The potential of siRNA based drug delivery in respiratory disorders: recent advances and progress

© 2019 Wiley Periodicals, Inc. Lung diseases are the leading cause of mortality worldwide. The currently available therapies are not sufficient, leading to the urgent need for new therapies with sustained anti-inflammatory effects. Small/short or silencing interfering RNA (siRNA) has potential therapeutic implications through post-transcriptional downregulation of the target gene expression. siRNA is essential in gene regulation, so is more favorable over other gene therapies due to its small size, high specificity, potency, and no or low immune response. In chronic respiratory diseases, local and targeted delivery of siRNA is achieved via inhalation. The effectual delivery can be attained by the generation of aerosols via inhalers and nebulizers, which overcomes anatomical barriers, alveolar macrophage clearance and mucociliary clearance. In this review, we discuss the different siRNA nanocarrier systems for chronic respiratory diseases, for safe and effective delivery. siRNA mediated pro-inflammatory gene or miRNA targeting approach can be a useful approach in combating chronic respiratory inflammatory conditions and thus providing sustained drug delivery, reduced therapeutic dose, and improved patient compliance. This review will be of high relevance to the formulation, biological and translational scientists working in the area of respiratory diseases

Study of role of serotonergic system in a murine model of acute Crohn's disease model

Il Morbo di Crohn (CD) è una delle forme più importante di Inflammatory Bowel Disease, caratterizzata dall’infiammazione della parete intestinale, con massiccia infiltrazione di macrofagi e linfociti. Questa patologia provoca non solo importanti manifestazione a livello intestinale ed è un fattore di rischio per il cancro colonrettale, ma presenta anche manifestazioni sistemiche, come osteoporosi , diabete di tipo II, trombosi ed ulcerazioni a livello epidermico . L'incidenza di CD è aumentata negli ultimi 10 anni, ed in particolare è fortemente incrementata nei centri urbani. La serotonina (5-HT) è uno dei più importanti neurotrasmettitori del tratto gastrointestinale, e la sua azione è modulata da un gran numero di recettori (5 - HTRs: 5-HT1A, 5-HT2, 5-HT3, 5-HT4, 5-HT7) . Diversi autori hanno dimostrato il ruolo fondamentale svolto dalla 5-HT nello sviluppo di questo tipo di patologia e la presenza di diversi 5-HTR sulla superficie di tutte le cellule del sistema immunitario. Scopo della nostra ricerca è quello di indagare il ruolo svolto dai 5-HTRs in un modello murino di CD acuta, realizzata con acido solfonico 2,4,6-trinitrobenzene (TNBS), attraverso la somministrazione di un antagonista del recettore 5-HT1A (WAY100135 ) ed un agonista del recettore 5-HT1A (8-OH DPAT∙HBr), nella prima parte del nostro studio, e attraverso la somministrazione di un antagonista del recettore 5- HT2 (Ketanserina), antagonista 5-HT3 (Ondansetron), antagonista 5-HT4 (GR125487) ed antagonista 5-HT7 (SB269970), nella seconda parte. Nella prima parte del nostro studio, abbiamo dimostrato che agonisti del recettore 5-HT1A svolgono un ruolo protettivo, mentre, l'antagonismo del recettore 5-HT1A provoca un peggioramento del quadro clinico. Nella seconda parte del nostro studio abbiamo dimostrato il ruolo protettivo svolto dagli antagonisti 5-HT2 e 5-HT4, il ruolo marginale svolto dal recettore 5-HT7 e l’effetto aggravante causatato dalla somministrazione di antagonisti del recettore 5-HT3. Tutti gli esperimenti sono stati eseguiti in conformità con principi guida nella cura e l'uso degli animali (DL117/92).Crohn’s Disease (CD) is one of the more important form of Inflammatory Bowel Disease, characterized by inflammation of intestinal wall, with a massive infiltration of macrophage and lymphocytes. This pathology causes not only important intestinal manifestation and a risk factor for colonrectal cancer, but also systemic effect, like osteoporosis, type II diabetes, thrombosis and skin ulceration . The incidence of CD is increase in the last 10 years, and in particular is strongly increase in the urban center. Serotonin (5-HT) in one of the most important neurotransmitter of gastrointestinal tract, and its action is modulated by a large number of receptor (5-HTRs: 5-HT1A, 5-HT2, 5-HT3, 5-HT4, 5-HT7). Many author have demonstrated the fundamental role of 5-HT in the development of this kind of pathology and the presence of 5-HTRs on the surface of all cell of immune system. Aim of our study is to investigate the role of 5-HTRs in a murine model of acute CD, realized using 2,4,6–trinitrobenzene sulphonic acid (TNBS), through the administration of a 5-HT1A receptor antagonist (WAY100135) and 5-HT1A receptor agonist (8-OH DPAT∙HBr) in the first part of our study, and through the administration of 5-HT2 antagonist (Ketanserin), 5-HT3 antagonist (Ondansetron), 5-HT4 antagonist (GR125487) and 5-HT7 antagonist (SB269970). In first part of our study, we have demonstrated that agonist of 5-HT1A receptor plays a protective role; by other hand, the antagonism of 5-HT1A receptor causes a clinical worsening. In second part of our study we demonstrate the protective role played by antagonist of 5-HT2 and 5-HT4 receptors, the marginal role played by 5-HT7 receptor antagonist and impaired effect caused by the administration of 5-HT3 receptor antagonist. All the experiments were performed in accordance with Guiding Principles in the Care and Use of Animals (DL117/92)

Sodium Channel Blocking Activity and In-vivo Testing of New Phenyl-imidazole Derivatives.

We previously reported the discovery of diphenylimidazoles as potent sodium channel blockers, potentially useful in the treatment of epilepsy. To further understand the structural requirements for the potency of these derivatives, we have synthesized new compounds introducing a carbonyl moyety between the imidazole and the phenyl ring in the two position, then reducing it to alchool, and we have tested them for their NaV1.6 sodium channel blocking activity and in rodent acute seizures models

Sodium channel blockers: a patent review (2010 - 2014)

Abnormal activity of voltage-gated sodium channels (VGSCs) is related to several pathological processes, including cardiac arrhythmias, epilepsy, cancer, neurodegenerative diseases, spasticity, chronic and neuropathic pain. As such VGSCs are considered important therapeutic targets

Emerging landscape in psoriasis management: From topical application to targeting biomolecules

© 2018 Elsevier Masson SAS Psoriasis is a chronic autoimmune skin disorder affecting 2–3% of the world population. It has characteristic features such as increased keratinocyte proliferation and production of inflammatory mediators. The treatment involves various strategies including topical, systemic, phototherapy and biologics. Topical therapies are preferred for mild to moderate psoriasis conditions over the systemic therapies which are ideal in severe disease conditions. The systemic therapies include immunosuppressants, biological agents and recently approved phosphodiesterase-4 (PDE4) inhibitors. There are various limitations associated with the existing therapies where the new findings in the pathogenesis of psoriasis are paving a path for newer therapeutics to target at the molecular level. Various small molecules, PDE-4 inhibitors, biologics, and immunomodulator proved efficacious including the new molecules targeting Janus kinases (JAK) inhibitors that are under investigation. Furthermore, the role of genetic and miRNAs in psoriasis is still not completely explored and may further help in improving the treatment efficacy. This review provides an insight into various emerging therapies along with currently approved treatments for psoriasis

MicroRNAs as biological regulators in skin disorders

© 2018 Elsevier Masson SAS microRNAs are being investigated as promising therapeutic targets and biomarkers for different disease conditions. miRNAs serve as essential regulators of cell differentiation, proliferation and survival. The involvement of miRNAs in the functioning and regulation of the skin cells and skin diseases is a rapidly advancing area in dermatological research. miRNAs have been identified to play a key role in the pathogenesis, diagnosis, and treatment of the skin diseases. Skin is one of the largest organs of the body, primarily functioning as the first line of defence against external insults including bacteria, virus and other pathogens. Various miRNAs have been identified to demonstrate significant effects in various skin inflammatory conditions such as wounds, cancer, psoriasis, scleroderma, dermatomyositis. The current review explores the possible roles of the miRNAs in skin disorders and reports relating to the clinical trials involving skin diseases and miRNAs. The review has also compiled the information of the databases available, which correlates the miRNAs with different diseases and give details about targeting interactions of miRNA