Co-Administration of iRGD with Sorafenib-Loaded Iron-Based Metal-Organic Framework as a Targeted Ferroptosis Agent for Liver Cancer Therapy.

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most common fatal cancers, with no curative therapy available. The concept of ferroptosis is attracting increasing attention in cancer research. Herein, we describe the use of a nanodevice as an effective strategy for inducing ferroptosis to manage HCC. METHODS: To improve ferroptosis-induced treatment of HCC, we constructed sorafenib (sor)-loaded MIL-101(Fe) nanoparticles (NPs) [MIL-101(Fe)@sor] and evaluated the efficacy of ferroptosis-based HCC therapy after co-administration with the iRGD peptide both in vitro and in vivo. RESULTS: The prepared MIL-101(Fe) NPs have several promising characteristics including drug-loading, controllable release, peroxidase activity, biocompatibility, and T2 magnetic resonance imaging ability. MIL-101(Fe)@sor NPs significantly induced ferroptosis in HepG2 cells, increased the levels of lipid peroxidation and malondialdehyde, and reduced those of glutathione and glutathione peroxidase 4 (GPX-4). The in vivo results showed that the MIL-101(Fe)@sor NPs significantly inhibited tumor progression and decreased GPX-4 expression levels, with negligible long-term toxicity. Meanwhile, co-administration of MIL-101(Fe)@sor NPs with iRGD significantly accelerated ferroptosis. CONCLUSION: Our findings suggest that MIL-101(Fe)@sor NPs co-administered with iRGD are a promising strategy for inducing HCC ferroptosis.

The efficacy and safety of Lianhua Qingwen (LHQW) for coronavirus disease 2019 (COVID-19): A protocol for systematic review and meta analysis.

BACKGROUND: Since the outbreak of Novel Coronavirus Pneumonia (NCP), it has swept the world with rapid development. Up to now, there is no effective drug to treat it. Lianhua Qingwen has been used in the treatment of COVID-19 in China, but there is no systematic review about it. This study will systematically evaluate its efficacy and safety in the treatment of COVID-19. METHODS: We will search electronic database of PubMed, EMBASE, Cochrane library, Web of Science (WOS), China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Chinese Scientific and Journal Database (VIP) and Wan Fang database (Wanfang) for the literature of RCTs of Lianhua Qingwen capsule for coronavirus disease 2019 (COVID-19). We will also search the Chinese Clinical Trial Registry (ChiCTR) and ClinicalTrials.gov (www.ClinicalTrials.gov) for ongoing trials with unpublished data, and the Conference abstracts will be searched manually. We will use the Cochrane Handbook for Systematic Reviews of Interventions to assess the risk of bias. The protocol will be conducted according to the approach and Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). RESULTS: The study results will provide evidence of the efficacy and safety of Lianhua Qingwen (LHQW) for coronavirus disease 2019 (COVID-19). CONCLUSION: The result of the study will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42020180877.

Efficacy of acupuncture and moxibustion in adjuvant treatment of patients with novel coronavirus disease 2019 (COVID-19): A protocol for systematic review and meta analysis.

BACKGROUND: Novel coronavirus has infected 4.33 million people in more than 200 countries in the current global outbreak of COVID-19. However, there is still no effective drug to treat the disease, and acupuncture and moxibustion is utilized as adjuvant therapy for the treatment of COVID-19 in China. METHODS: Nine electronic databases: PubMed, EMBASE, Cochrane library, Web of Science (WOS), Google Scholar, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Chinese Scientific and Journal Database (VIP), Wan Fang database (Wanfang) and 2 clinical trials register platforms: Chinese Clinical Trial Registry (ChiCTR), ClinicalTrials.gov (www.ClinicalTrials.gov/) will be searched for RCTs of A&M for COVID-19. The screening process will be developed by 2 independent reviewers, and meta-analysis will be performed with RevMan (V5.3.5) software. RESULTS: The study results will be contributed to a scientific journal after peer-reviewed for publication. CONCLUSION: The study will provide up-to-date evidence of the effectiveness and safety of A&M for patients with COVID-19. PROSPERO REGISTRATION NUMBER: CRD42020185776.

The efficacy and safety of Jinhua Qinggan granule (JHQG) in the treatment of coronavirus disease 2019 (COVID-19): A protocol for systematic review and meta analysis.

BACKGROUND: Currently, the global number of infected novel coronavirus has exceeded 2.6 million and the death toll has exceeded 170,000, but the specific drug for the treatment of COVID-19 has been not appears. In the process of fighting COVID-19 in China, JHQG has been promoted by the Chinese government and widely used in the treatment of COVID-19. The purpose of this study is to systematically evaluate the efficacy and safety of JHQG for COVID-19. METHODS: We are going to search the electronic databases: PubMed, EMBASE, Cochrane library, Web of Science (WOS), Google scholar, China National Knowledge Infrastructure (CNKI), Chinese Biomedical literature Database (CBM), Chinese Scientific and Journal Database (VIP), Wan Fang database (Wanfang) for published clinical trails and search clinical trials register platforms of Chinese Clinical Trial Registry (ChiCTR) and ClinicalTrials.gov (www.ClinicalTrials.gov/) for ongoing trials of Jinhua Qinggan granule for COVID-19. The primary outcomes of the included studies contain Clinical symptom disappearance rate and the secondary outcomes obtain: TCM syndrome scale score, Hamilton anxiety scale score, and adverse events. We will use RevMan V5.3 software to perform the calculations. PRISMA-P checklist was used in writing this report. RESULTS: The study results will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study will provide a high-quality evidence of the efficacy and safety of Jinhua Qinggan granule on patients with COVID-19. PROSPERO REGISTRATION NUMBER: CRD42020181919.

Delivery of Arsenic Trioxide by Multifunction Nanoparticles To Improve the Treatment of Hepatocellular Carcinoma.

Arsenic trioxide (ATO) is effective in the treatment of hematological malignancies and solid tumors. However, its toxicity and side effects are severe, posing an obstacle in its clinical application. A controlled-release ATO carrier with mitochondrial targeting was constructed in this study. The safety and efficacy in vitro were investigated using a hemolysis test, cytotoxicity, proliferation, migration, apoptosis, and other changes in cell behavior. The safety and efficacy were further evaluated in vivo by hematoxylin-eosin staining, terminal deoxyribonucleotide transferase-mediated dUTP nick end labeling staining, and blood testing in tumor-bearing mice. Immunohistochemically and western blotting experiments were conducted to explore the mechanism of combination therapy of material-based chemotherapy and microwave hyperthermia in vitro. We demonstrated that the nano-zirconia (ZrO2) loading platform may be used to administer the ATO, with local precision-controlled release and mitochondrial targeting. Furthermore, we showed the safety of this approach for delivering high doses of ATO. In addition, we explored this new method in combination with in vitro microwave heat therapy, providing a potentially novel intravenous approach to chemotherapy. We described a new non-invasive treatment that improved the efficacy of ATO chemotherapy against hepatocellular carcinoma through nano-ZrO2 carriers.

Transcatheter arterial chemoembolization (TACE) with iRGD peptide in rabbit VX2 liver tumor.

PURPOSE: Transcatheter arterial chemoembolization (TACE) is the first-line therapy for unresectable hepatocellular carcinoma (HCC). However, its therapeutic effects are hampered by the poor distribution of anticancer drugs in tumors. iRGD, a novel tumor-penetrating peptide, enhances the penetration distance and therapeutic efficacy of anticancer drugs. Herein, we evaluated the therapeutic effects of iRGD coupled with TACE in the rabbit VX2 liver tumor model. SUBJECTS AND METHODS: This study had two stages: tumor permeability assay and anticancer efficacy evaluation. In the tumor permeability assay, we coadministered TACE with either iRGD + lipiodol-doxorubicin emulsion (LDE) or LDE in the rabbit VX2 liver tumor model. We evaluated the doxorubicin (DOX) distribution at predetermined times by immunofluorescence microscopy. To evaluate anticancer efficacy, we administered saline, LDE, or iRGD + LDE to tumor-grafted rabbits. We measured tumor volume using magnetic resonance scanning. We quantified the expression levels of Bax, Bcl-2, and cleaved caspase-3 using Western blot (WB) analysis and determined the apoptosis rate in tumor cells using transferase-mediated dUTP nick-end labeling assay. RESULTS: The iRGD + LDE infusion significantly increased the DOX concentration and DOX penetration in tumors compared with the LDE infusion (P < 0.05). The antitumor efficacy of the iRGD + LDE in tumor inhibition was higher than that of the other treatments (P < 0.05). Besides, iRGD + LDE induced more apoptosis (P < 0.05). CONCLUSIONS: We demonstrated that iRGD coadministered with TACE is effective against HCC.

Transarterial Infusion of iRGD-Modified ZrO2 Nanoparticles with Lipiodol Improves the Tissue Distribution of Doxorubicin and Its Antitumor Efficacy.

PURPOSE: To evaluate the effect of transarterial infusion of iRGD-modified and doxorubicin-loaded zirconia-composite nanoparticles (R-DZCNs) with lipiodol in the improvement of the distribution of doxorubicin (DOX) in liver tumors and its antitumor efficacy. MATERIALS AND METHODS: The effect of R-DZCNs was evaluated in vitro by tumor cellular uptake and cytotoxicity assays. For the in vivo study, DOX distribution and antitumor efficiency were assessed. In the DOX distribution study, VX2 tumor-bearing rabbits received transarterial infusion of lipiodol with DOX, doxorubicin-loaded zirconia-composite nanoparticles (DZCNs), or R-DZCNs, respectively. DOX distribution was assessed by immunofluorescence. In the antitumor study, tumor-bearing rabbits received transarterial infusions of lipiodol with DOX, DZCNs, R-DZCNs, or saline respectively. Tumor volume was measured using magnetic resonance imaging, and the expression of apoptosis-related factors (caspase-3, Bax, Bcl-2) was analyzed by immunohistochemistry and Western blotting. RESULTS: R-DZCNs increased cellular uptake and caused stronger cytotoxicity. Compared with the DOX + lipiodol or DZCNs + lipiodol group, the R-DZCNs + lipiodol group showed more DOX fluorescence spots (2,449.15 ± 444.14 vs. 3,464.73 ± 632.75 or 5,062.25 ± 585.62, respectively; P < .001) and longer penetration distance (117.58 ± 19.36 vs 52.64 ± 8.53 or 83.37 ± 13.76 µm, respectively; P < .001). In the antitumor study, the R-DZCNs + lipiodol group showed smaller tumor volumes than the DOX + lipiodol or DZCNs + lipiodol group (1,223.87 ± 223.58 vs. 3,695.26 ± 666.25 or 2281.06 ± 457.21 mm3, respectively; P = .005).The greatest extent of tumor cell apoptosis was observed in R-DZCNs + lipiodol group immunohistochemistry and Western blotting results. CONCLUSIONS: Transarterial infusion of R-DZCNs with lipiodol improved the distribution of DOX and enhanced its antitumor efficacy.

Blocking and reversing hepatic fibrosis in patients with chronic hepatitis B treated by traditional Chinese medicine (tablets of biejia ruangan or RGT): study protocol for a randomized controlled trial.

BACKGROUND: Chronic hepatitis B (CHB) can progress to cirrhosis, hepatocellular carcinoma (HCC) and ultimately liver-related death. Although oral antiviral therapy for patients with CHB reduces the risk of such complications, once cirrhosis is established, the benefits of antiviral therapy are not robustly demonstrated. According to traditional Chinese medicine (TCM), some Chinese herbal medicines promote blood circulation and soften hard masses, and therefore they may block and reverse hepatic fibrosis. The aim of this study is to evaluate the effects of TCM tablets of the compound biejia ruangan (RGT) administered for fibrosis, and entecavir (ETV), on the development of HCC in patients with CHB or hepatitis B virus (HBV)-related compensated cirrhosis. METHODS/DESIGN: This multicenter, centrally randomized, double-blind, placebo-controlled, parallel-group study is planned to complete within 5 years. For the study, 1,000 with CHB or HBV-related compensated cirrhosis are randomly assigned in a 1:1 ratio to a treatment group (0.5 mg ETV once daily; 2 g RGT three times daily) or a control group (0.5 mg ETV once daily; 2 g RGT dummy agent three times daily). The primary end points are the development of HCC and liver-related death. Secondary end points include disease progression and overall survival. DISCUSSION: Although antiviral therapy can achieve sustained suppression of HBV replication, thereby preventing cirrhosis, patients with CHB treated with nucleos(t)ide analogs (NUCs) retain a higher risk for HCC compared with patients with inactive disease. Although previous clinical trials with RGT have confirmed the efficacy of blocking and reversing hepatic fibrosis in patients with CHB or compensated cirrhosis, the long-term risk for HCC or disease progression in these patients treated with combination of RGT and NUCs compared with NUCs alone is unclear. Therefore, it is necessary to investigate the effects of the RGT blockade and reversal of hepatic fibrosis on the development of HCC in patients with CHB or HBV-related compensated cirrhosis in large, prospective, multicenter, double-blind, randomized, controlled trials in China. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01965418. Date registered: 17 October 2013.

[Analysis of trace elements and macro elements in 13 anti-anoxic traditional Tibetan medicine].

Thirteen kinds of anti-anoxic Tibetan traditional medicine including Hongjingtianjiaonang, Anshensan, Wuweishiliusan, Zhangsongbaweichenxiangsan, Shiliuweidujuansan, Ershiwuweiyuganziwan, Ershiwuweizhuhuangjiaonang, Shiwuweilongdanwan, Mijueqingliangsan, Qishiweizhenzhuwan, Bawei-chenxiangsan, Liuweidingxiangsan and Qiweiputansan were digested with HNO3-HClO4 mixed acid. Fourteen trace elements and macro elements in the 13 kinds of anti-anoxic Tibetan traditional medicine, such as silver, aluminium, cadmium, cobalt, chromium, copper, ferrum, hydrargyrum, magnesium, manganese, nickel, lead, stannum and zinc were determined by flame atomic absorption spectrophotometry (FAAS). The results showed that there were comparatively rich trace elements and macro elements in kinds of anti-anoxic Tibetan traditional Medicine. The 13 Anti-anoxic Tibetan traditional medicine contains higher amount of ferrum, magnesium, copper, chromium, zinc and manganese than other elements. This provided useful data for discussing the relationship between trace elements and macro elements and anti-anoxic activities in Tibetan traditional medicine.