Using genetically matched azole-susceptible (AS) and azole-resistant (AR) clinical isolates ofCandida albicans, we recently demonstrated that CDR1 overexpression in AR isolates is due to its enhanced transcriptional activation and mRNA stability. This study examines the molecular mechanisms underlying enhanced CDR1 mRNA stability in AR isolates. Mapping of the 39 untranslated region (39 UTR) of CDR1 revealed that it was rich in adenylate/uridylate (AU) elements, possessed heterogeneous polyadenylation sites, and had putative consensus sequences for RNA-binding proteins. Swapping of heterologous and chimeric lacZ-CDR1 39 UTR transcriptional reporter fusion constructs did not alter the reporter activity in AS and AR isolates, indicating that cis-acting sequences within the CDR1 39 UTR itself are not sufficient to confer the observed differential mRNA decay. Interestingly, the poly(A) tail of the CDR1 mRNA of AR isolates was~35-50 % hyperadenylated as compared with AS isolates. C. albicans poly(A) polymerase (PAP1), responsible for mRNA adenylation, resides on chromosome 5 in close proximity to the mating type-like (MTL) locus. Two different PAP1 alleles, PAP1-a/PAP1-a, were recovered from AS (MTL-a/MTL-a), while a single type of PAP1 allele (PAP1-a) was recovered from AR isolates (MTL-a/MTL-a). Among the heterozygous deletions of PAP1-a (Dpap1-a/PAP1-a) and PAP1-a (PAP1-a/Dpap1-a), only the former led to relatively enhanced drug resistance, to polyadenylation and to transcript stability of CDR1 in the AS isolate. This suggests a dominant negative role of PAP1-a in CDR1 transcript polyadenylation and stability. Taken together, our study provides the first evidence, to our knowledge, that loss of heterozygosity at the PAP1 locus is linked to hyperadenylation and subsequent increased stability of CDR1 transcripts, thus contributing to enhanced drug resistance.
Background:
Salidroside is a glucoside of tyrosol found mostly in the roots of Rhodiola spp. It exhibits
diverse biological and pharmacological properties. In the last decade, enormous research is conducted to explore the
medicinal properties of salidroside; this research reported many activities like anti-cancer, anti-oxidant, anti-aging,
anti-diabetic, anti-depressant, anti-hyperlipidemic, anti-inflammatory, immunomodulatory, etc.
Objective:
Despite its multiple pharmacological effects, a comprehensive review detailing its metabolism and
therapeutic activities is still missing. This review aims to provide an overview of the metabolism of salidroside, its
role in alleviating different metabolic disorders, diseases and its molecular interaction with the target molecules in
different conditions. This review mostly concentrates on the metabolism, biological activities and molecular
pathways related to various pharmacological activities of salidroside.
Conclusion:
Salidroside is produced by a three-step pathway in the plants with tyrosol as an intermediate molecule.
The molecule is biotransformed into many metabolites through phase I and II pathways. These metabolites, together
with a certain amount of salidroside may be responsible for various pharmacological functions. The salidroside based
inhibition of PI3k/AKT, JAK/ STAT, and MEK/ERK pathways and activation of apoptosis and autophagy are the
major reasons for its anti-cancer activity. AMPK pathway modulation plays a significant role in its anti-diabetic
activity. The neuroprotective activity was linked with decreased oxidative stress and increased antioxidant enzymes,
Nrf2/HO-1 pathways, decreased inflammation through suppression of NF-κB pathway and PI3K/AKT pathways.
These scientific findings will pave the way to clinically translate the use of salidroside as a multi-functional drug for
various diseases and disorders in the near future.
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