Biology subjects

Sahu, P. K.

Publications and source records attributed to Sahu, P. K..

3 recordsLinked to original sources

bioRxiv2023

Upregulation of steroidogenesis is associated with coma in human cerebral malaria

P. falciparum parasites manipulate host metabolic processes during malaria to ensure their survival and progression, causing the host and parasite metabolic pathways to become intertwined. We analyzed metabolites to evaluate their potential as biomarkers for cerebral malaria (CM). Our analysis of CM (with coma) and CM-like (without coma) patients identified 835 metabolites, including lipids, amino acids, xenobiotics, peptides, nucleotides, carbohydrates, cofactors, and vitamins. Principal component analysis revealed clear segregation between CM-like and CM patients. Metabolite-by-metabolite analysis identified 103 differentially abundant metabolites, 26 of which were significantly lower in CM-like patients (primarily lipids), while 71% of those higher in CM patients were amino acids and xenobiotics. The results revealed significant differences in circulating levels of long chain free fatty acids and catecholamine metabolism and identified steroid biosynthesis as the most enriched lipid metabolism pathway, with eight endogenous steroids showing significantly higher levels in CM patients compared to CM-like patients (FC > 2, B-H FDR-adjusted P < 0.05). These steroids include pregnenolone sulfate, pregnenediol sulfate, pregnenetriol sulfate, androsterone monosulfate, 16-OH-DHEA-S, DHEA-S, cortisol, and cortisone. High levels of pregnenolone and its downstream metabolic derivatives were significantly associated with coma in CM patients. Our findings suggest that monitoring circulating neurosteroid levels in patients could aid in the early identification of those at risk of coma, and may important implications for the clinical management of CM patients.

systems biology↗

bioRxiv2021

Reversible brain edema in experimental cerebral malaria is associated with transcellular blood-brain barrier disruption and delayed microhemorrhages

Brain swelling occurs in cerebral malaria (CM) and may either reverse or result in fatal outcome. It is currently unknown how brain swelling in CM reverses, as investigations have been hampered by inadequate animal models. In this study, we show that reversible brain swelling in experimental murine cerebral malaria (ECM) can be induced reliably after single vaccination with radiation-attenuated sporozoites as revealed by in vivo high-field (9.4T) magnetic resonance imaging. Our results provide evidence that parenchymal fluid increase and consecutive brain swelling results from transcellular blood-brain barrier disruption (BBBD), as revealed by electron microscopy. This mechanism enables reversal of brain swelling but does not prevent persistent focal brain damage, evidenced by microhemorrhages, in areas of most severe BBBD. In a cohort of 27 pediatric and adult CM patients (n=4 fatal, n=23 non-fatal) two out of four fatal CM patients (50%) and 8 out of 23 non-fatal CM patients (35%) showed microhemorrhages on MRI at clinical field strength of 1.5T, emphasizing the translational potential of the experimental model. Our data suggest that targeting transcellular BBBD may represent a promising adjunct therapeutic approach in cerebral brain swelling to reduce edema and may ultimately lead to a reduced permanent brain damage and a better longtime neurological outcome. Author summaryBrain swelling, which occurs in diseases such as cerebral malaria, is not necessarily fatal, and may reverse. Even upon reversal of brain swelling, neurological sequelae can still occur. The factors contributing to the reversibility of brain edema are not known, and treatment options remain therefore limited. Identifying the mechanisms leading to such reversibility could inform clinical management aimed at decreasing brain swelling and consecutive brain injury. Here we introduce a reproducible and simple animal model that allows comprehensive in vivo studies of reversible brain swelling in cerebral malaria at the peak of disease and upon recovery. We identify a specific type of blood-brain barrier disruption (BBBD) as a mechanism that occurs in brain swelling. We show that BBBD can reverse, but also highlight remaining brain damage in areas of most severe BBBD. As the ECM model introduced here bares crucial similarities to the CM in humans, our findings open strategies to study new therapeutic avenues and point to compounds that specifically target transcellular BBBD to reduce brain edema, and increase survival rates.

neuroscience↗

bioRxiv2018

Cantharidin alters GPI-anchored protein sorting by targeting Cdc1 mediated remodeling in Endoplasmic Reticulum

Cantharidin (CTD) is a potent anticancer small molecule produced by several species of blister beetle. It has been a traditional medicine for the treatment of warts and tumors for many decades. CTD suppresses the tumor growth by inducing apoptosis, cell cycle arrest, and DNA damage. It is a known inhibitor of PP2A and PP1. In this study, we identified new molecular targets of CTD using Saccharomyces cerevisiae as a model organism which expresses a Cantharidin Resistance Gene (CRG1). CRG1 encodes a SAM-dependent methyltransferase that inactivates CTD by methylation. CTD alters lipid homeostasis, cell wall integrity, endocytosis, adhesion, and invasion in yeast cells. We found that CTD specifically affects the phosphatidylethanolamine (PE) associated functions which can be rescued by supplementation of ethanolamine (ETA) in the growth media. CTD also perturbed ER homeostasis and cell wall integrity by altering the GPI-anchored protein sorting. The CTD dependent genetic interaction profile of CRG1 revealed that Cdc1 activity in GPI-anchor remodeling is the key target of CTD, which we found to be independent of PP2A and PP1. Furthermore, our experiments with human cells suggest that CTD functions through a conserved mechanism in higher eukaryotes as well. Altogether, we conclude that CTD induces cytotoxicity by targeting Cdc1 activity in GPI-anchor remodeling in the endoplasmic reticulum (ER).

cell biology↗