Potential Therapeutic Targets of Rehmannia Formulations on Diabetic Nephropathy: A Comparative Network Pharmacology Analysis.

Background: Previous retrospective cohorts showed that Rehmannia-6 (R-6, Liu-wei-di-huang-wan) formulations were associated with significant kidney function preservation and mortality reduction among chronic kidney disease patients with diabetes. This study aimed to investigate the potential mechanism of action of common R-6 variations in a clinical protocol for diabetic nephropathy (DN) from a system pharmacology approach. Study Design and Methods: Disease-related genes were retrieved from GeneCards and OMIM by searching "Diabetic Nephropathy" and "Macroalbuminuria". Variations of R-6 were identified from a published existing clinical practice guideline developed from expert consensus and pilot clinical service program. The chemical compound IDs of each herb were retrieved from TCM-Mesh and PubChem. Drug targets were subsequently revealed via PharmaMapper and UniProtKB. The disease gene interactions were assessed through STRING, and disease-drug protein-protein interaction network was integrated and visualized by Cytoscape. Clusters of disease-drug protein-protein interaction were constructed by Molecular Complex Detection (MCODE) extension. Functional annotation of clusters was analyzed by DAVID and KEGG pathway enrichment. Differences among variations of R-6 were compared. Binding was verified by molecular docking with AutoDock. Results: Three hundred fifty-eight genes related to DN were identified, forming 11 clusters which corresponded to complement and coagulation cascades and signaling pathways of adipocytokine, TNF, HIF-1, and AMPK. Five variations of R-6 were analyzed. Common putative targets of the R-6 variations on DN included ACE, APOE, CCL2, CRP, EDN1, FN1, HGF, ICAM1, IL10, IL1B, IL6, INS, LEP, MMP9, PTGS2, SERPINE1, and TNF, which are related to regulation of nitric oxide biosynthesis, lipid storage, cellular response to lipopolysaccharide, inflammatory response, NF-kappa B transcription factor activity, smooth muscle cell proliferation, blood pressure, cellular response to interleukin-1, angiogenesis, cell proliferation, peptidyl-tyrosine phosphorylation, and protein kinase B signaling. TNF was identified as the seed for the most significant cluster of all R-6 variations. Targets specific to each formulation were identified. The key chemical compounds of R-6 have good binding ability to the putative protein targets. Conclusion: The mechanism of action of R-6 on DN is mostly related to the TNF signaling pathway as a core mechanism, involving amelioration of angiogenesis, fibrosis, inflammation, disease susceptibility, and oxidative stress. The putative targets identified could be validated through clinical trials.

Erythrocyte membrane bioengineered nanoprobes via indocyanine green-directed assembly for single NIR laser-induced efficient photodynamic/photothermal theranostics.

Traditional combinational photodynamic therapy (PDT) and photothermal therapy (PTT) were limited in clinical therapy of cancer due to exceptionally low drug payload and activation by light with separate wavelengths. We have accidentally discovered that zinc phthalocyanine (ZNPC, a typical hydrophobic photosensitizer) and indocyanine green (ICG, a clinically approved fluorescence probe) could be co-assembled into carrier-free nanodrugs (almost 100 wt%) for single NIR laser-induced efficient PDT/PTT. Interestingly, ICG could act as "transformers" for modulating the geometric shape of ZNPC/ICG co-assembling structures from needle-like/spindle-like structure via cubic structure finally to spherical structure. Unfortunately, the nanodrugs suffered from rapid immune clearance. The ZNPC-ICG nanoprobes were further embedded into the erythrocyte membrane (RBC)-camouflaged framework. The designed ZNPC-ICG@RBC could be efficiently accumulated within the tumor sites (continue for ~60 h) and rapidly internalized into cancer cells upon laser irradiation rather than macrophage RAW264.7 cells. Compared with the free ZnPC or ICG, the biomimetic ZNPC-ICG@RBC nanoprobes exhibited amplified therapeutic effects by simultaneously producing ROS and hyperthermia, thereby synergistically improving antitumor efficiency and eliminating the tumors without any regrowth under the guidance of fluorescence imaging. The co-delivery of ZnPC and ICG via a biomimetic carrier-free system might be a promising strategy for bimodal phototherapy of cancer.

Distinguish the Role of Radiotherapy From Chemoradiotherapy for Gastric Cancer With Behavior of Metastasis-Indolent in Lymph Node.

BACKGROUND: Although the landmark INT-0116 trial and National Comprehensive Cancer Network (NCCN) guidelines recommended pT3-4Nx gastric cancer (GC) patients to receive chemoradiotherapy, the role of radiotherapy has not been distinguished from chemoradiotherapy. METHODS: GC with behavior of metastasis-indolent in lymph node (MILN) being confirmed with more than 15 examined LNs after gastrectomy were identified using the Surveillance, Epidemiology and End Result (SEER) database. The cancer-specific survival (CSS) of subgroups for radiotherapy, chemotherapy, chemoradiotherapy and non-adjuvant-treatment were compared. Propensity score matching (PSM) was performed between radiotherapy and non-radiotherapy subgroups to further distinguish the role of radiotherapy from chemoradiotherapy. Cox regression was performed to identify whether radiotherapy or chemotherapy could independently improve prognosis. RESULTS: We identified 690 MILN GC patients in SEER database. 5-year CSS was 71.9% in radiotherapy subgroup and 75.1% in non-radiotherapy subgroup(HR = 1.013, 95% CI = 0.714-1.438, p = 0.940), 75.6% in chemotherapy subgroup and 68.5% in non-chemotherapy subgroup(HR = 0.616, 95% CI = 0.430-0.884, p = 0.008), 52.5% in radiotherapy-alone subgroup and 71.9% in non-adjuvant treatment group (HR = 1.604, 95% CI = 0.575-4.471, p = 0.360), 72.9% in chemoradiotherapy subgroup and 79.5% in chemotherapy-alone subgroup (HR = 1.365, 95% CI = 0.859-2.172, p = 0.185), respectively. Further, PSM markedly improved balance of variables between radiotherapy subgroup and non-radiotherapy subgroup. After PSM, the role of the variables of radiotherapy and chemotherapy in contributing to improving CSS are consistent with that before PSM. Cox regression showed chemotherapy, tumor size, tumor invasiveness and Lauren classification were independent prognostic factors, but not including radiotherapy. CONCLUSIONS: Chemoradiotherapy confers superior prognosis to MILN GC patients compared with surgery alone might only be attributed to chemotherapy rather than radiotherapy.

[Comparative study on differences of resin-containing drugs in Dracaena from different appearance based on HS-GC-MS and chemometrics].

Resin-containing drugs in Dracaena from four different appearances were analyzed by headspace sampling-gas chromatography-mass spectrometry(HS-GC-MS) metabolomics technique and hierarchical clustering analysis(HCA) chemometrics method. This study was to analyze differential volatile components in resin-containing drugs in Dracaena from different appearance and metabolic pathways. The results of partial least squares discriminant analysis(PLS-DA) and HCA analysis indicated that there was little difference in volatile components between fiber-rich sample and hollow cork cambium sample, however, the volatile components in the two samples compared with whole body resin-containing sample and resin-secreting aggregated sample had a large metabolic difference. Twenty differential metabolites were screened by VIP and P values of PLS-DA. The content of these differential metabolites was significantly higher in whole body resin-containing sample and resin-secreting aggregated sample than in fiber-rich sample and hollow cork cambium sample. Sixteen significant metabolic pathways were obtained through enrichment analysis(P<0.05), mainly involved in terpenoids biosynthesis and phenylpropanoid metabolism. This result provided a reference for further study of resin formation mechanism of resin-containing drugs in Dracaena from different appearances. At the same time, it also provided a reference for establishing a multi-index quality evaluation system.

Zinc phthalocyanine-soybean phospholipid complex based drug carrier for switchable photoacoustic/fluorescence image, multiphase photothermal/photodynamic treatment and synergetic therapy.

For the purpose of precision theranostic of tumor, multifunctional drug delivery systems are always receiving great attentions. Here, we developed a zinc phthalocyanine-soybean phospholipid (ZnPc-SPC) complex based drug delivery system with doxorubicin (Dox) as loading cargo to achieve additional chemotherapy while the carrier itself could serve as multifunctional and switchable theranostic agent. In the early phase, the ZnPc-SPC complex assembled to nanostructure displaying photothermal therapy (PTT) and photoacoustic (PA) properties while in the late phase, the prepared NPs dis-assembled into ZnPc-SPC complex again performing photodynamic therapy (PDT) and low-background fluorescence (FL) image. With the decoration of folate receptors α (FRα) targeted MTX, Dox-loaded, MTX-decorated self-assembled ZnPc-SPC complex NPs (DZSM) was formed. In vitro and in vivo evaluations both indicated that DZSM presented high selectivity for FRα over-expressed tumor cells, excellent switchable PA/FL image, significant multiphase PTT/PDT effect, as well as great synergetic therapy potential, leading to notable inhibition of tumor growth.

Light/magnetic hyperthermia triggered drug released from multi-functional thermo-sensitive magnetoliposomes for precise cancer synergetic theranostics.

Precise delivery of antineoplastic drugs to specific tumor region has drawn much attention in recent years. Herein, a light/magnetic hyperthermia triggered drug delivery with multiple functionality is designed based on methotrexate (MTX) modified thermo-sensitive magnetoliposomes (MTX-MagTSLs). In this system, MTX and oleic acid modified magnetic nanoparticles (MNPs) can be applied in biological and magnetic targeting. Meanwhile, lipophilic fluorescent dye Cy5.5 and MNPs are encapsulated into the bilayer of liposomes, which can not only achieve dual-imaging effect to verify the MTX-MagTSLs accumulation in tumor region, but also provide an appropriate laser irradiation region to release Doxorubicin (Dox) under alternating magnetic field (AMF). Both in vitro and in vivo results revealed that MTX-MagTSLs possessed an excellent targeting ability towards HeLa cells and HeLa tumor-bearing mice. Furthermore, the heating effect of MTX-MagTSLs was amplified 4.2-fold upon combination with AMF and local precise near-infrared laser irradiation (808nm) (DUAL-mode) to rapidly reach the phase change temperature (Tm) of MTX-MagTSLs in 5min compared with either AMF or laser stimulation alone, resulting in a significantly enhanced release of Dox at tumor region and precise cancer synergetic theranostics.

Chemotherapeutic drug-photothermal agent co-self-assembling nanoparticles for near-infrared fluorescence and photoacoustic dual-modal imaging-guided chemo-photothermal synergistic therapy.

Multimodal imaging-guided synergistic combination therapy has shown great potential for cancer treatment. However, the nanocarrier-based theranostic systems suffer from batch-to-batch variation, complexity of multicomponent, poor drug loading, and carrier-related toxicity issues. To address these issues, herein we developed a novel carrier-free theranostic system with nanoscale characteristics for near-infrared fluorescence (NIRF) and photoacoustic (PA) dual-modal imaging-guided synergistic chemo-photothermal therapy (PTT). Indocyanine green (ICG) and epirubicin (EPI) could co-self-assemble into small molecular nanoparticles (NPs) in aqueous solution without any molecular precursor or excipient via collaborative interactions (electrostatic, π-π stacking, and hydrophobic interactions). The exceptionally high dual-drug loading (∼92wt%) ICG-EPI NPs showed good physiological stability, preferable photothermal response, excellent NIRF/PA imaging properties, pH-/photo-responsive drug release behavior, and promoted cellular endocytosis compared with free ICG or EPI. Importantly, the ICG-EPI NPs showed excellent tumor targeting ability with high spatial resolution and deep penetration via in vivo NIRF/PA dual-modal imaging. Moreover, in comparison with individual chemotherapy or PTT, the combinational chemo-PTT therapy of ICG-EPI NPs with NIR laser irradiation synergistically induced apoptosis and death of cancer cells in vitro, and showed synergistic chemo-PTT efficiency in vivo as evidenced by highly efficient tumor ablation. Furthermore, the ICG-EPI NPs exhibited inappreciable toxicity. This co-self-assembly of both FDA-approved agents provides a safe and "Molecular economical" strategy in the rational design of multifunctional nano-theranostic systems for real-time self-monitoring intracellular drug delivery and targeting multimodal imaging-guided synergistic combination therapy.