Early improvement in cardiac tissue perfusion due to mesenchymal stem cells

The underlying mechanism(s) of improved left ventricular function (LV) due to mesenchymal stem cell (MSC) administration after myocardial infarction (MI) remains highly controversial. Myocardial regeneration and neovascularization, which leads to increased tissue perfusion, are proposed mechanisms. Here we demonstrate that delivery of MSCs 3 days after MI increased tissue perfusion in a manner that preceded improved LV function in a porcine model. MI was induced in pigs by 60-min occlusion of the left anterior descending coronary artery, followed by reperfusion. Pigs were assigned to receive intramyocardial injection of allogeneic MSCs (200 million, approximately 15 injections) (n = 10), placebo (n = 6), or no intervention (n = 8). Resting myocardial blood flow (MBF) was serially assessed by first-pass perfusion magnetic resonance imaging (MRI) over an 8-wk period. Over the first week, resting MBF in the infarct area of MSC-treated pigs increased compared with placebo-injected and untreated animals [0.17 +/- 0.03, 0.09 +/- 0.01, and 0.08 +/- 0.01, respectively, signal intensity ratio of MI to left ventricular blood pool (LVBP); P < 0.01 vs. placebo, P < 0.01 vs. nontreated]. In contrast, the signal intensity ratios of the three groups were indistinguishable at weeks 4 and 8. However, MSC-treated animals showed larger, more mature vessels and less apoptosis in the infarct zones and improved regional and global LV function at week 8. Together these findings suggest that an early increase in tissue perfusion precedes improvements in LV function and a reduction in apoptosis in MSC-treated hearts. Cardiac MRI-based measures of blood flow may be a useful tool to predict a successful myocardial regenerative process after MSC treatment.     

Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics

We have observed rapid and extensive depletion of cellular energy stores by Delta(9)-tetrahydrocannabinol (THC) in the pulmonary transformed cell line A549. ATP levels declined dose dependently with an IC(50) of 7.5 microg/ml of THC after 24-h exposure. Cell death was observed only at concentrations >10 microg/ml. Studies using JC-1, a fluorescent probe for mitochondrial membrane potential, revealed diminished mitochondrial function at THC concentrations as low as 0.5 microg/ml. At concentrations of 2.5 or 10 microg/ml of THC, a decrease in mitochondrial membrane potential was observed as early as 1 h after THC exposure. Mitochondrial function remained diminished for at least 30 h after THC exposure. Flow cytometry studies on cells exposed to particulate smoke extracts indicate that JC-1 red fluorescence was fivefold lower in cells exposed to marijuana smoke extract relative to cells exposed to tobacco smoke extract. Comparison with a variety of mitochondrial inhibitors demonstrates that THC produced effects similar to that of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, suggesting uncoupling of electron transport. Loss of red JC-1 fluorescence by THC was suppressed by cyclosporin A, suggesting mediation by the mitochondrial permeability transition pore. This disruption of mitochondrial function was sustained for at least 24 h after removal of THC by extensive washing. These results suggest that exposure of the bronchopulmonary epithelium to THC may have important health and physiological consequences.     

The Effects of Probiotics or Synbiotics Supplementation in Women with Polycystic Ovarian Syndrome: a Systematic Review and Meta-Analysis of Randomized Clinical Trials

Probiotics and Antimicrobial Proteins - We searched bibliographic databases from inception through May 2018 to evaluate the effect of probiotics (or synbiotics) supplementation in women suffering...     

More Protection of Lactobacillus acidophilus Than Bifidobacterium bifidum Probiotics on Azoxymethane-Induced Mouse Colon Cancer

Based on the ability of the probiotics in the gut microflora modification, they can have the beneficial effects on diseases in the short and/or the long term. In previous study, we revealed that unlike Bifidobacterium bifidum, the amount of Lactobacillus acidophilus remained almost unchanged in mice gut microflora in the long term, indicating more stability of L. acidophilus than B. bifidum which can be used to prevent some incurable diseases such as cancer. Thirty-eight male BALB/c mice were divided into four groups, control, azoxymethane (AOM), L. acidophilus, and B. bifidum probiotics, to evaluate the protective effects of the probiotics on AOM-induced mouse colon cancer. Except for the control group, the rest of the animals were weekly given AOM (15 mg/kg, s.c) in three consecutive weeks. Colon lesion incidence was 74% in the AOM group in comparison with the control (0%) (P < 0.05). The lesions were varied from mild to severe dysplasia and colonic adenocarcinoma. Administration of the probiotics inhibited the incidence of colonic lesions by about 57% in L. acidophilus (P < 0.05) and 27% in B. bifidum (P > 0.05) compared to the AOM group. The serum levels of CEA and CA19-9 tumor markers were significantly decreased in L. acidophilus in comparison with the AOM group (P < 0.05). Moreover, the serum levels of IFN-γ and IL-10 and the number of CD4⁺ and CD8⁺ cells were significantly increased in L. acidophilus compared to AOM (P < 0.05). Our study highlighted the more potential effects of L. acidophilus probiotic than B. bifidum on mouse colon cancer.

     

Carboxymethyl dextran-trimethyl chitosan coated superparamagnetic iron oxide nanoparticles: An effective siRNA delivery system for HIV-1 Nef

Gene therapy, including small interfering RNA (siRNA) technology, is one of the leading strategies that help to improve the outcomes of the current therapeutic systems against HIV-1 infection. The successful therapeutic application of siRNAs requires their safe and efficient delivery to specific cells. Here, we introduce a superparamagnetic iron oxide nanoparticle (SPION) for delivering siRNA against HIV-1 nef (anti-nef siRNA) into two cell lines, HEK293 and macrophage RAW 264.7. SPIONs were coated with trimethyl chitosan (TMC), and thereafter, different concentrations of SPION–TMC were coated with different ratios of a carboxymethyl dextran (CMD) to modify the physicochemical properties and improve the biological properties of the nanocarriers. The nanoparticles exhibited a spherical shape with an average size of 112 nm. The obtained results showed that the designed delivery route enhanced the uptake of siRNA into both HEK293 and RAW 264.7 cells compared with control groups. Moreover, CMD–TMC–SPIONs containing anti-nef siRNA significantly reduced the expression of HIV-1 nef in HEK293 stable cells. The modified siRNA-loaded SPIONs also displayed no toxicity or apoptosis-inducing effects on the cells. The CMD–TMC–SPIONs are suggested as potential nanocarriers for siRNA delivery in gene therapy of HIV-1 infection.     

Prevalence of Non-Tuberculosis Mycobacterial Infections among Tuberculosis Suspects in Iran: Systematic Review and Meta-Analysis

Introduction

The infections due to Non-Tuberculosis Mycobacteria (NTM) are becoming an important health problem in many countries in the world. Globally, an increase in NTM infections has been reported from many countries around the world. However, limited information is available about the prevalence of NTM infections in Iran.

Material and Methods

The data of the prevalence of NTM infections were collected from databases such as PubMed, Web of science, Cochrane Library, Embase, Scopus, Iranmedex, and Scientific Information Database. Comprehensive Meta-Analysis (V2.0, Biostat) software was used to analyze the data.

Results

The meta-analyses showed that the prevalence of NTM infections was 10.2% (95% confidence interval [95% CI] 6.3-15.9) among culture-positive cases of tuberculosis (TB) in Iran. The further stratified analyses indicated that the prevalence of NTM was higher in studies that were done after year 2000. Additionally, M. simiae (43.3% [95% CI 36.8-50.0]), M. intracellucar (27.3% [95% CI 0.7-95.5]) and M. fortuitum (22.7% [95% CI 16.1-30.9]) were the most prevalent NTM species, respectively.

Discussion

The relatively high prevalence of NTM infections (10.2%) among culture positive cases for TB underlines the need for greater enforcement of infection control strategies. Establishment of appropriate diagnostic criteria and management guidelines for NTM diseases and expanding the number and quality of regional reference laboratories may facilitate more accurate action for prevention and control of NTM infections in Iran.     

Enhanced Protective Efficacy of Nonpathogenic Recombinant Leishmania tarentolae Expressing Cysteine Proteinases Combined with a Sand Fly Salivary Antigen

Background

Novel vaccination approaches are needed to prevent leishmaniasis. Live attenuated vaccines are the gold standard for protection against intracellular pathogens such as Leishmania and there have been new developments in this field. The nonpathogenic to humans lizard protozoan parasite, Leishmania (L) tarentolae, has been used effectively as a vaccine platform against visceral leishmaniasis in experimental animal models. Correspondingly, pre-exposure to sand fly saliva or immunization with a salivary protein has been shown to protect mice against cutaneous leishmaniasis.

Methodology/Principal Findings

Here, we tested the efficacy of a novel combination of established protective parasite antigens expressed by L. tarentolae together with a sand fly salivary antigen as a vaccine strategy against L. major infection. The immunogenicity and protective efficacy of different DNA/Live and Live/Live prime-boost vaccination modalities with live recombinant L. tarentolae stably expressing cysteine proteinases (type I and II, CPA/CPB) and PpSP15, an immunogenic salivary protein from Phlebotomus papatasi, a natural vector of L. major, were tested both in susceptible BALB/c and resistant C57BL/6 mice. Both humoral and cellular immune responses were assessed before challenge and at 3 and 10 weeks after Leishmania infection. In both strains of mice, the strongest protective effect was observed when priming with PpSP15 DNA and boosting with PpSP15 DNA and live recombinant L. tarentolae stably expressing cysteine proteinase genes.

Conclusion/Significance

The present study is the first to use a combination of recombinant L. tarentolae with a sand fly salivary antigen (PpSP15) and represents a novel promising vaccination approach against leishmaniasis.     

Low-dose photons modify liver response to simulated solar particle event protons

The health consequences of exposure to low-dose radiation combined with a solar particle event during space travel remain unresolved. The goal of this study was to determine whether protracted radiation exposure alters gene expression and oxidative burst capacity in the liver, an organ vital in many biological processes. C57BL/6 mice were whole-body irradiated with 2 Gy simulated solar particle event (SPE) protons over 36 h, both with and without pre-exposure to low-dose/low-dose-rate photons ((57)Co, 0.049 Gy total at 0.024 cGy/h). Livers were excised immediately after irradiation (day 0) or on day 21 thereafter for analysis of 84 oxidative stress-related genes using RT-PCR; genes up or down-regulated by more than twofold were noted. On day 0, genes with increased expression were: photons, none; simulated SPE, Id1; photons + simulated SPE, Bax, Id1, Snrp70. Down-regulated genes at this same time were: photons, Igfbp1; simulated SPE, Arnt2, Igfbp1, Il6, Lct, Mybl2, Ptx3. By day 21, a much greater effect was noted than on day 0. Exposure to photons + simulated SPE up-regulated completely different genes than those up-regulated after either photons or the simulated SPE alone (photons, Cstb; simulated SPE, Dctn2, Khsrp, Man2b1, Snrp70; photons + simulated SPE, Casp1, Col1a1, Hspcb, Il6st, Rpl28, Spnb2). There were many down-regulated genes in all irradiated groups on day 21 (photons, 13; simulated SPE, 16; photons + simulated SPE, 16), with very little overlap among groups. Oxygen radical production by liver phagocytes was significantly enhanced by photons on day 21. The results demonstrate that whole-body irradiation with low-dose-rate photons, as well as time after exposure, had a great impact on liver response to a simulated solar particle event.     

Mechanism of inhibition of ribonucleotide reductase with motexafin gadolinium (MGd)

Motexafin gadolinium (MGd) is an expanded porphyrin anticancer agent which selectively targets tumor cells and works as a radiation enhancer, with promising results in clinical trials. Its mechanism of action is oxidation of intracellular reducing molecules and acting as a direct inhibitor of mammalian ribonucleotide reductase (RNR). This paper focuses on the mechanism of inhibition of RNR by MGd. Our experimental data present at least two pathways for inhibition of RNR; one precluding subunits oligomerization and the other direct inhibition of the large catalytic subunit of the enzyme. Co-localization of MGd and RNR in the cytoplasm particularly in the S-phase may account for its inhibitory properties. These data can elucidate an important effect of MGd on the cancer cells with overproduction of RNR and its efficacy as an anticancer agent and not only as a general radiosensitizer.