A mutation in caspase-9 decreases the expression of BAFFR and ICOS in patients with immunodeficiency and lymphoproliferation

Lymphocyte apoptosis is mainly induced by either death receptor-dependent activation of caspase-8 or mitochondria-dependent activation of caspase-9. Mutations in caspase-8 lead to autoimmunity/lymphoproliferation and immunodeficiency. This work describes a heterozygous H237P mutation in caspase-9 that can lead to similar disorders. H237P mutation was detected in two patients: Pt1 with autoimmunity/lymphoproliferation, severe hypogammaglobulinemia and Pt2 with mild hypogammaglobulinemia and Burkitt lymphoma. Their lymphocytes displayed defective caspase-9 activity and decreased apoptotic and activation responses. Transfection experiments showed that mutant caspase-9 display defective enzyme and proapoptotic activities and a dominant-negative effect on wild-type caspase-9. Ex vivo analysis of the patients' lymphocytes and in vitro transfection experiments showed that the expression of mutant caspase-9 correlated with a downregulation of BAFFR (B-cell-activating factor belonging to the TNF family (BAFF) receptor) in B cells and ICOS (inducible T-cell costimulator) in T cells. Both patients carried a second inherited heterozygous mutation missing in the relatives carrying H237P: Pt1 in the transmembrane activator and CAML interactor (TACI) gene (S144X) and Pt2 in the perforin (PRF1) gene (N252S). Both mutations have been previously associated with immunodeficiencies in homozygosis or compound heterozygosis. Taken together, these data suggest that caspase-9 mutations may predispose to immunodeficiency by cooperating with other genetic factors, possibly by downregulating the expression of BAFFR and ICO

Acne Supplementation: Probiotics, Vitamins, and Diet

Acne is an inflammatory disease of the pilo-sebaceous unit, which mainly affects young adolescents. The pathogenesis is multifactorial, as a combination of genetic predisposition, hormonal production, hyper-seborrhea, inflammation and overgrowth of C. acnes. Moreover, dietinduced hyperinsulinemia can lead to sebocyte stimulation, androgen production, and thus acne lesions. Pharmacological therapeutic approaches are varied and include topical and systemic antibiotics and, in severe cases, systemic retinoids, with several side-effects. However, increasing evidence has shown that adequate vitamin supplementation, use of probiotics, and proper nutrition with low carbohydrates and fats intake, can significantly contribute to the patient’s clinical improvement. In this review, we describe the role of probiotics, vitamins, alimentation, antioxidants, UV exposure, and plants in acne disease

Acne Supplementation: Probiotics, Vitamins, and Diet

Acne is an inflammatory disease of the pilo-sebaceous unit, which mainly affects young adolescents. The pathogenesis is multifactorial, as a combination of genetic predisposition, hormonal production, hyper-seborrhea, inflammation and overgrowth of C. acnes. Moreover, dietinduced hyperinsulinemia can lead to sebocyte stimulation, androgen production, and thus acne lesions. Pharmacological therapeutic approaches are varied and include topical and systemic antibiotics and, in severe cases, systemic retinoids, with several side-effects. However, increasing evidence has shown that adequate vitamin supplementation, use of probiotics, and proper nutrition with low carbohydrates and fats intake, can significantly contribute to the patient’s clinical improvement. In this review, we describe the role of probiotics, vitamins, alimentation, antioxidants, UV exposure, and plants in acne disease

Sr-containing mesoporous bioactive glasses bio-functionalized with recombinant ICOS-Fc: An in vitro study

Osteoporotic bone fractures represent a critical clinical issue and require personalized and specific treatments in order to stimulate compromised bone tissue regeneration. In this clinical context, the development of smart nano-biomaterials able to synergistically combine chemical and biological cues to exert specific therapeutic effects (i.e., pro-osteogenic, anti-clastogenic) can allow the design of effective medical solutions. With this aim, in this work, strontium-containing mesoporous bioactive glasses (MBGs) were bio-functionalized with ICOS-Fc, a molecule able to reversibly inhibit osteoclast activity by binding the respective ligand (ICOS-L) and to induce a decrease of bone resorption activity. N2 adsorption analysis and FT-IR spectroscopy were used to assess the successful grafting of ICOS-Fc on the surface of Sr-containing MBGs, which were also proved to retain the peculiar ability to release osteogenic strontium ions and an excellent bioactivity after functionalization. An ELISA-like assay allowed to confirm that grafted ICOS-Fc molecules were able to bind ICOS-L (the ICOS binding ligand) and to investigate the stability of the amide binding to hydrolysis in aqueous environment up to 21 days. In analogy to the free form of the molecule, the inhibitory effect of grafted ICOS-Fc on cell migratory activity was demonstrated by using ICOSL positive cell lines and the ability to inhibit osteoclast differentiation and function was confirmed by monitoring the differentiation of monocyte-derived osteoclasts (MDOCs), which revealed a strong inhibitory effect, also proven by the downregulation of osteoclast differentiation genes. The obtained results showed that the combination of ICOS-Fc with the intrinsic properties of Sr-containing MBGs represents a very promising approach to design personalized solutions for patients affected by compromised bone remodeling (i.e., osteoporosis fractures)

In vitro evidence for CCl4 metabolites covalently bound to lipoprotein micelles

AbstractCCl4-induced impairment of the lipoprotein secretion pathway of intact rat hepatocytes was carried out using 14CCl4 to check the possibility of binding to lipoproteins by CCl4 metabolites. After separation of different cell suspension fractions by means of ultracentrifugation and chemical precipitation procedures, a significant amount of the radioisotope was found covalently bound to the lipid and protein components of low density lipoproteins. Suitable experiments demonstrated that the bound radioisotope was represented by CCl4 metabolites and not by unactivated CCl4