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Black ginger is used as an herbal medicine for self-care and health promotion. Black ginger extract has been shown to alter the function of transporters in several cell types. This study demonstrates the interaction between the extract and 5,7-dimethoxyflavone (DMF) on drug efflux mediated by breast cancer resistance proteins (BCRP) and P-glycoprotein (P-gp) in Caco-2 cells and heterologous cell systems [Madin-Darby canine kidney type II (MDCKII) stably transfected with human BCRP (MDCKII/BCRP) or human P-gp (MDCKII/P-gp)]. The transepithelial flux of 3H-Digoxin and 3H-Estrone sulfate, prototypic substrates of P-gp, and BCRP, respectively, across Caco-2 cell monolayers, MDCKII/BCRP, and MDCKII/P-gp cells were determined. The results demonstrate that black ginger extract (10 µg/ml) significantly increases 3H-Digoxin and 3H-Estrone sulfate transport from the apical to basolateral side while decreasing transport from the basolateral to apical side of Caco-2 cells and MDCKII cell overexpression of BCRP or P-gp. The effect of the extract on 3H-Digoxin and 3H-Estrone sulfate transport was related to a decrease in efflux ratio. Likewise, DMF (5 µM) significantly increased 3H-Digoxin and 3H-Estrone sulfate absorption with a decreased efflux ratio compared to the control. Interestingly, the extract also significantly increased absorption of paclitaxel, an anti-cancer drug, which has poor oral absorption. Taken together, co-administration of drugs as substrates of BCRP and P-gp, with the black ginger extract containing DMF, might alter the pharmacokinetic profiles of the medicine.

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Topical film-forming sprays of chlorhexidine gluconate (CHG-FFS) were developed for antiseptic application. Various polymers and solvents were studied for their potential as film-forming polymers and solvent systems, respectively. To produce CHG-FFS, the optimal polymer and solvent were selected, and their physicochemical properties were evaluated. The in vivo evaluation of CHG-FFS was investigated for the satisfaction of the dosage forms, time required for the film formation, film appearance, and adhesion on the skin. Antibacterial activity was also studied in vitro and in vivo. The optimized formulation was assessed for the in vitro cell line evaluations of the cytotoxicity and wound healing. The results demonstrate that Eudragit® S100, Eudragit® L100, and polyvinyl alcohol (PVA) have the ability to be used as film-forming polymers in an ethanolic solution. A clear and flexible film was obtained from transparent homogenous solutions of CHG-FFS after actuation. They generated the fast thin film formation on the skin with the satisfaction of the dosage forms. Furthermore, the formulations inhibited the growth of Staphylococcus aureus in vitro and provided antiseptic activity in vivo. However, PVA was found to be an optimal film-forming polymer for promoting CHG adhesion on the skin. The CHG-FFS obtained from the PVA also provided a CHG film, which was non-toxic to human skin cells and did not interfere with the wound healing process. Therefore, the developed CHG-FFS could be a promising candidate for topical antiseptic application.

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BACKGROUND: Panduratin A is a bioactive cyclohexanyl chalcone exhibiting several pharmacological activities, such as anti-inflammatory, anti-oxidative, and anti-cancer activities. Recently, the nephroprotective effect of panduratin A in cisplatin (CDDP) treatment was revealed. The present study examined the potential of certain compounds derived from panduratin A to protect against CDDP-induced nephrotoxicity. METHODS: Three derivatives of panduratin A (DD-217, DD-218, and DD-219) were semi-synthesized from panduratin A. We investigated the effects and corresponding mechanisms of the derivatives of panduratin A for preventing nephrotoxicity of CDDP in both immortalized human renal proximal tubular cells (RPTEC/TERT1 cells) and mice. RESULTS: Treating the cell with 10 µM panduratin A significantly reduced the viability of RPTEC/TERT1 cells compared to control (panduratin A: 72% ± 4.85%). Interestingly, DD-217, DD-218, and DD-219 at the same concentration did not significantly affect cell viability (92% ± 8.44%, 90% ± 7.50%, and 87 ± 5.2%, respectively). Among those derivatives, DD-218 exhibited the most protective effect against CDDP-induced renal proximal tubular cell apoptosis (control: 57% ± 1.23%; DD-218: 19% ± 10.14%; DD-219: 33% ± 14.06%). The cytoprotective effect of DD-218 was mediated via decreases in CDDP-induced mitochondria dysfunction, intracellular reactive oxygen species (ROS) generation, activation of ERK1/2, and cleaved-caspase 3 and 7. In addition, DD-218 attenuated CDDP-induced nephrotoxicity by a decrease in renal injury and improved in renal dysfunction in C57BL/6 mice. Importantly, DD-218 did not attenuate the anti-cancer efficacy of CDDP in non-small-cell lung cancer cells or colon cancer cells. CONCLUSIONS: This finding suggests that DD-218, a derivative of panduratin A, holds promise as an adjuvant therapy in patients receiving CDDP.

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BACKGROUND: Cisplatin is an effective chemotherapy but its main side effect, acute kidney injury, limits its use. Panduratin A, a bioactive compound extracted from Boesenbergia rotunda, shows several biological activities such as anti-oxidative effects. The present study investigated the nephroprotective effect of panduratin A on cisplatin-induced renal injury. METHODS: We investigated the effect of panduratin A on the toxicity of cisplatin in both mice and human renal cell cultures using RPTEC/TERT1 cells. RESULTS: The results demonstrated that panduratin A ameliorates cisplatin-induced renal toxicity in both mice and RPTEC/TERT1 cells by reducing apoptosis. Mice treated with a single intraperitoneal (i.p.) injection of cisplatin (20 mg/kg body weight (BW)) exhibited renal tubule injury and impaired kidney function as shown by histological examination and increased serum creatinine. Co-administration of panduratin A (50 mg/kg BW) orally improved kidney function and ameliorated renal tubule injury of cisplatin by inhibiting activation of extracellular signal-regulated kinase (ERK)1/2 and caspase 3. In human renal proximal tubular cells, cisplatin induced cell apoptosis by activating pro-apoptotic proteins (ERK1/2 and caspase 3), and reducing the anti-apoptotic protein (Bcl-2). These effects were significantly ameliorated by co-treatment with panduratin A. Interestingly, panduratin A did not alter intracellular accumulation of cisplatin. It did not alter the anti-cancer efficacy of cisplatin in either human colon or non-small cell lung cancer cell lines. CONCLUSIONS: The present study highlights panduratin A has a potential protective effect on cisplatin's nephrotoxicity.

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Cisplatin is a widely used chemotherapy for solid tumors; however, its benefits are limited by serious nephrotoxicity, particularly in proximal tubular cells. The present study investigated the renoprotective effect and mechanisms of germacrone, a bioactive terpenoid compound found in Curcuma species on cisplatin-induced toxicity of renal cells. Germacrone (50 and 100 µM) attenuated apoptosis of human renal proximal tubular cells, RPTEC/TERT1 following treatment with 50 µM cisplatin and for 48 h. Co-treating RPTEC/TERT1 cells with cisplatin and germacrone significantly reduced cellular platinum content compared with cisplatin treatment alone. The effect of germacrone on organic cation transporter 2 (OCT2) which is a transporter responsible for cisplatin uptake was determined. Germacrone showed an inhibitory effect on OCT2-mediated methyl-4-phenylpyridinium acetate (3H-MPP+) uptake with IC50 of 15 µM with less effect on OCT1. The germacrone's protective effect on cisplatin-induced cytotoxicity was not observed in cancer cells; cisplatin's anti-cancer activity was preserved. In conclusion, germacrone prevents cisplatin-induced toxicity in renal proximal tubular cells via inhibition OCT2 transport function and reducing cisplatin accumulation. Thus germacrone may be a good candidate agent used for reducing cisplatin-induced nephrotoxicity.

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This research aimed to evaluate the effects of silymarin (SM)-loaded polymeric micelles (PMs) on the renal toxicity and anticancer activity of cisplatin. Amphiphilic chitosan derivatives were employed to develop SM-loaded PMs. The permeation across an intestinal membrane, cytotoxicity, and renal toxicity of cisplatin during the treatment were evaluated. The SM-loaded PMs had small particle sizes (326-336 nm), negative surface charge, high entrapment efficiency (47-70%), and demonstrated pH-sensitive release. Rapid drug release was obtained at pH 7.4 (81-87% in 4 h). The SM-loaded PMs exhibited higher flux than free SM. Moreover, the pretreatment of SM (50-100 µg/mL)-loaded PMs increased the killing efficacy of cisplatin on the cancer cells. The renoprotective effect was witnessed (p < 0.05) on the cells pretreated with SM-loaded benzyl-functionalized succinyl chitosan (BSC) PMs compared with those treated with only cisplatin, which the % cell viability increased from 29% to 82% and 96% for the PMs with SM concentration of 50 and 100 µg/mL, respectively. Moreover, the reduction in cell apoptosis and necrosis induced by cisplatin has been observed. In conclusion, SM-loaded BSC PMs could improve the bioavailability of SM, enhance the therapeutic effect, and protect renal damage during the treatment with cisplatin.

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Chemosensitization strategies have been used to sensitize cancer cells to conventional drugs, but their utility is often obstructed by additional off-target toxicity, limited access to intracellular targets and heterogeneous tumor pathogenesis. To address these challenges, we rationally developed a drug-free human serum albumin (HSA)-based therapeutic (KH-1) that functions extracellularly and exhibits pleiotropic effect on multiple intracellular signaling pathways. It is a two-step touch-trigger system that consists of a pretargeting anchor on surface receptor CD20 (anti-CD20 Fab' conjugated with a morpholino oligonucleotide 1) and a CD20 clustering actuator (HSA grafted with multiple copies of complementary morpholino oligonucleotide 2). The extracellular actuation by surface CD20 crosslinking boosts robust activations of numerous intracellular responses, and promotes cancer cell susceptibility to various anticancer drugs, including docetaxel (microtubule stabilizer), gemcitabine (nucleoside analogue) and GDC-0980 (PI3K/mTOR inhibitor). The broad applicability of KH-1 is demonstrated to result from simultaneous inhibition of survival pathways and augmentation of apoptotic pathways. In addition, KH-1 covalently conjugated with anthracycline anticancer agent, epirubicin, integrates the advantages of both chemosensitization function and improved intracellular drug delivery in a single system and takes effect on the same cell. Therefore, in the present study, we have provided mechanistic demonstration that crosslinking of surface receptors can be leveraged to elicit chemosensitization.

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Increasing evidences have shown that many pharmaceutical excipients are not pharmacologically inert but instead have effects on several transport function of uptake and efflux drug transporters. Herein, we investigated whether the excipients frequently used in many drug formulations affect transport function of organic cation transporters (OCTs) that are responsible for elimination of cationic drugs. Our finding revealed that solubilizing agents, Tweens, showed the most significant effect rbOCT1/2-mediated [3H]-MPP+ uptake in heterologous expressing cells. The haft inhibitory concentration (IC50) values of Tween 20, Tween 60, and Tween 80 for OCT1 were 85±1.12, 50±1.26, 106.00±1.20µg/ml, respectively, while the IC50 values for OCT2 were 295±1.48, 42±1.15, 185±1.20µg/ml, respectively. The inhibitory effect of Tween 20, Tween 60 and Tween 80 on OCT2-mediated [3H]-MPP+ uptake in the human renal proximal tubular cells (RPTEC/TERT1 cells) was found and the IC50 values was similar to heterologous OCT2 expressing cells. Interestingly, Tween 20, Tween 60 and Tween 80 exhibited less inhibitory effect on OCT1 functions in HepG2 cells expressing OCT1 compared with heterologous OCT1 expressing cells. In addition, clearance of [3H]-MPP+ was reduced in mice receiving Tween 20 compared with vehicle. The present study demonstrates that Tweens (solubilizing excipients) can inhibit the transport functions of OCT1 and OCT2, which play crucial roles for the pharmacokinetics, drug-drug interactions and tissue deposition of many cationic drugs.

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Cisplatin is widely used as a standard chemotherapy for solid tumors. The major adverse effect of cisplatin is nephrotoxicity in proximal tubular cells, via oxidative stress, DNA damage, cell apoptosis, and inflammation. The aim of this study was to investigate the pharmacological effect and mechanism of fibrate drugs on cisplatin-induced renal proximal tubular cell death. Cisplatin decreased cell viability of LLC-PK1 and HK-2 cells in a dose-dependent manner. Cisplatin-induced apoptosis was attenuated by co-treatment with fenofibrate while less so with clofibrate and bezafibrate. Fenofibrate's protective effect was not complimented by co-treatment with GW6471, a PPARα antagonist, indicating the protective effect occurred via a PPARα-independent mechanism. Treating cells with cisplatin induced reactive oxygen species (ROS), c-JUN N-terminal kinase (JNK), and p38 kinase (p38), but not extracellular signal-regulated kinase (ERK). Fenofibrate reversed cisplatin-induced JNK and p38 activation, but had no effect on ROS production. The findings suggest fenofibrate's protective effect on cisplatin-induced cytotoxicity is mediated by inhibition of JNK and p38. Moreover, fenofibrate did not alter cisplatin's antitumor effect on cancer cell lines including T84, SW-480, HepG2, and SK-LU-1 cells. Therefore, fenofibrate may be a candidate agent for further development as an adjuvant to cisplatin treatment.

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Liver X receptors (LXRs) including LXRα and LXRß are members of the nuclear receptor superfamily of ligand-activated transcription factors, which are expressed in high metabolic organs such as the liver, kidney, and adipose tissue. LXRs have been shown to act as antioxidants and anti-inflammatory in several organs. The present study investigated the effects of LXR activation on cadmium-induced cell death in renal proximal tubular cells. Treating human renal proximal tubular cells, HK-2 cells, with 20µM CdCl2 for 24h led to cell death via apoptosis but not necrosis. Interestingly, pretreating HK-2 cells with T0901317, a LXR agonist, significantly inhibited the apoptotic cell death induced by CdCl2. The protective effect of T0901317 was eliminated by incubation with fenofibrate, a LXR antagonist, indicating that the effect of T0901317 on cadmium-induced apoptotic cell death was mediated by LXR activation. In addition, the effect of CdCl2 was attenuated by a reactive oxygen species (ROS) scavenger, N-acetyl-l-cysteine (NAC). An increase in ROS induced by CdCl2 was mediated by inhibition of catalase but not superoxide dismutase (SOD) which was attenuated by T0901317. Western blot analysis revealed that CdCl2 stimulated expression of c-jun N-terminal kinase (JNK) phosphorylation and the stimulation were inhibited by NAC, indicating the induction of JNK phosphorylation was stimulated following ROS production. Moreover, the increases of ROS and JNK phosphorylation induced by CdCl2 were attenuated by LXR activation. This study provides the first evidence to show LXR activation reduces cadmium-induced apoptotic cell death of human renal proximal tubular cells by inhibition of ROS production and JNK activation.

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