Anti-rheumatoid arthritis effects of total saponins from Rhizoma Panacis Majoris on adjuvant-induced arthritis in rats and rheumatoid arthritis fibroblast-like synoviocytes.

BACKGROUND: Total saponins from Rhizoma Panacis Majoris (RPMTG) showed significant antitumour activity in our previous studies. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) with tumour-like characteristics have received attention as a therapeutic target for RA. However, the potential effect and mechanism of action of RPMTG against RA-FLS remain unclear. OBJECTIVE: The study investigated the therapeutic effect of RPMTG on adjuvant-induced arthritis (AIA) in rats, and the regulation effect and underlying mechanism on apoptosis, autophagy of RA-FLS. METHODS: The therapeutic effect of RPMTG was determined by the symptoms and signs of AIA rats. The production of inflammatory cytokines was detected by ELISA. Histopathological change of the ankle and synovial tissues were detected by HE staining. Flow cytometry, Hoechst 33342/PI staining, MDC staining, and TEM were used to determine the effects of RPMTG on apoptosis and autophagy. Western blotting was applied to detect the expression levels of proteins. RESULTS: In AIA rats, RPMTG treatment ameliorated paw swelling, and arthritis score, restored synovial histopathological changes, inhibited the expression of IL-6 and IL-1ß, exhibiting its potent anti-arthritis effect. In vitro, RPMTG depressed the proliferation of RA-FLS, arrested cell cycle in G0/G1 phase, and induced mitochondria-mediated apoptosis. Moreover, RPMTG significantly inhibited the autophagy in vivo and in vitro, proved by decreasing the expression of autophagy-related indicators (LC3II/LC3I, Beclin-1). Mechanistically, the study demonstrated that the activation of p38 MAPK and PI3K/Akt/mTOR pathways was mainly involved in the therapeutic effects of RPMTG. Interestingly, the effect of RPMTG on apoptosis was reversed after Rapamycin treatment, which preliminarily demonstrated that the inhibitory effect of RPMTG on autophagy was beneficial to the effect on inducing apoptosis. The regulation effect of RPMTG concurrently on apoptosis and autophagy revealed its unique advantages in RA treatment. CONCLUSION: RPMTG showed potent therapeutic effects on AIA rats and induced apoptosis, inhibited autophagy mainly through activating the p38 MAPK and PI3K/Akt/mTOR pathways in RA-FLS.

Network Pharmacology Integrated Molecular Docking to Reveal the Autism and Mechanism of Baohewan Heshiwei Wen Dan Tang.

BACKGROUND: In recent years, the prevalence and mortality of autism spectrum disorder (ASD) have been increasing. The clinical features are different with different cases, so the treatment ways are different for each one. OBJECTIVE: Baohewan Heshiwei Wen Dan Tang (BHWDT) has been recommended for treating autistic spectrum disorder. To investigate the mechanism of action and how the compounds interact with ASD targets, network pharmacology and molecular docking methods were used in this study. METHODS: Traditional Chinese Medicine Systems Pharmacology (TCMSP) was used to screen the active components according to index of oral bio-activity and drug-likeness. Then, TCMSP and Swiss Target Prediction databases were used to screen potential target genes of active components. The related target genes of ASD were obtained from the Gene Cards database. Matescape database was utilized to get gene ontology (GO) function enrichment and Kyoto Encyclopedia of Genes and Genomes pathway annotation of gene targets. Composition- target-pathway (C-T-P) and a protein-protein interaction (PPI) networks were built with Cytoscape 3.8.2 software. RESULTS: The interaction of the main active components of BHWDT was verified by molecular docking. The key targets of MAPK1, IL6, CXCL8 and TP53 of BHWDT were obtained. The key active components Quercetin, Kaempferol and Iuteolin of BHWDT could bind with MAPK1, IL6, CXCL8 and TP53 of BHWDT, respectively. CONCLUSION: BHWDT can be highly effective for treating ASD and this study can help us to understand multiple targets and multiple pathways mechanism.

A Smart Theranostic Nanocapsule for Spatiotemporally Programmable Photo-Gene Therapy.

The therapeutic performance of DNAzyme-involved gene silencing is significantly constrained by inefficient conditional activation and insufficient cofactor supply. Herein, a self-sufficient therapeutic nanosystem was realized through the delicate design of DNAzyme prodrugs and MnO2 into a biocompatible nanocapsule with tumor-specific recognition/activation features. The indocyanine green (ICG)-modified DNA prodrugs are designed by splitting the DNAzyme and then reconstituted into the exquisite catalyzed hairpin assembly (CHA) amplification circuit. Based on the photothermal activation of ICG, the nanocapsule was disassembled to expose the MnO2 ingredient which was immediately decomposed into Mn2+ ions to supplement an indispensable DNAzyme cofactor on-demand with a concomitant O2 generation for enhancing the auxiliary phototherapy. The endogenous microRNA catalyzes the amplified assembly of DNA prodrugs via an exquisite CHA principle, leading to the DNAzyme-mediated simultaneous silencing of two key tumor-involved mRNAs. This self-activated theranostic nanocapsule could substantially expand the toolbox for accurate diagnosis and programmable therapeutics.

Silver-Laden Black Phosphorus Nanosheets for an Efficient In Vivo Antimicrobial Application.

Nanobactericides represent one of the most efficient and promising strategies for eliminating bacterial infection considering the increasing resistance threats of conventional antibiotics. Black phosphorus (BP) is the most exciting postgraphene layered 2D nanomaterial with convincing physiochemical properties, yet the study of BP-based antibiotics is still in its infancy. Here, a compact silver nanoparticle (AgNP)-doped black phosphorus nanosheet (BPN) is constructed to synergistically enhance solar disinfection through the promoted reactive oxygen species (ROS) photogeneration, which is attributed to the improved electron-hole separation and recombination of BPNs as revealed from the systematic experimental studies. An in-depth density functional theory (DFT) calculation confirms that the integrated AgNPs provide a preferred site for facilitating the adsorption and activation of O2 , thus promoting the more efficient and robust ROS generation on BPN-AgNP nanohybrids. Besides the enhanced photoinduced ROS, the anchored AgNPs simultaneously lead to a dramatically increased affinity toward bacteria, which facilitates a synergetic pathogen inactivation. Significantly, the convincing antimicrobial BPN-AgNP contributes to the prominent wound healing and antimicrobial ability in vivo with minimized biological burden. This sophisticated design of new 2D nanohybrids opens a new avenue for further exploiting BP-based nanohybrids in portable bandage and broad-spectrum disinfection applications.

A negative feedback loop of H19/miR-675/VDR mediates therapeutic effect of cucurmin in the treatment of glioma.

Curcumin (CUR) shows a remarkable antitumor activity against a wide range of cancers such as glioma, but its underlying mechanism remains elusive. In this study, we aimed to explore the potential role of H19/miR-675/vitamin D receptor (VDR) in the effect of CUR against glioma. Real-time polymerase chain reaction and western-blot analysis were used to study the effect of CUR or 1,25-dihydroxyvitamin D (1,25(OH)2 D3 ) on the expression of H19, miR-675, and VDR. In addition, the effect of H19 on VDR expression was also studied. Furthermore, the expression of H19, miR-675, and VDR between CUR-loaded nanoparticles (NPs) and NP groups was compared, and the interaction among H19, miR-675, and VDR was analyzed by in-silicon and luciferase assays. In a dose-dependent manner, CUR and 1,25(OH)2 D3 both downregulated the expression of H19 and miR-675 but increased the expression of VDR. In addition, H19 evidently reduced the mRNA and protein levels of VDR. Furthermore, VDR was confirmed as a target gene of miR-675, which significantly reduced the expression of VDR. Finally, the administration of CUR evidently decreased tumor volume. CUR-loaded NP group exhibited lower levels of H19 and miR-675, while the NP group showed higher levels of VDR mRNA and protein. In summary, it is the first time that the involvement of a negative feedback loop of H19/miR-675/VDR has been demonstrated in the development of glioma. Therefore, H19 might serve as a new biomarker for the diagnosis and treatment of glioma.

Peptide Multifunctionalized Gold Nanorods with Dual pH/NIR Responsive Release of Doxorubicin for High-Efficiency Cancer Treatment.

In this study, gold nanorods (GNRs), uniformly coated with polydopamine (PDA), were developed as a multifunctional nanocarrier for targeted, pH, and near infrared (NIR) irradiation dual-stimuli triggered drug delivery. Doxorubicin (DOX), a hydrophobic chemotherapeutic drug, was conveniently and heavily loaded into the nanocarrier through π-π stacking and hydrogen bonding interactions. It was further passivated by thiolated poly(ethylene glycol)-tumor homing peptides (NGR and TAT) to improve its cancer tissue penetrating, and accurate targeting ability. The developed NGR/TAT-DOX-PDA@GNRs could not only specifically and effectively deliver therapeutic agents to the tumor sites, but also facilitated controlled release of DOX, triggered via pH and near infrared light dual-stimuli. The studies of tumor cell ablation confirmed that this chemo-photothermal synergistic therapy offered superior therapeutic efficacy, improved chemosensitivity, and enhanced chemotherapeutic efficacy. Therefore, this combination of photothermal therapy and chemotherapy, based on NGR/TAT-DOX-PDA@GNRs, can maximize the therapeutic efficacy, and minimize the dosage-related adverse effects in cancer treatment.

[Integripetal rhodiola herb attenuates high altitude-induced pulmonary arterial remodeling and expression of vascular endothelial growth factor in rats].

The aim of this study was to investigate the effect of integripetal rhodiola herb on pulmonary arterial remodeling and expression of vascular endothelial growth factor (VEGF) in high altitude pulmonary hypertension in rats. Fifty healthy male Wistar rats were divided into five groups randomly: Plain control group (LC group), 10-day plateau group (H(10) group), 30-day plateau group (H(30) group), 10-day rhodiola-treated plateau group (R(10) group), and 30-day rhodiola-treated plateau group (R(30) group). Each group included 10 rats. The rats in LC group were kept in Chengdu (500 meters above sea level), and rats in H and R groups were kept in Lhasa (3 700 meters above sea level). The rats in R group were daily treated with integripetal rhodiola herb extract (24%, 10 mL/kg) intragastrically for 10 d or 30 d, while rats in LC and H groups were treated with the same volume of saline. Mean pulmonary arterial pressure (mPAP) was detected via a catheter in the pulmonary artery by pressure waveform monitoring. The ratio value of right ventricle weight to left ventricle plus septum weight [RV/(LV + S)] was measured. The microstructure of pulmonary arterioles was examined by electron microscopy. The expression of VEGF in the lung was investigated using immunohistochemistry. The results showed that mPAP and [RV/(LV + S)] in H(10) group and H(30) group were higher than those in LC group (P < 0.05); but there was no significant difference between H(10) group and R(10) group (P < 0.05); and mPAP and [RV/(LV + S)] in H(30) group were lower than those in H(30) group (P < 0.05). Electron microscopy showed that compared to LC group, arteriolar endothelial cells were arranged in a columnar or palisading form, protruding into the lumen, accompanied with luminal stenosis, irregular internal elastic membrane, and proliferation of vascular smooth muscle cells in H groups, which was more obvious in H(30) group than in H(10) group; while these pathological changes were attenuated in the R groups compared to H groups. The levels of VEGF protein in H groups were also higher than those in LC group (P < 0.05); while the expression of VEGF in R(30) group was lower than that in H(30) group. In summary, the results show that the integripetal rhodiola herb can attenuate high altitude-induced pulmonary arterial remodeling in rats, and the inhibition of VEGF protein expression by rhodiola may be one of the mechanisms.

Integripetal rhodiola herb attenuates high altitude-induced pulmonary arterial remodeling and expression of vascular endothelial growth factor in rats / 生理学报

The aim of this study was to investigate the effect of integripetal rhodiola herb on pulmonary arterial remodeling and expression of vascular endothelial growth factor (VEGF) in high altitude pulmonary hypertension in rats. Fifty healthy male Wistar rats were divided into five groups randomly: Plain control group (LC group), 10-day plateau group (H(10) group), 30-day plateau group (H(30) group), 10-day rhodiola-treated plateau group (R(10) group), and 30-day rhodiola-treated plateau group (R(30) group). Each group included 10 rats. The rats in LC group were kept in Chengdu (500 meters above sea level), and rats in H and R groups were kept in Lhasa (3 700 meters above sea level). The rats in R group were daily treated with integripetal rhodiola herb extract (24%, 10 mL/kg) intragastrically for 10 d or 30 d, while rats in LC and H groups were treated with the same volume of saline. Mean pulmonary arterial pressure (mPAP) was detected via a catheter in the pulmonary artery by pressure waveform monitoring. The ratio value of right ventricle weight to left ventricle plus septum weight [RV/(LV + S)] was measured. The microstructure of pulmonary arterioles was examined by electron microscopy. The expression of VEGF in the lung was investigated using immunohistochemistry. The results showed that mPAP and [RV/(LV + S)] in H(10) group and H(30) group were higher than those in LC group (P < 0.05); but there was no significant difference between H(10) group and R(10) group (P < 0.05); and mPAP and [RV/(LV + S)] in H(30) group were lower than those in H(30) group (P < 0.05). Electron microscopy showed that compared to LC group, arteriolar endothelial cells were arranged in a columnar or palisading form, protruding into the lumen, accompanied with luminal stenosis, irregular internal elastic membrane, and proliferation of vascular smooth muscle cells in H groups, which was more obvious in H(30) group than in H(10) group; while these pathological changes were attenuated in the R groups compared to H groups. The levels of VEGF protein in H groups were also higher than those in LC group (P < 0.05); while the expression of VEGF in R(30) group was lower than that in H(30) group. In summary, the results show that the integripetal rhodiola herb can attenuate high altitude-induced pulmonary arterial remodeling in rats, and the inhibition of VEGF protein expression by rhodiola may be one of the mechanisms.