Hyaluronan-estradiol nanogels as potential drug carriers to target ER+ breast cancer cell line.

An innovative hyaluronan-based nano-delivery system is proposed for the active targeting towards ER+ breast cancer. Hyaluronic acid (HA), an endogenous and bioactive anionic polysaccharide, is functionalized with estradiol (ES), a sexual hormone involved in the development of some hormone-dependent tumors, to give an amphiphilic derivative (HA-ES) able to spontaneously self-assemble in water to form soft nanoparticles or nanogels (NHs). The synthetic strategy used to obtain the polymer derivatives and the physico-chemical properties of the obtained nanogels (ES-NHs) are reported. ES-NHs ability to entrap hydrophobic molecules has also been investigated, by loading curcumin (CUR) and docetaxel (DTX), both able to inhibit the growth of ER+ breast cancer. The formulations are studied for their capability to inhibit the growth of the MCF-7 cell line, thus evaluating their efficacy and potential as a selective drug delivery systems. Our results demonstrate that ES-NHs have not toxic effects on the cell line, and that both ES-NHs/CUR and ES-NHs/DTX treatments inhibit MCF-7 cell growth, with ES-NHs/DTX effect higher than that of free DTX. Our findings support the use of ES-NHs to deliver drugs to ER+ breast cancer cells, assuming a receptor-dependent targeting.

A semi-automated protocol for NGS metabarcoding and fungal analysis in forensic.

Metabarcoding through Next Generation Sequencing (NGS) has revolutionized environmental biological studies. The availability of this technical approach has opened the opportunity for a systematic implementation of fungal metabarcoding analysis in forensics, where standardized, sensitive and reproducible protocols are highly desirable. In the present paper, a pipeline including a semi-automated molecular protocol and user-friendly bioinformatics tools are applied to several kinds of environmental samples and forensic caseworks. The identification of fungi that characterize specific environments (like Aspergillus for indoor walls, or Penicillium, Debaryomices and Wickerhamomyces for food storage) can be informative for the provenance of samples. In some situations, fungal analysis cannot allow the identification of a defined environment but seems useful to cluster samples with similar provenance. Based on these considerations, fungal analysis can be included in a wider process of non-human DNA identification in order to provide clues on sample provenance.

Immunity to extracellular matrix antigens is associated with ultrastructural alterations of the stroma and stratified epithelium basement membrane in the skin of Hashimotos thyroiditis patients.

Employing purified extracellular matrix (ECM) proteins, i.e. type I, III, IV and V collagens (CI, CIII, CIV, CV), laminin (LM) and fibronectin (FN), as antigen sources we detected autoantibodies to conformational and/or denatured ECM antigens among 34 of 50 sera obtained from Hashimotos thyroiditis (HT) patients and 6 of 51 control sera obtained from non-autoimmune thyroid disease patients and healthy donors (HT sera vs. control sera p=4 x 10-9). Reactivity to conformational antigens, mostly due to autoantibodies of the IgG isotype, was observed in 30/50 HT sera and in 6/51 control sera (p=3.5 x 10-7) and was not always concomitant with that to linear antigens, found in 23/50 HT and in 6/51 control sera (p=1.6 x 10-4). Ultrastructural analysis of skin biopsies obtained from 18 HT patients without symptomatic cutaneous diseases revealed defects of the stratified squamous epithelium basement membrane in 11/18, alterations of the stroma in 13/18 and both basement membrane and stromal defects in 9/18. Interestingly, 13/13 (p=0.012) and 9/11 (p=0.012) patients with stromal and basement membrane defects respectively, exhibited serum antibodies to at least one ECM antigen involved in the organization of the altered tissue compartment. Lastly, 10/18 skin biopsies presented immunoglobulin (Ig) and/or complement (C3) deposits along the cutaneous basement membrane zone (BMZ) or in the papillary dermis and 9/10 sera from the same patients simultaneously showed antibodies to at least one ECM antigen involved in the organization of these two skin compartments. Besides, 8/11 HT patients with basement membrane defects exhibited Ig or C3 deposits along the BMZ. Our findings suggest that autoantibodies to ECM molecules might contribute to the development of asymptomatic extra-thyroid skin diseases in HT patients.

The epidemiology of partialandrogen deficiency in aging men (PADAM).

The quest for eternal youth has been prevalent in civilised societies in many cultures for many centuries. Preventing or deferring the disabilities and morbidities associated with aging through judicious pharmacotherapy has become a particularly relevant healthcare target with the rapid and relentless global demographic shift towards an increasingly elderly population in the 21th century. Aging men commonly loose muscle, become frail, have impaired sexual and cognitive functions, low mood, develop osteopenia and/or osteoporosis with increased risk for fractures and gain visceral fat which predisposes to diabetes, dyslipidaemia, and ischemic heart disease. These alterations in body function are reminiscent of states of androgen deficiency in younger patients. Indeed, aging is associated with a progressive age-related but variable decline in sex hormones. This condition has been named partial androgen deficiency in aging men (PADAM) and consists in a gradual decline in sex hormone levels over years resulting in physical and psychological changes as depression, impotence, decreased sex drive, loss of muscle tone or strength and lethargy. In this review we have tried to give a real identity to PADAM and quantify its entitiy, using the power of the epidemiology.

New achievement and novel therapeutic applications of PDE5 inhibithors in older males.

Erectile dysfunction (ED) increases in prevalence and severity because of aging processes and related organic, iatrogenic and social problems. Decline of testosterone (T) levels is observed with age and also in illnesses with a common basis of endothelial damage. The T deficiency may lead to decreased energy, mood depression, reduction of sexual desire, but no correlation has been reported between T level and severity of ED, which is mainly a neurovascular disease. In facts, inhibition of phosphodiesterase type 5 (PDE5) isoenzyme with sildenafil, tadalafil and vardenafil enhances vasodilatation in the corpus cavernosum and subsequent penile erection. Absolute pharmacological potency of PDE5 inhibitors is similar and non-selectivity defines the side-effects profile, while their elimination half-life explains not only the different duration of action, but also short and long-term tolerability. Efficacy of PDE5 inhibitors in younger patients is greater in respect to older subjects because of associated pathologies and the decline in hypothalamic-pituitary-gonadal function. T is essential in erectile function, controlling the expression and activity of PDE5 and therefore, androgen supplementation improves therapeutic response to PDE5 inhibitors in hypogonadal subjects. Since sexual behavior is a complex interplay of physical, psychological, and social factors, the possible effect of these drugs on androgen levels and brain function need to be deeply investigated. The ubiquitarious distribution of PDE5 and the availability of selective inhibitory molecules foster newer studies in the treatment of heart failure, pulmonary hypertension, inflammation, and depression. This new progress is certainly contributing to a better medical approach to sexuality and quality of life in aging people.

Androgens and body composition in the aging male.

The relevant age-related changes in male body composition are mainly related to the progressive decrease in the level of circulating anabolic hormones, among which testosterone (T) is rather important. Its decline, between the ages of 35 and 75, is associated to a loss of muscle mass and fibers number, a doubling of fat mass and a decrease in bone mineral density by 0.3% per yr after age 35; thus the relationship between age-related changes in body composition and T bioactivity reflects an important endocrine aspect of the aging male. The assessment of human body composition and in particular the evaluation of fat tissue and its distribution, is currently standardized by the use of dual-energy x-ray absorpiometry (DXA). In the present paper we review the mechanisms through which testosterone may inhibit adipogenesis, restore the myogenic programme enhancing the protein turnover at muscle level and maintain bone mineral density in elderly men.

Phosphodiesterase type 5 inhibithors in older males.

Although erectile dysfunction (ED) in older subjects needs a holistic approach, the pathophysiology consists mainly in chronic ischemia with deterioration of cavernous smooth muscles followed by development of corporeal fibrosis. Therefore, phosphodiesterase type 5 (PDE5) inhibition, enhancing vasodilatation in corpora cavernosa, represents a first-line therapy for ED. PDE5 is in fact the major cGMP hydrolizing enzyme in penile corpus cavernosum. The mechanisms of action, the pharmacokinetics and the contraindications of selective PDE5 inhibitors, are described in details. Furthermore, attention is focused on the interaction of PDE5 inhibitors on hypothalamus-pituitary gonadol (HPG) function. Finally, considering that androgens may influence sexual behavior by modifying the central nervous system neurotransmitter targeted system, the potentiation of PDE5 inhibitors with testosterone supplementation may be considered to improve erectile function and quality of life in older males.