Qizhi Yao

Current advances in research and clinical applications of PLGA-based nanotechnology

Co-polymer poly(lactic-co-glycolic acid) (PLGA) nanotechnology has been developed for many years and has been approved by the US FDA for the use of drug delivery, diagnostics and other applications of clinical and basic science research, including cardiovascular disease, cancer, vaccine and tissue engineering. This article presents the more recent successes of applying PLGA-based nanotechnologies and tools in these medicine-related applications. It focuses on the possible mechanisms, diagnosis and treatment effects of PLGA preparations and devices. This updated information will benefit to both new and established research scientists and clinical physicians who are interested in the development and application of PLGA nanotechnology as new therapeutic and diagnostic strategies for many diseases.

Ginseng Compounds: An Update on their Molecular Mechanisms and Medical Applications

Ginseng is one of the most widely used herbal medicines and is reported to have a wide range of therapeutic and pharmacological applications. Ginsenosides, the major pharmacologically active ingredients of ginseng, appear to be responsible for most of the activities of ginseng including vasorelaxation, antioxidation, anti-inflammation and anti-cancer. Approximately 40 ginsenoside compounds have been identified. Researchers now focus on using purified individual ginsenoside to reveal the specific mechanism of functions of ginseng instead of using whole ginseng root extracts. Individual ginsenosides may have different effects in pharmacology and mechanisms due to their different chemical structures. Among them the most commonly studied ginsenosides are Rb1, Rg1, Rg3, Re, Rd and Rh1. The molecular mechanisms and medical applications of ginsenosides have attracted much attention and hundreds of papers have been published in the last few years. The general purpose of this update is to provide information of recently described effects of ginsenosides on antioxidation, vascular system, signal transduction pathways and interaction with receptors. Their therapeutic applications in animal models and humans as well as the pharmacokinetics and toxicity of ginsenosides are also discussed in this review. This review concludes with some thoughts for future directions in the further development of ginseng compounds as effective therapeutic agents.

Chemical and molecular mechanisms of antioxidants: experimental approaches and model systems.

•  Introduction •  Free radical scavenging ‐  Scavenging superoxide and other ROS ‐  Scavenging hydroxyl radical and other ROS ‐  Stable radical scavenging •  Metal ion (Fe2+, Fe3+, Cu2+ and Cu+) chelating •  Inhibition of free radical generating enzymes •  Activation of internal antioxidant enzymes •  Prevention of lipid peroxidation •  Prevention of DNA damage •  Prevention of protein modification •  Conclusions

Shear Stress Induces Endothelial Differentiation From a Murine Embryonic Mesenchymal Progenitor Cell Line

Objective—Recent studies have illustrated that mesenchymal stem cells possess the potential to differentiate along an endothelial lineage, but the effect of shear on mesenchymal differentiation is unknown. Thus, we developed an in vitro shear stress system to examine the relationship between shear stress and the endothelial differentiation of a murine embryonic mesenchymal progenitor cell line, C3H/10T1/2. Methods and Results—The parallel plate system of fluid shear stress was used. Shear stress significantly induced expression of mature endothelial cell–specific markers in CH3H/10T1/2 cells such as CD31, von Willebrand factor, and vascular endothelial–cadherin at both the mRNA and protein levels with real-time polymerase chain reaction and immunofluorescence analyses, respectively. In addition, shear-induced augmentation of functional markers of the mature endothelial phenotype such as uptake of acetylated low-density lipoproteins and formation of capillary-like structures on Matrigel. Furthermore, shear stress significantly upregulated angiogenic growth factors while downregulating growth factors associated with smooth muscle cell differentiation. Conclusions—This study demonstrates, for the fist time, endothelial differentiation in a mesenchymal progenitor CH3H/10T1/2 cell line resulting from shear exposure. Thus, this analysis may serve as a basis for further understanding the effect of shear on mesenchymal and vascular cell differentiation.

Resistin: functional roles and therapeutic considerations for cardiovascular disease.

Resistin, originally described as an adipocyte‐specific hormone, has been suggested to be an important link between obesity, insulin resistance and diabetes. Although its expression was initially defined in adipocytes, significant levels of resistin expression in humans are mainly found in mononuclear leukocytes, macrophages, spleen and bone marrow cells. Increasing evidence indicates that resistin plays important regulatory roles apart from its role in insulin resistance and diabetes in a variety of biological processes: atherosclerosis and cardiovascular disease (CVD), non‐alcoholic fatty liver disease, autoimmune disease, malignancy, asthma, inflammatory bowel disease and chronic kidney disease. As CVD accounts for a significant amount of morbidity and mortality in patients with diabetes and without diabetes, it is important to understand the role that adipokines such as resistin play in the cardiovascular system. Evidence suggests that resistin is involved in pathological processes leading to CVD including inflammation, endothelial dysfunction, thrombosis, angiogenesis and smooth muscle cell dysfunction. The modes of action and signalling pathways whereby resistin interacts with its target cells are beginning to be understood. In this review, the current knowledge about the functions and pathophysiological implications of resistin in CVD development is summarized; clinical translations, therapeutic considerations and future directions in the field of resistin research are discussed.

Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression

Zinc is an essential trace element and catalytic/structural component used by many metalloenzymes and transcription factors. Recent studies indicate a possible correlation of zinc levels with the cancer risk; however, the exact role of zinc and zinc transporters in cancer progression is unknown. We have observed that a zinc transporter, ZIP4 (SLC39A4), was substantially overexpressed in 16 of 17 (94%) clinical pancreatic adenocarcinoma specimens compared with the surrounding normal tissues, and ZIP4 mRNA expression was significantly higher in human pancreatic cancer cells than human pancreatic ductal epithelium (HPDE) cells. This indicates that aberrant ZIP4 up-regulation may contribute to the pancreatic cancer pathogenesis and progression. We studied the effects of ZIP4 overexpression in pancreatic cancer cell proliferation in vitro and pancreatic cancer progression in vivo. We found that forced expression of ZIP4 increased intracellular zinc levels, increased cell proliferation by 2-fold in vitro, and significantly increased tumor volume by 13-fold in the nude mice model with s.c. xenograft compared with the control cells. In the orthotopic nude mice model, overexpression of ZIP4 not only increased the primary tumor weight (7.2-fold), it also increased the peritoneal dissemination and ascites incidence. Moreover, increased cell proliferation and higher zinc content were also observed in the tumor tissues that overexpressed ZIP4. These data reveal an important outcome of aberrant ZIP4 expression in contributing to pancreatic cancer pathogenesis and progression. It may suggest a therapeutic strategy whereby ZIP4 is targeted to control pancreatic cancer growth.

Development of Small-Diameter Vascular Grafts

IntroductionCardiovascular disease, including coronary artery and peripheral vascular pathologies, is the leading cause of mortality in the United States and Western countries. There is a pressing need to develop small-diameter vascular vessels for bypass surgery and other vascular reconstructive procedures. Tissue engineering offers the prospect of being able to meet the demand for replacement of diseased vessels. Significant advances have been made in recent studies and provide confidence that success is attainable. For instance, a completely cellular approach culturing cells into tissue sheets and wrapping these layers was able to form a layered cellular vascular graft with impressive strength.Methods/ResultsIn our experiments, decellularization and heparin immobilization grafts from porcine tissues implanted in a canine model could be repopulated from the host cells, indicating the grafts’ potential to develop into living tissues that can adapt and respond to changes in the body.ConclusionsThis review summarizes the current status of vascular grafts used clinically, updates the most recent developments on vascular tissue engineering, and discusses the challenges for the future.

HIV Protease Inhibitor Ritonavir Induces Cytotoxicity of Human Endothelial Cells

Objective—Although HIV protease inhibitors have been successfully used against HIV infection, many metabolic side effects and premature cardiovascular diseases are often associated with this therapy. The mechanisms of these complications are not clear. In this study, we investigated the effect of the HIV protease inhibitor ritonavir on human endothelial cell cultures. Methods and Results—By using nonradioactive cell proliferation and cytotoxicity assays, human endothelial cells treated with ritonavir showed a significant decrease in cell viability and an increase in cytotoxicity in a time- and dose-dependent fashion. Mitochondrial DNA was also substantially damaged with ritonavir treatment by long polymerase chain reaction analysis. In contrast, ritonavir had a very limited effect on endothelial apoptosis, as assessed by analyses of DNA fragmentation and cellular caspase-3 activity. Conclusions—These data demonstrate, for the first time, that the HIV protease inhibitor ritonavir at concentrations near clinical plasma levels is able to directly cause endothelial mitochondrial DNA damage and cell death mainly through necrosis pathways but not through apoptosis. This study suggests that HIV protease inhibitor–mediated endothelial injury may contribute to its cardiovascular complications.

MicroRNA-196: critical roles and clinical applications in development and cancer.

•  Introduction •  Gene structure and regulation •  Target molecules •  Role in development •  Role in cancer •  Other biological functions •  Summary and perspectives

Overcoming drug resistance in pancreatic cancer.

Introduction: Pancreatic cancer has the worst survival rate of all cancers. The current standard care for metastatic pancreatic cancer is gemcitabine, however, the success of this treatment is poor and overall survival has not improved for decades. Drug resistance (both intrinsic and acquired) is thought to be a major reason for the limited benefit of most pancreatic cancer therapies. Areas covered: Previous studies have indicated various mechanisms of drug resistance in pancreatic cancer, including changes in individual genes or signaling pathways, the influence of the tumor microenvironment, and the presence of highly resistant stem cells. This review summarizes recent advances in the mechanisms of drug resistance in pancreatic cancer and potential strategies to overcome this. Expert opinion: Increasing drug delivery efficiency and decreasing drug resistance is the current aim in pancreatic cancer treatment, and will also benefit the treatment of other cancers. Understanding the molecular and cellular basis of drug resistance in pancreatic cancer will lead to the development of novel therapeutic strategies with the potential to sensitize pancreatic cancer to chemotherapy, and to increase the efficacy of current treatments in a wide variety of human cancers.