Biology subjects

Rana, R.

Publications and source records attributed to Rana, R..

3 recordsLinked to original sources

bioRxiv2021

Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression

A major therapeutic obstacle in diabetes mellitus is the metabolic or hyperglycemic memory: the persistence of impaired organ function despite improvement of blood glucose. Therapies reversing the hyperglycemic memory and thus improving already established organ-dysfunction are lacking, but urgently needed considering the increasing prevalence of diabetes mellitus worldwide. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with sustained induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, in several independent human samples and in in vitro models. Tubular p21 expression and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans, suggesting that p21 may be a biomarker indicating persistent ("memorized") kidney damage. Glucose-mediated p21 induction and tubular senescence were enhanced in mice with reduced levels of the disease resolving protease activated protein C (aPC). Mechanistically, glucose-induced and sustained tubular p21 expression is linked with demethylation of its promoter and reduced DNMT1 expression. aPC reverses already established p21 expression independent of its anticoagulant function through receptor signaling. Accordingly, new pharmacological approaches specifically mimicking aPC signaling (3K3A-aPC, parmodulin-2) enabled the reversal of glucose-mediated sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence contributes to the hyperglycemic memory but can be therapeutically targeted. Single sentence summaryaPC signaling targets persistent p21 expression and tubular senescence and reverses the hyperglycemic memory in diabetic kidney disease.

molecular biology↗

bioRxiv2020

Discerning role of a functional arsenic resistance cassette in evolution and adaptation of a rice pathogen

Arsenic (As) is highly toxic element to all forms of life and is a major environmental contaminant. Understanding acquisition, detoxification, and adaptation mechanisms in bacteria that are associated with host in arsenic-rich conditions can provide novel insights into dynamics of host-microbe-microenvironment interactions. In the present study, we have investigated an arsenic resistance mechanism acquired during the evolution of a particular lineage in the population of Xanthomonas oryzae pv. oryzae (Xoo), which is a serious plant pathogen infecting rice. Our study revealed the horizontal acquisition of a novel chromosomal 12kb ars cassette in Xoo IXO1088 that confers high resistance to arsenate/arsenite. The ars cassette comprises several genes that constitute an operon induced in the presence of arsenate/arsenite. Transfer of cloned ars cassette to Xoo BXO512 lacking it confers arsenic resistance phenotype. Further, the transcriptional response of Xoo IXO1088 under arsenate/arsenite exposure was analyzed using RNA sequencing. Arsenic detoxification and efflux, oxidative stress, iron acquisition/storage, and damage repair are the main cellular responses to arsenic exposure. Our investigation has provided novel insights in to how a pathogenic bacterium is coping with arsenic-rich unique micro-environments like seen in rice growing in submerged water conditions. Impact statementArsenic accumulation in rice is a serious and unique agronomic issue. Arsenic contaminated groundwater used for irrigation purposes is adding to the accumulation of arsenic in rice. Submerged conditions in the paddy fields further induce the prevalence of toxic inorganic arsenic species in the environment. Our genomics and transcriptomics-based study reveals how a rice pathogen is coping with the lethal concentrations of arsenic by acquiring a novel resistance cassette during diversification into lineages. Acquisition of such detoxification mechanisms can provide a selective advantage to the bacterial population in avoiding toxicity or enhancing virulence and to their on-going evolutionary events. While there are numerous studies on plant-pathogen-environment interactions, our study highlights the importance of systematic studies on the role of unique micro-environmental conditions on the evolution of host-adapted pathogens/microbes.

microbiology↗

bioRxiv2020

Cannabidiol Interactions with Voltage-Gated Sodium Channels

Voltage-gated sodium channels are targets for a range of pharmaceutical drugs developed for treatment of neurological diseases. Cannabidiol (CBD), the non-psychoactive compound isolated from cannabis plants, was recently approved for treatment of two types of epilepsy associated with sodium channel mutations. This study used high resolution X-ray crystallography to demonstrate the detailed nature of the interactions between CBD and the NavMs voltage-gated sodium channel, showing CBD binds at a novel site at the interface of the fenestrations and the central hydrophobic cavity of the channel. Binding at this site blocks the transmembrane-spanning sodium ion translocation pathway, providing a molecular mechanism for channel inhibition. Modelling studies illuminate why the closely-related psychoactive compound THC may not bind to these channels. Finally, comparisons are made with the TRPV2 channel, also recently proposed as a target site for CBD. In summary, this study provides novel insight into a possible mechanism for CBD with sodium channels.

biophysics↗