Changes in bone mineral density during 5 years of adjuvant treatment in premenopausal breast cancer patients.

PURPOSE: Adjuvant treatment for breast cancer in postmenopausal women is a risk factor for bone loss. However, the association between bone mineral density (BMD) changes in premenopausal breast cancer patients and various adjuvant treatment regimens is not well characterized. In this study, we evaluated the changes in BMD according to adjuvant treatment in premenopausal women with breast cancer. METHODS: Between 2006 and 2010, BMD data of 910 premenopausal women with breast cancer before operation and 1, 2, 3.5, and 5 years post-operation were retrospectively analyzed. The patients were divided according to the type of treatment: observation (O), tamoxifen (T), chemotherapy (C), C followed by T (C → T), and gonadotropin-releasing hormone (GnRH) agonist with T (G + T). RESULTS: After 5 years of follow-up, BMD changes were similar between the T and O groups (all p > 0.05). Within 1 year of treatment, the C group showed the most significant BMD loss. The C → T and G + T groups showed more significant BMD loss in the lumbar spine and femur than the O and T groups (both p < 0.001, both). After 1 year of treatment, BMD loss in the lumbar spine was significantly greater in the C → T and G + T groups than in the T group; this tendency was maintained for 5 years of treatment (all p < 0.005). CONCLUSION: Premenopausal women who received adjuvant treatment which induced menopause showed significant bone loss which lasted for 5 years. Although no significant difference was observed between the O and T groups, tamoxifen treatment during chemotherapy or GnRH agonist treatment might prevent bone loss.

Anti-inflammatory Effects of Sanguisorbae Radix on Contact Dermatitis Induced by Dinitrofluorobenzene in Mice.

OBJECTIVE: To investigate the anti-inflflammatory effects of Sanguisorbae Radix on contact dermatitis (CD). METHODS: Mice were sensitized by painting 30 µL of 1-fluoro-2,4-dinitrofluorobenzene (DNFB) onto each ear for 3 days. Four days later, mice were challenged by painting with 50 µL of DNFB onto the shaved dorsum every 2 days. Sanguisorbae Radix methanol extract (MESR) was applied onto the shaved dorsum every 2 days. The effects of MESR on skin thickness, skin weights, histopathological changes, skin lesions and cytokine production in DNFB-induced CD mice were investigated, as well as its effects on body weights and spleen/body weight ratio. RESULTS: Topical application of MESR effectively inhibited enlargement of skin thickness and weight (P<0.05). MESR treatment also inhibited hyperplasia, spongiosis and immune cell infiltration induced by DNFB in inflamed tissues and improved lesions on dorsum skin in CD mice. Moreover, treatment with MESR suppressed the increase in the levels of tumor necrosis factor α (TNF-α,P<0.01) and interferon γ (IFN-γ,P<0.05), respectively. Finally, MESR had no effect on body weight gain or spleen/body weight ratio. CONCLUSION: These data suggest that MESR acts as an anti-inflflammatory agent that decreases the production of TNF-α and IFN-γ, resulting in reductions of skin lesions and histopathological changes in inflamed skin tissues.

Validity and Reliability of an Inertial Measurement Unit-based 3-Dimensional Angular Measurement of Cervical Range of Motion.

OBJECTIVE: This study aimed to assess the reliability and validity of an inertial measurement unit (IMU)-based 3-dimensional (3D) angular measurement system for evaluating cervical range of motion. METHODS: Thirty-three healthy participants (21.9 ± 2.1 years; 162.0 ± 6.0 cm; 55.8 ± 9.0 kg; 21.2 ± 2.4 kg/m2) were evaluated. Kinematic data of the cervical joints were simultaneously obtained using the IMU 3D angular, goniometer, and photographic measurements during cervical flexion (0°, 30°, and 50°), extension (30°, 50°), side-bending (0°, 20°, 40°), and rotation (45°). Test-retest reliability was investigated in each measurement method. Concurrent validity was assessed with the direct comparison between the IMU 3D angular measurement and other methods. RESULTS: The IMU 3D angular measurement showed mostly good to high test-retest reliability with relatively small standard error of measurement and the minimal detectable change values. The concurrent validity of IMU 3D angular measurements in the cervical range of motion was mostly reasonable. However, the measurement bias between the 2 methods tended to be larger at the end range of each plane. CONCLUSION: Using the IMU 3D angular measurement in cervical spine is recommended because of its mostly good to high reliability and reasonable validity. However, using the IMU 3D angular measurement at the end range of each plane should be carefully considered owing to the poorer validity.

Anti-inflammatory effects of Cryptotympana atrata Fabricius slough shed on contact dermatitis induced by dinitrofluorobenzene in mice.

BACKGROUND: The slough shed of Cryptotympana atrata Fabricius is widely used to treat skin diseases in China, Japan, and Korea. OBJECTIVE: To investigate the anti-inflammatory effects of C. atrata on contact dermatitis. MATERIALS AND METHODS: We investigated the effects of C. atrata methanol extract (MECA) on ear swelling, histophathological changes and cytokine production in 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced contact dermatitis (CD) mice. RESULTS: Topical application of MECA effectively inhibited enlargement of ear swelling (30 and 100 µ/ear, P < 0.05; 300 µg/ear, P < 0.01). MECA treatment also inhibited hyperplasia, spongiosis (100 and 300 µg/ear, P < 0.001), and immune cell infiltration (30 µg/ear, P < 0.05; 100 and 300 µg/ear, P < 0.001) induced by DNFB. In addition, treatment with MECA suppressed the increase in the levels of TNF-α (P < 0.05), IFN-g (3, 100 µg/ear, P < 0.05; 300 µg/ear, P < 0.01), and IL-6 (100 µg/ear, P < 0.05; 300 µg/ear, P < 0.01) production. CONCLUSION: These data suggest that MECA has the potential for use in the treatment of inflammatory skin diseases, including CD. Moreover, the results presented herein indicate that anti-inflammatory actions of MECA are mediated by decreasing production of TNF-α, IFN-γ, and IL-6 in inflamed tissues.

TorsinA rescues ER-associated stress and locomotive defects in C. elegans models of ALS.

Molecular mechanisms underlying neurodegenerative diseases converge at the interface of pathways impacting cellular stress, protein homeostasis and aging. Targeting the intrinsic capacities of neuroprotective proteins to restore neuronal function and/or attenuate degeneration represents a potential means toward therapeutic intervention. The product of the human DYT1 gene, torsinA, is a member of the functionally diverse AAA+ family of proteins and exhibits robust molecular-chaperone-like activity, both in vitro and in vivo. Although mutations in DYT1 are associated with a rare form of heritable generalized dystonia, the native function of torsinA seems to be cytoprotective in maintaining the cellular threshold to endoplasmic reticulum (ER) stress. Here we explore the potential for torsinA to serve as a buffer to attenuate the cellular consequences of misfolded-protein stress as it pertains to the neurodegenerative disease amyotrophic lateral sclerosis (ALS). The selective vulnerability of motor neurons to degeneration in ALS mouse models harboring mutations in superoxide dismutase (SOD1) has been found to correlate with regional-specific ER stress in brains. Using Caenorhabditis elegans as a system to model ER stress, we generated transgenic nematodes overexpressing either wild-type or mutant human SOD1 to evaluate their relative impact on ER stress induction in vivo. These studies revealed a mutant-SOD1-specific increase in ER stress that was further exacerbated by changes in temperature, all of which was robustly attenuated by co-expression of torsinA. Moreover, through complementary behavioral analysis, torsinA was able to restore normal neuronal function in mutant G85R SOD1 animals. Furthermore, torsinA targeted mutant SOD1 for degradation via the proteasome, representing mechanistic insight on the activity that torsinA has on aggregate-prone proteins. These results expand our understanding of proteostatic mechanisms influencing neuronal dysfunction in ALS, while simultaneously highlighting the potential for torsinA as a novel target for therapeutic development.

Anti-inflammatory activities of Dictamnus dasycarpus Turcz., root bark on allergic contact dermatitis induced by dinitrofluorobenzene in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The root bark of Dictamnus dasycarpus Turcz. is widely used as a medicinal herb for treatment of skin diseases such as eczema, pruritus and urticaria in China, Japan and Korea. MATERIALS AND METHODS: We investigated the effects of methanol extract of Dictamnus dasycarpus Turcz., root bark (MEDD) on ear thickness, ear weights, histopathological changes such as hyperplasia, edema, spongiosis and immune cell infiltration and cytokine productions in 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced contact dermatitis (CD) mice. We also investigated its effects on degranulation of histamine and ß-hexosaminidase and related mechanisms using RBL-2H3 cells. RESULTS: Topical application of MEDD effectively inhibited enlargement of ear thickness and weight (P<0.05). MEDD treatment also inhibited hyperplasia, edema and spongiosis induced by DNFB. Treatment with 300 µg/ear of MEDD suppressed the increase in IFN-γ and TNF-α levels (P<0.05). In addition, treatment with >50 µg/mL MEDD reduced the level of ß-hexosaminidase release, while >100 µg/mL MEDD lowered the level of histamine release in a dose-dependent manner (P<0.05). Finally, MEDD treatment prevented phosphorylation of p38 MAPK induced by phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 in RBL-2H3 cells. CONCLUSIONS: These data indicate that root bark of Dictamnus dasycarpus Turcz. has the potential for use in the treatment of allergic skin diseases. Furthermore, they suggest that root bark of Dictamnus dasycarpus Turcz. is involved in decreasing degranulation of MCs via inhibition of the p38 MAPK pathway as well as in the inhibition of Th1 skewing reactions.

Long-term exposure to [Cr(3)O(O (2)CCH (2)CH (3)) (6)(H (2)O) (3)] (+) in Wistar rats fed normal or high-fat diets does not alter glucose metabolism.

The essentiality of chromium(III) has been the subject of much debate, particularly in healthy subjects. Chromium(III)-containing supplements are widely used for body mass loss, building of lean muscle mass, and improving glucose and lipid metabolism. [Cr(3)O(O(2)CCH(2)CH(3))(6)(H(2)O)(3)](+), Cr3, is one of the most-studied chromium nutritional supplements. The current study evaluates the effects of long-term (15 months) supplementation with Cr3 on body mass and glucose metabolism in Wistar rats on traditional and cafeteria-style (high fat, high carbohydrate) diets. Male Wistar rats were randomly assigned to one of four treatment groups: (1) control diet (milled Harlan Teklad LM-485 rodent diet), (2) control diet+1 mg Cr3/kg body mass/day, (3) a cafeteria-style (CAF) diet (high fat, high carbohydrate), or (4) CAF diet+1 mg Cr3/kg/day. Cr3 supplementation had no effect on fasting blood glucose levels or blood glucose levels in response to glucose and insulin challenges. Rats consuming the CAF+Cr3 diet tended to have a significantly higher body mass than rats consuming the CAF diet, but necropsy results showed no difference in visceral fat or body wall thickness between groups. These data suggest that long-term Cr3 supplementation does not significantly affect body mass in rats consuming a normal diet or glucose levels or metabolism in rats consuming either diet.

Inhibition of Hypoxia Inducible Factor Alpha and Astrocyte-Elevated Gene-1 Mediates Cryptotanshinone Exerted Antitumor Activity in Hypoxic PC-3 Cells.

Although cryptotanshinone (CT) was known to exert antitumor activity in several cancers, its molecular mechanism under hypoxia still remains unclear. Here, the roles of AEG-1 and HIF-1α in CT-induced antitumor activity were investigated in hypoxic PC-3 cells. CT exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation and AEG-1 expression in hypoxic PC-3 cells. Also, AEG-1 was overexpressed in prostate cancer cells. Interestingly, HIF-1α siRNA transfection enhanced the cleavages of caspase-9,3, and PAPR and decreased expression of Bcl-2 and AEG1 induced by CT in hypoxic PC-3 cells. Of note, DMOG enhanced the stability of AEG-1 and HIF-1α during hypoxia. Additionally, CT significantly reduced cellular level of VEGF in PC-3 cells and disturbed tube formation of HUVECs. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1α to VEGF promoter. Furthermore, CT at 10 mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67, CD34, VEGF, carbonic anhydrase IX, and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1α, AEG1, and VEGF as a potent chemotherapeutic agent.

Exposure to green tea extract alters the incidence of specific cyclophosphamide-induced malformations.

BACKGROUND: Green tea extract (GTE) has been shown to have antioxidative properties due to its high content of polyphenols and catechin gallates. Previous studies indicated that catechin gallates scavenge free radicals and attenuate the effects of reactive oxygen species. Cyclophosphamide (CP) produces reactive oxidative species, which can have adverse effects on development, causing limb, digit, and cranial abnormalities. The current study was performed to determine if exposure to GTE can decrease teratogenic effects induced by CP in CD-1 mice. METHODS: From gestation days (GD) 6-13, mated CD-1 mice were dosed with 400 or 800 mg/kg/d GTE; 100, 200, 400, or 800 mg/kg/d GTE + CP; CP alone, or the vehicle. GTE was given by gavage. CP (20 mg/kg) was given by intraperitoneal injection on GD 10. Dams were sacrificed on GD 17, and their litters were examined for adverse effects. RESULTS: The highest GTE dose did not effectively attenuate, and in some cases exacerbated the negative effect of CP. GTE alone was also associated with an increased incidence of microblepharia. Conversely, moderate GTE doses (200 and/or 400 mg/kg/d) attenuated the effect of CP on fetal weight and (GTE 200 mg/kg/d) decreased the incidences of certain defects resulting from CP exposure. CONCLUSIONS: Exposure of a developing mammal to moderate doses of GTE can modulate the effects of exposure to CP during development, possibly by affecting biotransformation, while a higher GTE dose tended to exacerbate the developmental toxicity of CP. GTE alone appeared to cause an adverse effect on eyelid development.

Effect of lithospermi radix on contact dermatitis induced by dinitrofluorobenzene in mice.

OBJECTIVE: The root of Lithospermum erythrorhizon Sieb. et Zucc. (Lithospermi Radix, LR) is a kind of heat clearing and blood cooling medicinal herbs. It can clear away heat and cool the blood, reduce toxins and disperse maculae. LR has long been used as efficacious therapy for inflammation, burns, frostbite and skin diseases such as eczema and psoriasis. METHODS: In the present study, we investigate anti-allergic and anti-inflammatory effects of LR by using the 1-fluoro-2, 4- dinitrofluorobenzene (DNFB)-induced contact dermatitis mouse model. RESULTS: Topical application of 10 mg/mL of LR effectively inhibited skin lesions induced by repeated paintings with DNFB. Topical application of LR also inhibited hyperplasia, edema, spongiosis and infiltrations of mononuclear cells. In addition, production levels of total immunoglobulin and IgG1 in serum were decreased by using LR in vivo. CONCLUSION: These data suggest that LR acts as an antiinflammatory agent, improving skin lesions in CD mice.

HDAC inhibitors downregulate MRP2 expression in multidrug resistant cancer cells: implication for chemosensitization.

Although histone deacetylase (HDAC) inhibitors are emerging as a promising class of cancer chemotherapeutic agents, their effects on multidrug resistance (MDR) are poorly understood. In this study, we investigated whether HDAC inhibitors overcome MDR phenotype. HDAC inhibitors suppress the growth of both MDR positive cancer cells KBV20C and its parental cells KB with similar potencies. In parallel, histone acetylation and p21WAF1 expression by the HDAC inhibitors were similarly increased in both cell types, indicating that these HDAC inhibitors are poor substrates of ABC drug transporters and effective in MDR cancer cells. In addition, multidrug resistance protein 2 (MRP2) expression is selectively attenuated by HDAC inhibitors, especially SAHA and TSA, in KBV20C cells, whereas MDR1 and BCRP expressions are not affected. This downregulation of MRP2 contributes to increase in paclitaxel-induced G2/M arrest and apoptosis, which might be due to intracellular accumulation of paclitaxel. Collectively, our data provide a molecular rationale for the application of HDAC inhibitors to overcome MDR in cancer cells.

Long-term comparison of primary trabeculectomy with 5-fluorouracil versus mitomycin C in West Africa.

PURPOSE: To compare the long-term efficacy and safety of intraoperative 5-fluorouracil (5-FU) versus mitomycin-C (MMC) used adjunctively with primary trabeculectomy in a Black West African population. DESIGN: Retrospective comparative study supplemented with cross-sectional follow-up data. METHODS: Review of 68 eyes of 68 Black West African subjects that underwent primary trabeculectomy with the use of intraoperative 5-FU or MMC between January 1, 1988 and January 1, 2002 and had at least 3 years postoperative follow-up. Postoperative outcome measures included intraocular pressure (IOP) control, number of glaucoma medications, visual acuity, and complications. RESULTS: Thirty-eight of sixty-eight eyes received 5-FU and 30 received MMC. Mean postoperative follow-up was 7.5 and 6.5 years in the 5-FU and MMC groups, respectively (P=0.17). A higher proportion of eyes in the MMC group achieved "qualified" (with or without medical therapy) success with varying IOP targets relative to the 5-FU group, but the differences were not statistically significant. "Complete" (without medical therapy) postoperative success was greater in the MMC group with a significantly higher proportion achieving an IOP <21 mm Hg (P=0.02). MMC use was also associated with a lower likelihood of receiving IOP-lowering medications postoperatively (P=0.01). Baseline demographic characteristics, preoperative and postoperative IOP, visual acuity, and complications did not differ significantly between the 2 groups. CONCLUSIONS: Intraoperative MMC use is associated with a lower likelihood of requiring postoperative medications and a greater likelihood of achieving IOP lowering without medications relative to the use of 5-FU in a Black West African population.