Rapid proliferation of cancer cells assisted by endothelial cell-mediated angiogenesis and acquired inflammation at the tumor microenvironment (TME) lowers the success rate of chemotherapeutic regimens. Therefore, targeting these processes using localized delivery of a minimally toxic drug combination may be a promising strategy. Here, we present engineering of a biocompatible self-assembled lithocholic acid-dipeptide derived hydrogel (TRI-Gel) that can maintain sustained delivery of antiproliferating doxorubicin, antiangiogenic combretastatin-A4 and anti-inflammatory dexamethasone. Application of TRI-Gel therapy to a murine tumor model promotes enhanced apoptosis with a concurrent reduction in angiogenesis and inflammation, leading to effective abrogation of tumor proliferation and increased median survival with reduced drug resistance. In-depth RNA-sequencing analysis showed that TRI-Gel therapy induced transcriptome-wide alternative splicing of many genes responsible for oncogenic transformation including sphingolipid genes. We demonstrate that TRI-Gel therapy targets the reversal of a unique intron retention event in β-glucocerebrosidase 1 (Gba1), thereby increasing the availability of functional Gba1 protein. An enhanced Gba1 activity elevates ceramide levels responsible for apoptosis and decreases glucosylceramides to overcome drug resistance. Therefore, TRI-Gel therapy provides a unique system that affects the TME via post-transcriptional modulations of sphingolipid metabolic genes, thereby opening a new and rational approach to cancer therapy.

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Murraya koenigii (L.) Spreng (Curry leaf) is a commercially important medicinal plant in South Asia, containing therapeutically valuable carbazole alkaloids (CAs). Thus, the quantitative evaluation of these compounds from different climatic zones of India are an important aspect for quality assessment and economic isolation of targeted compounds from the plant. In this study, quantitative estimation of CAs among 34 Indian natural populations of M. koenigii was assessed using UPLC/MS/MS. The collected populations represent the humid subtropical, tropical wet & dry, tropical wet, semi-arid, arid, and montane climatic zones of India. A total of 11 CAs viz. koenine-I, murrayamine A, koenigine, koenimbidine, koenimbine, O-methylmurrayamine A, girinimbine, mahanine, 8,8''-biskoenigine, isomahanimbine, and mahanimbine were quantified using multiple reaction monitoring (MRM) experiments within 5.0 min. The respective range for natural abundance of CAs were observed as 0.

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: Tuberculosis (TB) is the foremost cause of mortality from single infectious agent Mycobacterium tuberculosis (MTB). Current therapeutic regimes suffer from several problems including side effects, costs and emergence of multidrug resistance (MDR). Moreover, conventional diagnostic methods are either too slow, lack accurate or robust biomarkers. Under such circumstances, identification of rapid metabolite based biomarkers as novel drug targets could be a potential approach to circumvent MDR. In the era of “OMIC” sciences, lipidomics has gain significant attention to unravel the complexity of lipid loaded Mycobacterium species. Lipidomics is a sub-branch of metabolomics with extreme atomic diversity between the metabolites. There is no single principle on which the metabolite diversity can be defined, unlike other biomolecules viz. nucleic acid, proteins or carbohydrates. MTB encodes 10% of the genome for lipid metabolism and lipids accounts for 60% of its dry weight. Mycobacterium harbor wide spectra of lipid repertoire ranging from highly apolar to highly polar lipids adding the complexity in their identification and analysis. Compared to targeted approaches, untargeted or global lipidomics of MTB is still more challenging. This review describes recent advances in lipidomic technology with regard to chromatography, detection methods and assessment on the existing mass spectrometry based lipidomics tools to study the untargeted or global MTB lipidomics. It also identifies the limitations associated with present technologies as well as explores solutions to practical challenges concurrent in establishing MTB lipidome. Together we endorse, that the emerging tool of lipidomics have provided broader vision to comprehend role of lipid molecules in MTB pathogenesis and the need for further improvement.

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