Francesco Carini

Hsp60, a novel target for antitumor therapy: Structure-function features and prospective drugs design

Heat shock protein 60 kDa (Hsp60) is a chaperone classically believed to be involved in assisting the correct folding of other mitochondrial proteins. Hsp60 also plays a role in cytoprotection against cell stressors, displaying for example, antiapoptotic potential. Despite the plethora of studies devoted to the mechanism of Hsp60s function, especially in prokaryotes, fundamental issues still remain unexplored, including the definition of its role in cancer. Key questions still unanswered pertain to the differences in structure-function features that might exist between the well-studied prokaryotic GroEL and the largely unexplored eukaryotic Hsp60 proteins. In this article we discuss these differences in sequence, structure, and roles of Hsp60, focusing on the human ortholog with the view of devising compounds to block its ability to favour tumor-cell growth and survival. Compounds currently known to directly or indirectly affect Hsp60 functions, such as protein folding, HIF-1α accumulation, or Hsp60-induced cell proliferation, are discussed along with strategies that might prove effective for developing Hsp60-targeting drugs for anticancer therapy.

Do fat supplements increase physical performance

Fish oil and conjugated linoleic acid (CLA) belong to a popular class of food supplements known as “fat supplements”, which are claimed to reduce muscle glycogen breakdown, reduce body mass, as well as reduce muscle damage and inflammatory responses. Sport athletes consume fish oil and CLA mainly to increase lean body mass and reduce body fat. Recent evidence indicates that this kind of supplementation may have other side-effects and a new role has been identified in steroidogenensis. Preliminary findings demonstrate that fish oil and CLA may induce a physiological increase in testosterone synthesis. The aim of this review is to describe the effects of fish oil and CLA on physical performance (endurance and resistance exercise), and highlight the new results on the effects on testosterone biosynthesis. In view of these new data, we can hypothesize that fat supplements may improve the anabolic effect of exercise.

Doxorubicin anti-tumor mechanisms include Hsp60 post-translational modifications leading to the Hsp60/p53 complex dissociation and instauration of replicative senescence

The chaperone Hsp60 is pro-carcinogenic in certain tumor types by interfering with apoptosis and with tumor cell death. In these tumors, it is not yet known whether doxorubicin anti-tumor effects include a blockage of the pro-carcinogenic action of Hsp60. We found a doxorubicin dose-dependent viability reduction in a human lung mucoepidermoid cell line that was paralleled by the appearance of cell senescence markers. Concomitantly, intracellular Hsp60 levels decreased while its acetylation levels increased. The data suggest that Hsp60 acetylation interferes with the formation of the Hsp60/p53 complex and/or promote its dissociation, both causing an increase in the levels of free p53, which can then activate the p53-dependent pathway toward cell senescence. On the other hand, acetylated Hsp60 is ubiquitinated and degraded and, thus, the anti-apoptotic effect of the chaperonin is abolished with subsequent tumor cell death. Our findings could help in the elucidation of the molecular mechanisms by which doxorubicin counteracts carcinogenesis and, consequently, it would open new roads for the development of cancer treatment protocols targeting Hsp60.

Hsp60 and human aging: Les liaisons dangereuses.

Stressors can cause abnormal intracellular accumulation of Hsp60 and its localization in extramitochondrial sites, secretion, and circulation, with immune system activation. Dysfunction of chaperones associated with their quantitative and qualitative decline with aging (chaperonopathies of aging) characterizes senescence and is a potential causal factor in the physiological deterioration that occurs with it. The role of Hsp60 in aging is not easy to elucidate, because aging is accompanied by pathologies (e.g., cardiovascular and neurodegenerative disorders, osteoporosis, diabetes, cancer, etc.) in which Hsp60 has been implicated but, although those disorders are more frequent in the elderly, they are not unique to them. Therefore, it is difficult to determine what is due to aging and what to an associated disease that can occur regardless of age. Does Hsp60 contribute to the pathogenesis? How and when does Hsp60 interact with the immune system and, thus, contributes to the initiation-progression of the generalized chronic inflammation characteristic of aging? These and related issues are discussed here in the light of reports showing the participation of Hsp60 in aging-associated disorders.

Association between COX-2 rs 6681231 genotype and interleukin-6 in periodontal connective tissue. A pilot study.

Objectives The aim of this pilot study was to investigate associations between IL-6 and COX-2 expression in gingival biopsies and both clinical diagnosis and genotypes in the IL-6 and COX-2 genes. Design A case-control study included 41 gingival biopsies obtained from Caucasian patients grouped according to clinical diagnosis of gingival health (n = 10), gingivitis (n = 15) or chronic periodontitis (n = 16). Immunohistochemistry analyses were performed to determine COX-2 expression in lamina propria, IL-6 expression in lamina propria and gingival epithelium and level of inflammatory cell infiltrate. Individual DNA was extracted and genotyped by real-time PCR for IL6 SNPs rs 2069827 and rs 2069825 and for COX-2 rs 6681231. Results The percentage of cellular COX-2 expression was associated with the extent of periodontal disease (Arbes index p = 0.026) and inflammatory infiltrate (p<0.0001). No association was observed between IL6 haplotypes and cells positive to IL-6 or COX-2 in gingival tissues. The COX-2 rs 6681231 was associated with cells positive to IL-6 in the connective tissue (p = 0.032). Conclusions COX-2 expression in gingival tissues may be a marker of periodontal disease severity. COX-2 rs 6681231 may be associated with IL-6 local production in gingival tissues.

The long-term effects of probiotics in the therapy of ulcerative colitis: A clinical study

AIM Intestinal dysbiosis seems to be the leading cause of inflammatory bowel diseases, and probiotics seems to represent the proper support against their occurrence. Actually, probiotic blends and anti-inflammatory drugs represent a weapon against inflammatory bowel diseases. The present study evaluates the long-term (2 years) effects of combination therapy (mesalazine plus a probiotic blend of Lactobacillus salivarius, Lactobacillus acidophilus and Bifidobacterium bifidus strain BGN4) on ulcerative colitis activity. METHOD Sixty patients with moderate-to-severe ulcerative colitis were enrolled: 30 of them were treated with a single daily oral administration of mesalazine 1200 mg; 30 patients received a single daily oral administration of mesalazine 1200 mg and a double daily administration of a probiotic blend of Lactobacillus salivarius, Lactobacillus acidophilus and Bifidobacterium bifidus strain BGN4. The treatment was carried out for two years and the clinical response evaluated according to the Modified Mayo Disease Activity Index. RESULTS All patients treated with combination therapy showed better improvement compared to the controls. In particular, the beneficial effects of probiotics were evident even after two years of treatment. CONCLUSIONS A long-term treatment modality of anti-inflammatory drugs and probiotics is viable and could be an alternative to corticosteroids in mild-to moderate ulcerative colitis.

Quantitative patterns of Hsps in tubular adenoma compared with normal and tumor tissues reveal the value of Hsp10 and Hsp60 in early diagnosis of large bowel cancer

Large bowel carcinogenesis involves accumulation of genetic alterations leading to transformation of normal mucosa into dysplasia and, lastly, adenocarcinoma. It is pertinent to elucidate the molecular changes occurring in the pre-neoplastic lesions to facilitate early diagnosis and treatment. Heat shock proteins (Hsps), many of which are molecular chaperones, are implicated in carcinogenesis, and their variations with tumor progression encourage their study as biomarkers. There are many reports on Hsps and cancer but none to our knowledge on their systematic quantification in pre-neoplastic lesions of the large bowel. We performed immunohistochemical determinations of Hsp10, Hsp60, Hsp70, and Hsp90 in biopsies of large bowel tubular adenomas with moderate grade of dysplasia and compared to normal mucosa and adenocarcinoma with a moderate grade of differentiation (G2). A significant elevation of Hsp10 and Hsp60 only, i.e., in the absence of elevation of Hsp70 or Hsp90, in both epithelium and lamina propria was found in tubular adenoma by comparison with normal mucosa. In contrast, adenocarcinoma was characterized by the highest levels of Hsp10 and Hsp60 in epithelium and lamina propria, accompanied by the highest levels of Hsp70 only in epithelium and of Hsp90 only in lamina propria, by comparison with normal and tubular adenoma counterparts. Hsp10 and Hsp60 are promising biomarkers for early diagnosis of tubular adenoma and for its differentiation from more advanced malignant lesions. Hsp10 and Hsp60 may be implicated in carcinogenesis from its very early steps and, thus, are potentially convenient targets for therapy.

Microcirculation in the healing of surgical wounds in the oral cavity

The aim of this research is to evaluate in vivo the characteristics of microcirculation after taking a biopsy sample from the oral mucosa. 20 patients were recruited to the study and all underwent an oral mucosa biopsy for the excision of benign neoformations. The modifications in the oral microcirculation were evaluated in vivo in correspondence to the surgical site through videocapillaroscopy at three different times: 30 min before the biopsy; 48 h after the biopsy; and 7 days after the biopsy. The statistical significance was checked with the Mann-Whitney U-test (P<0.05). The analysis of videocapillaroscopic patterns showed statistically significant variations relative to the capillary loop density; the diameter of the outgoing loop; and the length of the capillary loop. In conclusion, the study describes a simple and reproducible model for the study of wound healing from a microcirculatory point of view.

Intestinal dysbiosis and hormonal neuroendocrine secretion in the fibromyalgic patient: Relationship and correlations

Fibromyalgia is a rheumatic syndrome and its pathogenesis is controversial. The recent literature has placed considerable attention on the link between alteration of the intestinal microbiota and fibromyalgia, emphasizing the close connection between the neuroenteric system and the CNS. This study aims to evaluate the probable relationship between intestinal dysbiosis and altered secretion of hormones and vitamins such as cortisol, serotonin, Vitamin D and thyroid hormones in a patient with fibromyalgia.

POSTURE AND POSTUROLOGY, ANATOMICAL AND PHYSIOLOGICAL PROFILES: OVERVIEW AND CURRENT STATE OF ART

Background and aim of work: posture is the position of the body in the space, and is controlled by a set of anatomical structures. The maintenance and the control of posture are a set of interactions between muscle-skeletal, visual, vestibular, and skin system. Lately there are numerous studies that correlate the muscle-skeletal and the maintenance of posture. In particular, the correction of defects and obstruction of temporomandibular disorders, seem to have an impact on posture. The aim of this work is to collect information in literature on posture and the influence of the stomatognathic system on postural system. Methods: Comparison of the literature on posture and posturology by consulting books and scientific sites. Results: the results obtained from the comparison of the literature show a discrepancy between the thesis. Some studies support the correlation between stomatognathic system and posture, while others deny such a correlation. Conclusions: further studies are necessary to be able to confirm one or the other argument. (www.actabiomedica.it)