SUMMARY: Candida albicans is an opportunistic fungal pathogen that is found in the normal gastrointestinal flora of most healthy humans. However, under certain environmental conditions, it can become a life-threatening pathogen. The shift from commensal organism to pathogen is often correlated with the capacity to undergo morphogenesis. Indeed, under certain conditions, including growth at ambient temperature, the presence of serum or N -acetylglucosamine, neutral pH, and nutrient starvation, C. albicans can undergo reversible transitions from the yeast form to the mycelial form. This morphological plasticity reflects the interplay of various signal transduction pathways, either stimulating or repressing hyphal formation. In this review, we provide an overview of the different sensing and signaling pathways involved in the morphogenesis and pathogenesis of C. albicans . Where appropriate, we compare the analogous pathways/genes in Saccharomyces cerevisiae in an attempt to highlight the evolution of the different components of the two organisms. The downstream components of these pathways, some of which may be interesting antifungal targets, are also discussed.

Reactive oxygen species (ROS) are noxious to cells because their increased level interacts with the body’s defense mechanism. These species also cause mutations and uncontrolled cell division, resulting in oxidative stress (OS). Prolonged oxidative stress is responsible for incorrect protein folding in the endoplasmic reticulum (ER), causing a stressful condition, ER stress. These cellular stresses (oxidative stress and ER stress) are well-recognized biological factors that play a prominent role in the progression of hepatocellular carcinoma (HCC). HCC is a critical global health problem and the third leading cause of cancer-related mortality. The application of anti-oxidants from herbal sources significantly reduces oxidative stress. Kaempferol (KP) is a naturally occurring, aglycone dietary flavonoid that is present in various plants (Crocus sativus, Coccinia grandis, Euphorbia pekinensis, varieties of Aloe vera, etc.) It is capable of interacting with pleiotropic proteins of the human body. Efforts are in progress to develop KP as a potential candidate to prevent HCC with no adverse effects. This review emphasizes the molecular mechanism of KP for treating HCC, targeting oxidative stress.

Pre-eclampsia (PE) is a pregnancy-specific disorder, characterized by hypertension and proteinuria. In PE, trophoblasts mediated inadequate remodeling of uterine spiral arteries seem to interrupt uteroplacental blood flow, one of the hallmarks in the early onset of PE (EO-PE). This, in turn, results in placental ischemia–reperfusion injury during hypoxia and reoxygenation episodes, leading to the generation of reactive oxygen species (ROS) and oxidative stress (OS). But still it is debatable if OS is a cause or consequence of PE. In this present study, we have investigated the effects of OS on PE placentae and trophoblast cell functions using BeWo and HTR8/SVneo cell lines. PE placental tissues showed abnormal ultrastructure, high level of reactive oxygen species (ROS) with altered unfolded protein responses (UPR) in compare with term placental tissues. Similar to PE placentae, during OS induction, the trophoblast cells showed altered invasion and migration properties with significantly variable expression of differentiation and invasion markers, e.g., syncytin and MMPs. The effect was rescued by antioxidant, N-acetyl cysteine, thereby implying a ROS-specific effect and in the trophoblast cells, OS triggers UPR pathway through IRE1α-XBP1 axis. Taken together, these findings highlight the harmful effect of unfolded protein response, which was induced due to OS on trophoblast cells and deformed invasion and differentiation programme and can be extended further to clinical settings to identify clinically approved antioxidants during pregnancy as a therapeutic measure to reduce the onset of PE.

Hepatocellular carcinoma (HCC) is an aggressive tumor with limited systemic and locoregional modalities of treatment. Although microRNA (miRNA) based therapies have significant potential, their targeted delivery remains a major challenge. miR‐199a‐3p functions as an important tumor suppressor in HCC, which regulates various cellular processes. Recently, peptide‐based nanoparticles (NPs) have been developed to deliver oligonucleotides including miRNA. Here, we describe the synthesis and characterization of arginine α,β‐dehydrophenylalanine (RΔF) nanoparticles for the selective delivery of miR‐199a‐3p to restore dysregulated gene expression in HCC. Targeted delivery was achieved by conjugating lactobionic acid (LA) with RΔF NPs (RΔF‐LA NPs), a ligand for the asialoglycoprotein receptor known to be overexpressed in HCC cell lines. RΔF‐LA NPs condensed miR‐199a‐3p had an average size of ∼60nm and a zeta potential of ∼+2.54 mV. RΔF‐LA/miR NPs were found to be stable in serum as well as against RNase attack. RΔF‐LA/miR NPs showed an enhanced cellular uptake and an efficient delivery of miR‐199a‐3p leading to a significant increase in miR‐199a‐3p levels (over 500 fold). The increased miR‐199a‐3p levels remarkably suppressed cell proliferation and migration as well as induced cellular apoptosis and downregulation of the specific target gene (mTOR) in vitro . RΔF‐LA/miR NPs showed high tumor/ low organ ratios after intravenous injection into HCC tumor bearing nude mice. RΔF‐LA/miR NPs treated mice demonstrated>50% decline in tumor growth, which also corresponded well with suppression of mTOR protein expression, tumor cell proliferation and increased survival rate ( P < 0.05). Conclusion : RΔF‐LA/miR NPs showed significantly enhanced delivery of the miRNA which underscores their potential for further development as a therapeutic approach for HCC. (H epatology 2018;67:1392‐1407)

Candida albicansis able to grow in a variety of reversible morphological forms (yeast, pseudohyphal and hyphal) in response to various environmental signals, noteworthy among them beingN-acetylglucosamine (GlcNAc). The geneCaGAP1, homologous toGAP1, which encodes the general amino acid permease fromSaccharomyces cerevisiae, was isolated on the basis of its induction by GlcNAc through differential screening of aC. albicansgenomic library. The gene could functionally complement anS. cerevisiae gap1mutant by rendering it susceptible to the toxic amino acid analogue mimosine in minimal proline media. As inS. cerevisiae, mutation of theCaGAP1gene had an effect on citrulline uptake inC. albicans. Northern analysis showed that GlcNAc-induced expression ofCaGAP1was further enhanced in synthetic minimal media supplemented with single amino acids (glutamate, proline and glutamine) or urea (without amino acids) but repressed in minimal ammonium media. Induction ofCaGAP1expression by GlcNAc was nullified inC. albicansdeleted for the transcription factorCPH1and the hyphal regulatorRAS1, indicating the involvement of Cph1p-dependent Ras1p signalling inCaGAP1expression. A homozygous mutant of this gene showed defective hyphal formation in solid hyphal-inducing media and exhibited less hyphal clumps when induced by GlcNAc. Alteration of morphology and short filamentation under nitrogen-starvation conditions in the heterozygous mutant suggested thatCaGAP1affects morphogenesis in a dose-dependent manner.