Paracrine Effects of IGF-1 Overexpression on the Functional Decline Due to Skeletal Muscle Disuse: Molecular and Functional Evaluation in Hindlimb Unloaded MLC/mIgf-1 Transgenic Mice.

Paracrine Effects of IGF-1 Overexpression on the Functional Decline Due to Skeletal Muscle Disuse: Molecular and Functional Evaluation in Hindlimb Unloaded MLC/mIgf-1 Transgenic Mice.

PLoS One. 2013; 8(6): e65167
Pierno S, Camerino GM, Cannone M, Liantonio A, De Bellis M, Digennaro C, Gramegna G, De Luca A, Germinario E, Danieli-Betto D, Betto R, Dobrowolny G, Rizzuto E, Musarò A, Desaphy JF, Camerino DC

Slow-twitch muscles, devoted to postural maintenance, experience atrophy and weakness during muscle disuse due to bed-rest, aging or spaceflight. These conditions impair motion activities and can have survival implications. Human and animal studies demonstrate the anabolic role of IGF-1 on skeletal muscle suggesting its interest as a muscle disuse countermeasure. Thus, we tested the role of IGF-1 overexpression on skeletal muscle alteration due to hindlimb unloading (HU) by using MLC/mIgf-1 transgenic mice expressing IGF-1 under the transcriptional control of MLC promoter, selectively activated in skeletal muscle. HU produced atrophy in soleus muscle, in terms of muscle weight and fiber cross-sectional area (CSA) reduction, and up-regulation of atrophy gene MuRF1. In parallel, the disuse-induced slow-to-fast fiber transition was confirmed by an increase of the fast-type of the Myosin Heavy Chain (MHC), a decrease of PGC-1? expression and an increase of histone deacetylase-5 (HDAC5). Consistently, functional parameters such as the resting chloride conductance (gCl) together with ClC-1 chloride channel expression were increased and the contractile parameters were modified in soleus muscle of HU mice. Surprisingly, IGF-1 overexpression in HU mice was unable to counteract the loss of muscle weight and the decrease of fiber CSA. However, the expression of MuRF1 was recovered, suggesting early effects on muscle atrophy. Although the expression of PGC-1? and MHC were not improved in IGF-1-HU mice, the expression of HDAC5 was recovered. Importantly, the HU-induced increase of gCl was fully contrasted in IGF-1 transgenic mice, as well as the changes in contractile parameters. These results indicate that, even if local expression does not seem to attenuate HU-induced atrophy and slow-to-fast phenotype transition, it exerts early molecular effects on gene expression which can counteract the HU-induced modification of electrical and contractile properties. MuRF1 and HDAC5 can be attractive therapeutic targets for pharmacological countermeasures and then deserve further investigations. HubMed – drug


Green tea polyphenols stimulate mitochondrial biogenesis and improve renal function after chronic cyclosporin a treatment in rats.

PLoS One. 2013; 8(6): e65029
Rehman H, Krishnasamy Y, Haque K, Thurman RG, Lemasters JJ, Schnellmann RG, Zhong Z

Our previous studies showed that an extract from Camellia sinenesis (green tea), which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A (CsA). Since polyphenols are stimulators of mitochondrial biogenesis (MB), this study investigated whether stimulation of MB plays a role in green tea polyphenol protection against CsA renal toxicity. Rats were fed a powdered diet containing green tea polyphenolic extract (0.1%) starting 3 days prior to CsA treatment (25 mg/kg, i.g. daily for 3 weeks). CsA alone decreased renal nuclear DNA-encoded oxidative phosphorylation (OXPHOS) protein ATP synthase-? (AS-?) by 42%, mitochondrial DNA (mtDNA)-encoded OXPHOS protein NADH dehydrogenase-3 (ND3) by 87% and their associated mRNAs. Mitochondrial DNA copy number was also decreased by 78% by CsA. Immunohistochemical analysis showed decreased cytochrome c oxidase subunit IV (COX-IV), an OXPHOS protein, in tubular cells. Peroxisome proliferator-activated receptor-? coactivator (PGC)-1?, the master regulator of MB, and mitochondrial transcription factor-A (Tfam), the transcription factor that regulates mtDNA replication and transcription, were 42% and 90% lower, respectively, in the kidneys of CsA-treated than in untreated rats. These results indicate suppression of MB by chronic CsA treatment. Green tea polyphenols alone and following CsA increased AS-?, ND3, COX-IV, mtDNA copy number, PGC-1? mRNA and protein, decreased acetylated PGC-1?, and increased Tfam mRNA and protein. In association with suppressed MB, CsA increased serum creatinine, caused loss of brush border and dilatation of proximal tubules, tubular atrophy, vacuolization, apoptosis, calcification, and increased neutrophil gelatinase-associated lipocalin expression, leukocyte infiltration, and renal fibrosis. Green tea polyphenols markedly attenuated CsA-induced renal injury and improved renal function. Together, these results demonstrate that green tea polyphenols attenuate CsA-induced kidney injury, at least in part, through the stimulation of MB. HubMed – drug


Patients’ insight of interpreting prescriptions and drug labels – a cross sectional study.

PLoS One. 2013; 8(6): e65019
Patel MJ, Khan MS, Ali F, Kazmi Z, Riaz T, Awan S, Sorathia AL

Errors in consuming drugs are associated with significant morbidity and mortality, besides an impact on the already overburdened health-care system. Misunderstanding drug labels and prescriptions plays an important role in contributing to adverse drug events.To evaluate abilities to understand prescriptions and drug labels among patients attending tertiary care hospital in Karachi.A cross sectional study was conducted at the Aga Khan University Hospital (AKUH), from January to March 2009. After informed consent, 181 adult patients and their healthy attendants were interviewed at AKUH using a standardized questionnaire, which ascertained patient demographics, factors that might increase exposure to health-care personnel as well as the basic knowledge and understanding of prescriptions and drug labels.Out of 181, majority 137(76%) had received graduate or post-graduate degrees. 16 (9%) had received no formal education; of which all were females and 89(84%) of the total females were housewives. Overall, 130(72%) followed only a single doctor’s prescription. Majority failed to understand various medical terminologies related to dosage. In the high literacy group, 45(33%) understood once daily OD (p?=?0.003), 27(20%) thrice daily TID (p?=?0.05), 29(21%) twice daily BD (p?=?0.01), 31(23%) thrice daily TDS (p?=?0.002) and 43(31%) as needed SOS (p?=?0.003) as compared to the group with no formal education, who were unable to comprehend the terms. The most common reason for using more than one prescription was decreased satisfaction with the doctor in 19(39%) and multiple co-morbids as responded by 17(35%) of patients. Knowledge regarding various medical terminologies used for dosage and routes of drug administration were also understood more frequently among the English medium respondents. The elderly identified medicine through color (47%, p<0.001), and were less likely to understand drug indications (p?=?0.05) compared to younger subjects.Understanding of drug prescriptions is alarmingly low in the community, even amongst the educated. Care givers need to revisit this often ignored aspect of patient care. HubMed – drug


The Cell Wall-Targeting Antibiotic Stimulon of Enterococcus faecalis.

PLoS One. 2013; 8(6): e64875
Abranches J, Tijerina P, Avilés-Reyes A, Gaca AO, Kajfasz JK, Lemos JA

Enterococcus faecalis is an opportunistic nosocomial pathogen that is highly resistant to a variety of environmental insults, including an intrinsic tolerance to antimicrobials that target the cell wall (CW). With the goal of determining the CW-stress stimulon of E. faecalis, the global transcriptional profile of E. faecalis OG1RF exposed to ampicillin, bacitracin, cephalotin or vancomycin was obtained via microarrays. Exposure to the ?-lactams ampicillin and cephalotin resulted in the fewest transcriptional changes with 50 and 192 genes differentially expressed 60 min after treatment, respectively. On the other hand, treatment with bacitracin or vancomycin for 60 min affected the expression of, respectively, 377 and 297 genes. Despite the differences in the total number of genes affected, all antibiotics induced a very similar gene expression pattern with an overrepresentation of genes encoding hypothetical proteins, followed by genes encoding proteins associated with cell envelope metabolism as well as transport and binding proteins. In particular, all drug treatments, most notably bacitracin and vancomycin, resulted in an apparent metabolic downshift based on the repression of genes involved in translation, energy metabolism, transport and binding. Only 19 genes were up-regulated by all conditions at both the 30 and 60 min time points. Among those 19 genes, 4 genes encoding hypothetical proteins (EF0026, EF0797, EF1533 and EF3245) were inactivated and the respective mutant strains characterized in relation to antibiotic tolerance and virulence in the Galleria mellonella model. The phenotypes obtained for two of these mutants, ?EF1533 and ?EF3245, support further characterization of these genes as potential candidates for the development of novel preventive or therapeutic approaches. HubMed – drug


The effect of antineoplastic drugs in a male spontaneous mammary tumor model.

PLoS One. 2013; 8(6): e64866
Shishido SN, Faulkner EB, Beck A, Nguyen TA

Male breast cancer is a rare disease. The limited number of clinical cases has led to the primary treatments for men being derived from female breast cancer studies. Here the transgenic strain FVB/N-Tg(MMTV-PyVT)634Mul/J (also known as PyVT) was used as a model system for measuring tumor burden and drug sensitivity of the antineoplastic drugs tamoxifen, cisplatin, and paclitaxel on tumorigenesis at an early stage of mammary carcinoma development in a male mouse model. Cisplatin treatment significantly reduced tumor volume, while paclitaxel and tamoxifen did not attenuate tumor growth. Cisplatin treatment was shown to induce apoptosis, grossly observed by reduced tumor formation, through reduced Bcl-2 and survivin protein expression levels with an increase in caspase 3 expression compared to control tumors. Tamoxifen treatment significantly altered the hormone receptor expression levels of the tumor, while additionally upregulating Bcl-2 and Cyclin D1. This suggests an importance in hormonal signaling in male breast cancer pathogenesis. The results of this study provide valuable information toward the better understanding of male breast cancer and may help guide treatment decisions. HubMed – drug