Potential role of PRKCSH in lung cancer: bioinformatics analysis and a case study of Nano ZnO.

PRKCSH, also known as glucosidase II beta, functions as a contributor to lung tumorigenesis by regulating the cell cycle in a p53-dependent manner under severe environmental stress. However, the prognostic value and molecular mechanisms by which the level of PRKCSH is significantly increased in cancer cells are not clearly understood. Here, we first generated a biological profile of PRKCSH expression changes in cancers by analysing bioinformatic data from cancer databases. We found that higher PRKCSH expression was correlated with a poorer prognosis and greater infiltration of most immune cell types in patients with lung cancer. In particular, PRKCSH expression showed significant negative correlations with the level of STAT6 (r = -0.31, p < 0.001) in lung cancer tissues. We further found that PRKCSH deficiency promoted G2/M arrest in response to zinc oxide nanoparticle (Nano ZnO) treatment in A549 cells. With regard to the mechanism, PRKCSH deficiency may induce STAT6 translocation to the nucleus to activate p53 expression through binding to the p53 promoter region from -365 bp to +126 bp. Eventually, activated p53 contributed to Nano-ZnO-induced G2/M arrest in lung cancer cells. Taken together, our data provide new insights into immunotherapy target choices and the prognostic value of PRKCSH. Since the G2/M cell cycle checkpoint is crucial for lung cancer prognosis, targeting PRKCSH expression to suppress the activation of the STAT6/p53 pathway is a potential therapeutic strategy for managing lung cancer.

Cardiac response to enzyme replacement therapy in infantile Pompe disease with severe hypertrophic cardiomyopathy.

Classic infantile-onset Pompe disease (IOPD), characterized by predominantly cardiac involvement, used to be considered uniformly lethal within months. The availability of enzyme replacement therapy (ERT) has transformed the course of the disease. Decrease in ventricular hypertrophy and improvement in ventricular function have been suggested as proof for efficacy. We report the cardiac response to ERT of a child with IOPD and severe hypertrophic cardiomyopathy. The myocardial hypertrophy resolved. Change in ejection fraction, however, was slow. We discuss the potential benefit of other parameters beyond ejection to assess cardiac function in IOPD, including speckle tracking-based strain.

Niemann-Pick disease type C or Gaucher's disease type 3? A clinical conundrum.

We describe a patient who presented with a neurovisceral syndrome characterised by ataxia, bulbar dysfunction, supranuclear gaze palsy, splenomegaly and foamy histiocytes in the bone marrow. This presentation was suggestive of a lysosomal storage disorder such as Niemann-Pick disease type C or Gaucher's disease type 3. We review the presentation of these disorders, with a focus on the neurological features. In addition, we briefly discuss the disease-modifying therapeutic options which have recently become available.

Transglucosidase improves the gut microbiota profile of type 2 diabetes mellitus patients: a randomized double-blind, placebo-controlled study.

BACKGROUND: Recently, the relationship between gut microbiota and obesity has been highlighted. The present randomized, double-blind, placebo-controlled study aimed to evaluate the efficacy of transglucosidase (TGD) in modulating blood glucose levels and body weight gain in patients with type 2 diabetes mellitus (T2DM) and to clarify the underlying mechanism by analyzing the gut microbiota of T2DM patients. METHODS: This study included 60 patients who received placebo or TGD orally (300 or 900 mg/day) for 12 weeks, and blood and fecal samples were collected before and after 12 weeks. Comparisons of fecal bacterial communities were performed before and after the TGD treatment and were performed between T2DM patients and 10 healthy individuals, using the terminal-restriction fragment length polymorphism analysis. RESULTS: The Clostridium cluster IV and subcluster XIVa components were significantly decreased, whereas the Lactobacillales and Bifidobacterium populations significantly increased in the T2DM patients compared with the healthy individuals. By dendrogram analysis, most of the healthy individuals (6/10) and T2DM patients (45/60) were classified into cluster I, indicating no significant difference in fecal bacterial communities between the healthy individuals and the T2DM patients. In the placebo and TGD groups, the bacterial communities were generally similar before and after the treatment. However, after 12 weeks of TGD therapy, the Bacteroidetes-to-Firmicutes ratio in the TGD groups significantly increased and was significantly higher compared with that in the placebo group, indicating that TGD improved the growth of the fecal bacterial communities in the T2DM patients. CONCLUSIONS: Therefore, TGD treatment decreased blood glucose levels and prevented body weight gain in the T2DM patients by inducing the production of oligosaccharides in the alimentary tract and modulating gut microbiota composition. TRIAL REGISTRATION: UMIN-CTR UMIN000010318.

Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease.

Enzyme replacement has been under consideration as a therapeutic strategy for patients with Gaucher disease for more than two decades. Previous studies indicated that single injections of purified glucocerebrosidase reduced the amount of storage material in the liver. It was important to determine whether administration of exogenous enzyme on a regular basis would be of clinical benefit. We report here that weekly i.v. infusions of a macrophage-targeted preparation of human placental glucocerebrosidase in a child with type 1 Gaucher disease increased hemoglobin from 6.9 +/- 0.8 g/dl (+/- 1 SD) to 10.2 +/- 0.4 g/dl (+/- 1 SD) over a 20-week period. The platelet count also increased from a pretreatment value of 30,000 +/- 7000/mm3 (+/- 1 SD) to 54,000 +/- 11,000/mm3 (+/- 1 SD). Phagocytic activity in the spleen decreased during the period of enzyme administration, and there was radiographic evidence of skeletal improvement. These observations document objective clinical responses to enzyme supplementation in a patient with a sphingolipid storage disorder.

Clinical uses of an enzyme-containing dentifrice.

Previous studies have shown that the inclusion of certain enzymes in mouthrinses and dentifrices will reduce plaque and gingivitis scores. The enzymes that are most effective clinically have, as their active ingredients, amyloglucosidase and glucose oxidase. These produce hydrogen peroxide from dietary fermentable carbohydrates which in turn converts thiocyanate to hypothiocyanite in the presence of salivary lactoperoxidase. The resultant hypothiocyanite acts as a bacterial inhibitor by interfering with cell metabolism; thus, there is a reduction in plaque accumulation and therefore in gingival inflammation. Pilot studies have compared over a short period the action of the trial dentifrice with enzymes and fluoride at 1100 ppm, using as controls the paste without enzymes but with fluoride and a commercial fluoride paste. There was an expected reduction in all scores with all products due to the mechanical removal of plaque, but a significantly greater reduction in gingivitis was noted in the paste with enzymes. This study is of longer duration with many more subjects. Baseline data include plaque and gingival indices and Periotron readings for crevicular fluid. The trial is of a double-blind non-crossover study design using a split-mouth technique. One side of the mouth is given a prophylaxis and the subject given one of the 3 test pastes to use. Readings were repeated every 2 weeks for 3 months. The results show a significant reduction in gingivitis scores in the enzyme-containing dentifrice group.

Plaque growth-inhibiting effects of an abrasive fluoride-chlorhexidine toothpaste and a fluoride toothpaste containing oxidative enzymes.

The aim of this 4 times cross-over double-blind clinical trial was to test the plaque-inhibiting effect of 2 fluoride-containing toothpastes. One toothpaste contained 0.8% chlorhexidine together with amine fluoride (0.1% F degrees) and a suitable abrasive agent. The other contained 1.7 U/g glucose oxidase and 8.0 U/g amyloglucosidase, added to an amine fluoride (0.1% F degrees) toothpaste. 1% Hibitane dental gel was used as a positive and a conventional fluoride toothpaste (Vademecum MFP Fluor) as a negative control. 9 dental students, in a randomized sequence, applied the 4 dentifrices twice daily from Monday afternoon to Friday morning with cap splints, designed to cover the teeth and about 2 mm of gingiva. No other oral hygiene measures were allowed during the 4 test periods. On Fridays, the teeth were cleaned professionally and good oral hygiene was maintained during the week-ends. At the beginning and at the end of each test period, per student plaque thickness was recorded using the plaque index, the visible plaque index, and plaque fresh weight as parameters, and the area of plaque as related to the area of the tooth surface was recorded planimetrically and according to the PLQ index. The best plaque growth-inhibiting effect was recorded for the positive control (CHX) with the test chlorhexidine toothpaste (TX) as next best. The enzyme-containing toothpaste (TE) did not differ significantly from the negative control (C). All the significant differences in anti-plaque effect between the 4 toothpastes were obtained by recordings of plaque thickness and none on the basis of area of plaque.

Effect of zendium toothpaste on recurrent aphthous stomatitis.

A double-blind clinical trial with cross-over was conducted for a period of 12 months in 25 patients with recurrent aphthous stomatitis (RAS). The effect of the amyloglucosidase and glucoseoxidase containing Zendium toothpaste on the discomfort, number of exacerbations, duration of exacerbation, number of ulcers and number of days with pain caused by RAS was studied. The use of Zendium significantly reduced the sensation of discomfort from RAS as compared to the use of placebo toothpaste (0.025 greater than p greater than 0.01). However, the patients were unable to discriminate significantly between Zendium and placebo when asked to choose one of the toothpastes (0.10 greater than p greater than 0.05) and no significant differences were demonstrated as far as the above mentioned parameters of disease severity were concerned. Therefore, it is concluded that the reducing effect of Zendium containing amyloglucosidase and glucoseoxidase on RAS is weak as compared to a similar toothpaste without these enzymes.

Gaucher disease: a century of delineation and research. Enzyme replacement therapy: model and clinical studies.

A number of investigators have attempted to treat Gaucher disease with exogenous glucocerebrosidase. Although at times encouraging biochemical changes and suggestive alterations in organomegaly have been reported, overall, the results of enzyme replacement therapy must be judged to be a failure. In order to understand this lack of success with a promising treatment modality, four aspects of enzyme replacement therapy require examination: 1. The purification of glucocerebrosidase to a form which can hydrolyze glucocerebroside under in vivo conditions; 2. The delivery of the enzyme to cells of the macrophage-monocyte system; 3. The intracellular fate of the administered enzyme; 4. The capacity of the enzyme to effectively contact intracellular glycolipid deposits. A model system for the study of the latter three of these aspects of enzyme replacement therapy has been developed. Monocytes from normal subjects and patients with Gaucher disease were maintained in tissue culture for several months using horse serum-containing culture media. When such cells were "fed" glucocerebrosidase, their enzyme deficiency was corrected for at least 72 hours. Cells from Gaucher disease patients do not spontaneously accumulate glucocerebroside in this system. When loaded with 14C-labeled glucocerebroside, they do not become Gaucher cells but rather manifest a remarkable capacity to catabolize glucocerebroside, so that the labeled fatty acid quickly appears in neutral fats and in phospholipids. Therefore, this model is not yet suitable for study of the effectiveness of enzyme therapy.

alpha1,4-Glucosidase-albumin polymers: in vitro properties and advantages for enzyme replacement therapy.

Soluble polymers of rat (or human) albumin and alpha-1,4-glucosidase are prepared using the cross-linking agent glutaraldehyde. The resulting polymer has an average molecular weight of 800 000 indicating an average composition of 12 albumin molecules for each enzyme molecule. Compared with an equivalent amount of free enzyme, the enzyme-albumin polymer has an increased resistance to heat denaturation (half-life of 15 h compared with 1 h for free enzyme at 37 degrees C) and to proteolysis by trypsin (half-life of 180 min compared with 10 min). The high degree of resistance to bioinactivation of the enzyme-albumin polymer is discussed in relation to requirements for enzyme replacement therapy in a range of metabolic diseases including type II glycogenosis (Pompe's disease) where alpha-1,4-glucosidase is the defective enzyme.

Status of enzyme replacement therapy for Gaucher disease.

At this point in time, enzyme replacement therapy for Gaucher disease appears both biochemically effective (patients 1-3, and 10) as well as clinically promising (patients 4 and 5), although these salutary responses have not been obtained consistently (patients 6-9). The discrepancy may be due to the method employed for the isolation of the enzyme. One current opinion is that glucocerebrosidase prepared by conventional fractionation and ion exchange chromatographic procedures may have been more effective in vivo than enzyme prepared by butanol extraction and hydrophobic column chromatography, which we developed because of the difficulty in obtaining large quantities of glucocerebrosidase by the conventional method. It should be remembered that the enzyme prepared by the latter procedure was fully active on glucocerebroside in liver biopsy specimens in vitro. Furthermore, glucocerebrosidase prepared by the second method exerted a positive effect in 2 young patients, who received relatively large amounts of enzyme, and in an adult who was treated with corticosteroid prior to infusion of the enzyme. At this moment, a possible explanation is that a necessary associated factor, perhaps a lipid, may have been removed by the large-scale isolation procedure. We are attempting to improve the biochemical and clinical responses to enzyme infusion by investigating the effects of lysosomal modifying agents and by enhancing the uptake and localization of the infused enzyme in lysosomes of cells that contain the stored glucocerebroside.