bioRxiv Science⌕ Search

bioRxiv · 10.1101/2020.09.21.305953

Antioxidant enriched fraction from Pueraria tuberosa alleviates ovariectomized-induced osteoporosis in rats, and inhibits growth of breast and ovarian cancer cell lines in vitro

Abstract

Pueraria tuberosa (P. tuberosa), known as Indian Kudzu belongs to family Fabaceae and it is solicited as "Rasayana" drugs in Ayurveda. In the present study, we analyzed the efficacy an antioxidant enriched fraction (AEF) from the tuber extract of P. tuberosa against menopausal osteoporosis and breast and ovarian cancer cell lines. The AEF from P. tuberosa was identified by determining phenolic composition (total phenolic and flavonoid amount). Antioxidant property (in vitro assays) was also carried out followed by analysis of the AEF for its antiosteoporotic and anticancer potentials. Antiosteoporotic activity of AEF was investigated in ovariectomy-induced osteoporosis in rats and in vitro anticancer activity by MTT assay. Also, the GC/MS analysis of AEF was performed to determine various phytoconstituents. A docking analysis was performed to verify the interaction of bioactive molecules with estrogen receptors (ERs). Ethyl acetate fraction of the mother extract was proved as the AEF. AEF significantly improved various biomechanical and biochemical parameters in a dose dependent manner in the ovariectomized animals. AEF also controlled the increased body weight and decreased uterus weight following ovariectomy. Histopathology of femur revealed the restoration of typical bone structure and trabecular width in ovariectomized animals after AEF and raloxifene treatment. AEF also exhibited in vitro cytotoxicity in breast (MCF-7 and MDA-MB-231) and ovarian (SKOV-3) cancer cells. Further, genistein and daidzein exhibited a high affinity towards both estrogen receptors ( and {beta}) in docking study revealing the probable mechanism of the antiosteoporotic activity. GC/MS analysis confirmed the presence of bioactive molecules such as stigmasterol, {beta}-sitosterol, and stigmasta-3,5-dien-7-one. The observations of this study vindicate the potency of AEF from P. tuberosa in the treatment of menopausal osteoporosis and cancer.

Source connections

Explore related subjects

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Satpathy, S., Patra, A., Hussain, M. D., Kazi, M., Aldughaim, M. S., Ahirwar, B., Swaha Satpathy, Arjun Patra, Muhammad Delwar Hussain, Mohsin Kazi, Mohammed S Aldughaim, Bharti Ahir,. 2020-09-21. Antioxidant enriched fraction from Pueraria tuberosa alleviates ovariectomized-induced osteoporosis in rats, and inhibits growth of breast and ovarian cancer cell lines in vitro. https://doi.org/10.1101/2020.09.21.305953

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

Lipid-ASO therapeutics exhibit differential tissue targeted delivery upon systemic or local CNS administration

Antisense oligonucleotides (ASOs) are a powerful therapeutic modality, but their full potential is hindered by pharmacokinetic properties that affect tissue and cellular delivery. Lipid conjugation is increasingly used to modulate ASO's biodistribution and promote extrahepatic activity, yet lipid dependent effects on in vivo functional delivery, particularly in the central nervous system (CNS), remain less explored. Here, we performed a side by side in vivo comparison of cholesterol, palmitic acid (C16:0), docosanoic acid (C22:0), and eicosapentaenoic acid (C20:5) conjugated to a fully phosphorothioated 3 10 3 LNA gapmer ASO targeting the Malat1 long non coding RNA. Lipid-ASO conjugates were administered systemically or locally in the brain of mice and evaluated for tissue level and cellular level distribution by imaging, qPCR and single-cell RNA sequencing, simultaneously annotating cell origin and global transcriptional changes within the cell. Following systemic administration in mice, lipid conjugation improved overall multi organ efficacy compared to unconjugated ASO, but with pronounced tissue specific differences. Single cell sequencing of liver and heart transcriptomes revealed lipid dependent cellular uptake patterns and transcriptional responses distinct from administration of unconjugated ASO. After intracerebroventricular administration, selected fatty acid conjugates enhanced silencing in deep brain regions such as the striatum, whereas cholesterol conjugation impaired functional delivery despite increased CNS retention. Light-sheet microscopy showed restricted parenchymal penetration of cholesterol ASOs compared with broader but heterogeneous distribution of palmitic acid conjugate. Together, these findings demonstrate that lipid identity critically determines ASO efficacy, productive cellular uptake, and regional CNS engagement, emphasizing the need for context specific lipid design in ASO therapeutic development.

pharmacology and toxicology↗

Novel Dissymmetric Ionizable Lipid-Assembled Lipid Nanoparticles for Delivery of Ferroptosis-Related siRNA in Diabetic Treatment

Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, enhanced in vivo gene silencing potency, and favorable biosafety relative to the clinical benchmark MC3-LNP. In both streptozotocin-induced and spontaneous db/db type 2 diabetes (T2D) mouse models, lead LNPs delivering ferroptosis-related siRNAs effectively ameliorated glucose and lipid metabolic disorders, restored islet function, and alleviated hepatic steatosis. This study not only lays a theoretical foundation for the rational design of novel ionizable lipids, but also validates the therapeutic potential of siRNA therapy targeting ferroptosis, providing a versatile delivery platform and targeted therapeutic strategy for the treatment of T2D.

pharmacology and toxicology↗

Blocking mitochondrial alanine and pyruvate metabolism in hepatocytes worsens acetaminophen-induced liver injury in mice

Pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, as well as NADH production. As a result, there is growing interest in targeting the mitochondrial pyruvate carrier (MPC) complex in liver and metabolic diseases. However, recent in vitro data indicate that MPC inhibition diverts glutamine/glutamate away from glutathione synthesis and toward glutaminolysis to compensate for loss of pyruvate oxidation, possibly sensitizing cells to oxidative insult. Here, we explored this using the clinically relevant acetaminophen (APAP) overdose model of acute liver injury, which is driven by oxidative stress. We report that MPC inhibition does indeed sensitize the liver to APAP-induced injury in vivo, but only with concomitant loss of alanine aminotransferase 2 (ALT2). Pharmacologic and genetic manipulation of neither MPC2 nor ALT2 alone affected APAP toxicity, but liver-specific double knockout (DKO) of these proteins significantly worsened the liver damage. Further investigation confirmed that DKO impaired glutathione synthesis and increased urea cycle flux, consistent with increased glutaminolysis. Furthermore, APAP toxicity was exacerbated by inhibition of both the MPC and ALT in vitro. Thus, increased glutaminolysis and susceptibility to oxidative stress requires loss of both the MPC and ALT2 in vivo and exacerbates them in vitro. Finally, induction of ALT2 reduced APAP-induced injury.

pharmacology and toxicology↗