Adv Exp Med Biol
-
The Cannabis plant has been used for many of years as a medicinal agent in the relief of pain and seizures. It contains approximately 540 natural compounds including more than 100 that have been identified as phytocannabinoids due to their shared chemical structure. The predominant psychotropic component is Δ9-tetrahydrocannabinol (Δ9-THC), while the major non-psychoactive ingredient is cannabidiol (CBD). ⋯ The legalization of cannabis for medicinal purposes and for recreational use in some regions will allow for much needed research on the pharmacokinetics and pharmocology of medical cannabis. This brief review focuses on the use of cannabis as a medicinal agent in the treatment of pain, epilepsy and neurodegenerative diseases. Despite the paucity of information, attention is paid to the mechanisms by which medical cannabis may act to relieve pain and seizures.
-
Mitochondrial disease can arise due to pathogenic sequence variants in the mitochondrial DNA (mtDNA) that prevent cells from meeting their energy demands. Mitochondrial diseases are often fatal and currently there are no treatments directed towards the underlying cause of disease. Pathogenic variants in mtDNA often exist in a state of heteroplasmy, with coexistence of pathogenic and wild type mtDNA. ⋯ Heteroplasmy shift approaches in patients are of two categories: nuclease dependent and nuclease independent strategies. Despite initial success in mouse models and patient cells, these techniques have not reached clinical use. Translational attempts in this area are urgently needed to improve therapies for a currently untreatable set of disorders.
-
Polycystic kidney disease (PKD) is a common genetic disorder characterized by formations of numerous cysts in kidneys and most caused by PKD1 or PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). The interstitial inflammation and fibrosis is one of the major pathological changes in polycystic kidney tissues with an accumulation of inflammatory cells, chemokines, and cytokines. The immune response is observed across different stages and occurs prior to or coincident with cyst formation in ADPKD. ⋯ Several fibrosis associated signaling pathways, such as TGFβ-SMAD, Wnt, and periostin-integrin-linked kinase are also activated in polycystic kidney tissues. Although the effective anti-fibrotic treatments are limited at the present time, slowing the cyst expansion and fibrosis development is very important for prolonging life span and improving the palliative care of ADPKD patients. The inhibition of pro-fibrotic cytokines involved in fibrosis might be a new therapeutic strategy for ADPKD in the future.
-
Adoptive T cell transfer (ACT) is a new era for cancer treatment, involving infusion of autologous lymphocytes. Chimeric antigen receptors (CAR) on the surface of T cells are emerging as a novel therapeutic that is giving other direction to T-cell specificity and precision medicine. ⋯ Solid tumors have heterogeneous antigens and tumor microenvironment that hinder CAR-T cell efficacy and increase the risk of on-target/off-tumor. Novel strategies to increase CAR-Ts specificity, safety and efficacy are ongoing in clinical trials to improve clinical outcomes in hematological and solid malignances.
-
Short upstream open reading frames (uORFs) are cis-acting elements located within the 5'-leader sequence of transcripts and are defined by an initiation codon in-frame with a termination codon located upstream or downstream of its main ORF (mORF) initiation codon. Recent genome-wide ribosome profiling studies have confirmed the widespread presence of uORFs and have shown that many uORFs can initiate with non-AUG codons. uORFs can impact gene expression of the downstream mORF by triggering mRNA decay or by regulating translation. Thus, disruption or creation of uORFs can elicit the development of several genetic diseases. ⋯ We also show some examples of uORF deregulation in human genetic diseases, focusing mainly on cancer. The knowledge of how uORF deregulation drives the onset of a disease, points out the need to screen the 5'-leader sequences of the transcripts in search for potential disease-related variants. This information will be relevant for the implementation of new diagnostic and/or therapeutic tools.