Hepatitis C virus NS5A protein impairs TNF-mediated hepatic apoptosis, but not by an anti-FAS antibody, in transgenic mice

Hepatitis C virus (HCV) is a major etiologic agent of chronic hepatitis worldwide and may lead to the development of hepatocellular carcinoma. However, the mechanism of development of chronic hepatitis or hepatocarcinogenesis by HCV remains unclear. In the present study, we have investigated the effect of nonstructural protein 5A (NS5A) on TNF- and Fas-mediated apoptosis in the liver of transgenic mice. For this purpose, transgenic mice were generated by targeting the HCV NS5A genomic region cloned under the control of a liver-specific apoE promoter. The transgenic animals were phenotypically similar to their normal littermates and did not exhibit a detectable histological change in the liver at 8-12 weeks of age. Intraperitoneal injection of recombinant TNF induced hepatic injury and apoptosis in normal mice. In contrast, transgenic mice expressing NS5A protein were protected against hepatic apoptosis after injection of TNF. However, injection of anti-Fas antibody into transgenic mice did not significantly influence hepatic apoptosis compared to the normal littermates. These results suggested distinct effects of TNF and anti-Fas antibody in transgenic mice expressing NS5A. We subsequently investigated the effect of NS5A in signaling pathways involved in these two cytokine-mediated apoptosis. A physical association between NS5A and TRADD was observed by pull-down assay, coimmunoprecipitation, and colocalization experiments. Furthermore, NS5A prevented the association between TRADD and FADD and blocked TRADD-mediated NF-kappaB activation. Together, our results suggest that NS5A impairs TNF-mediated apoptosis by interfering upstream of the signal transduction pathway and may play a role in HCV-mediated pathogenesis.     

Auto-catalytic ceria nanoparticles offer neuroprotection to adult rat spinal cord neurons

This paper describes the evaluation of the auto-catalytic anti-oxidant behavior and biocompatibility of cerium oxide nanoparticles for applications in spinal cord repair and other diseases of the central nervous system. The application of a single dose of nano-ceria at a nano-molar concentration is biocompatible, regenerative and provides a significant neuroprotective effect on adult rat spinal cord neurons. Retention of neuronal function is demonstrated from electrophysiological recordings and the possibility of its application to prevent ischemic insult is suggested from an oxidative injury assay. A mechanism is proposed to explain the auto-catalytic properties of these nanoparticles.     

Protein Profiling Reveals Antioxidant and Signaling Activities of NAP (Davunetide) in Rodent Hippocampus Exposed to Hypobaric Hypoxia

NAP (davunetide) is a clinical octapeptide and reportedly possesses neuroprotective, neurotrophic and cognitive protective properties. The information for NAP-mediated neuroproteome changes and associated signaling pathways during hypoxia will help in drug development programmes across the world. In the present study, we have evaluated the antioxidant activities of NAP in rat hippocampus exposed to hypobaric hypoxia (25,000 ft, 282 mm Hg) for 3, 6 and 12 h respectively. Using 2D-gel electrophoresis (2D-GE) with matrix-assisted laser desorption ionization time of flight (MALDI-TOF/TOF) mass spectrometry, we have identified altered expression of 80 proteins in NAP-supplemented hippocampus after hypoxia. Pathway analysis revealed that NAP supplementation significantly regulated oxidative stress response, oxidoreductase activity and cellular response to stress pathways during hypoxia. Additionally, NAP supplementation also regulated energy production pathways along with AMP-activated protein kinase (AMPK) signaling and signaling by Rho family GTPases pathways. We observed higher expression of antioxidant Sod1, Eno1, Prdx2 and Prdx5 proteins that were subsequently validated by Western blotting. A higher level of Prdx2 was also observed by immunohistochemistry in NAP-supplemented hippocampus during hypoxia. In corroboration, we are able to detect significant lower level of protein carbonyls in NAP-supplemented hypoxic hippocampus suggesting amelioration of oxidant molecules by NAP supplementation. These results emphasize the antioxidant and signaling properties of NAP in rodent hippocampus during hypobaric hypoxia.     

Transcriptomics,proteomics and metabolomics driven biomarker discovery in COPD: an update

Introduction: Diagnosis of chronic obstructive pulmonary disease (COPD), characterized by progressive irreversible airflow limitation, remains a challenge. Lack of sensitive diagnostic markers and alternative treatments have limited patients’ survival rate. Herein, we provide for clinicians and scientists a comprehensive review on the various omics platforms used to investigate COPD.

Areas covered: This review consists of articles from PubMed (2009–2016) as well as views of the contributing authors. The review highlights the need for COPD biomarker identification and also provides an update on promising candidate markers identified in various biological fluids using omics technologies.

Expert commentary: The multi-omics approach holds promise for the development of robust early stage COPD diagnostic markers, screening of high-risk population, and also improved prognosis which could lead to personalized medicine in future. Various factors regulating an omics study including sample size, control selection, disease phenotyping, usage of complementary techniques and result replication in omics-based research are outlined.     

Diode laser cyclophotocoagulation paves way to a safer trabeculectomy in eyes with medically uncontrollable intraocular pressure

High intraocular pressure (IOP) not responding to systemic and topical anti-glaucoma medications renders the eye at risk for both intra- and post-operative complications of glaucoma filtration surgery. Laser cyclophotocoagulation is able to lower IOP in such refractory glaucoma eyes and may make the surgical event safer. This study assessed diode laser cyclophotocoagulation (DLCP) when used as a temporary measure for lowering IOP prior to performing trabeculectomy. This study is a  retrospective analysis of cases planned for trabeculectomy surgery, uncontrolled on maximally tolerable systemic anti-glaucoma medications. They were analysed for response to DLCP in terms of IOP control, vision-related complications, increased inflammation, post-trabeculectomy hypotony and chances of phthisis and ciliary shutdown. Twelve eyes of ten patients aged 35–65 years were identified and all followed up for at least 2 years. One week following DLCP, the IOP (mean ± SD) declined by 51 % from 46.8 ± 5.4 to 22.8 ± 3.3 mmHg. The IOP was further reduced to 15.4 ± 2.7 mmHg at 4 weeks after trabeculectomy; it remained in the mid-teens for a minimum of 2 years in all cases. The mean (±SD) visual acuity improved from 1.4 ± 0.4 to 0.8 ± 0.4 LogMAR equivalents following trabeculectomy. In four eyes, phacoemulsification was performed 5–7 months after trabeculectomy with improvement in best-corrected visual acuity. One patient developed transient hypotony, post-trabeculectomy, which resolved by 6 days. There were no other complications like increased inflammation, prolonged hypotony or suprachoroidal haemorrhage. DLCP is, thus, effective and safe for temporarily controlling IOP; thereby trabeculectomy can be performed in a quieter ocular milieu.     

Preputial adhesions — A misunderstood entity

Objective

To assess the trends and outcomes in referrals of ‘phimosis for circumcision’ to a tertiary care pediatric surgical department.

Methods

This is a prospective study of 100 consecutive children of presumed phimosis referred for circumcision. They were assessed and classified by the senior author as having either preputial adhesions or phimosis. The patients in the former group underwent outpatient preputial adhesiolysis while those in the latter group were offered circumcision primarily. All were followed up till resolution.

Results

All 100 were referred with a non-retractile prepuce and an additional reason — preputial ballooning at voiding, dysuria or suspect UTI. Eight (mean age ?58 months, referred for preputial ballooning at voiding ?6/8 and dysuria ?2/8) had phimosis and were primarily offered circumcision. The remaining 92 (mean age — 22 months, referred for preputial ballooning at voiding ?52/92, dysuria ?28/92 and suspect UTI ?12/92) had preputial adhesions. In the latter group, none has a documented urinary infection on specific investigations. These 92 underwent outpatient preputial adhesiolysis. Seventy three (79 %) required a single sitting, 11 (12%) required 2 ?4 sittings and 4(4.5%) required 5?8 sittings over a follow up period of 1 ?24 months (median ?3 weeks). 4/92(4.5%) were deemed non-responders to adhesiolysis and were circumcised later.

Conclusion

The majority of children referred with ‘phimosis for circumcision’ to this tertiary pediatric surgical centre were actually physiologic preputial adhesions that were managed with outpatient preputial adhesiolysis. This study underscores a lack of awareness amongst referring primary care physicians regarding preputial adhesions and the potential for an erroneous diagnosis of phimosis translating into unnecessary circumcisions in many young boys.