Metformin Ameliorates D-Galactose-Induced Senescent Human Bone Marrow-Derived Mesenchymal Stem Cells by Enhancing Autophagy.

Human bone marrow-derived mesenchymal stem cells (hBMSCs) are promising candidates for stem cell therapy in clinical trials. Applications of hBMSCs in clinical therapy are limited by cellular senescence due to long-term ex vivo expansion. Metformin, an oral hypoglycemic drug for type 2 diabetes, has been shown to have antiaging effects. However, the mechanisms of metformin in antiaging treatment remain controversial. Here, we used D-galactose (D-gal) to establish an appropriate model of senescent hBMSCs to explore the antiaging effects of metformin. Following metformin treatment with a low concentration range, senescence phenotypes induced by D-gal significantly changed, including generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and cell cycle arrest. In contrast, no apparent change was found in unsenescent hBMSCs. Furthermore, the results show that activation of 5'AMP-activated protein kinase (AMPK) by metformin enhances cell autophagy in senescent hBMSCs. These findings suggest that metformin exerts antiaging function within the low concentration range by enhancing autophagy and exhibits potential benefits for clinical stem cell therapy by ameliorating the ex vivo replicative senescence of hBMSCs.

The Mechanisms of lncRNA-Mediated Multidrug Resistance and the Clinical Application Prospects of lncRNAs in Breast Cancer.

Breast cancer (BC) is a highly heterogeneous disease and presents a great threat to female health worldwide. Chemotherapy is one of the predominant strategies for the treatment of BC; however, multidrug resistance (MDR) has seriously affected or hindered the effect of chemotherapy. Recently, a growing number of studies have indicated that lncRNAs play vital and varied roles in BC chemoresistance, including apoptosis, autophagy, DNA repair, cell cycle, drug efflux, epithelial-mesenchymal transition (EMT), epigenetic modification and the tumor microenvironment (TME). Although thousands of lncRNAs have been implicated in the chemoresistance of BC, a systematic review of their regulatory mechanisms remains to be performed. In this review, we systematically summarized the mechanisms of MDR and the functions of lncRNAs mediated in the chemoresistance of BC from the latest literature. These findings significantly enhance the current understanding of lncRNAs and suggest that they may be promising prognostic biomarkers for BC patients receiving chemotherapy, as well as therapeutic targets to prevent or reverse chemoresistance.

Biodegradable oxygen-producing manganese-chelated metal organic frameworks for tumor-targeted synergistic chemo/photothermal/ photodynamic therapy.

Photodynamic therapy (PDT) is an effective noninvasive therapeutic strategy that can convert oxygen to highly cytotoxic singlet oxygen (1O2) through the co-localization of excitation light and photosensitizers. However, compromised by the hypoxic tumor microenvironment, the therapeutic efficacy of PDT is reduced seriously. Herein, to overcome tumor-associated hypoxia, and further achieve tumor-targeted synergistic chemotherapy/PDT/photothermal therapy (PTT), we have constructed a biodegradable oxygen-producing nanoplatform (named Ini@PM-HP), which was composed of the porous metal-organic framework (PCN-224(Mn)), the poly (ADP-ribose) polymerase (PARP) inhibitor (Iniparib), and the polydopamine-modified hyaluronic acid (HA-PDA). Since HA can specifically bind to the overexpressed HA receptors (cluster determinant 44, CD44) on tumor cell, Ini@PM-HP prefers to accumulate at the tumor site once injected intravenously. Then iniparib can be released in tumor environment (TME), thereby dysfunctioning DNA damage repair and promoting cell apoptosis. At the same time, the chelating of Mn and tetrakis(4-carboxyphenyl) porphyrin (Mn-TCPP) can generate O2 in situ by reacting with endogenous H2O2, relieving the hypoxic TME and achieving enhanced PDT. Moreover, owing to the high photothermal conversion efficiency of PDA, PTT can be driven by the 808 nm laser irradiation. As systematically demonstrated in vitro and in vivo, this nanotherapeutic approach enables the combined therapy with great inhibition on tumor. Overall, the as-prepared nanoplatform provide a promising strategy to overcome tumor-associated hypoxia, and shows great potential for combination tumor therapy. STATEMENT OF SIGNIFICANCE: A delicately designed biodegradable oxygen-producing nanoplatform Ini@PM-HP is constructed to achieve combination therapy of solid tumors. Taking advantage of the active-targeting, PTT, enhanced PDT and PARPi, this nanotherapeutic approach successfully enables the combined chemo/photothermal/photodynamic therapy with great inhibition of solid tumors.

Surgery Plus Chemotherapy Versus Surgery Alone for Limited-Stage Small-Cell Lung Cancer: A Population-Based Survival Outcome Analysis.

INTRODUCTION: For patients with limited-stage small-cell lung cancer (LS-SCLC), effective treatment methods still remain a clinical challenge. The aim of this study is to evaluate the survival outcome of surgery plus chemotherapy vs. surgery alone in patients with LS-SCLC. METHODS: LS-SCLC patients selected from the Surveillance, Epidemiology and End Results (SEER) database diagnosed between January 1, 2004, and December 31, 2015. Comparison of overall survival (OS) and cancer-specific survival (CSS) between two groups performed propensity score matching (PSM), inverse probability of treatment weight (IPTW), and overlap weighting analysis. RESULTS: Of the 477 LS-SCLC patients identified from the SEER database between 2004 and 2015, 262 (54.9%) received surgery-plus-chemotherapy treatment and the others received surgery-alone treatment. Univariate and multivariate analyses showed that treatment option (P< 0.001), tumor location (P= 0.02) and AJCC stage (P< 0.001) were independent prognostic predictors of OS in LS-SCLC patients. Median OS was 35 months in surgery-plus-chemotherapy group vs. 23 months in surgery-alone group. Survival analysis showed that surgery plus chemotherapy offered significantly improved OS as compared with surgery-alone treatment before and after IPTW, PSM and overlap weighting method (all P< 0.05). According to AJCC stage stratification, OS of the unmatched patients with stage I (P= 0.049) and II (P= 0.001) SCLC who received surgery-plus-chemotherapy treatment was significantly better than that of surgery-alone patients. CONCLUSIONS: This cohort study showed that surgery plus chemotherapy was associated with longer survival time than surgery alone in LS-SCLC patients, especially in those with stage I and II SCLC. Further prospective studies are required to confirm our conclusions.

Synthesis and biological activity of new bisbenzofuran-imidazolium salts.

A series of novel bisbenzofuran-imidazolium salts were designed and prepared. The in vitro antitumor activity of these derivatives was evaluated against a panel of human tumor cell lines (A549, HL-60, MCF-7, SMMC-7721 and SW480). Results demonstrated that 2-methyl-benzimidazole ring and substitution of the imidazolyl-3-position with a 4-methoxyphenacyl or 2-naphthylacyl substituent were important for promoting cytotoxic activity. Notably, compound 23 was found to be the most potent compound with IC50 values of 0.64-1.47 µM against five human tumor cell lines, and exhibited higher selectivity to MCF-7 and SW-480 cell lines with IC50 values 15.3-fold and 9.1-fold lower than DDP.

Iodine-catalyzed efficient synthesis of xanthene/thioxanthene-indole derivatives under mild conditions.

An iodine-catalyzed nucleophilic substitution reaction of xanthen-9-ol and thioxanthen-9-ol with indoles has been developed, providing an efficient procedure for the synthesis of xanthene/thioxanthene-indole derivatives with good to excellent yields. This protocol offers several advantages, such as short reaction times, green solvent, operational simplicity, easily available catalyst and mild reaction conditions. Moreover, this method showed good tolerance of functional groups and a wide range of substrates.

Synthesis and biological evaluation of novel 3-benzylcoumarin-imidazolium salts.

A series of novel 3-benzylcoumarin-imidazolium salts were prepared and evaluated in vitro against a panel of human tumor cell lines. The results showed that the existence of 5,6-dimethyl-benzimidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl group were vital for modulating cytotoxic activity. Notably, compound 38 was found to be the most potent derivative with IC50 values of 2.04-4.51 µM against five human tumor cell lines, while compound 34 were more selective to SW-480 cell lines with IC50 value 40.0-fold lower than DDP. Mechanism of action studies indicated that compound 38 can cause the G0/G1 phase cell cycle arrest and apoptosis in SMMC-7721 cell lines.

A simple and convenient synthesis of 3-salicyloylquinoline-4-carboxylic esters from chromone and isatin.

A simple and convenient synthesis of 3-salicyloylquinoline-4-carboxylic esters has been developed through an AlCl3-catalyzed reaction of easily available Baylis-Hillman adducts from chromones and isatin-derivatives. This reaction involves esterification, cyclization and ring opening in a one-step process, and provides an efficient approach for easy access to a series of valuable salicyloylquinoline derivatives with high yields. Moreover, this protocol offers several advantages, such as availability of starting materials, economic availability, operational simplicity and mild reaction conditions.