In vitro studies on drug- induced metabolic alterations

Behl, Shalini (2019) In vitro studies on drug- induced metabolic alterations. Doctoral thesis, University of Central Lancashire.

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Over the last few decades some mechanisms of diseases, especially those which are associated with recently described dysregulation of the adipose tissue due to certain medications/drugs, have been discovered, shedding light on the pathophysiology of obesity-associated metabolic alterations. Investigation of the functions of distinct cytokines, overall redox status, transcriptional regulation and protein expression of crucial adipogeneic markers may provide new comprehension of the pathophysiology of obesity, diabetes and cardiovascular diseases, as well as specific targets for future therapeutic approaches. This study was particularly designed with the knowledge that certain medications and drugs such as paracetamol, caffeine, rilpivirine, estradiol and β-naphthoflavone (BNF) may contribute significantly to the process of adipogenesis, broadly termed drug-induced metabolic alterations. Furthermore, the present study investigated the combined effects of some of these drugs for comparison.
The results from the treatment of adipose cells with caffeine, paracetamol and β-naphthoflavone either alone or in combination have shown anti-adipogenic effects of caffeine, paracetamol and β-naphthoflavone through inhibition of adipogenesis and enhancement of the lipolytic process. A combination of β-naphthoflavone with caffeine and paracetamol was further shown to attenuate triglyceride accumulation.
This study also investigated the inflammatory status of 3T3-L1 human pre-adipocytes when treated with different concentrations of either rilpivirine or estradiol alone and in combination with β-naphthoflavone (BNF). The results show that either rilpivirine or estradiol individually or during their combination can evoke significant increases in glycerol release and a concomitant significant decrease of adiponectin from adipocytes in a dose dependent manner. The effects of combined treatments were much larger than individual concentration for each drug. Both drugs had little or no effect on leptin levels, except for a small decrease with 10 µM rilpivirine alone or when combined with estradiol. In addition, both drugs evoked small increases in the release of resistin and interleukin-8 with significant values at higher doses compared to untreated adipocytes.When adipocytes were pretreated with BNF, either rilpivirine or, estradiol or when combined evoked a much larger release in glycerol and a much larger decrease in adiponectin compared to the absence of BNF.
The study further investigated the lipodystrophic effects of rilpivirine on adipose cells and its nutritional management using quercetin. The results have shown that rilpivirine exerts lipoatrophic effects on adipose cells by impairing triglyceride accumulation, increasing inflammation, repressing anti-oxidant enzymes and inhibiting the expression of genes controlling adipogenesis (PPARg, C/EBPα, SREBP-1c, fatty acid synthase and aP2). A combination of rilpivirine and quercetin shows that quercetin was able to decrease inflammation and restore the levels of anti-oxidant enzymes but failed to overcome the lipoatrophic effects of rilpivirine.
The present study also elucidated the role of 17β-estradiol on human subcutaneous cells in vitro either individually or in combination with quercetin. The results revealed that both estradiol and quercetin can promote leanness in part by reducing adipocyte size through reduced uptake of fatty acids and reduced lipogenesis. Experimental data show a decrease in the expression of adipogenesis target genes suggesting anti-adipogenic as well as anti-lipogenic action of estradiol and quercetin in adipose cells.
In conclusion, the results from this study revealed complex interactions between metabolic and inflammatory pathways during the process of adipogenesis. However, the data further suggests that HIV and obese patients who are under increased risk should seek advice from their physicians to offer differentiated and optimized therapeutic approaches.

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