Iva Potočnjak

Nephroprotective activities of rosmarinic acid against cisplatin-induced kidney injury in mice.

Rosmarinic acid (RA) is a natural phenolic compound with a broad range of applications, from food preservatives to cosmetics. Increasing amounts of evidence suggests its beneficial effects against various pathological conditions. The aim of this study was to investigate the therapeutic activity of rosmarinic acid (RA) against cisplatin (CP)-induced nephrotoxicity. RA was administered by oral gavage at doses of 1, 2 and 5mg/kg for two successive days, 48 h after intraperitoneal CP injection (13 mg/kg). Twenty four hours later, mice were sacrificed. Treatment with RA significantly ameliorated histopathological changes and the increase in serum creatinine and blood urea nitrogen (BUN) induced by CP. Oxidative stress induced by CP, evidenced by increased renal 4-hydroxynonenal (4-HNE), cytochrome P450 2E1 (CYP2E1) and heme oxygenase (HO-1) expression, was significantly reduced by RA administration. Moreover, RA inhibited the expression of nuclear factor-kappaB (NF-κB) and tumor necrosis factor-α (TNF-α), indicating the inhibition of inflammation. Additionally, RA exhibited antiapoptotic activity through the reduction of p53, phosphorylated p53 and active caspase-3 expression in the kidneys. These findings show that RA ameliorates CP-induced oxidative stress, inflammation and apoptosis in the kidneys. The nephroprotective activity of RA could be, at least in part, attributed to reduced CYP2E1 expression.

A comprehensive overview of hepatoprotective natural compounds: mechanism of action and clinical perspectives

Hepatoprotective effects of natural compounds have been frequently attributed to their antioxidant properties and the ability to mobilize endogenous antioxidant defense system. Because of involvement of oxidative stress in virtually all mechanisms of liver injury, it is a reasonable presumption that antioxidant properties of these compounds may play a key role in the mechanism of their hepatoprotective activity. Nevertheless, growing evidence suggests that other pharmacological activities of natural compounds distinct from antioxidant are responsible for their therapeutic effects. In this review, we discussed currently known molecular mechanisms of the hepatoprotective activity of 27 most intensively studied phytochemicals. These compounds have been shown to possess anti-inflammatory, antisteatotic, antiapoptotic, cell survival and antiviral activity through interference with multiple molecular targets and signaling pathways. Additionally, antifibrotic properties of phytochemicals have been closely associated with apoptosis of hepatic stellate cells and stimulation of extracellular matrix degradation. However, although these compounds exhibit a pronounced hepatoprotective effects in animal and cell culture models, the lack of clinical studies remains a bottleneck for their official acceptance by medical experts and physicians. Therefore, controlled clinical trials have an imperative in confirmation of the therapeutic activity of potentially hepatoprotective compounds. Understanding the principles of the hepatoprotective activity of phytochemicals could guide future drug development and help prevention of clinical trial failure. Also, the use of new delivery systems that enhances bioavailability of poorly water soluble compounds may improve the results already obtained. Most importantly, available data suggest that phytochemicals possess a various degree of modulation of specific signaling pathways, pointing out a need for usage of combinations of several hepatoprotective compounds in both experimental studies and clinical trials.

Oral administration of oleuropein attenuates cisplatin-induced acute renal injury in mice through inhibition of ERK signaling

SCOPE Oleuropein possesses numerous health beneficial effects. We investigated the renoprotective effects of oleuropein against cisplatin (CP) induced kidney injury. METHODS AND RESULTS Male BALB/cN mice were orally gavaged with 5, 10 and 20 mg oleuropein/kg body weight for 2 days, 48 h after intraperitoneal injection of CP (13 mg/kg). Four days after CP administration, serum creatinine and blood urea nitrogen (BUN) levels were significantly elevated, with histopathological changes in renal tissue. In addition, renal oxidative stress was evidenced by increased expression of 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE), cytochrome P450 E1 (CYP2E1) and heme oxygenase-1 (HO-1). The expression of nuclear factor-kappaB (NF-κB) p65, phospho-p65, tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2) in the kidneys increased upon CP treatment, suggesting renal inflammation. CP intoxication increased the expression of p53, Bax and caspase-3 and induced apoptosis in the kidneys. CP administration also resulted in enhanced phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). All these effects were dose dependently diminished by oleuropein. Oral administration of PD0325901, an MEK inhibitor, coincided with the oleuropein-mediated suppression of apoptotic, inflammatory and antioxidant markers. CONCLUSION The results of the current study suggest that oleuropein attenuated CP-induced acute renal injury, which was mediated through the inhibition of ERK signaling.

Carvacrol induces cytotoxicity in human cervical cancer cells but causes cisplatin resistance: involvement of MEK-ERK activation

Carvacrol has been shown to possess anticancer activity, but the mechanism is unknown, as well as the possibility of interaction with anticancer drugs. The aim of this study was to investigate the role of mitogen‐activated protein kinase kinase (MEK)/extracellular signal‐regulated kinase (ERK) signaling in carvacrol‐induced human cervical cancer HeLa cell cytotoxicity. In addition, we studied sensitization of HeLa cells to cisplatin (CP) by carvacrol. Both carvacrol and CP showed dose‐dependent cytotoxicity against HeLa cells and activated ERK1/2. The MEK inhibitor PD325901 suppressed ERK expression and further increased cytotoxicity of carvacrol but increased viability of CP‐treated cells by modulating apoptosis. The MEK inhibitor also increased microtubule‐associated protein 1A/1B‐light chain 3 beta expression in CP treatment. Cotreatment with CP and carvacrol resulted in increased viability of the cancer cells compared with CP treatment, which was associated with the suppression of apoptosis. MEK inhibition decreased the cell viability, without changes in apoptosis. Concomitantly, carvacrol increased CP‐induced expression of light chain 3 beta, which was enhanced by MEK inhibition. The results of the current study suggest the opposite role of ERK1/2 in carvacrol and CP‐induced HeLa cell cytotoxicity. Interestingly, carvacrol induced CP resistance in HeLa cells through ERK1/2‐independent suppression of apoptosis and ERK1/2‐dependent modulation of autophagy.

Chlorogenic acid ameliorates experimental colitis in mice by suppressing signaling pathways involved in inflammatory response and apoptosis

Chlorogenic acid (ChA) exhibits a multitude of positive health effects, however, the signaling mechanisms by which ChA could influence the inflammatory response in experimental colitis are unknown. To answer this question, we induced colitis in mice by administration of 2.5% dextran sulfate sodium (DSS) in drinking water for seven days. Oral administration of ChA significantly ameliorated clinical symptoms, improved disease activity index and colon shortening induced by DSS. Furthermore, ChA administration resulted in a suppression of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinases 1 and 2 (JNK1/2), Akt and signal transducer and activator of transcription 3 (STAT3) with concomitant upregulation of phosphatase and tensin homolog (PTEN) expression. Immunohistochemical analysis showed a dose-dependent decrease in expression and nuclear translocation of nuclear factor-kappa B (NF-κB) p65 subunit, which was accompanied by suppression of pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) expression. Induction of apoptosis and oxidative stress was attenuated in a dose-dependent manner by suppressing Bax, caspase-8, caspase-9 and heme oxygenase-1 (HO-1) protein expression in mice administrated with ChA. The results of the current study suggest that ChA could be useful for the treatment of inflammation and attenuating colitis severity by suppressing activation of pro-inflammatory and apoptotic signaling pathways.