Pharmacologic characterization of TBP1901, a prodrug form of aglycone curcumin, and CRISPR-Cas9 screen for therapeutic targets of aglycone curcumin.

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 ß-D-glucuronide sodium salt (TBP1901), a prodrug form of aglycone curcumin. In this study, we aimed to clarify the pharmacologic characteristics of TBP1901. In ß-glucuronidase (GUSB)-proficient mice, both curcumin ß-D-glucuronide and its active metabolite, aglycone curcumin, were detected in the blood after TBP1901 injection, whereas only curcumin ß-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.

Study protocol to determine the effects of highly absorbable oral curcumin on the indicators of cognitive functioning: a double-blind randomised controlled trial.

INTRODUCTION: Mild cognitive impairment (MCI) refers to a state in which cognitive functions, such as memory, have diminished but daily activities are largely unhampered. MCI is often overlooked but carries the risk of leading to development of dementia later. Curcumin is the main component of the natural herbal medicine turmeric. Curcumin is widely used as a health food and is an antioxidant that has anti-inflammatory and anti-amyloid actions. The current trial was designed to determine the effects of curcumin on indicators of cognitive functioning. METHODS AND ANALYSIS: The current trial will be a single-centre randomised placebo-controlled double-blind parallel group trial. The participants will be 60 members of the general public with potential MCI, based on dementia screening using the Japanese version of the Mini Mental State Examination (MMSE-J). The investigational health food used in this trial will be a recently developed preparation for highly absorbable oral curcumin. This trial will determine the effects of the highly absorbable oral curcumin (brand name: curcuRouge) on the indicators of cognitive functioning, including the scores obtained with the MMSE-J, which is an interview-based measure of cognitive functioning, and the blood biomarkers that have been reported to be associated with dementia. ETHICS AND DISSEMINATION: Informed written consent will be obtained from all the participants. The Ethical Review Board of the National Hospital Organization Kyoto Medical Center approved the study protocol. TRIAL REGISTRATION NUMBER: University Hospital Medical Information Network (UMIN000042471).

A Novel Method of Intra-Abdominal Cavity Obliteration: A Case Report of a Colonic Seromuscular Flap.

Obliteration of an organized subphrenic abscess with an enteric fistula is a great challenge, especially after hepatectomy, as most of the conventional flaps used to fill the abscess cavity are not feasible. A seromuscular flap is an innovative option for this purpose because of its proximity to the pathology, flexibility in the size and volume of the flap harvested, antibacterial ability of the muscle flap, and preservation of trunk musculature. We illustrate the use of a colonic seromuscular flap for filling such an abscess and show its long-term change. A 66-year-old man developed a right subphrenic abscess after subsegmentectomy for his hepatocellular carcinoma. Prolonged percutaneous drainage of the abscess was unsuccessful because of the enteric communication with the transverse colon and resulted only in the organization of the abscess cavity. Through the previous laparotomy incision, the involved part of the transverse colon was detached from the abscess. The transverse colon including the fistula was isolated for 16 cm based on the middle colic vessels. Following an enterotomy along the antimesenteric border and mucosal stripping, a colonic seromuscular flap was made. The debrided abscess cavity was properly filled with this flap. The donor colon was repaired. The postoperative course was uneventful without showing any signs of infection for more than 3 years. During this period, the volume of the flap filling the cavity showed significant reduction of 50%. The seromuscular colonic flap is an effective option for filling the intra-abdominal abscess cavity when most of the conventional flaps are not feasible.

One-stage reconstruction of the complex defects of the Achilles tendon and the adjoining calcaneus using the chimeric superolateral thigh flap: A case report.

Reconstruction of the composite defects of the Achilles tendon and the overlying skin is a great challenge. Should the tendon insertion and adjoining calcaneal defects coexist, such reconstruction becomes far more complicated. A chimeric superolateral thigh flap based on the ascending branch of the lateral circumflex femoral artery provides all the components for this complex defect. We aim to illustrate a case underwent one-stage reconstruction of such defects with this chimeric flap. A 55-year-old man presented with composite defects of Achilles tendon (11 cm), adjoining calcaneus (2 × 2 × 3 cm), and the overlying skin (15 × 3.5 cm) due to unsuccessful repair for his right chronic Achilles tendon rupture, which was complicated by infection. This complex defect was reconstructed using a chimeric superolateral thigh flap consisting of the superolateral thigh skin (8.5 × 17.5 cm), full-thickness iliac bone (4 × 3 cm), and the intervening iliotibial tract preserving the fascia-bone junction, which substituted for the lost insertion of the Achilles tendon. Bone union and full weight bearing were achieved by 11 and 24 weeks, respectively, after surgery. Two debulking procedures were performed. Isometric plantar flexion muscle strength was comparable to the healthy side, but isotonic strength was somewhat reduced at 18 months after reconstruction. This chimeric flap provided all the possible components necessary for the complex Achilles tendon defect, and led functional outcomes.

Newly Developed Highly Bioavailable Curcumin Formulation, curcuRougeTM, Reduces Neutrophil/Lymphocyte Ratio in the Elderly: A Double-Blind, Placebo-Controlled Clinical Trial.

Elevated neutrophil/lymphocyte ratio (NLR) has been reported as a sensitive marker for predicting poor prognosis in chronic inflammation-based diseases such as stroke, heart failure, cancers, and diabetes, as well as acute inflammatory diseases such as bacterial and viral infections, including COVID-19. NLR is also known to increase with age and is considered to be an aging marker. We conducted a double-blind, placebo-controlled trial in elderly volunteers to examine the effect of a newly developed, highly bioavailable curcumin formulation (curcuRougeTM) on NLR. Both the white blood cell count and the neutrophil rate decreased significantly, and the lymphocyte rate increased significantly from baseline to after curcuRougeTM administration for 4 wk. curcuRougeTM significantly reduced the NLR (p=0.020). On the other hand, in the placebo group, there were no changes in white blood cell count, neutrophil ratio, lymphocyte ratio, or NLR. The present study demonstrates for the first time, in elderly volunteers, that administration of curcuRougeTM significantly reduces NLR, an indicator of prognosis in cardiovascular diseases, cancer, infectious diseases, and aging. Thus, curcuRougeTM might be expected to improve the prognosis of these diseases as well as exhibit anti-aging effects.

Intra-Articular Injections of Curcumin Monoglucuronide TBP1901 Suppresses Articular Cartilage Damage and Regulates Subchondral Bone Alteration in an Osteoarthritis Rat Model.

OBJECTIVE: Curcumin monoglucuronide (TBP1901) is highly water soluble and can convert to free form curcumin, which has pharmacological effects, on intravenous administration. This study aimed to investigate the effectiveness of TBP1901 intra-articular injections in an osteoarthritis (OA) rat model. METHODS: Sixty-four male Wistar rats (12 weeks old) who underwent destabilized medial meniscus (DMM) surgery were randomly separated into the TBP1901 injection or saline solution (control) injection group. They were sacrificed at 1, 2, 6, or 10 weeks postoperatively (weeks 1, 2, 6, and 10; n = 8 for each group). TBP1901 (30 mg/mL) or saline solution of 50 µL was injected into the knee joints twice a week during weeks 1 and 2 to investigate the effects in the acute phase of posttraumatic (PT) OA or once a week during weeks 6 and 10 to investigate it in the chronic phase of PTOA. Histology, immunohistochemistry, and micro-computed tomography were performed to evaluate the changes in OA. RESULTS: TBP1901 injections significantly reduced synovial inflammation at weeks 1 and 2, and tumor necrosis factor-α expression in the articular cartilage at week 6. The TBP1901 injections also significantly suppressed articular cartilage damage, subchondral bone (SB) plate thickening, SB plate perforation, and osteophyte formation at week 10. CONCLUSIONS: TBP1901 intra-articular injections suppressed synovial inflammation in the acute phase of PTOA in DMM rats. In the chronic phase, TBP1901 suppresses articular cartilage damage and regulates SB plate changes.

Perforator Branch Flaps.

BACKGROUND: Modern microsurgical reconstruction aims to achieve functional and satisfactory esthetic outcome and the primary thinning procedure results in one-stage reconstruction. However, current techniques are lacking preoperative knowledge of the peripheral perforator in the adipose layer. We hypothesized that the combination of the knowledge of microvasculature and visualization of such small vessels in the adipose layer by Color Doppler ultrasonography (CDU) will make the dissection of these vessels with simultaneous flap thinning of the perforator branch flap technique feasible and provide consistent results in variety of flaps. METHODS: Retrospective chart review of consecutive cases in which perforator branch flap technique was used from 2011 to 2019 was conducted. Entire course of branch of the perforator in the adipose layer were traced up to the dermis by CDU, and marked on the skin surface. Based on CDU finding, perforator branches were dissected in the adipose layer simultaneously with the primary thinning of the skin flap. RESULTS: Thirty perforator branch flaps in 28 cases were elevated. Courses of the perforator branches detected by CDU accurately corresponded to surgical findings in all cases. There was no total flap loss in any of the cases and partial necrosis in one case. In five flaps, a secondary debulking procedure was needed. CONCLUSIONS: The combination of knowledge of microvasculature with CDU guidance has made the perforator branch technique possible and allowed to safely transfer the skin flap from various body areas to the defect, thereby, achieving "like with like" reconstruction in one-stage.

Curcumin ß-D-glucuronide exhibits anti-tumor effects on oxaliplatin-resistant colon cancer with less toxicity in vivo.

The NF-kappa B (NF-κB) pathway plays a pivotal role in tumor progression and chemoresistance, and its inhibition has been shown to suppress tumor growth in a variety of preclinical models. Recently, we succeeded in synthesizing a water-soluble injectable type of curcumin ß-D-glucuronide (CMG), which is converted into a free-form of curcumin by ß-glucuronidase in vivo. Herein, we aimed to clarify the efficacy, safety and pharmacokinetics of CMG in a xenograft mouse model. First, we confirmed that the presence of KRAS/TP53 mutations significantly increased the IC50 of oxaliplatin (L-OHP) and NF-κB activity in HCT116 cells in vitro. Then, we tested the efficacy of CMG in an HCT116 colon cancer xenograft mice model. CMG demonstrated superior anticancer effects compared to L-OHP in an L-OHP-resistant xenograft model. With regard to safety, significant bodyweight loss, severe myelosuppression and AST/ALT elevation were observed in L-OHP-treated mice, whereas none of these toxicity was noted in CMG-treated mice. The combination of CMG and L-OHP exhibited additive effects in these xenograft models without increasing toxicity. Pharmacokinetic analysis revealed that high levels of free-form curcumin were maintained in the tumor tissue after 48 hours following CMG administration, but it was not detected in other major organs, such as the heart, liver and spleen. Immunohistochemistry revealed reduced NF-κB activity in the tumor tissue extracted from CMG-treated mice compared with that from control mice. These results indicated that CMG could be a promising anticancer prodrug for treating colon cancer with minimal toxicity.

Successful local use of heparin calcium for congested fingertip replants.

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.

Highly Dispersible and Bioavailable Curcumin but not Native Curcumin Induces Brown-Like Adipocyte Formation in Mice.

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.

Duplex Ultrasonography-Assisted Freestyle Pedicled Perforator Flaps for the Repair of Myelomeningocele Defects.

BACKGROUND: Perforator flaps have unique advantages that may overcome the shortcomings of conventional approaches to myelomeningocele reconstruction. However, identifying and dissecting tiny perforators in neonates is arduous. We have overcome these obstacles with a freestyle flap approach that uses duplex ultrasonography to locate perforator vessels, allowing for limited superficial dissection. This report describes the duplex ultrasonography-assisted freestyle pedicled perforator flap technique for closure of myelomeningocele defects, with long-term clinical outcomes. METHODS: The surgical technique is described in detail. Case records of surgeries between 2004 and 2017 were retrospectively reviewed, focusing on whether potential perforators for flap pedicle were identified by duplex ultrasonography and subsequently used. RESULTS: Among 18 neonates who underwent repair of thoraco-lumbo-sacral myelomeningocele, 8 had reconstruction of soft tissue defects with freestyle pedicled perforator flaps. Defect size ranged from 1.6 × 2.2 cm to 6.0 × 7.0 cm. Potential flap pedicle perforators were identified by intraoperative ultrasonography and used as the vascular supply of the flap. All perforator flaps survived intact. Complications were transient and uncommon. Over a median follow-up of 1.65 years (range, 0.3-12.8 years), there was 1 transient pressure sore due to severe kyphosis with some tenderness along the flap suture line. All other reconstructions were durable and well-padded without late sequelae. Cases with a corrected age of more than 12 months could walk, stand, and crawl without muscular dysfunction due to flap surgery. CONCLUSIONS: Freestyle pedicled perforator flaps combined with duplex ultrasonography delineates perforator anatomy and obviates the need for tiny perforator dissection during myelomeningocele reconstruction, achieving reliable closure with excellent long-term results.

Curcumin ß-D-Glucuronide Plays an Important Role to Keep High Levels of Free-Form Curcumin in the Blood.

Curcumin, a polyphenol derived from the rhizome of the naturally occurring plant Curcuma longa, has various pharmacological actions such as antioxidant and anti-inflammatory effects. In this paper, we evaluated the role of its internal metabolite, curcumin ß-D-glucuronide (curcumin monoglucuronide, CMG), by investigating curcumin kinetics and metabolism in the blood. Firstly, we orally administered highly bioavailable curcumin to rats to elucidate its kinetics, and observed not only the free-form of curcumin, but also, curcumin in a conjugated form, within the portal vein. We confirmed that curcumin is conjugated when it passes through the intestinal wall. CMG, one of the metabolites, was then orally administered to rats. Despite its high aqueous solubility compared to free-form curcumin, it was not well absorbed. In addition, CMG was injected intravenously into rats in order to assess its metabolic behavior in the blood. Interestingly, high levels of free-form curcumin, thought to be sufficiently high to be pharmacologically active, were observed. The in vivo antitumor effects of CMG following intravenous injection were then evaluated in tumor-bearing mice with the HCT116 human colon cancer cell line. The tumor volume within the CMG group was significantly less than that of the control group. Moreover, there was no significant loss of body weight in the CMG group compared to the control group. These results suggest that CMG could be used as an anticancer agent without the serious side effects that most anticancer agents have.

Preventive effect of curcumin and its highly bioavailable preparation on hearing loss induced by single or repeated exposure to noise: A comparative and mechanistic study.

We sought to determine the preventive effects of curcumin and its highly bioavailable preparation on noise-induced hearing loss in a novel murine model of permanent hearing loss developed by repeated exposure to noise. Upon exposure to noise (8-kHz octave band noise, 90 dB sound pressure level, 1 h), hearing ability was impaired in a temporary and reversible manner. During repeated noise exposure (1-h exposure per day, 5 days), there was a progressive increase in the auditory threshold shift at 12 and 20 kHz. The threshold shift persisted for at least 6 days after noise exposure. Oral administration of curcumin for 3 days before and each day during noise exposure significantly alleviated the hearing loss induced by repeated noise exposure. Curcumin abolished intranuclear translocation of nuclear factor-κB-p65 and generation of 4-hydroxynonenal-adducted proteins found in the cochlea after noise exposure. Theracurmin®, a highly absorbable and bioavailable preparation of curcumin, had strong preventive effects on hearing loss induced by repeated noise exposure. Together, these data suggest that curcumin exerts a preventive effect on noise-induced hearing loss and is therefore a good therapeutic candidate for preventing sensorineural hearing loss.

Expression and significance of Pim-3 kinase in adult T-cell leukemia.

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.

Curcumin improves glucose tolerance via stimulation of glucagon-like peptide-1 secretion.

SCOPE: Glucagon-like peptide-1 (GLP-1) is a type of incretin secreted from enteroendocrine L-cells. Our previous studies demonstrated that curcumin (a yellow pigment of turmeric) significantly increases the secretion of GLP-1 in enteroendocrine L cell line (GLUTag cells). However, it is not clear whether its action in vivo directly enhances GLP-1 secretion, which then leads to a reduction in blood glucose levels via the stimulation of insulin secretion. In addition, the molecular target of curcumin-induced GLP-1 secretion has not been clarified. METHODS AND RESULTS: Glucose tolerance was significantly improved in rats after pre-administered curcumin (1.5 mg/kg) followed by intraperitoneal glucose injections via the stimulation of GLP-1 secretion and the induction of insulin secretion. In GLUTag cells, curcumin-induced GLP-1 secretion was associated with G protein-coupled receptor (GPR) 40/120. Furthermore, the glucose-lowering effect induced by curcumin was significantly reduced after the administration of a GPR40/120 antagonist in rats. CONCLUSION: These findings demonstrate the biological function of curcumin as a GLP-1 secretagogue and the possible molecular target that mediates GLP-1 secretion. Increases in the secretion of endogenous GLP-1 induced by curcumin may allow the dosages of other diabetic medicines to be reduced and aid in the prevention of diabetes.

An extended transcaruncular approach for naso-orbito-ethmoid and Le Fort II fracture repair.

BACKGROUND: Recent advancements in computed tomography have enabled the diagnosis of naso-orbito-ethmoid (NOE) fractures to be made in much greater detail. Surgical access to the upper nasofrontal buttress in NOE fractures, however, has remained unchanged over the past decades. All approaches to these fractures using skin incisions have individual drawbacks. The transcaruncular approach is free of the drawbacks of the cutaneous approaches. We further extended the transcaruncular approach for the treatment of NOE and Le Fort II fractures. METHODS: Eight patients; six with Markowitz's Type I NOE fractures and two with Le Fort II fractures, underwent fracture repair using an extended transcaruncular approach to access the upper nasofrontal buttress. RESULTS: In all but one case, which required an additional small skin incision on the glabella, the fracture on the upper nasofrontal buttress was repaired through an extended transcaruncular approach without making any skin incisions. All showed excellent fracture re-alignment on post-surgical CT. Complications happened in three cases; those in two cases were attributed to the extended transcaruncular approach, whereas those in the other were not. CONCLUSIONS: The extended transcaruncular approach is a promising alternative to current conventional approaches for NOE and Le Fort II fractures, achieving accurate repair without the need for skin incision.

Highly absorptive curcumin reduces serum atherosclerotic low-density lipoprotein levels in patients with mild COPD.

PURPOSE: COPD is mainly caused by tobacco smoking and is associated with a high frequency of coronary artery disease. There is growing recognition that the inflammation in COPD is not only confined to the lungs but also involves the systemic circulation and can impact nonpulmonary organs, including blood vessels. α1-antitrypsin-low-density lipoprotein (AT-LDL) complex is an oxidatively modified LDL that accelerates atherosclerosis. Curcumin, one of the best-investigated natural products, is a powerful antioxidant. However, the effects of curcumin on AT-LDL remain unknown. We hypothesized that Theracurmin(®), a highly absorptive curcumin with improved bioavailability using a drug delivery system, ameliorates the inflammatory status in subjects with mild COPD. PATIENTS AND METHODS: This is a randomized, double-blind, parallel-group study. Subjects with stages I-II COPD according to the Japanese Respiratory Society criteria were randomly assigned to receive 90 mg Theracurmin(®) or placebo twice a day for 24 weeks, and changes in inflammatory parameters were evaluated. RESULTS: There were no differences between the Theracurmin(®) and placebo groups in terms of age, male/female ratio, or body mass index in 39 evaluable subjects. The percent changes in blood pressure and hemoglobin A1c and LDL-cholesterol, triglyceride, or high-density lipoprotein-cholesterol levels after treatment were similar for the two groups. However, the percent change in the AT-LDL level was significantly (P=0.020) lower in the Theracurmin(®) group compared with the placebo group. CONCLUSION: Theracurmin(®) reduced levels of atherosclerotic AT-LDL, which may lead to the prevention of future cardiovascular events in mild COPD subjects.

Extensor Hallucis Brevis Tendon Transfer for the Correction of Drop Toe Deformity After Dorsalis Pedis Tendocutaneous Free Flap Harvest.

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.

A Food-Derived Flavonoid Luteolin Protects against Angiotensin II-Induced Cardiac Remodeling.

Oxidative stress has been implicated in cardiac remodeling (cardiac fibrosis and hypertrophy), which impairs cardiac function and metabolism; therefore, it is anticipated antioxidative compounds will have protective properties against cardiac remodeling. Luteolin (3',4',5,7-tetrahydroxyflavone), a widely distributed flavonoid found in many herbal extracts including celery, green pepper, perilla leaves and seeds, and chamomile, is a known to be a potent antioxidant and was previously demonstrated to exert an antifibrotic effect in the lungs and the liver. In this study, we clearly demonstrate that oral pretreatment with the higher-luteolin diet (0.035% (wt/wt)) protected against cardiac fibrosis and hypertrophy as well as a hyperoxidative state in Ang II-infused rats. In cardiac tissue, increased gene expression levels of TGFß1, CTGF, Nox2, Nox4, ANP, and BNP induced by Ang II were restored by oral pretreatment of this high-luteolin diet. In cultured rat cardiac fibroblasts, H2O2-induced TGFß1 expression and the phosphorylation of JNK were suppressed by luteolin pretreatment. In conclusion, food-derived luteolin has protective actions against Ang II-induced cardiac remodeling, which could be mediated through attenuation of oxidative stress.