Urinary metabolic profiling of cisplatin nephrotoxicity and nephroprotective effects of Orthosiphon stamineus leaves elucidated by 1 H NMR spectroscopy

Abstract

Orthosiphon stamineus (OS) is a popular medicinal herb used in traditional Chinese medicine as a diuretic agent and for renal system disorders. This study employed H NMR based metabolomics approach to investigate the possible protective activity of OS in cisplatin induced nephrotoxicity owing to its diuretic and antioxidant activities. Aqueous (OSAE) and 50% aqueous ethanolic (OSFE) extracts of OS leaves were orally administered at 400mg/kg BW doses to rats which were then intraperitoneally injected with cisplatin at 5mg/kg BW dose. The H NMR profile of the urine samples collected on day 5 after cisplatin administration were analyzed by multivariate pattern recognition techniques, whereby 19 marker metabolites suggestive in the involvement of TCA cycle, disturbed energy metabolism, altered gut microflora and BCAA metabolism pathways were identified. It was observed that OSFE caused significant changes (p<0.05) in the levels of 8 markers namely leucine, acetate, hippurate, lysine, valine, 2-oxoglutarate, 3-HBT and acetoacetate resulting in a moderate ameliorative effect, however, it did not completely protect from nephrotoxicity. OSAE did not demonstrate significant down regulatory effects on any markers, albeit, it potentiated the cisplatin nephrotoxicity by inducing significant increase in glucose, glycine, creatinine, citrate, TMAO, acetate and creatine levels. A Principal Component Analysis (PCA) of the H NMR spectra of OS extracts identified that OSFE had higher concentrations of the secondary metabolites such as caffeic acid, chlorogenic acid, protocatechuic acid and orthosiphol, among others. Whereas, OSAE was characterized by higher concentrations of acetate, lactate, succinic acid, valine and phosphatidylcholine. This research denotes the first comprehensive analysis to identify the effects of OS extracts on cisplatin nephrotoxicity.

Peer Review #2 of "Metabolomic and biochemical characterization of a new model of the transition of acute kidney injury to chronic kidney disease induced by folic acid (v0.2)"

“…However, increased intensity of signal of two metabolites related to amino acid metabolism, creatine and glycine, separate the cluster of FAIG-Mi, while creatine alone contribute for FAIG-S. Increased urinary glycine was also observed in cisplatin nephrotoxicity rats (Pariyani et al 2017;Ryu et al 2019). It is possible the result from injury in the proximal tubule, given that an increased presence of glycine in urine has been described in animals treated with proximal tubule toxins, or with pathologies affecting the proximal tubule (Zuppi et al 1997).…”

Urinary metabolomics study on the protective role of Orthosiphon stamineus in Streptozotocin induced diabetes mellitus in rats via 1H NMR spectroscopy

“…The HPLC quantification of two major marker compounds of OS, namely rosmarinic acid and sinensetin, in OS aqueous extract was carried out, in accordance with the methods described in our published report on OS [21]. …”

Lipidomics Reveals the Therapeutic Effects of EtOAc Extract of Orthosiphon stamineus Benth. on Nephrolithiasis

“…Published literature showed that the main compounds in OS are flavonoids, terpenes, and caffeic acid derivatives (Sumaryono et al, 1991;Tezuka et al, 2000). At present, researches on OS for the treatment of kidney diseases such as nephritis, kidney infection and cisplatin nephrotoxicity have been widely carried out (Hiromitsu et al, 2003;Pariyani et al, 2017;Sarshar et al, 2017), especially in the treatment of kidney stones. For instance, the 50% methanol extract of OS inhibits the calcium oxalate crystal growth (Dharmaraj et al, 2006) and aqueous extract of OS has protective effect in a calcium oxalate stone forming (Akanae et al, 2010).…”