Remodeling of sorafenib as an orally bioavailable ferroptosis inducer for Lung Cancer by chemical modification of adenine-binding motif.

Sorafenib (BAY 43-9006) was developed as a multi-kinase inhibitor to treat advanced renal cell, hepatocellular, and thyroid cancers. The cytotoxic effect of sorafenib on cancer cells results from not only inhibiting the MEK/ERK signaling pathway (the on-target effect) but also inducing oxidative damage (the off-target effect). The inhibitory effect of sorafenib on system Xc- (xCT), a cystine/glutamate antiporter, promotes ferroptosis induction and accounts for oxidative damage. While emerging studies on ferroptosis in cancers have garnered increasing attention, the lack of consideration for ferroptosis inducers (FINs) with favorable pharmacokinetics could be problematic. Herein, we remodeled the chemical structure of sorafenib, of which pharmacokinetics and safety are already assured, to customize the off-target effect (i.e., ferroptosis induction) to on-target by disrupting the adenine-binding motif. JB3, a sorafenib derivative (i.e., JB compounds), with a tenfold higher IC50 toward RAF1 because of chemical remodeling, induced strong cytotoxicity in the elastin-sensitive lung cancer cells, while it was markedly reduced by ferrostatin-1. The 24% oral bioavailability of JB3 in rats accounted for a significant anti-tumor effect of orally administrated JB3 in xenograft models. These results indicate that JB3 could be further developed as an orally bioavailable FIN in novel anti-cancer therapeutics.

Enhancement of the therapeutic efficacy of the MAP regimen using thiamine pyrophosphate-decorated albumin nanoclusters in osteosarcoma treatment.

Recent studies on osteosarcoma regimens have mainly focused on modifying the combination of antineoplastic agents rather than enhancing the therapeutic efficacy of each component. Here, an albumin nanocluster (NC)-assisted methotrexate (MTX), doxorubicin (DOX), and cisplatin (MAP) regimen with improved antitumor efficacy is presented. Human serum albumin (HSA) is decorated with thiamine pyrophosphate (TPP) to increase the affinity to the bone tumor microenvironment (TME). MTX or DOX (hydrophobic MAP components) is adsorbed to HSA-TPP via hydrophobic interactions. MTX- or DOX-adsorbed HSA-TPP NCs exhibit 20.8- and 1.64-fold higher binding affinity to hydroxyapatite, respectively, than corresponding HSA NCs, suggesting improved targeting ability to the bone TME via TPP decoration. A modified MAP regimen consisting of MTX- or DOX-adsorbed HSA-TPP NCs and free cisplatin displays a higher synergistic anticancer effect in HOS/MNNG human osteosarcoma cells than conventional MAP. TPP-decorated NCs show 1.53-fold higher tumor accumulation than unmodified NCs in an orthotopic osteosarcoma mouse model, indicating increased bone tumor distribution. As a result, the modified regimen more significantly suppresses tumor growth in vivo than solution-based conventional MAP, suggesting that HSA-TPP NC-assisted MAP may be a promising strategy for osteosarcoma treatment.

Bone tumor-homing nanotherapeutics for prolonged retention in tumor microenvironment and facilitated apoptotic process via mevalonate pathway inhibition.

Bone malignancy features a mineralized extracellular matrix primarily composed of hydroxyapatite, which interferes with the distribution and activity of antineoplastic agents. Herein, we report bone tumor-homing polymeric nanotherapeutics consisting of alendronate-decorated chondroitin sulfate A-graft-poly(lactide-co-glycolide) and doxorubicin (DOX), named PLCSA-AD, which displayed a prolonged retention profile in the tumor microenvironment and augmented therapeutic efficacy via inhibition of the mevalonate pathway. PLCSA-AD exhibited a 1.72-fold lower IC50 value than free DOX and a higher affinity for hydroxyapatite than PLCSA in HOS/MNNG cell-based 2D bone tumor-mimicking models. The inhibition of the mevalonate pathway by PLCSA-AD in tumor cells was verified by investigating the cytosolic fraction of unprenylated proteins, where blank PLCSA-AD significantly increased the expression of cytosolic Ras and RhoA without changing their total cellular amounts. In a bone tumor-mimicking xenografted mouse model, AD-decorated nanotherapeutics significantly increased tumor accumulation (1.73-fold) compared with PLCSA, and higher adsorption to hydroxyapatites was observed in the histological analysis of the tumor. As a result, inhibition of the mevalonate pathway and improvement in tumor accumulation led to markedly enhanced therapeutic efficacy in vivo, suggesting that PLCSA-AD could be promising nanotherapeutics for bone tumor treatment.

Arsenic induces platelet shape change through altering focal adhesion kinase-mediated actin dynamics, contributing to increased platelet reactivity.

Arsenic, an environmental contaminant in drinking water worldwide is well-established to increase cardiovascular diseases (CVDs) in humans. Of these, thrombotic events represent a major adverse effect associated with arsenic exposure, for which an abundance of epidemiological evidence exists. Platelet aggregation constitutes a pivotal step in thrombosis but arsenic alone doesn't induce aggregation and the mechanism underlying arsenic-induced thrombosis still remains unclear. Here we demonstrated that arsenic induces morphological changes of platelets, i.e., contraction and pseudopod projection, the primal events of platelet activation, which can increase platelet reactivity. Arsenite induced prominent platelet shape changes in a dose-dependent manner in freshly isolated human platelets. Of note, arsenite suppressed focal adhesion kinase (FAK) activity, which in turn activated RhoA, leading to altered actin assembly through LIMK activation, and subsequent cofilin inactivation. Arsenic-induced platelet shape change appeared to increase the sensitivity to thrombin and ADP-induced aggregation. Supporting this, latrunculin A, an inhibitor of actin-dynamics abolished it. Taken together, we demonstrated that arsenic induces cytoskeletal changes and shape changes of platelets through FAK-mediated alteration of actin dynamics, which renders platelets reactive to activating stimuli, ultimately contributing to increased thrombosis.

Relationships among ketosis, serum metabolites, body condition, and reproductive outcomes in dairy cows.

We determined the relationships among ketosis, serum metabolites, body condition, and reproductive disorders and performance in dairy cows. Blood samples from 213 dairy cows were collected at 4 and 2 weeks prepartum, just after calving, and at 1, 2, 4, 6, and 8 weeks postpartum to measure serum ß-hydroxybutyrate, nonesterified fatty acids (NEFAs), glucose, total cholesterol, urea nitrogen, aspartate aminotransferase, γ-glutamyltransferase, and progesterone concentrations. Cows were grouped on the basis of the ß-hydroxybutyrate concentration at 1 and/or 2 weeks postpartum into two groups: the ketotic group (≥1200 µmol/L, n = 59) and the nonketotic group (<1200 µmol/L, n = 154). The body condition score (BCS) was assessed simultaneously with blood collection. Clinical endometritis was diagnosed by observation of vaginal discharges (>50% pus), and subclinical endometritis was diagnosed by evaluation of uterine cytology (>18% neutrophils) at 4 weeks postpartum. Ovarian cysts were diagnosed by ultrasonography, and resumption of postpartum cyclicity was evaluated by progesterone concentrations (≥1 ng/mL) at 4, 6, and 8 weeks postpartum. In the ketotic group, NEFA levels were higher (P ≤ 0.0005), whereas glucose (P < 0.05-0.0005) and urea nitrogen levels (P < 0.05-0.01) were lower than those in the nonketotic group during the postpartum period. Aspartate aminotransferase levels were higher (P < 0.01) in the ketotic group than those in the nonketotic group at 2 weeks postpartum. The BCS of the ketotic group was higher than the nonketotic group during the prepartum (P < 0.001) and postpartum (P < 0.05-0.001) periods. The probabilities of clinical endometritis (odds ratio = 2.55) and ovarian cysts (odds ratio = 2.80) were higher (P < 0.05) in the ketotic group than those in the nonketotic group. The hazards of resumption of postpartum cyclicity by 8 weeks postpartum (hazard ratio = 0.67) and pregnancy by 360 days postpartum (hazard ratio = 0.68) were lower (P < 0.05) in the ketotic group. In conclusion, a higher BCS during prepartum and postpartum period and increased NEFA and aspartate aminotransferase levels, along with decreased glucose and urea nitrogen levels during postpartum, were associated with ketosis, increased reproductive disorders, and decreased reproductive performance in dairy cows.

Indirubin derivative E804 inhibits angiogenesis.

BACKGROUND: It has previously been shown that indirubin derivative E804 (IDR-E804) blocks signal transducer and activator of transcription-3 signaling in human breast and prostate cancer cells and inhibits Src kinase activity. To further establish its role in angiogenesis, we tested its potential using human umbilical vein endothelial cells (HUVECs) and analyzed the effects of IDR-E804 on cellular and molecular events related to angiogenesis. METHODS: The anti-angiogenic effects of IDR-E804 were examined by assessing the proliferation, migration and capillary tube formation of HUVECs were induced by vascular endothelial growth factor (VEGF) with or without various concentrations of IDR-E804. The inhibitory effect of IDR-E804 angiogenesis and tumor growth in vivo was also investigated in Balb/c mice subcutaneously transplanted with CT-26 colon cancer cells. RESULTS: IDR-E804 significantly decreased proliferation, migration and tube formation of vascular endothelial growth factor VEGF-treated HUVECs. These effects were accompanied by decreased phosphorylation of VEGF receptor (VEGFR)-2, AKT and extracellular signal regulated kinase in VEGF-treated HUVECs. Intratumor injections of IDR-E804 inhibited the growth of subcutaneously inoculated CT-26 allografts in syngenic mice. Immunohistochemistry revealed a decreased CD31 microvessel density index and Ki-67 proliferative index, but an increased apoptosis index in IDR-E804-treated tumors. CONCLUSIONS: These data revealed that IDR-E804 is an inhibitor of angiogenesis and also provide evidence for the efficacy of IDR-E804 for anti-tumor therapies.

Comparison of four diagnostic methods for detecting rabies viruses circulating in Korea.

It is essential to rapidly and precisely diagnose rabies. In this study, we evaluated four diagnostic methods, indirect fluorescent antibody test (FAT), virus isolation (VI), reverse transcriptase polymerase chain reaction (RT-PCR), and rapid immunodiagnostic assay (RIDA), to detect rabies in animal brain homogenates. Out of the 110 animal brain samples tested, 20 (18.2%) were positive for rabies according to the FAT. Compared to the FAT, the sensitivities of VI, RT-PCR, and RIDA were 100, 100, and 95%, respectively. The specificities of VI, RT-PCR and RIDA were found to be 100, 100, and 98.9%, respectively. Rabies viruses circulating in Korea were isolated and propagated in murine neuroblastoma (NG108-15) cells with titers ranging from 10(1.5) to 10(4.5) TCID(50)/mL. Although the RIDA findings did not completely coincide with results obtained from FAT, VI, and RT-PCR, RIDA appears to be a fast and reliable assay that can be used to analyze brain samples. In summary, the results from our study showed that VI, RT-PCR, and RIDA can be used as supplementary diagnostic tools for detecting rabies viruses in both laboratory and field settings.

Indirubin-3'-monoxime, a derivative of a chinese antileukemia medicine, inhibits angiogenesis.

Although the antiangiogenic activity of indirubin-3-monoxime (I3M), a derivative of a Chinese anti-leukemia medicine, has been demonstrated using transgenic zebrafish, the detail molecular mechanism has not been elicited. To further establish its role in antiangiogenic activity, we tested its potential against human umbilical vein endothelial cells (HUVECs) and the in vivo Matrigel plug model was applied to evaluate new vessel formation. We also investigated the molecular mechanisms of I3M-induced antiangiogenic effects in HUVECs. We found that I3M significantly inhibited HUVEC proliferation (2.5-20 µM), migration (2.5-20 µM), and tube formation (10-20 µM) in HUVECs. The number of microvessels growing from the aortic rings was suppressed by I3M treatment. Moreover, I3M suppressed neovascularization in Matrigel plugs in mice. The underlying antiangiogenic mechanism of I3M was correlated with down-regulation of the vascular endothelial growth factor receptor-2 activation, at least a part. These findings emphasize the potential use of I3M in pathological situations involving stimulated angiogenesis, such as tumor development.

Antiangiogenic effect of licochalcone A.

To date, no antiangiogenic activity has been demonstrated for licochalcone A (LicA), a major phenolic constituent of Glycyrrhiza inflata, although it shows significant antitumor activity in human malignant cell lines. Our previous work demonstrated that LicA down-regulates inflammatory responses to lipopolysaccharide in murine macrophages. The purpose of the present study was to evaluate whether LicA inhibits angiogenesis, which is crucial for cancer development and progression. LicA significantly inhibited proliferation (20 microM), migration (5-20 microM), and tube formation (10-20 microM) of human umbilical vascular endothelial cells (HUVECs) as well as microvessel growth from rat aortic rings (10-20 microM). Furthermore, LicA significantly inhibited the growth of CT-26 colon cancer implants in BALB/c mice, with fewer CD31- and Ki-67-positive cells but more apoptotic cells. The underlying antiangiogenic mechanism of LicA correlated with down-regulation of vascular endothelial growth factor receptor (VEGFR)-2 activation. Our findings provide the first evidence that LicA inhibits angiogenesis in vitro and in vivo, perhaps by blocking VEGF/VEGFR-2 signaling. Inhibition of tumor growth may be attributed, at least in part, to decreased angiogenesis in LicA-treated mice. These findings emphasize the potential use of LicA against tumor development and progression in which angiogenesis is stimulated.

Anti-angiogenic activity of methanol extract of Phellinus linteus and its fractions.

AIM OF THE STUDY: The aim of the present study was to investigate the effects of MeOH extract of PL (PLME) and its fractions on angiogenesis. MATERIALS AND METHODS: PLME and its subsequent fractions (methylene chloride, ethyl acetate, n-butanol and aqueous fractions) were evaluated in vitro. Specifically, the anti-angiogenic activities of PLME and its fractions were investigated by measuring their effects on the proliferation, migration, tube formation and phosphorylation of vascular endothelial growth factor receptor (VEGFR)-2 in human umbilical vein endothelial cells (HUVECs). In addition, the in vivo Matrigel plug model was applied to evaluate new vessel formation. RESULTS: The results revealed that PLME and its subsequent fractions, except for the aqueous fraction, led to significant inhibition of the proliferation, migration, tube formation and VEGFR-2 phosphorylation of HUVECs as well as in vivo angiogenesis. CONCLUSIONS: These findings indicate the potential for the use of PLME in pathological situations involving stimulated angiogenesis, such as inflammation and tumor development.

[Effect of combination pretreatment of polyethylene glycol solution and magnesium hydroxide for colonoscopy].

BACKGROUND/AIMS: This study was designed to compare the efficacy and patient tolerance between standard bowel preparation using 4 liters of polyethylene glycol (PEG) solution and 4 liters of PEG preceded by the osmotic laxative, magnesium hydroxide in constipation and non-constipation group. METHODS: 173 outpatient colonoscopy, except for three patients who were not taking magnesium, were divided into constipation and non-constipation group. Then, the patients were randomly assigned to receive 4-liter of PEG solution or 4-liter of PEG plus magnesium hydroxide. The quality of bowel preparation was assessed using Ottawa scale, and satisfaction score was assessed using questionnaires. Solid stool, cecal intubation time, compliance, and side effects were assessed. RESULTS: Non-constipation group showed no significant differences between two groups. In constipation group, 4-liter PEG solution plus magnesium hydroxide induced the more effective colonic preparation (Ottawa scale 2.47+/-0.99 vs. 5.92+/-2.39, p<0.05), and less solid stool (0.67+/-0.72 vs. 1.38+/-0.65, p<0.05) compared with 4-liter PEG solution. CONCLUSIONS: Bowel preparation with magnesium hydroxide and 4 liters of PEG solution might reduce solid stool in constipation group, but could not improve preparation quality.

Antitumor and antimetastatic effects of licochalcone A in mouse models.

Licochalcone A (LicA), a major phenolic constituent of licorice, has antiproliferative and anti-inflammatory properties in human and murine cell lines. We previously showed that LicA down-regulates the expression of cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) via the modulation of nuclear factor-kappaB and activator protein-1 activation in cell culture. We therefore tested whether LicA inhibits carcinogenesis and metastasis in mouse models. To induce colon carcinogenesis, C57BL/6 mice were given a single intraperitoneal injection of azoxymethane (10 mg/kg body weight), followed by 1% dextran sulfate sodium in the drinking water. Additionally, we also assessed the effect of LicA on liver metastasis by intrasplenic injection of BALB/c mice with CT-26 cells. Feeding the mice with LicA (5, 15, and 30 mg/kg body weight) significantly reduced tumor formation as well as the number of cells expressing proliferating cell nuclear antigen, beta-catenin, COX-2, and iNOS in the colon. LicA also decreased colon levels of proinflammatory cytokines and chemokines. In addition, LicA significantly increases survival of animals and inhibited liver metastasis as well as the expression of matrix metalloproteinase-9 in the liver. These preclinical studies indicate that LicA has potent antitumor and antimetastatic activity, suggesting that LicA could increase efficacy and improve patient outcomes in colorectal cancer.

The anti-inflammatory effects of a methanolic extract from Radix Isatidis in murine macrophages and mice.

Radix Isatidis is the dried root of the plant Isatidis indigotica Fort (family Cruciferae) and traditionally used as an anti-viral, anti-bacterial, anti-endotoxic, and immune regulatory agent in the folk medicine of Korea and China. The aim of the present study was to determine the anti-inflammatory effects of methanolic extracts of Radix Isatidis (RIME) in lipopolysaccharide (LPS)-stimulated murine macrophages and in a TPA-induced ear edema animal model. Anti-inflammatory effects of RIME were examined in LPS-stimulated RAW 264.7 macrophages. In order to investigate the effects of RIME in vivo, activation of myeloperoxidase, and histological assessment were examined in the 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced mouse ear edema model. RIME significantly inhibited the release from macrophages of inflammatory mediators such as nitric oxide, prostaglandin E(2), and pro-inflammatory cytokines. Topical administration of RIME at 1-5 mg/ear resulted in reduction of ear inflammation in mice. Thus, our results indicate that the anti-inflammatory effects of RIME involve decreased production of inflammatory mediators, which suggests that RIME may have therapeutic potential in a variety of inflammation-related diseases.

3,3'-diindolylmethane attenuates colonic inflammation and tumorigenesis in mice.

BACKGROUND: 3,3-Diindolylmethane (DIM) is a major in vivo product of acid-catalyzed oligomerization of indole-3-carbinol (I3C) derived from Brassica food plants. Although DIM is known as a chemopreventive and chemotherapeutic phytochemical, the effects of DIM on inflammation in vivo are still unknown. In the present study we investigated the antiinflammatory effects of DIM on experimental colitis and colitis-associated colorectal carcinogenesis. METHODS: To determine if DIM has an antiinflammatory effect in vivo, we examined the therapeutic effects of DIM in dextran sodium sulfate (DSS)-induced experimental colitis and colitis-associated colon carcinogenesis induced by azoxymethane (AOM)/DSS in BALB/c mice. RESULTS: Treatment with DIM significantly attenuated loss of body weight, shortening of the colon, and severe clinical signs in a colitis model. This was associated with a remarkable amelioration of the disruption of the colonic architecture and a significant reduction in colonic myeloperoxidase activity and production of prostaglandin E(2), nitric oxide, and proinflammatory cytokines. Further, DIM administration dramatically decreased the number of colon tumors in AOM/DSS mice. CONCLUSIONS: These results suggest that DIM-mediated antiinflammatory action at colorectal sites may be therapeutic in the setting of inflammatory bowel disease and colitis-associated colon cancer.

[A case of idiopathic pancreatitis in a patient with Crohn's disease].

Pancreatitis has been occasionally associated with Crohn's disease (CD). A definite etiology of pancreatitis can be identified in most patients, but a very small proportion remain idiopathic. We report a case of idiopathic pancreatitis resolved along with the clinical improvement of CD in a 25-year-old man. He presented with abdominal pain and diarrhea for 8 years. Ileocolonoscopy and enteroclysis showed multiple, longitudinal ulcers and strictures at the ileojejunum. The laboratory findings showed elevated serum amylase (951 IU/L) and lipase (326 IU/L) without positive autoantibodies. Esophagogastroduodenoscopy, enhanced pancreatic CT, and MRCP showed no abnormalities at ampulla of Vater, pancrease, and pancreaticobiliary duct. With the treatment with antibiotics, 5-aminosalicylic acid, steroid, and azathioprine, as a whole, decreasing pattern and intermittent fine coordinated fluctuation of the levels of amylase and lipase along with the decrease of Crohn's disease activity index (CDAI) and the CRP levels were observed. Then, three months after the start of the treatment, normalization of the pancreatic enzymes was observed, and there was recurrent elevation of pancreatic engyme during 12 months maintenance therapy. This report supports the concept of an association between idiopathic pancreatitis and CD, based on a significant and close relation between the levels of serum amylase and lipase, and CDAI.

Chrysin, a natural flavone, improves murine inflammatory bowel diseases.

Chrysin (5,7-dihydroxyflavone) is a natural flavone commonly found in many plants. It has previously been shown to be an anti-tumor agent. In this study, we investigated whether chrysin could alleviate the symptoms of dextran sodium sulfate (DSS)-induced colitis in mice and whether chrysin has an inhibitory effect on nuclear factor (NF)-kappaB activation in vitro. A significant blunting of weight loss and clinical signs was observed in DSS-exposed, chrysin-treated mice when compared to vehicle-treated mice. This was associated with a remarkable amelioration of the disruption of the colonic architecture, a significant reduction in colonic myeloperoxidase (MPO) activity, and a decrease in the production of inflammatory mediators such as nitric oxide (NO), prostaglandin (PG) E(2), and pro-inflammatory cytokines. In addition, chrysin inhibited tumor necrosis factor (TNF)-alpha-induced activation of NF-kappaB in IEC-6 cells. These findings suggest that chrysin exerts potentially clinically useful anti-inflammatory effects mediated through the suppression of NF-kappaB activation.

[A case of giant colonic lipoma showing spontaneous resolution after endoscopic partial resection].

Generally, colon lipoma is mildly symptomatic or asymptomatic. However, sometimes it may present with symptoms, such as pain, constipation, obstruction, or bleeding and may be the leading point for intussusception, particularly in large size (>20 mm). Giant colon lipoma may warrant the removal to exclude confusion with other lesions that have a malignant potential and to control symptoms. Currently, surgical resection should be considered for giant lipoma more than 20 mm in diameter due to the high risk of perforation or bleeding, especially when the lesion is broadly-based. We report here a case of spontaneous resolution acquired after endoscopic partial resection for the symptomatic giant colon lipoma with broad-base requiring surgery.

[A case of Cowden's disease associated with breast cancer].

Cowden's disease, also known as various hamartomatous malformations of multiple organs, is a rare autosomal dominant disorder. The most important feature of Cowden's disease is its frequent association with malignant neoplasm, particularly in the breast and thyroid gland. Cowden's disease with malignant neoplasms is quite rare in Korea so far. We report a case of Cowden's disease associated with breast cancer in a 41-year-old female who underwent routine health cheek-up.

Body composition changes with age have gender-specific impacts on bone mineral density.

Body weight, smoking, alcohol, physical activity, and diet have been proven to affect bone mineral density (BMD) directly or indirectly. Of these, body weight is perhaps best known to affect BMD. However, there is some debate as to whether lean body mass (LBM) or fat mass (FM), the two components of body weight, most determines BMD. Recently, newer peripheral densitometry devices have been developed, which have the advantages of low cost and portability, and this has made field epidemiologic study of osteoporosis possible. As the number of studies that have focused on the contribution made by body composition to BMD is limited, we investigated the relative contribution of LBM and FM to BMD in healthy Korean subjects. 402 age- and weight-matched subjects over 45 years old were selected from a population-based cohort. The mean ages of men and women were 64.1 +/- 8.7 (mean +/- SD) and 64.2 +/- 12.7 years, and mean weights were 63.0 +/- 8.2 and 63.1 +/- 8.2 kg, respectively. BMD was measured by peripheral dual-energy X-ray absorptiometry (DEXA) and body composition by bioelectrical impedance. Sociodemographic characteristics and physical activities were investigated using a standard questionnaire delivered by face-to-face interview. BMDs were 0.48 +/- 0.01 and 0.37 +/- 0.11 g/cm2 in men and women, respectively. In men, age, weight, body mass index (BMI), LBM, FM, physical activity, smoking, alcohol, and education were significantly correlated with BMD. In women, age, weight, BMI, LBM, FM, education, years since menopause, number of deliveries, and number of children breast-fed were significantly correlated with BMD. By multiple regression, LBM, education, smoking, and alcohol in men, and age, LBM, FM, smoking, and number of delivery in women were independent determinants of BMD. LBM was an important contributor for BMD in men, but both LBM and FM were equally important contributors in female to BMD. This stems from the fact that body composition changes with age differ in men and women. Thus, the augmentation of muscle mass in men and the maintenance of an optimal weight in women act to prevent osteoporosis.

Self-assembled nanoparticles of hydrophobically-modified polysaccharide bearing vitamin H as a targeted anti-cancer drug delivery system.

Vitamin H (biotin) was incorporated into a hydrophobically modified polysaccharide, pullulan acetate (PA), in order to improve the cancer-targeting activity and internalization of self-assembled nanoparticles. The biotinylated pullulan acetate (BPA) nanoparticles were prepared by a diafiltration method and the mean diameter was approximately 100 nm. Three samples of biotinylated pullulan acetate (BPA), comprising 7 (BPA 1), 20 (BPA 2), and 39 (BPA 3) vitamin H groups per 100 anhydroglucose units of PA, were synthesized. The critical aggregation concentrations (CAC) of the BPA nanoparticles in distilled water were 3.1 x 10(-3), 4.3 x 10(-3) and 6.8 x 10(-3) mg/ml for BPA 1, BPA 2, and BPA 3, respectively. Adriamycin (ADR) was loaded into the BPA nanoparticles as a model drug. The loading efficiencies and ADR content in the BPA nanoparticles decreased with increasing vitamin H content due to a lower hydrophobicity. The RITC-labeled BPA nanoparticles exhibited very strong adsorption to the HepG2 cells, while the RITC-labeled PA nanoparticles did not show any significant interaction. The degree of the interaction increased with increasing vitamin H content. Confocal laser microscopy also revealed that internalization of the BPA nanoparticles into the cancer cells depended on the vitamin H content.