Secretome Derived from Mesenchymal Stem/Stromal Cells: A Promising Strategy for Diabetes and its Complications.

Diabetes is a complex metabolic disease with a high global prevalence. The health and quality of life of patients with diabetes are threatened by many complications, including diabetic foot ulcers, diabetic kidney diseases, diabetic retinopathy, and diabetic peripheral neuropathy. The application of mesenchymal stem/stromal cells (MSCs) in cell therapies has been recognized as a potential treatment for diabetes and its complications. MSCs were originally thought to exert biological effects exclusively by differentiating and replacing specific impaired cells. However, the paracrine function of factors secreted by MSCs may exert additional protective effects. MSCs secrete multiple compounds, including proteins, such as growth factors, chemokines, and other cytokines; nucleic acids, such as miRNAs; and lipids, extracellular vesicles (EVs), and exosomes (Exos). Collectively, these secreted compounds are called the MSC secretome, and usage of these chemicals in cell-free therapies may provide stronger effects with greater safety and convenience. Recent studies have demonstrated positive effects of the MSC secretome, including improved insulin sensitivity, reduced inflammation, decreased endoplasmic reticulum stress, enhanced M2 polarization of macrophages, and increased angiogenesis and autophagy; however, the mechanisms leading to these effects are not fully understood. This review summarizes the current research regarding the secretome derived from MSCs, including efforts to quantify effectiveness and uncover potential molecular mechanisms in the treatment of diabetes and related disorders. In addition, limitations and challenges are also discussed so as to facilitate applications of the MSC secretome as a cell-free therapy for diabetes and its complications.

Myeloid-derived suppressor cells: Are they involved in gestational diabetes mellitus?

Gestational diabetes mellitus (GDM) is currently the most common metabolic complication during pregnancy, with an increasing prevalence worldwide. Maternal immune dysregulation might be partly responsible for the pathophysiology of GDM. Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells, emerging as a new immune regulator with potent immunosuppressive capacity. Although the fate and function of these cells were primarily described in pathological conditions such as cancer and infection, accumulating evidences have spotlighted their beneficial roles in homeostasis and physiological conditions. Recently, several studies have explored the roles of MDSCs in the diabetic microenvironment. However, the fate and function of these cells in GDM are still unknown. The current review summarized the existing knowledges about MDSCs and their potential roles in diabetes during pregnancy in an attempt to highlight our current understanding of GDM-related immune dysregulation and identify areas where further study is required.

A comparative lipidomic study of the human placenta from women with or without gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is always accompanied by lipid disorders. The placenta serves as a center for lipid synthesis and transport and plays a critical role in establishing GDM. Thus, the changes in the type and content of lipids in the placenta may contribute to the development of GDM. Here, we performed an untargeted lipidomic analysis to profile the alterations of lipids in the placenta induced by GDM. Principal component analysis (PCA) was used to reduce the dimensionality of lipid data, and orthogonal projections to latent structures-discriminate analysis (OPLS-DA) was launched to show the differences in the lipid profile between the GDM group and normal controls. Additional multivariate data processing was carried out, including classification, pathway analysis and correlation analysis between dysregulated lipids and maternal blood glucose levels. We finally identified 1202 lipids in positive mode and 924 lipids in negative mode, of which 63 lipids were strongly associated with GDM. Notably, most dysregulated lipids were clustered in two major subtypes: glycerophospholipids and glycerolipids. Consistently, a significant down-regulation of glycerophospholipid metabolism was observed from pathway analysis. In addition, we found that SHexCer(d50:1), TAG(15:0/20:6/20:6) and PE(18:1e/21:2) were positively correlated with blood glucose levels, while PC(12:0/22:3), PC(22:4e/18:5) and PE(18:1e/26:4) showed negative correlations. Combining these lipids with fasting blood glucose showed high accuracy in the discrimination of women with GDM. In general, we explored the placental lipidomic abnormalities induced by GDM, and these findings may help us understand the pathological mechanisms of GDM.

Multifunction in One Molecule: Mitochondrial Imaging and Photothermal & Photodynamic Cytotoxicity of Fast-Response Near-Infrared Fluorescent Probes with Aggregation-Induced Emission Characteristics.

HJS and DHJS, two near-infrared emissive and mitochondria-targeted therapy probes, have been designed. They exhibited photothermal & photodynamic cytotoxicity and aggregation-induced emission (AIE) characteristics. Interestingly, we could receive fluorescence immediately after adding the probes without washing in 1 min. They could quickly enter cancer cells and selectively localized to the mitochondria firstly. When the concentration of probes was low (<5 µM), they could respond sensitively to the mitochondrial membrane potential and would selectively enter the mitochondria with red fluorescence. However, when the concentration was high (≥5 µM), they would preferentially enter the mitochondria and have the property of dual-channel fluorescence imaging (red and near-infrared) even after 24 h. What's more, they increased the intracellular reactive oxygen species (ROS) levels, decreased the mitochondrial membrane potentials, and then induced apoptosis, which were proved by confocal imaging and flow cytometry experiments. In addition, the results of photothermal experiment and cytotoxicity test showed that the probes had good photothermal and photodynamic toxicity to cancer cells. In vitro and in vivo experiments also proved the excellent near-infrared (NIR) imaging ability, good biocompatibility and certain inhibition of tumor growth ability of DHJS.

Near-infrared Zn-doped Cu2S quantum dots: an ultrasmall theranostic agent for tumor cell imaging and chemodynamic therapy.

Theranostic agents that integrated chemodynamic therapy (CDT) and imaging functions have great potential application in personalized cancer therapy. However, most theranostic agents were fabricated by chemically coupling two or more independent functional units with diagnostic or therapeutic capabilities, and therefore have a large size. To date, one-step synthesis of unmodified ultrasmall quantum dots (QDs) integrating CDT and fluorescence imaging capabilities remains a challenge. Herein, we reported a simple one-step synthesis method of ultrasmall (2.46 nm) Zn-doped Cu2S (Zn:Cu2S) QDs with inherent properties of both high CDT activity and near-infrared fluorescence imaging capability. The fluorescence of Cu2S QDs was significantly enhanced approximately tenfold after Zn doping due to the compensation of defects. In vitro and in vivo experiments demonstrated that the Zn:Cu2S QDs could specifically and significantly inhibit the cancer cell growth (inhibition rate exceeded 65%) without damaging the normal cells. Furthermore, the CDT mechanism study suggested that a Fenton-like reaction occurred after the Zn:Cu2S QDs entered the tumor cells, inducing apoptosis via the mitochondrial signaling pathway, and activating the production of reactive oxygen species (ROS) and autophagy to selectively eliminate tumor cells to achieve CDT. This work proposed a simple one-step synthesis of unmodified ultrasmall QDs with fluorescence imaging and CDT, which provides a promising strategy for QDs to act as multi-functional theranostic agents.

The Effect of FOXC2-AS1 on White Adipocyte Browning and the Possible Regulatory Mechanism.

Obesity has become a worldwide epidemic, and obesity-related problems are becoming more severe in public health. Increasing brown adipose tissue (BAT) mass or/and activity in mice and humans has been demonstrated to help lose weight and improve whole-body metabolism. Studies on the conversion of white adipose tissue (WAT) to BAT under certain conditions have provided new possibilities for treating obesity and the related disorders. It has been established that long non-coding RNAs (lncRNAs) play an important role in the regulation of mouse adipocyte differentiation and thermogenic programs; however, the function and potential mechanism of lncRNA in the process of human white adipocyte browning remains unclear. In the present study, we identified a lncRNA called Forkhead Box C2 antisense RNA 1 (FOXC2-AS1), which was first identified in osteosarcoma, and it was highly expressed in human adipocytes but decreased during the white adipocyte differentiation program. FOXC2-AS1 expression was also induced by the thermogenic agent forskolin. Lentivirus-mediated overexpression of FOXC2-AS1 in human white adipocytes did not affect lipid drop accumulation, but significantly promoted the browning phenotype, as revealed by the increased respiratory capacity and the enhanced protein expression levels of brown adipocyte-specific markers. In contrast, inhibiting FOXC2-AS1 with small interfering RNA led to attenuated thermogenic capacity in human white adipocytes. RNA-sequencing analysis and western blot were used to identify a possible regulatory role of the autophagy signaling pathway in FOXC2-AS1 to mediate white-to-brown adipocyte conversion. The autophagy inhibitor 3-methyladenine restored the reduced UCP1 protein level and thermogenic capacity caused by inhibiting FOXC2-AS1. Overall, the present study characterized the potential role of FOXC2-AS1 and further identified a lncRNA-mediated mechanism for inducing browning of human white adipocytes and maintaining thermogenesis, further providing a potential strategy for treating obesity and related disorder.

Inhibition of Autophagy via Lysosomal Impairment Enhances Cytotoxicity of Fullerenol under Starvation Condition.

Autophagy is well-known as a common cellular response to nanomaterials. As one of the most comprehensively studied carbon-based nanomaterials, fullerene and its derivatives have been reported to bring about autophagic features in various cell lines, but little is known about the role of fullerenol (C60(OH)44) on the modulation of autophagy in human gastric tumor cell line SGC-7901. Fullerenol treatment led to the accumulation of autophagosomes, as evidenced by the increased fluorescent intensity of monodansylcadaverine (MDC) staining cells, an elevated level of LC3 protein, and the observation of auotphagosomes in cytoplasm. Subsequent results of the p62 level demonstrated that the accumulation of autophagosomes resulted from the blockade of autophagic flux rather than the activation of autophagy. Fullerenol disrupted autophagic flux by impairing lysosomal function, including lysosome membrane permeabilization (LMP), alkaline of lysosomes, and reduced activity of capthesin B. Interestingly, fullerenol treatment was noncytotoxic under a nutrient-rich condition. When serum was deprived, cytotoxicity occurred in a concentration- and time-dependent manner, along with massive vacuoles in cytoplasm, a large amount of ROS generation, and finally cell death, which can be ascribed to the disruption of essential autophagy in cells. Taken together, understanding this autophagy-lysosome pathway will shed light on the potential anticancer application of fullerenol.

Synthesis, characterization, and antitumor properties of Au(i)-thiourea complexes.

The anticancer property of cisplatin has stimulated the development of metal complexes as antitumor agents. Among these complexes, metal thiourea complexes have attracted sufficient attention, and they possess the potential possibility to become new antitumor metallodrugs. Herein, four Au(i) complexes derived from N,N-disubstituted cyclic thiourea ligands were synthesized and characterized. The crystal structure analysis indicated that the complex Au(i)(3c)2OTf was a mononuclear crystal structure with Au(i) coordinated by two sulfur atoms. These Au(i) complexes exhibited excellent toxicities against several tumor cell lines, especially complex Au(i)(3c)2OTf (IC50 = 8.06 µM against HeLa). It was found that Au(i)(3c)2OTf triggered a burst of ROS, disrupted the mitochondrial membrane potential (MMP), subsequently released Cyt-c, and then triggered the activation of caspase 9, caspase 7 and caspase 3. Mechanism experiments manifested that Au(i)(3c)2OTf induced the down-regulation of Bcl-2 and up-regulation of Bax, which further indicated that Au(i)(3c)2OTf triggered mitochondria-mediated apoptosis. In addition, the ROS scavenger-NAC completely blocked the apoptosis and inhibited the reduction of MMP, showing that Au(i)(3c)2OTf induced a ROS-dependent apoptosis pathway. These results indicate that Au(i)(3c)2OTf is worthy of in-depth research as an antitumor agent and may throw light on a better understanding of the effect of thiourea derivatives on antitumor mechanisms.

Graphene Quantum Dots Induce Autophagy and Reveal Protection Against Hydrogen Peroxide-Induced Oxidative Stress Injury.

As zero-dimension nanomaterials, graphene quantum dots (GQDs) have the excellent characteristics of graphene as well as photoluminescence (PL) features that ordinary graphene does not possess for its virtue of quantum confinement effect and boundary effect, which attract lots of researchers interested in the field of biomedical applications. In this work, we found GQDs can be internalized into SGC-7901 cells, and the labeled cells exhibited bright yellow fluorescence in the form of aggregated dots. Meanwhile, GQDs effectively mitigated the injury hydrogen peroxide (H2O2)-induced in SGC-7901 cells including cytotoxicity and apoptosis. While H2O2 exposure increased ROS and decreased mitochondrial membrane potential, it could be arrested by GQDs. Furthermore, GQDs showed protective effects against the reduction of the ratio of mitochondrial apoptosis-related proteins Bcl-2/Bax in SGC-7901 cells. Our work revealed that GQDs had the antioxidant ability against oxidative stress, which meant they had the potential to be an antioxidants. Besides, GQDs increased the level of autophagy-related protein LC3-II and induced autophagic structure observed via TEM, and subsequent the results of LC3 turnover and p62 degradation demonstrated GQDs treatment led to the activation of autophagic flux. Ultimately, GQDs were found to affect autophagy through the mTOR signaling pathway.

Characterization of fullerenol-protein interactions and an extended investigation on cytotoxicity.

Fullerenols, known as polyhydroxylated derivatives of fullerene, have attracted great attention due to their distinctive material properties and potential applications in biology and medicine. As a step toward the elucidation of basic behavior in biological systems, a variety of spectroscopic measurements as well as isothermal titration calorimetry (ITC) were applied to study the interaction between fullerenol (C60(OH)44) and serum proteins (bovine serum albumin (BSA) and γ-globulins). The results of fluorescence spectra indicated that the intrinsic fluorescence of proteins could be effectively quenched by the dynamic mechanism. The affinity values of both proteins bound to fullerenol were of the same order of magnitude. Meanwhile, ITC results showed that the interaction between fullerenol and BSA was enthalpy favorable, while the interaction with γ-globulins was enthalpy unfavorable. Furthermore, fullerenol had little influence on the secondary structure of both proteins. Additional cytotoxicity tests showed that the presence of proteins attenuated the toxic effect of fullerenol on human normal gastric epithelial cell line (GES-1). Thus, the interaction between fullerenol and proteins is indispensable to evaluate the biosafety of fullerenol, which may in turn promotes the development of its biological applications.