Therapeutic Potential of Gnetin C in Prostate Cancer: A Pre-Clinical Study

Natural stilbenes have gained significant attention in the scientific community owing to their potential anticancer effects against prostate cancer. We recently reported that Gnetin C, a resveratrol (Res) dimer, demonstrated more potent inhibition of metastasis-associated protein 1/v-ets avian erythroblastosis virus E26 oncogene homolog 2 (MTA1/ETS2) axis in prostate cancer cell lines than other stilbenes. In this study, we investigated in vivo antitumor effects of Gnetin C in two doses (50 and 25 mg/kg, i.p.) using PC3M-Luc subcutaneous xenografts and compared these to Res and pterostilbene (Pter). We found that while vehicle-treated mice revealed rapid tumor progression, compounds-treated mice showed noticeable delay in tumor growth. Gnetin C in 50 mg/kg dose demonstrated the most potent tumor inhibitory effects. Gnetin C in 25 mg/kg dose exhibited tumor inhibitory effects comparable with Pter in 50 mg/kg dose. Consistent with the effective antitumor effects, Gnetin C-treated tumors showed reduced mitotic activity and angiogenesis and a significant increase in apoptosis compared to all the other groups. The data suggest that Gnetin C is more potent in slowing tumor progression in prostate cancer xenografts than Res or Pter. Taken together, we demonstrated, for the first time, that Gnetin C is a lead compound among stilbenes for effectively blocking prostate cancer progression in vivo.     

Estrogen,migraine, and vascular risk

Migraine has a predilection for female sex and the course of symptoms is influenced by life stage (presence of menstrual cycle, pregnancy, puerperium, menopause) and use of hormone therapy, such as hormonal contraception and hormone replacement therapy. Hormonal changes figure among common migraine triggers, especially sudden estrogen drop. Moreover, estrogens can modulate neuronal excitability, through serotonin, norepinephrine, dopamine, and endorphin regulation, and they interact with the vascular endothelium of the brain. The risk of vascular disease, and ischemic stroke in particular, is increased in women with migraine with aura (MA), but the link is unclear. One hypothesis posits for a causal association: migraine may cause clinical or subclinical brain lesions following repeated episodes of cortical spreading depression (CSD) and a second hypothesis that may explain the association between migraine and vascular diseases is the presence of common risk factors and comorbidities. Estrogens can play a differential role depending on their action on healthy or damaged endothelium, their endogenous or exogenous origin, and the duration of their treatment. Moreover, platelet activity is increased in migraineurs women, and it is further stimulated by estrogens.This review article describes the course of migraine during various life stages, with a special focus on its hormonal pathogenesis and the associated risk of vascular diseases.     

TPO genetic variants and risk of differentiated thyroid carcinoma in two European populations

Thyroid cancer risk involves the interaction of genetic and environmental factors. The thyroperoxidase (TPO) has a key role in the iodine metabolism, being essential for the thyroid function. Mutations in the TPO gene are common in congenital hypothyroidism, and there are also signs of the implication of TPO in thyroid cancer. We performed a case–control association study of genetic variants in TPO and differentiated thyroid carcinoma (DTC) in 1,586 DTC patients and 1,769 controls including two European populations (Italy: 1,190 DTC and 1,290 controls; Spain: 396 DTC and 479 controls). Multivariate logistic regression analyses were performed separately for each population and each single‐nucleotide polymorphism (SNP). From the three studied polymorphisms, significant associations were detected between DTC and rs2048722 and rs732609 in both populations (p < 0.05). In the Italian population, both SNPs showed a negative association (rs2048722, odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.63–1.00, p = 0.045; rs732609, OR = 0.72, 95% CI = 0.55–0.94, p = 0.016), whereas in the Spanish population, these SNPs showed a positive association (rs2048722, OR = 1.39, 95% CI = 1.03–1.89, p = 0.033; rs732609, OR = 1.41, 95% CI = 1.06–1.87, p = 0.018). The corresponding associations for papillary or follicular thyroid cancer were similar to those for all DTC, within population. No association was detected for the third TPO polymorphism in the Italian and the Spanish populations. Our results, for the first time, point to TPO as a gene involved in the risk of DTC, and suggest the importance of interactions between TPO variants and other unidentified population‐specific factors in determining thyroid cancer risk.     

New evidence for a critical role of elastin in calcification of native heart valves: immunohistochemical and ultrastructural study with literature review

Perrotta I, Russo E, Camastra C, Filice G, Di Mizio G, Colosimo F, Ricci P, Tripepi S, Amorosi A, Triumbari F & Donato G
(2011) Histopathology 59 , 504–513 New evidence for a critical role of elastin in calcification of native heart valves: immunohistochemical and ultrastructural study with literature review Aims: Calcific aortic stenosis is a progressive disease characterized by massive fibrosis andmineralization of the valve leaflets. The aim of this study was to determine whether the onset of native calcific aortic stenosis is associated primarily with matrix remodelling events, and particularly with elastin degradation. Methods and results: The immunohistochemical expression profile of matrix degradating enzymes and tenascin‐C was investigated in both healthy and native calcified aortic valves. Collagen and elastic tissue were studied by light microscopy and electron microscopy. Immunophenotypic analysis of inflammatory cells was carried out by using monoclonal antibodies to macrophages, T and B lymphocytes. Immunoreactivity for tenascin‐C and matrix metalloproteinase‐12 (MMP‐12) was associated with areas of dense mineralization, which were characterized by fibrosis, fragmentation and calcification of elastic fibres a positive reaction was also found around small islands of calcification. MMP‐11 was not detected in the diseased valves. Osteopontin and osteonectin were also found at sites of mineralization. All calcified valves examined showed inflammatory cell infiltration. Conclusions: Our results demonstrate the direct involvement of MMP‐12 in native aortic valve stenosis. MMP‐mediated degradation of elastic fibres might contribute actively to valve mineralization by inducing calcium deposition onto fragmented elastin.     

Persistence of recipient-type endothelium after allogeneic hematopoietic stem cell transplantation

Background

The possibility that allogeneic hematopoietic stem cell transplantation performed across the ABO blood group-barrier is associated with an increase of graft-versus-host disease, in particular endothelial damage, has not been elucidated so far. For this reason, we investigated the level of endothelial cell chimerism after allogeneic hematopoietic stem cell transplantation in order to delineate the role of hematopoietic stem cells in endothelial replacement.

Design and Methods

The frequency of donor-derived endothelial cells was analyzed in 52 hematopoietic stem cell transplant recipients, in 22 normal skin biopsies, in 12 skin samples affected by graft-versus-host disease, various tissues from five autopsies and four secondary solid tumors by ABH immunohistochemistry, XY fluorescence in situ hybridization and short tandem repeat analysis of laser captured endothelial cells.

Results

Skin biopsies from two patients transplanted with minor ABO-incompatible grafts (i.e. O in A) showed 3.3% and 0.9% H antigen-positive donor-derived endothelial cells by ABH immunohistochemistry. Tumor biopsies from two recipients showed 1.2% and 2.5% donor-derived endothelial cells by combined immunohistochemistry/ fluorescence in situ hybridization. All other skin samples, heart, liver, bone-marrow, and tumor tissues failed to reveal donor-type endothelial cells up to several years after ABO-incompatible hematopoietic stem cell transplantation.

Conclusions

Endothelial cell replacement by bone marrow-derived donor cells after allogeneic hematopoietic stem cell transplantation is a rare event. It does not seem to represent a major mechanism of physiological in vivo blood vessel formation, tumor neoangiogenesis, vascular repair after graft-versus-host disease episodes or acceptance of ABO-incompatible grafts.     

The Styrene Metabolite, Phenylglyoxylic Acid, Induces Striatal-Motor Toxicity in the Rat: Influence of Dose Escalation/Reduction over Time

Exposure to the industrial solvent, styrene, induces locomotor and cognitive dysfunction in rats, and parkinsonian-like manifestations in man. The antipsychotic, haloperidol (HP), well known to induce striatal toxicity in man and animals, and styrene share a common metabolic pathway yielding p-fluoro phenylglyoxylic acid and phenylglyoxylic acid (PGA), respectively. Using an exposure period of 30 days and the vacous chewing movement (VCM) model as an expression of striatal-motor toxicity, we found that incremental PGA dosing (220-400 mg/kg) significantly increased VCMs up to day 25, but decreased to control levels shortly after reaching maximum dose. However, a diminishing dose of PGA (400-200 mg/kg) did not evoke an immediate worsening of VCMs but precipitated a significant increase in VCMs following dosage reduction to 200 mg/kg on day 22. PGA exposure, therefore, compromises striatal-motor function that is especially sensitive to changes in exposure dose. Longer alternating dose exposure studies are needed to establish whether motor dysfunction is progressive in severity or longevity. These findings are of significance for the environmental toxicology of styrene in the chemical industry.     

Ear acupuncture in the treatment of migraine attacks: a randomized trial on the efficacy of appropriate versus inappropriate acupoints

Ear acupuncture can be a useful mean for controlling migraine pain. It has been shown that a technique called the Needle Contact Test (NCT) can identify the most efficacious ear acupoints for reducing current migraine pain through just a few seconds of needle contact. The majority of the points were located on the antero-internal part of the antitragus (area M) on the same side of pain. The aim of this study was to verify the therapeutic value of area M and to compare it with an area of the ear (representation of the sciatic nerve, area S) which probably does not have a therapeutic effect on migraine attacks. We studied 94 females suffering from migraine without aura, diagnosed according to the ICHD-II criteria, during the attack. They were randomly subdivided into two groups: in group A, tender points located in area M, positive to NCT were inserted; in group B, the unsuitable area (S) was treated. Changes in pain intensity were measured using a VAS scale at various times of the study. During treatment, there was a highly significant trend in the reduction of the VAS value in group A (Anova for repeated measures: p < 0.001), whereas no significance was observed in group B. VAS values were significantly lower in group A than in group B at 10, 30, 60 and 120 min after needle insertion. This study suggests that the therapeutic specificity of auricular points exists and is linked to the somatotopic representation of our body on the ear.     

Acupuncture in primary headache treatment

Acupuncture has a long tradition of use for the treatment of many pain conditions, including headache. Its effectiveness has been studied mainly for primary headaches, particularly for migraine and tension-type headache (TTH). Traditional Chinese Medicine (TCM) has two diagnostic frameworks for headaches: meridian diagnoses, based on the location of the pain and on the meridians (or channels) that pass through it; syndrome diagnoses, dependent on external or internal factors and on the characteristics of the pain. The four meridians involved in headache are Shaoyang (TE-GB channels, on the temporal sides of the head); Taiyang (SI-BL channels, occiput); Yangming (LI-ST channels, forehead) and Jueyin (PC-LR channels, vertex). The syndromes may be due to excess or deficit. Very generally, the excess syndromes correspond in the majority of cases to migraine and the deficit syndromes to TTH. Acupuncture is a complex intervention, which is also characterized by a close interaction between patient and therapist. The complicated system of TCM classification of headaches has frequently generated great diversity among the various therapeutic approaches used in the different studies on acupuncture in headache treatment. Despite these differences, the recent Cochrane systematic reviews on acupuncture in migraine and in TTH suggest that acupuncture is an effective and valuable option for patients suffering from migraine or frequent TTH. Moreover, acupuncture seems to be a cost-effective treatment.