Kaempferide ameliorates cisplatin-induced nephrotoxicity via inhibiting oxidative stress and inducing autophagy.

Acute kidney injury (AKI) caused by anti-tumor drugs, such as cisplatin, is a severe complication with no effective treatment currently, leading to the reduction or discontinuation of chemotherapy. Natural products or herbal medicines are gradually considered as promising agents against cisplatin-induced AKI with the advantages of multi-targeting, multi-effects, and less resistance. In this study, we investigated the effects of kaempferide, a natural flavonoid extracted from the rhizome of Kaempferia galanga, in experimental AKI models in vitro and in vivo. We first conducted pharmacokinetic study in mice and found a relative stable state of kaempferide with a small amount of conversion into kaempferol. We showed that both kaempferide (10 µM) and kaempferol (10 µM) significantly inhibited cisplatin-caused injuries in immortalized proximal tubule epithelial cell line HK-2. In AKI mice induced by injection of a single dose of cisplatin (15 mg/kg), oral administration of kaempferide (50 mg/kg) either before or after cisplatin injection markedly improved renal function, and ameliorated renal tissue damage. We demonstrated that kaempferide inhibited oxidative stress and induced autophagy in cisplatin-treated mice and HK-2 cells, thus increasing tubular cell viability and decreasing immune responses to attenuate the disease progression. In addition, treatment with kaempferide significantly ameliorated ischemia-reperfusion-induced renal injury in vitro and in vivo. We conclude that kaempferide is a promising natural product for treating various AKI. This study has great implications for promotion of its use in healthcare products, and help to break through the limited use of cisplatin in the clinic.

Sapidolide A alleviates acetaminophen-induced acute liver injury by inhibiting NLRP3 inflammasome activation in macrophages.

Macrophages play a critical role in the pathogenesis of acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure or even death. Sapidolide A (SA) is a sesquiterpene lactone extracted from Baccaurea ramiflora Lour., a folk medicine used in China to treat inflammatory diseases. In this study, we investigated whether SA exerted protective effects on macrophages, thus alleviated the secondary hepatocyte damage in an AILI. We showed that SA (5-20 µM) suppressed the phosphorylated activation of NF-κB in a dose-dependent manner, thereby inhibiting the expression and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptosis in LPS/ATP-treated mouse bone marrow-derived primary macrophages (BMDMs). In human hepatic cell line L02 co-cultured with BMDMs, SA (10 µM) protected macrophages from the pyroptosis induced by APAP-damaged L02 cells. Moreover, SA treatment reduced the secondary liver cell damage aggravated by the conditioned medium (CM) taken from LPS/ATP-treated macrophages. The in vivo assessments conducted on mice pretreated with SA (25, 50 mg/kg, ip) then with a single dose of APAP (400 mg/kg, ip) showed that SA significantly alleviated inflammatory responses of AILI by inhibiting the expression and activation of the NLRP3 inflammasome. In general, the results reported herein revealed that SA exerts anti-inflammatory effects by regulating NLRP3 inflammasome activation in macrophages, which suggests that SA has great a potential for use in the treatment of AILI patients.

Natural products: potential treatments for cisplatin-induced nephrotoxicity.

Cisplatin is a clinically advanced and highly effective anticancer drug used in the treatment of a wide variety of malignancies, such as head and neck, lung, testis, ovary, breast cancer, etc. However, it has only a limited use in clinical practice due to its severe adverse effects, particularly nephrotoxicity; 20%-35% of patients develop acute kidney injury (AKI) after cisplatin administration. The nephrotoxic effect of cisplatin is cumulative and dose dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI result in impaired renal tubular function and acute renal failure, chronic kidney disease, uremia, and hypertensive nephropathy. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, apoptosis, oxidative stress, inflammation, and vascular injury in the kidneys. At present, there are no effective drugs or methods for cisplatin-induced kidney injury. Recent in vitro and in vivo studies show that numerous natural products (flavonoids, saponins, alkaloids, polysaccharide, phenylpropanoids, etc.) have specific antioxidant, anti-inflammatory, and anti-apoptotic properties that regulate the pathways associated with cisplatin-induced kidney damage. In this review we describe the molecular mechanisms of cisplatin-induced nephrotoxicity and summarize recent findings in the field of natural products that undermine these mechanisms to protect against cisplatin-induced kidney damage and provide potential strategies for AKI treatment.

Novel Hsp90 inhibitor platycodin D disrupts Hsp90/Cdc37 complex and enhances the anticancer effect of mTOR inhibitor.

Heat shock protein 90 (Hsp90) is a critically conserved molecular chaperone protein and promising therapeutic target for cancer treatment. In this study, platycodin D (PD), a saponin isolated from traditional Chinese herb Platycodonis Radix, was identified as a novel Hsp90 inhibitor. We verified that PD did not affect the ATPase activity of Hsp90. However, PD disrupted the co-chaperone interaction of Hsp90/cell division cycle protein 37 (Cdc37) and subsequently degraded multiple Hsp90 client proteins without the feedback increase of Hsp70. In different genotypes of non-small cell lung cancer cells, co-treatment with the mTOR inhibitor Everolimus and PD enhanced antiproliferation activity and apoptotic effect. The feedback survival signal upon mTOR inhibition was fully terminated by the co-administration with PD through reduced epidermal growth factor receptor (EGFR) and insulin growth factor 1 receptor (IGF1R) expression, suppressed AKT activity, and reinforced 4E-BP1 inhibition. Our results not only identified PD as a novel Hsp90 inhibitor by disrupting the protein-protein interaction of Hsp90/Cdc37 complex, but also provided mechanistic insights into the ineffectiveness of mTOR inhibitors and identified therapeutic strategy for cancer treatment.

Synergistic anti-cancer activity by the combination of TRAIL/APO-2L and celastrol.

The present study demonstrates that the combination of TRAIL/APO-2L and celastrol exerts strong synergistic antiproliferative effect against human cancer cells including ovary cancer OVCAR-8, colon cancer SW620, and lung cancer 95-D, with the combination indices below 0.8. Moreover, the in vivo antitumor efficacy of TRAIL/APO-2L was dramatically increased by celastrol. These enhanced anticancer activities were accompanied by the prompt onset of caspase-mediated apoptosis. Taken together, our data firstly demonstrate the synergistic anticancer capabilities achieved by combining TRAIL/APO-2L and celastrol, and moreover, open new opportunities to enhance the effectiveness of future treatment regimens using TRAIL/APO-2L.

[Q39 induces apoptosis in human leukemia cell line K562 in hypoxia].

OBJECTIVE: To determine whether a novel compound, 3-(4-bromophenyl)-2-(ethyl sulfonyl)-6-methylquinoxaline 1, 4-dioxide (Q39), induces apoptosis in human leukemia cell line k562 in hypoxic environment. METHODS: MTT assay was used to determine the 50% inhibitory concentrations (IC50). Flow cytometry and DAPI staining were employed to determine the apoptosis; JC-1 staining was used to determine mitochondria membrane potential (DeltaPsim); Western-blotting was used to determine protein expression of procaspase-3, cleaved caspase-3, PARP, Bax, Bcl-2 and HIF-1alpha. RESULTS: In hypoxic environment, Q39 exerted higher antiproliferative activity in K562 cells, and the IC50 value was (0.21+/- 0.05) micromol/L. The apoptotic phenomenon was observed at 6 h after cells exposed to Q39, and apoptotic body emerged as exposure time increased. After K562 cells were incubated with Q39 for 0, 6, 12 and 24 h, the ratio of apoptotic cells was 2.8%, 3.2%, 5.9% and 19.2%, respectively. By fluorescence stain assay, an significant Delta Psim loss in K562 cells induced by Q39 was shown in a time-dependent manner. Western blot assay demonstrated that Q39 decreased the protein expression of Bcl-2, procaspase-3, and HIF-1alpha, meanwhile increased protein expression of Bax and cleaved caspase-3, and induced the cleavage of PARP. CONCLUSIONS: The novel compound Q39 exhibits great anticancer activity against K562 cells in hypoxic environment. Q39 can downregulate the protein expression of HIF-1alpha, and regulate the apoptosis-related protein expression to cause a drop of DeltaPsim, suggesting that mitochondria and HIF-1alpha pathway might be involved in the antiproliferative effect of Q39.