The Akt inhibitor,triciribine, ameliorates chronic hypoxia-induced vascular pruning and TGFβ-induced pulmonary fibrosis

Background and Purpose

Interstitial lung disease accounts for a group of chronic and progressive disorders associated with severe pulmonary vascular remodelling, peripheral vascular rarefaction and fibrosis, thus limiting lung function. We have previously shown that Akt is necessary for myofibroblast differentiation, a critical event in organ fibrosis. However, the contributory role of the Akt-mTOR pathway in interstitial lung disease and the therapeutic benefits of targeting Akt and mTOR remain unclear.

Experimental Approach

We investigated the role of the Akt-mTOR pathway and its downstream molecular mechanisms in chronic hypoxia- and TGFβ-induced pulmonary vascular pruning and fibrosis in mice. We also determined the therapeutic benefits of the Akt inhibitor triciribine and the mTOR inhibitor rapamycin for the treatment of pulmonary fibrosis in mice.

Key Results

Akt1^−/− mice were protected from chronic hypoxia-induced peripheral vascular pruning. In contrast, hyperactivation of Akt1 induced focal fibrosis similar to TGFβ-induced fibrosis. Pharmacological inhibition of Akt, but not the Akt substrate mTOR, inhibited hypoxia- and TGFβ-induced pulmonary vascular rarefaction and fibrosis. Mechanistically, we found that Akt1 modulates pulmonary remodelling via regulation of thrombospondin1 (TSP1) expression. Hypoxic Akt1^−/− mice lungs expressed less TSP1. Moreover, TSP1^−/− mice were resistant to adMyrAkt1-induced pulmonary fibrosis.

Conclusions and Implications

Our study identified Akt1 as a novel target for the treatment of interstitial lung disease and provides preclinical data on the potential benefits of the Akt inhibitor triciribine for the treatment of interstitial lung disease.     

Cost-Effective Isolation of a Process Impurity of Pregabalin

Cost-effective isolation methods were developed on preparative HPLC, flash LC, and simulated moving bed (SMB) to prepare the process impurity, 3-(aminomethyl)-5-methylhex-4-enoic acid (4-ene impurity), of pregabalin. By a thorough experimental study on the different isolation techniques available, it was concluded that SMB was the most cost-effective. Hence, it was a continuous chromatography that utilized the advantage of SMB so that a high quantity of the impurity was generated in a short period of time. SMB was equipped with eight reversed-phased columns and was used to separate the process impurity of pregabalin. The effects of flow rate in zone 2 (Q2) and 3 (Q3), as well as switching time, on the operating performance parameters like purity, productivity, and desorbent consumption were studied. Operating conditions leading to more than 90% purity in the raffinate outlet stream were identified, together with those achieving optimal performance. All of these developed methods are novel, cost-effective, and can be applied to the isolation of other process- and stability-related impurities of pregabalin.     

Protecting effect of caffeine against vinblastine (an anticancer drug) induced genotoxicity in mice

Vinblastine a DNA non-intercalating agent has wide application against several human neoplasms, and found to cause cytogenotoxicity. In this study, clastogenotoxicity of vinblastine (1.5?mg/kg b w) and its prevention by caffeine at different doses (25, 50 and 100?mg/kg b w) administered intraperitoneally was assessed in in vivo mice. It was found that micronucleus level had decreased significantly (up to 28.8%) in 100?mg caffeine treated group at 30?h post treatment. However, it did not exhibit protective effect against chromosomal aberration in spaermatogonial cells at 24?h post treatment. The frequencies of aberrant primary spermatocytes had decreased significantly in 25 and 100?mg caffeine at 4th week of post treatment. Similarly, in 100?mg of caffeine administered, abnormal sperm level had reduced (4.01%) significantly at 8th week post treatment. Thus, caffeine decreased the vinblastine induced chromosomal aberrations and mitotic index in bone marrow cells. In conclusion, this study shows that caffeine exerts protective effect against vinblastin induced cytogenotoxicity. Further studies on molecular mechanism are interesting in order to develop it as an effective drug in cancer chemotherapy.     

Molecular Epidemiology and Genetic Diversity of Orientia tsutsugamushi from Patients with Scrub Typhus in 3 Regions of India

Scrub typhus, an acute febrile illness that is widespread in the Asia-Pacific region, is caused by the bacterium Orientia tsutsugamushi, which displays high levels of antigenic variation. We conducted an investigation to identify the circulating genotypes of O. tsutsugamushi in 3 scrub typhus–endemic geographic regions of India: South India, Northern India, and Northeast India. Eschar samples collected during September 2010–August 2012 from patients with scrub typhus were subjected to 56-kDa type-specific PCR and sequencing to identify their genotypes. Kato-like strains predominated (61.5%), especially in the South and Northeast, followed by Karp-like strains (27.7%) and Gilliam and Ikeda strains (2.3% each). Neimeng-65 genotype strains were also observed in the Northeast. Clarifying the genotypic diversity of O. tsutsugamushi in India enhances knowledge of the regional diversity among circulating strains and provides potential resources for future region-specific diagnostic studies and vaccine development.     

Mycophenolate in idiopathic inflammatory myositis: outcome data of a large South Asian cohort

Clinical Rheumatology - Consensus on treatment of idiopathic inflammatory myositis (IIM), particularly with regard to flares and interstitial lung disease (ILD), does not exist. We studied the...     

Phenotypes of sickle cell intensive care admissions: an unsupervised machine learning approach in a single-center retrospective cohort

Annals of Hematology - Sickle cell disease (SCD) is associated with multiple known complications and increased mortality. This study aims to further understand the profile of intensive care unit...     

Influence of estrogen-progesterone combinations on gonadotropin secretion in castrate female rats(1).

In order to study the effect of progesterone in modulating the secretion of gonadotropins, various doses of progesterone were administered to castrated immature and mature female rats. Progesterone did not prevent the postcastration rise of FSH and LH in these animals. Various amounts of progesterone were then administered to castrated rats that were treated with a constant low dose of estradiol. In animals given doses of estradiol that were able to decrease serum FSH and LH below castrate levels, but not to prevent the post-castration rise, the effect of progesterone was dose-dependent. A very low dose of progesterone lowered serum gonadotropins, an intermediate dose brought about an increase in secretion, and high doses were suppressive. The modifying action of progesterone appears to be dependent upon the level of estrogen, the dose of progesterone, and the time of administration.