularly, medium screening activated the production of alloaureothin, whereas brominated and chlorinated pimprinine derivatives were identified through precursor-directed feeding. Moreover, antiproliferative activities against Hela and A549 cancer cell lines were observed for five compounds, of which two also elicited potent growth inhibition in Enterococcus faecalis and Staphylococcus aureus, respectively. Our results demonstrated the robust secondary metabolism of S. netropsis WLXQSS-4, which may serve as a biocontrol agent upon further investigation.

Ataxia telangiectasia mutated inhibitor-loaded copper sulfide nanoparticles for low-temperature photothermal therapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer, and is ranked the sixth most common neoplasm and the third leading cause of cancer-related deaths. Photothermal therapy (PTT) for thermal ablation of local tumors has recently emerged as a therapeutic strategy. However, the relatively high temperature of over 50 °C may lead to unexpected heat-related damage to tumor-adjacent normal tissues. Herein, we designed and synthesized ataxia telangiectasia mutated (ATM) inhibitor loaded hollow-structured CuS NPs with surface modification with anti-TGF-ß antibody (CuS-ATMi@TGF-ß NPs). CuS-ATMi@TGF-ß NPs are highly photo-stable, can release encapsulated drugs, and increase the temperature to an effective level in a near-infrared (NIR)-responsive manner. Moreover, CuS-ATMi@TGF-ß NPs specifically target tumors and thereby significantly inhibit tumor growth on contribution to synergistic low-temperature PTT and chemotherapy. This system not only achieved low-temperature PTT but also resulted in reduced damage to normal tissues. Modification with anti-TGF-ß antibody enhanced target specificity and immune activation. The combination of PTT and ATM inhibitor showed synergistic effects and significantly attenuated the growth of the HCC via down regulation of heat shock protein (HSP). CuS-ATMi@TGF-ß NPs are a highly promising platform for targeted tumor ablation via hyperthermia-mediated tumor death with minimal damage to normal tissues at a low temperature. STATEMENT OF SIGNIFICANCE: We constructed ataxia telangiectasia mutated (ATM) inhibitor-loaded hollow-structured CuS NPs with surface modification with anti-TGF-ß antibody (CuS-ATMi@TGF-ß NPs). CuS-ATMi@TGF-ß NPs not only achieved low-temperature photothermal therapy (PTT) but also resulted in reduced damage to normal tissues and sufficient biocompatibility. The modification with anti-TGF-ß antibody enhanced targeted specificity, cell endocytosis, and immune activation. In addition, the combination of PTT and ATM inhibitor synergistically attenuated the growth of the HCC via downregulation of heat shock protein (HSP). This study provided proof-of-concept for the ATM inhibitor that mediated low-temperature PTT with a potential for future clinical applications.

Ginsenoside Rg1-Notoginsenoside R1-Protocatechuic Aldehyde Reduces Atherosclerosis and Attenuates Low-Shear Stress-Induced Vascular Endothelial Cell Dysfunction.

Background: The Fufang Danshen formula is a clinically important anti-atherosclerotic preparation in traditional Chinese medicine. However, its anti-atherosclerotic effect is not well recognized, and the mechanisms of its combined active ingredients, namely Ginsenoside Rg1-Notoginsenoside R1-Protocatechuic aldehyde (RRP), remain unclear. The purpose of this study was to investigate the anti-atherosclerotic effects and potential mechanism of RRP in ApoE-/- mice and in low-shear stress-injured vascular endothelial cells. Methods: ApoE-/- mice were randomly divided into three groups: model group, rosuvastatin group, and RRP group, with C57BL/6J mice as the control group. Oil-red O, hematoxylin and eosin, Masson, and Movat staining were utilized for the observation of aortic plaque. Changes in the blood lipid indexes were observed with an automatic biochemistry analyzer. ET-1, eNOS, TXA2, and PGI2 levels were analyzed by enzyme-linked immunosorbent assay. In vitro, a fluid shear stress system was used to induce cell injury. Piezo1 expression in HUVECs was silenced using siRNA. Changes in morphology, proliferation, migration, and tube formation activity of cells were observed after RRP treatment. Quantitative Real-Time PCR and western blot analysis were employed to monitor mRNA and protein expression. Results: RRP treatment reduced the atherosclerotic area and lipid levels and improved endothelial function in ApoE-/- mice. RRP significantly repaired cell morphology, reduced excessive cell proliferation, and ameliorated migration and tube formation activity. In addition, RRP affected the FAK-PI3K/Akt signaling pathway. Importantly, Piezo1 silencing abolished the protective effects of RRP. Conclusion: RRP has anti-atherosclerotic effects and antagonizes endothelial cell damage via modulating the FAK-PI3K/Akt signaling pathway. Piezo1 is a possible target of RRP in the treatment of atherosclerosis. Thus, RRP has promising therapeutic potential and broad application prospect for atherosclerosis.