Recent studies have suggested that statins may play a role in the protection against renal failure which is independent of cholesterol reduction. Activation of RhoGTPases is a key step in renal ...tubular cells' epithelial-to-mesenchymal transition (EMT) which contributes to renal interstitial fibrosis. We hypothesized that statins could act by inhibiting the synthesis of the isoprenoids, such as geranylgeranyl pyrophosphate, which is essential for membrane attachment and biological activity of RhoGTPases, RhoA and Rac1.
Human proximal tubular epithelial cells (HK2) were used to examine the inhibitory effect of statins on EMT induced with medium conditioned by activated peripheral blood mononuclear cells.
Our study demonstrates that the statins lovastatin, simvastatin, and pravastatin inhibit HK2 cells to undergo EMT. Inhibition of EMT in HK2 cells with these statins resulted in a reduction of RhoA and Rac1 activation in both the cytoplasmic and membrane-bound forms, in preservation of the expression of the epithelial cell markers E-cadherin and cytokeratin-19, and in a decrease in Fn-EDA expression, a marker for the myofibroblast phenotype. The decreased levels of activated RhoA and Rac1 in both the cytoplasmic and membrane fractions of the cells were reversed by geranylgeranyl pyrophosphate and mevalonate, and thus attributable to the inhibition of isoprenylation of RhoGTPases by statins.
This phenomenon could explain the beneficial effect of statins on EMT and on renal fibrosis prevention.
Background
More and more preclinical studies support the idea that curcumin, a plant-derived natural polyphenol, could be a promising anticancer drug. However, poor bioavailability has limited its ...efficacy in clinical trials, and plasma curcumin levels remain low despite patients taking gram doses of curcumin.
Methods
This study aimed to evaluate the safety and pharmacokinetics of newly developed nanoparticle curcumin with increased water solubility (named THERACURMIN). Six healthy human volunteers were recruited and received THERACURMIN at a single oral dose of 150 mg. After an interval of 2 weeks, the same subjects then received THERACURMIN at a single dose of 210 mg. Plasma curcumin levels were measured at 0, 1, 2, 4, 6, and 24 h after THERACURMIN intake using high-performance liquid chromatography (HPLC).
Results
One subject reported grade 1 diarrhea after intake of 150 mg THERACURMIN. No other toxicities were observed in this study.
C
max
for THERACURMIN at 150 and 210 mg was 189 ± 48 and 275 ± 67 ng/ml (mean ± SEM), respectively, and the area under the curve for 24 h was estimated to be 2,649 ± 350 and 3,649 ± 430 ng/ml × h (mean ± SEM), respectively. The
t
1/2
was estimated to be 9.7 ± 2.1 h for 150 mg and 13.0 ± 3.3 h for 210 mg.
Conclusion
THERACURMIN can safely increase plasma curcumin levels in a dose-dependent manner at least up to 210 mg without saturating the absorption system. To the best of our knowledge, THERACURMIN is the first nanoparticle formulation of curcumin that demonstrates improved bioavailability in human subjects. We believe this compound could be a promising tool when testing the potential anticancer effects of curcumin in clinical trials.
Purpose
Curcumin, a plant-derived natural polyphenol, could be a promising anti-cancer drug and shows synergic effects with cytotoxic agents. We evaluated the safety and feasibility of combination ...therapy using curcumin with gemcitabine-based chemotherapy.
Methods
Gemcitabine-resistant patients with pancreatic cancer received 8 g oral curcumin daily in combination with gemcitabine-based chemotherapy. The primary endpoint was safety for phase I and feasibility of oral curcumin for phase II study.
Results
Twenty-one patients were enrolled. No dose-limiting toxicities were observed in the phase I study and oral curcumin 8 g/day was selected as the recommended dose for the phase II study. No patients were withdrawn from this study because of the intolerability of curcumin, which met the primary endpoint of the phase II study, and the median compliance rate of oral curcumin was 100% (Range 79–100%). Median survival time after initiation of curcumin was 161 days (95% confidence interval 109–223 days) and 1-year survival rate was 19% (4.4–41.4%). Plasma curcumin levels ranged from 29 to 412 ng/ml in five patients tested.
Conclusions
Combination therapy using 8 g oral curcumin daily with gemcitabine-based chemotherapy was safe and feasible in patients with pancreatic cancer and warrants further investigation into its efficacy.
•We examined the effects of curcumin on oxidative stress after downhill running.•Curcumin suppressed downhill running-induced hydrogen peroxide production in muscle.•Downhill running-induced ...macrophage migration in muscle was suppressed by curcumin.•Curcumin may be beneficial for the prevention of oxidative stress in muscle damage.
Downhill running causes muscle damage, and induces oxidative stress and inflammatory reaction. Recently, it is shown that curcumin possesses anti-oxidant and anti-inflammatory potentials. Interestingly, curcumin reduces inflammatory cytokine concentrations in skeletal muscle after downhill running of mice. However, it is not known whether curcumin affects oxidative stress after downhill running-induced muscle damage. Therefore, the purpose of this study was to investigate the effects of curcumin on oxidative stress following downhill running induced-muscle damage. We also investigated whether curcumin affects macrophage infiltration via chemokines such as MCP-1 and CXCL14. Male C57BL/6 mice were divided into four groups; rest, rest plus curcumin, downhill running, or downhill running plus curcumin. Downhill running mice ran at 22m/min, −15% grade on the treadmill for 150min. Curcumin (3mg) was administered in oral administration immediately after downhill running. Hydrogen peroxide concentration and NADPH-oxidase mRNA expression in the downhill running mice were significantly higher than those in the rest mice, but these variables were significantly attenuated by curcumin administration in downhill running mice. In addition, mRNA expression levels of MCP-1, CXCL14 and F4/80 reflecting presence of macrophages in the downhill running mice were significantly higher than those in the rest mice. However, MCP-1 and F4/80 mRNA expression levels were significantly attenuated by curcumin administration in downhill running mice. Curcumin may attenuate oxidative stress following downhill running-induced muscle damage.
Scope
The induction of brown‐like adipocytes in white adipose tissue (WAT) is a potential therapeutic target for the treatment of obesity and metabolic disorders via the ability of these cells to ...release excess energy as heat in association with uncoupling protein 1. Some experimental trials suggest that curcumin (a yellow pigment from turmeric) has a suppressive effect on the accumulation of body fat. However, there is little evidence to show that curcumin induces the formation of brown‐like adipocytes and the molecular mechanisms involved remain elusive. In addition, in most experimental trials, high doses of curcumin are administered.
Methods and results
Highly dispersible and bioavailable curcumin (HC, i.e., 4.5 mg native curcumin kg–1) but not the same dose of native curcumin induces the formation of brown‐like adipocytes in mouse inguinal WAT. Moreover, the formation of brown‐like adipocytes induced by HC in inguinal WAT may be mediated by the production of local norepinephrine from accumulated alternatively activated macrophages.
Conclusion
These novel findings suggest that curcumin increases energy expenditure by inducing the formation of brown‐like adipocytes via a unique molecular mechanism. Importantly, they show that HC has significant bioactive effects in vivo at lower doses of curcumin.
The induction of brown‐like adipocytes in white adipose tissue (WAT) is a potential therapeutic target for the treatment of obesity and metabolic disorders. In the present study, it is demonstrated that highly dispersible and bioavailable curcumin but not the same dose of native curcumin induces the formation of brown‐like adipocytes in mouse inguinal WAT. Moreover, this effect may be mediated by the production of local norepinephrine following the accumulation of alternatively activated macrophages in iWAT.
Background
Human T‐cell leukemia virus type 1 (HTLV‐1) causes adult T‐cell leukemia (ATL). Viral Tax protein plays a major role in ATL development. Pim family of serine/threonine kinases is composed ...of Pim‐1, ‐2, and ‐3. The potential of Pim family as a target in ATL was analyzed.
Methods
RT‐PCR and Western blotting were used to determine the expression of Pim kinases, Tax, and intracellular signal molecules. Knockdown of Pim‐3 and RelA was performed using small interfering RNA. The effects on cell proliferation, viability, cell cycle, and apoptosis were analyzed by WST‐8, propidium iodide, and APO2.7 assay. NF‐κB DNA binding activity was investigated by electrophoretic mobility shift assay.
Results
Pim‐3 expression was restricted to HTLV‐1–infected T‐cell lines. Tax induced Pim‐3 expression through NF‐κB. Knockdown of Pim‐3 showed growth inhibition of HTLV‐1–infected T cells. NJC97‐NH, a novel inhibitor of the Pim‐1/3 kinases, inhibited cell viability. NJC97‐NH induced G2/M cell cycle arrest associated with downregulation of cyclin A and cyclin B1 expression, as well as apoptosis accompanied with downregulation of XIAP and Mcl‐1 expression through inhibition of NF‐κB pathway, mediated through decrease in IκBα and RelA phosphorylation.
Conclusion
Pim‐3 is a potentially suitable target for the development of novel therapeutic agents against ATL.
The dorsalis pedis tendocutaneous (DPTC) free flap is an ideal option for the reconstruction of the combined defect of the dorsal hand skin and multiple extensor tendons, whereas it possess not only ...soft tissue problems, but also symptomatic drop toe deformity in the donor site. We have corrected this drop toe deformity with a tendon transfer technique, using the extensor hallucis brevis muscle, which was preserved during the DPTC free flap harvest. The donor site exposing the transferred tendons was covered with another thin free flap. Two cases that underwent this technique exhibited satisfactory alignment and active extension of the toes. This tendon transfer technique combined with free flap coverage overcomes almost all the problems in the donor site of the DPTC free flap, achieving excellent contours of both the dorsal hand and the foot.
Background Conventional methods of external bleeding for congested fingertip replants exhibit notable problems, including uncontrollable bleeding and unpredictable survival of the replant. We have ...added a local injection of heparin calcium to the routine use of systemic heparinization for inducing external bleeding. We retrospectively examined patients who underwent external bleeding using our method. Methods Local subcutaneous injections of heparin calcium were made in 15 congested replants in addition to systemic heparinization. Each injection ranged from 500 to 5,000 U. The average duration of the injections was 4.1 days. Surgical outcomes were analyzed and compared with a control group of patients who underwent external bleeding without heparin calcium. Results The overall survival rate was 93.3%, which was higher than that of the control group (83.3%), but the difference was not statistically significant (P=0.569). The survival rate for subzones I and II by the Ishikawa subzone classification was 100%, whereas it was 87.5% in subzones III and IV. No statistically significant difference was observed. The rate of partial necrosis was 0% in subzones I and II, whereas it was significantly higher (66.7%) in subzones III and IV (P=0.015). The mean total blood loss via external bleeding was 588 g in 10 fingers. No patients required blood transfusion. Conclusions Congestion of a replanted fingertip can be successfully managed without blood transfusion by our method. Although complete relief from congestion in replants in subzones I and II is achievable, there is a higher risk of partial necrosis in subzones III and IV.
Curcumin (aglycone curcumin) has antitumor properties in a variety of malignancies via the alteration of multiple cancer-related biological pathways; however, its clinical application has been ...hampered due to its poor bioavailability. To overcome this limitation, we have developed a synthesized curcumin β-D-glucuronide sodium salt (TBP1901), a prodrug form of aglycone curcumin. In this study, we aimed to clarify the pharmacologic characteristics of TBP1901. In β-glucuronidase (GUSB)-proficient mice, both curcumin β-D-glucuronide and its active metabolite, aglycone curcumin, were detected in the blood after TBP1901 injection, whereas only curcumin β-D-glucuronide was detected in GUSB-impaired mice, suggesting that GUSB plays a pivotal role in the conversion of TBP1901 into aglycone curcumin in vivo. TBP1901 itself had minimal antitumor effects in vitro, whereas it demonstrated significant antitumor effects in vivo. Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screen disclosed the genes associated with NF-κB signaling pathway and mitochondria were among the highest hit. In vitro, aglycone curcumin inhibited NF-kappa B signaling pathways whereas it caused production of reactive oxygen species (ROS). ROS scavenger, N-acetyl-L-cysteine, partially reversed antitumor effects of aglycone curcumin. In summary, TBP1901 can exert antitumor effects as a prodrug of aglycone curcumin through GUSB-dependent activation.
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