Naishun Liao

Magnetite nanocluster@poly(dopamine)-PEG@ indocyanine green nanobead with magnetic field-targeting enhanced MR imaging and photothermal therapy in vivo

Multifunctional nanomaterials with the magnetic resonance imaging (MRI) guided tumor photothermal ablation ability have been extensively applied in biomedical research as one of the most exciting and challenging strategies for cancer treatment. Nevertheless, most of these nanomaterials still suffer from low accumulation in tumor tissues and insufficient photothermal ablation of tumors so far. Here, we report a novel approach to overcome these limitations using a core-shell magnetite nanocluster@poly(dopamine)-PEG@ICG nanobead compositing of magnetite nanocluster core with coating of poly(dopamine), then further conjugating with polyethylene glycol (PEG) and adsorbing indocyanine green (ICG) on the surface. The adsorbed ICG in the nanobead displays a higher photostability and photothermal conversion ability than free ICG, as well as additional photothermal effect rather than magnetite nanocluster and poly(dopamine), which endow the nanobead with enhanced photothermal killing efficiency against cancer cells under near-infrared (NIR) laser irritation. Furthermore, it is proved that these nanobeads have excellent biocompatibility, T2-weighted MR imaging and magnetic field targeting ability. By applying an external magnetic field (MF) focused on the targeted tumor, a magnetic targeting mediated enhanced accumulation is observed at tumor site as proved by a darker T2-weighted MR image. Utilizing the magnetic targeting strategy, enhanced photothermal tumor ablation was achieved under laser irradiation in vivo, which is reflected by the degree of tumor tissue damage and tumor growth delay. Therefore, this nanobead integrates the abilities of magnetic field-targeting, MR imaging and photothermal cancer therapy, and might be a promising theranostic platform for tumor treatment.

Poly (dopamine) coated superparamagnetic iron oxide nanocluster for noninvasive labeling, tracking, and targeted delivery of adipose tissue-derived stem cells

Tracking and monitoring of cells in vivo after transplantation can provide crucial information for stem cell therapy. Magnetic resonance imaging (MRI) combined with contrast agents is believed to be an effective and non-invasive technique for cell tracking in living bodies. However, commercial superparamagnetic iron oxide nanoparticles (SPIONs) applied to label cells suffer from shortages such as potential toxicity, low labeling efficiency, and low contrast enhancing. Herein, the adipose tissue-derived stem cells (ADSCs) were efficiently labeled with SPIONs coated with poly (dopamine) (SPIONs cluster@PDA), without affecting their viability, proliferation, apoptosis, surface marker expression, as well as their self-renew ability and multi-differentiation potential. The labeled cells transplanted into the mice through tail intravenous injection exhibited a negative enhancement of the MRI signal in the damaged liver-induced by carbon tetrachloride, and subsequently these homed ADSCs with SPIONs cluster@PDA labeling exhibited excellent repair effects to the damaged liver. Moreover, the enhanced target-homing to tissue of interest and repair effects of SPIONs cluster@PDA-labeled ADSCs could be achieved by use of external magnetic field in the excisional skin wound mice model. Therefore, we provide a facile, safe, noninvasive and sensitive method for external magnetic field targeted delivery and MRI based tracking of transplanted cells in vivo.

The structural basis of the Tle4-Tli4 complex reveals the self-protection mechanism of H2-T6SS in Pseudomonas aeruginosa.

The type VI secretion system (T6SS) has recently been demonstrated to mediate interbacterial competition and to discriminate between self and nonself. T6SS(+) bacteria employ toxic effectors to inhibit rival cells and concurrently use effector cognate immunity proteins to protect their sibling cells. The effector and immunity pairs (E-I pairs) endow the bacteria with a great advantage in niche competition. Tle4-Tli4 (PA1510-PA1509) is a newly identified E-I pair that is controlled by H2-T6SS in Pseudomonas aeruginosa. Tle4 exhibits phospholipase activity, which destroys the cell membrane of rival cells, and the periplasm-located Tli4 in donor cells eliminates this toxic effect of Tle4. In this paper, the structure of the Tle4-Tli4 complex is reported at 1.75 Å resolution. Tle4 consists of two domains: a conserved α/β-hydrolase domain and an unusual cap domain in which two lid regions (lid1 and lid2) display a closed conformation that buries the catalytic triad in a deep funnel. Tli4 also displays a two-domain structure, in which a large lobe and a small lobe form a crab claw-like conformation. Tli4 uses this crab claw to grasp the cap domain of Tle4, especially the lid2 region, which prevents the interfacial activation of Tle4 and thus causes enzymatic dysfunction of Tle4 in sister cells.

Intrahepatic transplantation of adipose‑derived stem cells attenuates the progression of non‑alcoholic fatty liver disease in rats

Non‑alcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury affecting the general health of various populations. In the present study, adipose tissue‑derived stem cells (ADSCs), which were isolated from the adipose tissues of Sprague‑Dawley rats, were transplanted into the liver of high‑fat‑diet‑induced NAFLD rats via the portal vein to attenuate the disease progression of NAFLD. The results demonstrated that ADSC transplantation reduced the serum levels of alanine aminotransferase, total bilirubin, total cholesterol, triglycerides and fatty acids, and reduced the content of malondialdehyde in the liver homogenates. By contrast, ADSC transplantation caused a significant increase in superoxide dismutase activity. These data suggested that the ADSC transplantation improved the liver function, and reduced lipid metabolism and oxidative stress. In addition, the hepatic pathological changes were decelerated, lipid accumulation was reduced, and serum levels of the pro‑inflammatory factors, tumor necrosis factor‑α and interleukin‑6, were downregulated by the ADSC transplantation. Taken together, transplantation with ADSCs attenuates the disease progression of high‑fat‑diet induced NAFLD, therefore, may offer a potential therapeutic approach for the treatment of NAFLD.

Chemotherapeutic Drug Based Metal-Organic Particles for Microvesicle-Mediated Deep Penetration and Programmable pH/NIR/Hypoxia Activated Cancer Photochemotherapy

Abstract A novel metal–organic particle (MOP) based nanodrug formed by mild self‐assembly of chemotherapeutic drugs, including banoxantrone and doxorubicin, through Cu(II)‐mediated coordination effects, is reported. In this nanodrug, Cu(II) acts as a bridge to join AQ4N and DOX, and then, self‐assembly of [‐AQ4N‐Cu(II)‐(DOX)2‐Cu(II)‐]n complexes forms nanosized MOPs (referred to as ADMOPs) through multiple interactions including host–metal–guest coordination, hydrophobic interactions, π‐stacking, and van der Waals force. The ADMOPs reported here have several important features over conventional drugs, including tumor microenvironment pH‐sensitive drug release that can be tracked by “turning on” the fluorescence of AQ4N or DOX through proton competition with Cu(II) to break the coordination bonds and much deeper penetration into solid tumors via microvesicle‐mediated intercellular transfer. Most strikingly, the ADMOPs can serve as stimuli‐responsive nanocarriers to efficiently load the photosensitizer phthalocyanine due to their inherent highly porous characteristics. Thus, the ADMOPs significantly enhance the chemotherapeutic efficacy by “on‐demand” photodynamic therapy, which further induces a hypoxic environment that enhances the reduction of AQ4N to systematically increase the therapeutic efficiency. Taken together, the designed ADMOPs composed of chemotherapeutic drugs may serve as a potential programmable controlled synergistic agent for cancer therapy.

Adipose tissue-derived stem cells promote the reversion of non-alcoholic fatty liver disease: An in vivo study

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver injury and seriously affects human health. In the present study, we aimed to investigate whether adipose tissue-derived stem cell (ADSC) transplantation in combination with dietary modification was capable of reversing the progression of NAFLD. After establishing a rat model of NAFLD by feeding them a high-fat diet (HFD), ADSCs were transplanted via the portal vein into rats with HFD-induced NAFLD, and simultaneously fed a modified diet. Thereafter, gross liver morphology, the hepatosomatic (HSI) index and indicators of liver function, including alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) were evaluated. Subsequently, the serum levels of total cholesterol (TC), triglycerides (TGs) and fatty acids (FAs) were also assayed. Furthermore, H&E and oil red O staining were used to confirm the pathological effects of NAFLD in the rat livers. Although dietary modification alone caused liver function to recover, ADSC transplantation in combination with dietary modification further decreased the HSI index, the serum levels of ALT, TBIL, TC, TGs, FAs, reduced lipid accumulation to normal levels, and reversed the hepatic pathological changes in the rat livers. Taken together, these findings suggest that ADSC transplantation assists in the reversion of NAFLD by improving liver function and promoting lipid metabolism, thereby exerting hepatoprotective effects. Thus, we suggest that ADSC transplantation is a promising, potential therapeutic strategy for NAFLD treatment.

Reveal the molecular signatures of hepatocellular carcinoma with different sizes by iTRAQ based quantitative proteomics

Tumor size of hepatocellular carcinoma (HCC) is a key parameter for predicting prognosis of HCC patients. The biological behaviors of HCC, such as tumor growth, recurrence and metastasis are significantly associated with tumor size. However, the underlying molecular mechanisms remain unclear. Here, we applied iTRAQ-based proteomic strategy to analyze the proteome differences among small, media, large and huge primary HCC tissues. In brief,88 proteins in small HCC, 69 proteins in media HCC, 118 proteins in large HCC and 215 proteins in huge HCC, were identified by comparing the proteome of cancerous tissues with its corresponding non-cancerous tissues. Further analysis of dysregulated proteins involved in signaling revealed that alteration of ERK1/2 and AKT signaling played important roles in the tumorigenesis or tumor growth in all subtypes. Interestingly, alteration of specific signaling was discovered in small and huge HCC, which might reflect specific molecular mechanisms of tumor growth. Furthermore, the dysregulation degree of a group of proteins has been confirmed to be significantly correlated with the tumor size; these proteins might be potential targets for studying tumor growth of HCC. Overall, we have revealed the molecular signatures of HCC with different tumor sizes, and provided fundamental information for further in-depth study. BIOLOGICAL SIGNIFICANCE In this study, we compared the protein expression profiles among different HCC subtypes, including small HCC, media HCC, large HCC and huge HCC for the first time. The results clearly proved that different molecular alterations and specific signaling pathways were indeed involved in different HCC subtypes, which might explain the different malignancy biological behaviors. In addition, the dysregulation degree of a group of proteins has been confirmed to be significantly correlated with the tumor size. We believe that these findings would help us better understand the underlying molecular mechanisms of the tumorigenesis and development of HCC.

Co-culture system of hepatocytes and endothelial cells: two in vitro approaches for enhancing liver-specific functions of hepatocytes

Although hepatocyte transplantation and bioartificial liver support system provide new promising opportunities for those patients waiting for liver transplantation, hepatocytes are easily losing liver-specific functions by using the common in vitro cultured methods. The co-culture strategies with mimicking the in vivo microenvironment would facilitate the maintenance of liver-specific functions of hepatocytes. Considering that hepatocytes and endothelial cells (ECs) account for 80–90% of total cell populations in the liver, hepatocytes and ECs were directly co-cultured with hepatic stellate cells (HSCs) or adipose tissue-derived stem cells (ADSCs) at a ratio of 700:150:3 or 14:3:3 in the present study, and the liver-specific functions were carefully analyzed. Our results showed that the two co-culture systems presented the enhanced liver-specific functions through promoting secretion of urea and ALB and increasing the expressions of ALB, CYP3A4 and HNF4α, and the vessel-like structure in the co-culture system consisted of hepatocytes, ECs and ADSCs. Hence, our results suggested that the directly co-culture of hepatocytes and ECs with HSCs or ADSCs could significantly improve liver-specific functions of hepatocytes, and the co-culture system could further promote angiogenesis of ECs at a later stage. Therefore, this study provides potential interesting in vitro strategies for enhancing liver-specific functions of hepatocytes.

Adipose tissue-derived stem cells ameliorate hyperglycemia, insulin resistance and liver fibrosis in the type 2 diabetic rats

BackgroundType 2 diabetes (T2D) is closely associated with liver fibrosis, but no effective treatments are currently available. This study was designed to investigate the therapeutic effects of ADSCs on insulin resistance, hyperglycemia, and liver fibrosis on T2D rats.MethodsWe first established a T2D rat model with liver fibrosis by using the combination of a high-fat diet (HFD), low-dose streptozotocin (STZ), and carbon tetrachloride (CCl4). Subsequently, the model rats were administrated by tail vein injection of PBS or ADSCs, respectively. Thereafter, insulin resistance and liver function were assessed by biochemical analysis, ELISA, histopathological examination, and q-PCR assay, respectively. Moreover, the molecular mechanisms of ADSCs on the effect of the TGF-β1/SMAD3 signaling pathway were further analyzed.ResultsOur data showed that ADSC transplantation significantly alleviated insulin resistance and hyperglycemia in the liver-injured T2D rats. We also found that ADSC transplantation could attenuate liver injury by improving liver function and inhibiting pathological changes of liver fibrosis, as well as through downregulation of TGF-β1 and phosphorylated SMAD3 both in vitro and in vivo.ConclusionsThese findings suggested that ADSC transplantation can ameliorate insulin resistance, hyperglycemia, and liver fibrosis via suppressing TGF-β1/SMAD3 signaling, which may provide a potential treatment strategy for liver fibrosis of T2D.

3D-cultured adipose tissue-derived stem cells inhibit liver cancer cell migration and invasion through suppressing epithelial-mesenchymal transition

Adipose tissue-derived stem cells (ADSCs) are considered promising candidates for stem cell therapy; however, the tumorigenicity of ADSCs remains controversial. The present study aimed to investigate the association between ADSCs and liver cancer cells, and to determine whether culture methods could influence the effects of ADSCs on liver cancer cell growth in vitro. Liver cancer cells were treated with ADSCs-conditioned medium (CM) that was collected using the two-dimensional (2D) culture method, sphere culture method, or three-dimensional (3D) culture method. After that, cell viability and apoptosis were measured using CCK-8 and Annexin V-FITC assay, respectively; the cell motility and adhesive capacity were analyzed by scratch wound healing and cell adhesion assay, respectively; the cell migration and invasion were examined by Transwell units; and the molecular mechanisms of ADSCs on effecting epithelial mesenchymal transition signaling pathway were further analyzed. The results demonstrated that ADSCs-CM was able to inhibit the growth of liver cancer cells by inhibiting cell proliferation and promoting cell apoptosis, as well as by suppressing cell motility, adhesive capacity, migration and invasion. In addition, ADSCs-CM was able to suppress cell growth via the downregulation of epithelial-mesenchymal transition signaling. Notably, the enhanced inhibitory effects of ADSCs on liver cancer cell growth could be achieved after cultu ring using a 3D approach. These findings suggested that ADSCs may provide a novel promising therapeutic approach for the treatment of patients with liver cancer, and the 3D culture method may provide a novel approach to explore the association between ADSCs and cancer.