Shikonin, acetylshikonin, and isobutyroylshikonin inhibit VEGF-induced angiogenesis and suppress tumor growth in lewis lung carcinoma-bearing mice

Lithospermum erythrorhizon has been used for treatment of inflammatory diseases and cancer as a folk remedy. Based on the evidences that anti-inflammatory agents frequently exert antiangiogenic activity, thus we examined comparatively the antiangiogenic activities of three naphthoquinone derivatives (shikonin, acetylshikonin, and isobutyroylshikonin) isolated from the plant. Three derivatives exhibited weak cytotoxicity against human umbilical vein endothelial cells (HUVECs) with IC50 of over 20 microM. Shikonin had more specific inhibitory effects on proliferation and vascular endothelial growth factor (VEGF) production by VEGF compared with different derivatives. All of derivatives significantly suppressed the migration of VEGF treated HUVECs at different optimal concentrations. Also, shikonin and acetylshikonin significantly disrupted VEGF-induced tube formation. Furthermore, three derivatives effectively downregulated the expression of urokinase-type plasminogen activator (uPA), but not its receptor uPAR. Additionally, shikonin significantly inhibited tumor growth in LLC-bearing mice, whereas its derivatives had relatively mild effects. Taken together, our findings suggest that shikonin and its derivatives exhibit the antiangiogenic and antitumorigenic effects by suppressing proliferation and angiogenic factors.     

A hospital-based study of splenomegaly with special reference to the group of indeterminate origin

In any study there remains a proportion of cases, about 25-40%, where cause of splenomegaly is not identified on usual evaluation, that is labelled as indeterminate group. The aim of this study was to evaluate various causes of splenomegaly. Thereafter the patients with splenomegaly of indeterminate origin were to be re-evaluated with detailed investigations (for the cause of splenomegaly). Causes of splenomegaly were looked into 100 adult patients with splenomegaly, admitted over a period of ten months in a teaching hospital in South India. Patients having ascites were excluded from the study. Malaria was the commonest cause of splenomegaly, observed in 22 patients. Other causes, in order of importance, were chronic myeloid leukaemia (n=11), non-cirrhotic portal fibrosis (n=9), enteric fever (n=9), cirrhosis of liver (n=8) and hyper-reactive malarial splenomegaly also called as tropical splenomegaly syndrome (n=7) and so on. Hyper-reactive malarial splenomegaly was the commonest cause (7 of 24 patients) of massive splenomegaly. Twenty-three patients had splenomegaly of indeterminate origin ie, cause could not be detected on first assessment. Detailed re-evaluation with repeat investigations including liver biopsy revealed the causes as follows: Hyper-reactive malarial splenomegaly -7 (30.4%), non-cirrhotic portal fibrosis - 4 (17.4%), cirrhosis of liver - 4 (17.4%) and iron deficiency anaemia - 5 (21.7%). In 3 patients (13.0%), no diagnosis could be arrived at despite best efforts. Obscure splenomegalies may be due to conditions like hyper-reactive malarial splenomegaly, non-cirrhotic portal fibrosis, iron deficiency anaemia, and even cirrhosis of liver, while malaria is still the most important cause of splenomegaly in India. Whereas the overall incidence of hyper-reactive malarial splenomegaly was only 7% in this study, it stood as the leading cause (29.2%), when analysed among patients with massive splenomegaly. Liver biopsy should be performed in all cases of obscure splenomegaly to arrive at the final diagnosis.     

Formulation,optimization and characterization of raloxifene hydrochloride loaded PLGA nanoparticles by using Taguchi design for breast cancer application

Multidrug resistance in breast cancer and the associated side-effects of anticancer therapies are significant hurdles in chemotherapy-based treatment. Biodegradable polymeric nano-based targeted drug delivery technologies showed tremendous advantages in targeted local delivery with limited off-targeted side effects. Therefore, there is a persistent need to develop targeted nanomedicine systems for treatment of breast cancer. The current research attempted to develop poly (lactic-co-glycolic acid) nanoparticles loaded with raloxifene by modified emulsification solvent diffusion evaporation method to improve oral bioavailability by using Taguchi design. It was observed that the optimized formulation (1:4 drug to polymer ratio) poly (lactic-co-glycolic acid) showed a mean particle size and Polydispersity index of 218 ± 23.7 nm and 0.231 ± 0.04, respectively. The entrapment efficiency was found to be 82.30% ± 1.02%. In vitro drug delivery was found to be 92.5% ± 1.48% in 40 h. The nanoparticles were to remain stable at 2°C–8°C even after 30 days. Differential scanning calorimetry and Fourier transform infrared spectroscopy characterization techniques showed that there was no interaction between the drug and excipient. Stability studies indicate that polymeric nanoparticles were stable at 2°C–8°C after 6 months. Raloxifene nanoparticles may be the most potent targeting moieties to treat highly invasive and metastatic MCF-7 breast cancer cells.     

Lymph node yield during radical prostatectomy does not impact rate of biochemical recurrence in patients with seminal vesicle invasion and node-negative disease

Objectives

Seminal vesicle invasion (SVI) is a risk factor for poor oncologic outcome in patients with prostate cancer. Modifications to the pelvic lymph node dissection (PLND) during radical prostatectomy (RP) have been reported to have a therapeutic benefit. The present study is the first to determine if lymph node yield (LNY) is associated with a lower risk of biochemical recurrence (BCR) for men with SVI.

Management of deficient anterior maxillary alveolus with mandibular parasymphyseal bone graft for implants

This paper discusses the use of autogenous bone graft from the symphyseal region of the mandible to widen the deficient anterior maxilla. Compressing short or narrow implants into deficient ridges is a poor technique that often fails to correctly replace ridge anatomy or afford stable restorations. Patients who were missing a maxillary incisor, and exhibiting a loss of supporting bone in the area, were found suitable for this technique. Ten patients were included in the study. In the anterior maxilla, the thin cortices can be split, and a corticocancellous bone graft from the mandibular symphyseal region can be positioned on the labial-buccal cortex. This surgical procedure enables implant placement in previously deficient bone within the maxilla. In comparison with other techniques, the use of a mandibular symphysis graft technique offers ease of access, good bone quantity for localized repair, a corticocancellous block graft morphology, low morbidity, decreased complaints of postoperative sensory disturbances and discomfort, and minimal graft resorption. An improved bone density results along with a shorter healing time as compared with other methods for bone repair. A success rate of 81.2% was obtained after a mean follow-up period of 3 years.     

Effect of 17beta-estradiol on apoptosis, IGF system components and gelatinases A and B in prostate cancer cells (PC-3)

BACKGROUND: Previous studies have indicated that estrogen administration in the advanced stage of prostate cancer provide some benefits to the patients. Estrogen action was thought to be mediated via the blockade of the pituitary-testicular axis that effectively lowered the circulating levels of androgen and, thus, results in tumor regression; however, the effect of estrogens on prostate epithelial cells is still unclear. We investigated the effects of estradiol on insulin-like growth factor type I receptor (IGF-IR), IGF-binding protein 3 (IGFBP-3), IGFBP-4, and matrix metalloproteinase 2 (MMP-2) and MMP-9 in androgen-independent prostate cancer cells (PC-3). METHODS: The cells were treated with different concentrations of estradiol (1, 10 and 100 nmol/l) for different time periods (24, 48, 72 and 96 h). Cell proliferation was assessed using MTT assay, and IGFBP-3 and IGFBP-4 were assessed using immunoradiometric and enzyme immunoassays, respectively. MMP-2, MMP-9 and IGF-IR expression levels were analyzed using western-blot analysis, and MMP-2 and MMP-9 activities were analyzed using gelatin zymography. Apoptosis was confirmed by Annexin V-FITC and acridine orange and ethidium bromide staining methods. DNA fragmentation studies were also performed. RESULTS: Cell proliferation assay revealed that 10 and 100 nmol/l estradiol concentrations inhibit the proliferation of PC-3 cells when incubated for 48-96 h. The secretory levels of IGFBP-3 and IGFBP-4 were increased significantly. The western-blot results showed that estradiol is capable of decreasing the expression of MMP-2 and MMP-9 significantly. Gelatin zymography showed that activities of MMP-2 and MMP-9 are decreased in estradiol-treated cells. Estradiol-induced apoptosis was studied using annexin V-binding and propidium iodide influx. Estradiol also induced nuclear fragmentation in higher doses (100 nmol/l) in PC-3 cells. CONCLUSION: Inhibition of MMPs in cancer cells and increased levels of IGFBP-3 and IGFBP-4 associated with apoptosis may be one of the targets for anticancer function of estradiol. Estradiol inhibits the proliferation of prostate cancer cells by inducing apoptosis.