The Pharmacological Mechanism of Curcumin against Drug Resistance in Non-Small Cell Lung Cancer: Findings of Network Pharmacology and Bioinformatics Analysis.

The pharmacological mechanism of curcumin against drug resistance in non-small cell lung cancer (NSCLC) remains unclear. This study aims to summarize the genes and pathways associated with curcumin action as an adjuvant therapy in NSCLC using network pharmacology, drug-likeness, pharmacokinetics, functional enrichment, protein-protein interaction (PPI) analysis, and molecular docking. Prognostic genes were identified from the curcumin-NSCLC intersection gene set for the following drug sensitivity analysis. Immunotherapy, chemotherapy, and targeted therapy sensitivity analyses were performed using external cohorts (GSE126044 and IMvigor210) and the CellMiner database. 94 curcumin-lung adenocarcinoma (LUAD) hub targets and 41 curcumin-lung squamous cell carcinoma (LUSC) hub targets were identified as prognostic genes. The anticancer effect of curcumin was observed in KEGG pathways involved with lung cancer, cancer therapy, and other cancers. Among the prognostic curcumin-NSCLC intersection genes, 20 LUAD and 8 LUSC genes were correlated with immunotherapy sensitivity in the GSE126044 NSCLC cohort; 30 LUAD and 13 LUSC genes were associated with immunotherapy sensitivity in the IMvigor210 cohort; and 12 LUAD and 13 LUSC genes were related to chemosensitivity in the CellMiner database. Moreover, 3 LUAD and 5 LUSC genes were involved in the response to targeted therapy in the CellMiner database. Curcumin regulates drug sensitivity in NSCLC by interacting with cell cycle, NF-kappa B, MAPK, Th17 cell differentiation signaling pathways, etc. Curcumin in combination with immunotherapy, chemotherapy, or targeted drugs has the potential to be effective for drug-resistant NSCLC. The findings of our study reveal the relevant key signaling pathways and targets of curcumin as an adjuvant therapy in the treatment of NSCLC, thus providing pharmacological evidence for further experimental research.

A Novel Diagnostic and Therapeutic Strategy for Cancer Patients by Integrating Chinese Medicine Syndrome Differentiation and Precision Medicine.

Applying Chinese medicine (CM) is an important strategy for malignant tumor treatment in China. One of the significant characteristics of CM is to treat diseases based on syndrome differentiation. For Western medicine, it is of important clinical significance to formulate guidelines for the diagnosis and treatment of cancer patients based on the characteristics of disease differentiation. In Chinese clinical practice, the combination of disease differentiation and syndrome differentiation is an important feature for cancer treatment in the past. Currently, molecular profiling and genomic analysis-based precision medicine optimizes the anticancer drug design and holds the greatest success in treating cancer patients. Therefore, we want to know which populations of cancer patients can benefit more from CM treatment if the theory of precision medicine is applied to CM clinical practice. So, we developed a novel diagnostic and therapeutic strategy "disease-syndrome differentiation-genomic profiling-prescriptions" for cancer patients by CM syndrome differentiation and precision medicine. As a result, this strategy has greatly enhanced the anti-tumor efficacy of CM and improved clinical outcomes for cancer patients with some gene mutations. Our idea will hopefully establish a novel approach for the inheritance and innovation of CM.

An ATF24 peptide-functionalized ß-elemene-nanostructured lipid carrier combined with cisplatin for bladder cancer treatment.

Objective: In this study, we aimed to develop an amino-terminal fragment (ATF) peptide-targeted liposome carrying ß-elemene (ATF24-PEG-Lipo-ß-E) for targeted delivery into urokinase plasminogen activator receptor-overexpressing bladder cancer cells combined with cisplatin (DDP) for bladder cancer treatment. Methods: The liposomes were prepared by ethanol injection and high-pressure microjet homogenization. The liposomes were characterized, and the drug content, entrapment efficiency, and in vitro release were studied. The targeting efficiency was investigated using confocal microscopy, ultra-fast liquid chromatography, and an orthotopic bladder cancer model. The effects of ATF24-PEG-Lipo-ß-E combined with DDP on cell viability and proliferation were evaluated by a Cell Counting Kit-8 (CCK-8) assay, a colony formation assay, and cell apoptosis and cell cycle analyses. The anticancer effects were evaluated in a KU-19-19 bladder cancer xenograft model. Results: ATF24-PEG-Lipo-ß-E had small and uniform sizes (˜79 nm), high drug loading capacity (˜5.24 mg/mL), high entrapment efficiency (98.37 ± 0.95%), and exhibited sustained drug release behavior. ATF24-PEG-Lipo-ß-E had better targeting efficiency and higher cytotoxicity than polyethylene glycol (PEG)ylated ß-elemene liposomes (PEG-Lipo-ß-E). DDP, combined with ATF24-PEG-Lipo-ß-E, exerted a synergistic effect on cellular apoptosis and cell arrest at the G2/M phase, and these effects were dependent on the caspase-dependent pathway and Cdc25C/Cdc2/cyclin B1 pathways. Furthermore, the in vivo antitumor activity showed that the targeted liposomes effectively inhibited the growth of tumors, using the combined strategy. Conclusions: The present study provided an effective strategy for the targeted delivery of ß-elemene (ß-E) to bladder cancer, and a combined strategy for bladder cancer treatment.

The Effect of Autologous Platelet Concentrates on Maxillary Sinus Augmentation: A Meta-Analysis of Randomized Controlled Trials and Systematic Review.

INTRODUCTION: To assess the efficacy of the autologous platelet concentrates (APCs) combined with autologous bone or bone substitute for the maxillary sinus floor lifting by a meta-analysis. MATERIALS AND METHODS: Electronic databases (PUBMED, Web of Science, EMBASE through OVID, and Cochrane Library) were searched until Dec 31, 2019, and only randomized controlled trials (RCTs) in English were identified. Outcome variables included histologic evaluation, the implant stability quotient values, and radiographic evaluation. Data were analyzed by Revman5.3; the estimate of effect sizes was expressed as the 95% confidence interval; and the risk of bias was evaluated using the Cochrane Collaboration tool. RESULTS: 11 RCTs involving 141 patients (214 sites) were included in our meta-analysis, which indicated that the differences in the percentage of contact length among newly formed bone (2.61%, 95% CI, -1.18% to 7.09%), soft tissue area (-0.15%, 95% CI, -0.54% to 0.24%), and residual bone substitute material (-5.10%, 95% CI, -10.56% to 0.36%) in the APC group lacked statistical significance. Besides, there was the same effect on the implant stability quotient (ISQ) values of APC group who underwent implant placement 4 months after sinus augmentation and control group who received implant placement 8 months after sinus augmentation (-0.48, 95% CI, -1.68 to 0.72). No significant effect of APCs on the bone density was found (1.05%, 95% CI, -1.69% to 3.82%). CONCLUSIONS: The use of APCs in sinus augmentation may be further shorten the time required for bone graft maturation and allow earlier implant placement, but cannot enhance the bone formation in the long term. It is not currently recommended for routine use APCs as an osteoinductive material to bone grafting in sinus augmentation.

Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis.

Ferroptosis, a novel form of programmed cell death, is characterized by iron-dependent lipid peroxidation and has been shown to be involved in multiple diseases, including cancer. Stimulating ferroptosis in cancer cells may be a potential strategy for cancer therapy. Therefore, ferroptosis-inducing drugs are attracting more attention for cancer treatment. Here, we showed that erianin, a natural product isolated from Dendrobium chrysotoxum Lindl, exerted its anticancer activity by inducing cell death and inhibiting cell migration in lung cancer cells. Subsequently, we demonstrated for the first time that erianin induced ferroptotic cell death in lung cancer cells, which was accompanied by ROS accumulation, lipid peroxidation, and GSH depletion. The ferroptosis inhibitors Fer-1 and Lip-1 but not Z-VAD-FMK, CQ, or necrostatin-1 rescued erianin-induced cell death, indicating that ferroptosis contributed to erianin-induced cell death. Furthermore, we demonstrated that Ca2+/CaM signaling was a critical mediator of erianin-induced ferroptosis and that blockade of this signaling significantly rescued cell death induced by erianin treatment by suppressing ferroptosis. Taken together, our data suggest that the natural product erianin exerts its anticancer effects by inducing Ca2+/CaM-dependent ferroptosis and inhibiting cell migration, and erianin will hopefully serve as a prospective compound for lung cancer treatment.

[Metabonomics research strategy based on microdialysis technique].

Metabonomics is the branch of systems biology. It has been widely used in the fields of diagnostic markers discovery, disease prognosis, drug action mechanism, drug efficacy and toxicity evaluation, traditional Chinese medicine syndromes differentiation. There are shortcomings in the conventional metabonomics research. Microdialysis technology is a new type of biosampling technology, and metabonomics research based on microdialysis technology is in the ascendant. In view of the particularity of microdialysis technology and its great differences from traditional sampling and pretreatment methods, the metabonomics process based on microdialysis technology has certain similarities with traditional metabonomics research, and its basic process has some particularity. Advantages and basic strategies of metabonomics research by microdialysis technology are systematically summarized for researchers' reference.

Combinative treatment of ß-elemene and cetuximab is sensitive to KRAS mutant colorectal cancer cells by inducing ferroptosis and inhibiting epithelial-mesenchymal transformation.

Background and Purpose: RAS mutations limit the effectiveness of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in combination with chemotherapy for metastatic colorectal cancer (mCRC) patients. Therefore, new cell death forms have focused on identifying indirect targets to inhibit Ras-induced oncogenesis. Recently, emerging evidence has shown the potential of triggering ferroptosis for cancer therapy, particularly for eradicating aggressive malignancies that are resistant to traditional therapies. Methods: KRAS mutant CRC cell HCT116 and Lovo were treated with cetuximab and ß-elemene, a bioactive compound isolated from Chinese herb Curcumae Rhizoma. Ferroptosis and epithelial-mesenchymal transformation (EMT) were detected in vitro and in vivo. Orthotopic CRC animal model were established and the tumor growth was monitored by IVIS bioluminescence imaging. Tumor tissues were collected to determine ferroptosis effect and the expression of EMT markers after the treatment. Results: CCK-8 assay showed that synergetic effect was obtained when 125 µg/ml ß-elemene was combined with 25 µg/ml cetuximab in KRAS mutant CRC cells. AV/PI staining suggested a non-apoptotic mode of cell death after the treatment with ß-elemene and cetuximab. In vitro, ß-elemene in combination with cetuximab was shown to induce iron-dependent reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, upregulation of HO-1 and transferrin, and downregulation of negative regulatory proteins for ferroptosis (GPX4, SLC7A11, FTH1, glutaminase, and SLC40A1) in KRAS mutant CRC cells. Meanwhile, combinative treatment of ß-elemene and cetuximab inhibited cell migration and decreased the expression of mesenchymal markers (Vimentin, N-cadherin, Slug, Snail and MMP-9), but promoted the expression of epithelial marker E-cadherin. Moreover, ferroptosis inhibitors but not other cell death suppressors abrogated the effect of ß-elemene in combination with cetuximab on KRAS mutant CRC cells. In vivo, co-treatment with ß-elemene and cetuximab inhibited KRAS mutant tumor growth and lymph nodes metastases. Conclusions: Our data for the first time suggest that the natural product ß-elemene is a new ferroptosis inducer and combinative treatment of ß-elemene and cetuximab is sensitive to KRAS mutant CRC cells by inducing ferroptosis and inhibiting EMT, which will hopefully provide a prospective strategy for CRC patients with RAS mutations.

Efficacy and safety of elemene combined with chemotherapy in advanced gastric cancer: A Meta-analysis.

BACKGROUND: Elemene is a natural compound extracted from Zingiberaceae plants, and is used in various cancer. However, the efficacy and safety elemene combined with chemotherapy in advanced gastric cancer (GC) are lack of systematic assessment. METHODS: we searched the PubMed, EMBASE, Web of Science, Cochrane Library, China Academic Journals (CNKI), Chinese Science and Technology Journals (CQVIP) and Chinese Biomedical Literature databases. Randomized controlled trials (RCTs) comparing elemene plus chemotherapy with chemotherapy alone in participants with advanced GC and reporting at least one of the following outcomes were selected and assessed for inclusion. JADAD scale was used to assess the quality. Data was screened and extracted by two independent investigators. The primary clinical outcome was overall response rate (ORR); the secondary outcomes were quality of life (QOL) and adverse events (AEs). Analysis was performed using Review Manager 5.3. RESULTS: Sixteen RCTs matched the selection criteria, which reported on 969 subjects. Risk ratios (RR) and corresponding 95% confidence intervals (CIs) were pooled for ORR, life quality based on KPS, and risk of AEs. Compared to chemotherapy alone, elemene combined with chemotherapy in the treatment of GC may increase the efficiency of ORR(RR: 1.41; 95% CI: 1.23-1.60; P < .0001), improve their life quality based on KPS (RR: 1.84; 95% CI: 1.45-2.34; P < .00001), and reduce the adverse reactions, including leukopenia(RR: 0.73; 95% CI: 0.62-0.85; P < .00001), neutropenia (RR: 0.75; 95% CI: 0.60-0.95; P = .02), anemia (RR: 0.76; 95% CI: 0.60-0.95; P = .02), thrombocytopenia (RR: 0.56; 95% CI: 0.43-0.73; P < .00001). Nausea and vomiting (RR: 0.84; 95% CI: 0.84-1.07; P = .39), diarrhea (RR: 0.69; 95% CI: 0.41-1.15; P = .15), neurotoxicity (RR: 0.77; 95% CI: 0.59-1.00; P = .05) and hepatic dysfunction (RR: 0.95; 95% CI: 0.58-1.54; P = .83) were similar between two groups. CONCLUSIONS: Elemene may have the potential to improve the efficacy and reduce the AEs of chemotherapy for gastric cancer. However, the long-term, high-quality researches with a large sample size in different populations are required.

[Brain lipidomics of intervention effect of Salviae Miltiorrhizae Radix et Rhizoma and Chuanxiong Rhizoma on ischemic stroke based on UPLC-Q-TOF-MS technique].

The aim of this paper was to investigate the intervention effect of Salviae Miltiorrhizae Radix et Rhizoma and Chuanxiong Rhizoma on brain lipid metabolism in rats with ischemic stroke. The ischemic stroke rat model was established by middle cerebral artery occlusion( MCAO) method. The brain tissues were collected after the last administration with Salviae Miltiorrhizae Radix et Rhizoma and Chuanxiong Rhizoma decoction lyophilizate. UPLC-Q-TOF-MS was used to carry out the brain lipidomics study. The lipidomics data were processed with the OPLS-DA model to find out the lipid regulation effect of Salviae Miltiorrhizae Radix et Rhizoma combined with Chuanxiong Rhizoma on ischemic stroke. The results showed that Salviae Miltiorrhizae Radix et Rhizoma and Chuanxiong Rhizoma decoction lyophilized powder can significantly alleviate brain lipidomics profiles in middle cerebral artery occlusion model rats. Eleven differential lipid metabolites in ischemic stroke model were identified. In this experiment,the protective effects of Salviae Miltiorrhizae Radix et Rhizoma and Chuanxiong Rhizoma decoction lyophilized powder on cerebral ischemia injury was verified,which might be related to the regulation of abnormal lipid metabolism.

Genome shuffling for improving the activity of alkaline pectinase in Bacillus subtilis FS105 and its molecular mechanism.

Genome shuffling for improving the activity of alkaline pectinase in Bacillus subtilis FS105 and its molecular mechanism were investigated. The fused strain B. subtilis FS105 with the highest activity of alkaline pectinase was obtained after two rounds of genome shuffling. The activity of alkaline pectinase in B. subtilis FS105 was 499 U/ml, which was improved by 1.6 times compared to that in original strain. To elucidate its molecular mechanism, rpsL gene sequences from original and fused strains were cloned and aligned, and the space structure of their coding proteins were also analyzed and compared. The alignment of the rpsL gene sequences indicated that three bases G, G and C were respectively replaced by A, A and G in the positions 52, 408 and 409 after genome shuffling. This resulted in the substitution of two amino acid residues in ribosomal protein S12: D18N and P137A, and therefore improving the biosynthesis of alkaline pectinase. This study lays a foundation for improving the activity of alkaline pectinase by genome shuffling and understanding its molecular mechanism.