Saikosaponin-d, a novel SERCA inhibitor, induces autophagic cell death in apoptosis-defective cells.

Autophagy is an important cellular process that controls cells in a normal homeostatic state by recycling nutrients to maintain cellular energy levels for cell survival via the turnover of proteins and damaged organelles. However, persistent activation of autophagy can lead to excessive depletion of cellular organelles and essential proteins, leading to caspase-independent autophagic cell death. As such, inducing cell death through this autophagic mechanism could be an alternative approach to the treatment of cancers. Recently, we have identified a novel autophagic inducer, saikosaponin-d (Ssd), from a medicinal plant that induces autophagy in various types of cancer cells through the formation of autophagosomes as measured by GFP-LC3 puncta formation. By computational virtual docking analysis, biochemical assays and advanced live-cell imaging techniques, Ssd was shown to increase cytosolic calcium level via direct inhibition of sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase pump, leading to autophagy induction through the activation of the Ca(2+)/calmodulin-dependent kinase kinase-AMP-activated protein kinase-mammalian target of rapamycin pathway. In addition, Ssd treatment causes the disruption of calcium homeostasis, which induces endoplasmic reticulum stress as well as the unfolded protein responses pathway. Ssd also proved to be a potent cytotoxic agent in apoptosis-defective or apoptosis-resistant mouse embryonic fibroblast cells, which either lack caspases 3, 7 or 8 or had the Bax-Bak double knockout. These results provide a detailed understanding of the mechanism of action of Ssd, as a novel autophagic inducer, which has the potential of being developed into an anti-cancer agent for targeting apoptosis-resistant cancer cells.

Global guidelines for treatment of tuberculosis among persons living with HIV: unresolved issues.

The Revised National Tuberculosis Control Programme (RNTCP) in India uses a fully intermittent thrice-weekly rifampicin-containing regimen for all tuberculosis (TB) patients, including those who are human immunodeficiency virus (HIV) infected, whereas the World Health Organization (WHO) recommends daily anti-tuberculosis treatment at least during the intensive phase. The WHO recommendation was based on the results of a meta-analysis demonstrating increased risk of recurrence and failure among HIV-infected TB patients receiving intermittent TB treatment compared to a daily regimen. Review of the primary evidence indicates limited, low-quality information on intermittency, mostly from observational studies in the pre-antiretroviral treatment (ART) era. Molecular epidemiology in India indicates that most of the recurrences and many of the failures result from exogenous re-infection, suggesting poor infection control and high transmission rather than poor regimen efficacy. Subsequently published studies have shown acceptable treatment outcomes among HIV-infected TB patients receiving intermittent anti-tuberculosis regimens with concomitant ART. Treatment outcomes among HIV-infected TB patients treated under programmatic conditions show low failure rates but high case fatality; death has been associated with lack of ART. The highest priority is therefore to reduce mortality by linking all HIV-infected TB patients to ART. While urgently seeking to reduce death rates among HIV-infected TB patients, given the poor evidence for change and operational advantages of an intermittent regimen, the RNTCP intends to collect the necessary evidence to inform national policy decisions through randomised clinical trials.

Gestational diabetes mellitus in the last trimester - a feature of maternal iron excess?

AIM: To determine whether non-anaemic women with gestational diabetes mellitus (GDM) diagnosed in third trimester pregnancy have evidence of increased iron stores compared with matched non-diabetic controls. METHODS: In a prospective study, women who had antenatal booking before 20 weeks' gestation and without anaemia or diabetes mellitus were recruited at the time of the oral glucose tolerance test (OGTT) at 28-31 weeks' gestation for the study of serum ferritin, iron and transferrin concentrations. The results were blinded to the managing obstetricians. After delivery, the records were reviewed. The cases diagnosed as GDM were compared with a control group (two controls for each index case matched for parity) selected at random from the at-risk but nondiabetic cases. RESULTS: GDM was diagnosed in 97 of the 401 women recruited. Compared with the 194 controls, there was no difference in the weight, body mass index, booking and third trimester haemoglobin, or third trimester red cell indices, but concentrations of serum ferritin, iron, transferrin saturation, and the post-natal haemoglobin were significantly higher. On multiple regression analysis, maternal BMI and the log-transformed ferritin concentration remained significant determinants of the OGTT 2-h glucose value. CONCLUSION: The results suggest an association between increased iron stores and glucose intolerance at the third trimester in non-anaemic women. The role of iron excess in the pathogenesis of GDM needs to be examined.