Targeting integrins for cancer management using nanotherapeutic approaches: Recent advances and challenges.

Integrins are the main cell surface receptors and execute multifaceted functions such as the bidirectional transmission of signals (i.e., inside-out and outside-in) and provide communication between cells and their microenvironments. Integrins are the key regulators of critical biological functions and contribute significantly to the promotion of cancer at almost every stage of disease progression from initial tumor formation to metastasis. Integrin expressions are frequently altered in different cancers, and consequently, several therapeutic strategies targeting integrins have been developed. Furthermore, nanotechnology-based approaches have been devised to overcome the intrinsic limitations of conventional therapies for cancer management, and have been shown to more precise, safer, and highly effective therapeutic tools. Although nanotechnology-based approaches have achieved substantial success for the management of cancer, certain obstacles remain such as inadequate knowledge of nano-bio interactions and the challenges associated with the three stages of clinical trials. This review highlights the different roles of integrins and of integrin-dependent signaling in various cancers and describes the applications of nanotherapeutics targeting integrins. In addition, we discuss RGD-based approaches and challenges posed to cancer management.

Prospective cohort study of patients with early gastric cancer to detect prodromal Parkinson disease (EGC-PPD): A study protocol and baseline characteristics.

The aim of the current study is to determine the predictive value of alpha-synuclein (AS) aggregation in stomach surgical specimens in combination with selected clinical prodromal markers (CPMs) for development of Parkinson disease (PD) in a normal population. We organized a prospective, long-term, clinicopathologic cohort of patients without neurological diseases who received a radical operation for early gastric cancer (EGC) between ages 50 and 65 years. The participants will be followed for up to 10 years and screened for CPMs and motor symptoms by annual telephone interview. If a participant reports one or more positive answers to screening questions about motor symptoms, they will be regarded as having possible parkinsonism. A movement disorder specialist will then evaluate whether that participant has PD. The primary outcome is the development of PD during the 10-year follow-up. The recruitment period has been completed, and the baseline clinical characteristics are compared between participants with and without possible parkinsonism. A total of 718 participants (mean age: 60.1 ±â€¯5.9) was recruited. The motor symptom screening questionnaire revealed 65 patients with possible parkinsonism (9.0%) at baseline. Patients with possible parkinsonism answered that they had subjective loss of smell more than those without parkinsonism at the time of recruitment (18.5% vs 8.3%) and operation (15.4% vs 6.3%). However, the objective odor discrimination test showed no difference between patients with and without possible parkinsonism. Baseline assessments revealed a sufficient number of patients with possible parkinsonism, which will be confirmed as PD or not in subsequent follow-up visits.

A Feasibility Study and Technical Tips for the Use of an Articulating Bipolar Vessel Sealer in da Vinci Robot-Assisted Gastrectomy.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of a new articulating bipolar energy device, the EndoWrist® One™ Vessel Sealer (VS), in da Vinci® robot-assisted gastrectomy. MATERIALS AND METHODS: Patients (n = 17) with cT1/2 gastric cancer who underwent robotic gastrectomy using the VS were prospectively enrolled in the study group (VS group). The clinicopathological outcomes, including operative time, intraoperative blood loss, amount of postoperative drainage, postoperative biochemical analysis results, and complication rates, were prospectively collected and compared with those of patients who underwent robotic gastrectomy using conventional ultrasonic shear force ([US] group, n = 52) during the same time period. RESULTS: Although the VS provided a good direction for dissection because of the articulating function, the ancillary use of conventional bipolar coagulation was occasionally needed due to the blunt, nonactive end tip of the VS. The operative time, intraoperative blood loss, postoperative drainage, and absence of complication rates did not differ between the VS and US groups, but the C-reactive protein levels on the second postoperative day (8.06 versus 11.7, P = .002) and serum albumin levels on the fifth postoperative day (3.51 versus 3.32, P = .019) were superior in the VS group. CONCLUSION: Use of the VS in robotic gastrectomy was feasible and provided good configuration in the direction of dissection. The learning process for use of the VS in the initial series was relatively rapid, resulting in comparable results between the VS and US groups. Reduced inflammation and albumin loss were identified as possible benefits of the VS.

Deoxyactein protects pancreatic ß-cells against methylglyoxal-induced oxidative cell damage by the upregulation of mitochondrial biogenesis.

Methylglyoxal (MG) is one of the major precursors of advanced glycation end products (AGEs), which are considered to be one of the causes of diabetes and its complications. The root and rhizomes of black cohosh (Cimicifuga racemosa) have long been used medicinally, and deoxyactein is one of its major constituents. In the present study, the protective effects of deoxyactein against MG-induced oxidative cell damage were investigated in insulin-producing pancreatic ß-cells. We found that deoxyactein protected the pancreatic ß-cells against MG-induced cell death. Pre-treatment with deoxyactein significantly reduced the levels of intracellular reactive oxygen species (ROS), interleukin-1ß (IL-1ß), cardiolipin peroxidation, and protein adduct accumulation induced by MG. Pre-treatment of the cells with deoxyactein restored glyoxalase I activity and insulin secretion which were reduced by MG, and increased the mRNA expression of insulin 2 (INS2) and pancreatic and duodenal homeobox protein-1 (PDX-1). It also increased the levels of endogenous antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPX). Furthermore, treatment with deoxyactein increased the levels of sirtuin 1 (SIRT1) and peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α). These findings indicate that deoxyactein may exert beneficial effects on pancreatic ß-cells via the upregulation of mitochondrial biogenesis. Taken together, these results suggest that deoxyactein may be used for the prevention of pancreatic ß-cell damage.

Perfluorooctanoic acid induces oxidative damage and mitochondrial dysfunction in pancreatic ß-cells.

Several environmental contaminants have been linked to the development of diabetes and increased diabetes­associated mortality. Perfluorooctanoic acid (PFOA) is a widely used perfluoroalkane found in surfactants and lubricants, and in processing aids used in the production of polymers. Furthermore, PFOA has been detected in humans, wildlife and the environment. The present study investigated the toxic effects of PFOA on rat pancreatic ß­cell­derived RIN­m5F cells. Cell viability, apoptosis, reactive oxygen and nitrogen species, cytokine release and mitochondrial parameters, including membrane potential collapse, reduced adenosine triphosphate levels, cardiolipin peroxidation and cytochrome c release were assessed. PFOA significantly decreased RIN­m5F cell viability and increased apoptosis. Exposure to PFOA increased the formation of reactive oxygen species, mitochondrial superoxide, nitric oxide and proinflammatory cytokines. Furthermore, PFOA induced mitochondrial membrane potential collapse and reduced adenosine triphosphate levels, cardiolipin peroxidation and cytochrome c release. These results indicate that PFOA is associated with the induction of apoptosis in RIN-m5F cells, and induces cytotoxicity via increased oxidative stress and mitochondrial dysfunction.

Glabridin Alleviates the Toxic Effects of Methylglyoxal on Osteoblastic MC3T3-E1 Cells by Increasing Expression of the Glyoxalase System and Nrf2/HO-1 Signaling and Protecting Mitochondrial Function.

Methylglyoxal (MG) contributes to the pathogenesis of age- and diabetes-associated complications. The present study investigated the effects of glabridin on MG-induced cytotoxicity in MC3T3-E1 osteoblastic cells. MC3T3-E1 cells were treated with glabridin in the presence of MG, and markers of mitochondrial function and oxidative damage were examined. Pretreatment of MC3T3-E1 osteoblastic cells with glabridin prevented MG-induced cell death, the production of intracellular reactive oxygen species and mitochondrial superoxides, cardiolipin peroxidation, and the production of inflammatory cytokines. The soluble form of receptor for advanced glycation end products (sRAGEs)/RAGE ratio increased upon MG treatment, but less so after pretreatment with glabridin, which also increased the level of reduced glutathione and the activities of glyoxalase I and heme oxygenase-1, all of which were reduced by MG. In addition, glabridin elevated the level of nuclear factor erythroid 2-related factor 2. These findings suggest that glabridin protects against MG-induced cell damage by inhibiting oxidative stress and increasing MG detoxification. Pretreatment of MC3T3-E1 osteoblastic cells with glabridin reduced MG-induced mitochondrial dysfunction. Additionally, the nitric oxide level significantly increased upon glabridin pretreatment. Together, these data show that glabridin may potentially serve to prevent the development of diabetic bone disease associated with MG-induced oxidative stress.

Differential white matter connectivity in early mild cognitive impairment according to CSF biomarkers.

Mild cognitive impairment (MCI) is a heterogeneous group and certain MCI subsets eventually convert to dementia. Cerebrospinal fluid (CSF) biomarkers are known to predict this conversion. We sought evidence for the differences in white matter connectivity between early amnestic MCI (EMCI) subgroups according to a CSF phosphorylated tau181p/amyloid beta1-42 ratio of 0.10. From the Alzheimer's Disease Neuroimaging Initiative database, 16 high-ratio, 25 low-ratio EMCI patients, and 20 normal controls with diffusion tensor images and CSF profiles were included. Compared to the high-ratio group, radial diffusivity significantly increased in both sides of the corpus callosum and the superior and inferior longitudinal fasciculus in the low-ratio group. In widespread white matter skeleton regions, the low-ratio group showed significantly increased mean, axial, and radial diffusivity compared to normal controls. However, the high-ratio group showed no differences when compared to the normal group. In conclusion, our study revealed that there were significant differences in white matter connectivity between EMCI subgroups according to CSF phosphorylated tau181p/amyloid beta1-42 ratios.

Expression of Secreted Protein Acidic and Rich in Cysteine in the Stroma of a Colorectal Carcinoma is Associated With Patient Prognosis.

PURPOSE: Secreted protein acidic and rich in cysteine (SPARC), also known as osteonectin or basement-membrane-40 (BM-40), is a member of a family of matricellular proteins, whose functions are to modulate cell-matrix interactions, growth and angiogenesis in colorectal cancer. In this study, the expression of SPARC was evaluated and its correlations with clinicopathological parameters were investigated. METHODS: The researchers analyzed the expression patterns of SPARC by using immunohistochemistry in 332 cases of colorectal cancer of tissue microarray. The clinicopathological characteristics were defined by using the TNM criteria of the Union for International Cancer Control. Clinicopathological factors such as age, sex, histologic type of the tumor, pathologic tumor stage, TNM stage, and lymphovascular invasion were evaluated according to the SPARC expression. RESULTS: The hazard ratios expressing SPARC in tumor cells, in the stroma, and in both tumor cells and the stroma were 2.10 (P = 0.036), 3.27 (P = 0.003) and 2.12 (P = 0.038), respectively. Patient survival was decreased in patient expressing SPARC in the stroma, and this result showed statistical significance (P = 0.016). CONCLUSION: These findings suggest that SPARC expression in a tumor and in the stroma correlates with disease progression and may be used as a prognostic marker for colorectal cancer.

Therapeutic advantages of medicinal herbs fermented with Lactobacillus plantarum, in topical application and its activities on atopic dermatitis.

The use of herbal medicines in the therapeutic treatment of atopic dermatitis (AD) has been suggested recently. The present study examined whether selected herbal extracts fermented in Lactobacillus plantarum (FHE) possessed anti-AD properties. In addition, the study assessed the increased bioavailability of these herbal extracts both in vitro and in vivo. The data from these experiments revealed that FHE inhibited the proliferation of splenic T and B cells in a dose-dependent manner, when activated with their mitogens. Moreover, the expression of Th1/Th2 mRNA cytokines (IL-2, IL-4, IL-5, IL-13) from mouse splenocytes was inhibited severely as was cyclosporine A. Furthermore, the release of beta-hexosaminidase in RBL-2H3 mast cells was suppressed significantly. FHE also reduced the plasma level of IgE in dust mite extract-induced AD-like NC/Nga mice. More dramatic results were found in the histological changes, which were observed by hematoxylin-eosin and toluidine blue staining, as well as in the macroscopic features on dorsal lesions of AD-like NC/Nga mice. In conclusion, the results presented in this study suggest that FHE may have therapeutic advantages for the treatment of AD due to its increased immune-suppressive and increased absorptive effects, which were fortified by L. plantarum fermentation.