Dauferulins A-L, daucane-type sesquiterpenes from the roots of Ferula communis: Their structures and biological activities.

Phytochemical study on the roots of a medicinal plant Ferula communis L. (Apiaceae) resulted in the isolation of 20 sesquiterpenes including 12 previously undescribed compounds, dauferulins A-L (1-12). The detailed spectroscopic analysis revealed 1-12 to be daucane-type sesquiterpenes with a p-methoxybenzoyloxy group at C-6. The absolute configurations of 1-12 were deduced by analysis of the ECD spectra. Dauferulins A-L (1-12), known sesquiterpenes (13-20), and analogues (14a-14l) derived from 6-O-p-methoxybenzoyl-10α-angeloyloxy-jeaschkeanadiol (14) were evaluated for their effects on AMPK phosphorylation in human hepatoma HepG2 cells as well as inhibitory activities against erastin-induced ferroptosis on human hepatoma Hep3B cells and IL-1ß production from LPS-treated murine microglial cells.

TJ-17 (Goreisan) mitigates renal fibrosis in a mouse model of folic acid-induced chronic kidney disease.

BACKGROUND AND PURPOSE: TJ-17 (Goreisan), a traditional Japanese Kampo medicine, has been generally used to treat edema, such as heart failure, due to its diuretic effect. In the present study, we investigate the effects of TJ-17 on chronic kidney disease (CKD). METHODS: We the preventive action of TJ-17 against acute kidney injury (AKI) transition to CKD in vivo using a folic acid (FA)-induced mouse model. Mice were treated with food containing TJ-17 at 48 h after FA intraperitoneal injection (AKI phase). RESULTS: Histological analysis, as well as renal function and renal injury markers, deteriorated in mice with FA-induced CKD and were ameliorated by TJ-17 treatment. Increased levels of inflammatory cytokines and macrophage infiltration were also alleviated in mice treated with TJ-17. Renal fibrosis, a crucial factor in CKD, was induced by FA administration and inhibited by TJ-17 treatment. Pretreatment with TJ-17 did not exert an inhibitory effect on FA-induced AKI. The increase in urinary volume in FA-induced CKD mice was ameliorated by TJ-17 treatment, with a concurrent correction of reduced aquaporins expression in the kidney. CONCLUSION: TJ-17 may have a novel preventive effect against inflammation, oxidative stress, and fibrosis, contributing to innovation in the treatment of CKD.

The novel preventive effect of a Japanese ethical Kampo extract formulation TJ-90 (Seihaito) against cisplatin-induced nephrotoxicity.

BACKGROUND AND PURPOSE: Chinese herbal medicine has been developed as the traditional Japanese Kampo medicine, and it has been widely used to cure various symptoms in clinical practice. However, only a few studies are currently available on the effect of the Kampo medicine on renal disease. Nephrotoxicity is one of major side effect of cisplatin, the first metal-based anticancer drug. In the present study, we examined the effect of the Kampo medicine against cisplatin-induced nephrotoxicity (CIN). METHODS: First, we screened the ethical Kampo extract formulation having positive effect against CIN using HK-2 cells. Next, we examined the preventive action of the selected ethical Kampo extract formulation against CIN in vivo using a mouse model. RESULTS: Cisplatin-induced cell death was significantly suppressed by TJ-43 (Rikkunshito) and TJ-90 (Seihaito); however, cisplatin-induced cleaved caspase-3 expression was inhibited only by TJ-90. In an in vivo mouse model of cisplatin-induced kidney injury with dysfunction and increased inflammatory cytokine expression, TJ-90 showed amelioration of these damaging effects. Cisplatin-induced apoptosis and superoxide production were inhibited by treatment with TJ-90. The expression of cleaved caspase-3, 4-hydroxynonenal, and MAPK phosphorylation increased after cisplatin administration, but decreased after the administration of TJ-90. Among 16 crude drug extracts present in Seihaito, Bamboo Culm (Chikujo in Japanese) inhibited cisplatin-induced cell death and cleaved caspase-3 expression in HK-2 cells. Moreover, the anti-tumor effect of cisplatin was not affected by TJ-90 co-treatment in cancer cell lines. CONCLUSION: TJ-90 might have a novel preventive action against CIN through the suppression of inflammation, apoptosis, and oxidative stress without interfering with the anti-tumor effect of cisplatin. Collectively, these findings might contribute to innovations in supportive care for cancer treatment-related side effects.

Administration of Kampo medicine through a tube at an advanced critical care center.

n emergency and critical care medical centers, tube administration is employed for patients who have difficulty swallowing oral drugs owing to decreased consciousness or mechanical ventilation. However, tube clogging due to drug injection is a concern. We compared the crushing method with the simple suspension method for the passage of amlodipine, an antihypertensive drug, in combination with rikkunshito, which has been used to treat upper gastrointestinal disorders such as functional dyspepsia and gastroesophageal reflux in emergency and critical care medical centers, to ascertain the effect of Kampo products on the passage of other drugs during tube administration. When the crushing method was employed, poorly water-soluble solid products were formed, while a uniformly dispersed suspension was obtained using the simple suspension method. In addition, the passage rate of amlodipine through the tube was 64% and 93% in the crushing and simple suspension methods, respectively, thereby indicating that the simple suspension method provided more favorable than the crushing method. The results of this study suggested that the passage rate of amlodipine for patients who received Kampo products concurrently was higher when the simple suspension method was used, and an appropriate drug amount might well be able to administered to patients using this method. J. Med. Invest. 65:32-36, February, 2018.

Potential Usefulness of Early Potassium Supplementation for Preventing Severe Hypokalemia Induced by Liposomal Amphotericin B in Hematologic Patients: A Retrospective Study.

PURPOSE: Liposomal amphotericin B (L-AMB) is an essential antifungal agent for patients with hematologic diseases; however, the drug causes severe hypokalemia at a high frequency. Meanwhile, there is little evidence regarding the risk factors for L-AMB-induced severe hypokalemia, and the prevention protocol has not been established. The goal of this study was to identify the risk factors related to severe hypokalemia induced by L-AMB in hematologic patients. METHODS: Seventy-eight hematologic patients with a first administration of L-AMB were enrolled in the study. Eleven patients who had serum potassium levels <3.0 mmol/L before L-AMB administration and 12 patients who received L-AMB administration within 3 days were excluded. Patients who had a serum potassium level <3.0 mmol/L during L-AMB administration were classified into a hypokalemia group (n = 26), and those who had a serum potassium level ≥3.0 mmol/L were classified into a non-hypokalemia group (n = 29). The patient characteristics were analyzed retrospectively. In addition, the usefulness of potassium supplementation was analyzed for those patients who received potassium formulations (non-hypokalemia group, n = 15; hypokalemia group, n = 24). FINDINGS: Twenty-six patients had hypolalemia after L-AMB administration. Hypokalemia with serum potassium levels <3.0 mmol/L was observed ~7 days after starting L-AMB administration. The patient characteristics, L-AMB dose, and L-AMB administration period did not differ between the 2 groups. In the patients who received potassium formulations, the period between starting L-AMB administration and starting potassium supplementation was significantly shorter in the non-hypokalemia group than in the hypokalemia group (median, 0 vs 4 days, respectively; P < 0.01); the potassium dose was not different between the 2 groups. A receiver-operating characteristic curve revealed that the cutoff time for the start of potassium supplementation to reduce the incidence of L-AMB-induced hypokalemia was 3 days. Multivariate logistic regression analysis revealed that beginning potassium supplementation within 2 days from the start of L-AMB administration was an independent factor reducing the risk of L-AMB-induced hypokalemia (odds ratio, 0.094 [95% CI, 0.019-0.47]). IMPLICATIONS: This study showed that starting administration of a potassium formulation within 2 days from the start of L-AMB administration was a risk reduction factor for L-AMB-induced hypokalemia. This finding indicates that early potassium supplementation should be incorporated into the regimen of hypokalemia management when L-AMB is used.

Nitrosonifedipine ameliorates the progression of type 2 diabetic nephropathy by exerting antioxidative effects.

Diabetic nephropathy (DN) is the major cause of end-stage renal failure. Oxidative stress is implicated in the pathogenesis of DN. Nitrosonifedipine (NO-NIF) is a weak calcium channel blocker that is converted from nifedipine under light exposure. Recently, we reported that NO-NIF has potential as a novel antioxidant with radical scavenging abilities and has the capacity to treat vascular dysfunction by exerting an endothelial protective effect. In the present study, we extended these findings by evaluating the efficacy of NO-NIF against DN and by clarifying the mechanisms of its antioxidative effect. In a model of type 2 DN (established in KKAy mice), NO-NIF administration reduced albuminuria and proteinuria as well as glomerular expansion without affecting glucose metabolism or systolic blood pressure. NO-NIF also suppressed renal and systemic oxidative stress and decreased the expression of intercellular adhesion molecule (ICAM)-1, a marker of endothelial cell injury, in the glomeruli of the KKAy mice. Similarly, NO-NIF reduced albuminuria, oxidative stress, and ICAM-1 expression in endothelial nitric oxide synthase (eNOS) knockout mice. Moreover, NO-NIF suppressed urinary angiotensinogen (AGT) excretion and intrarenal AGT protein expression in proximal tubular cells in the KKAy mice. On the other hand, hyperglycemia-induced mitochondrial superoxide production was not attenuated by NO-NIF in cultured endothelial cells. These findings suggest that NO-NIF prevents the progression of type 2 DN associated with endothelial dysfunction through selective antioxidative effects.