Extracellular HMGB1 as a therapeutic target in inflammatory diseases

Introduction: High-mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that promotes inflammation when released extracellularly after cellular activation, stress, damage or death. HMGB1 operates as one of the most intriguing molecules in inflammatory disorders via recently elucidated signal and molecular transport mechanisms. Treatments based on antagonists specifically targeting extracellular HMGB1 have generated encouraging results in a wide number of experimental models of infectious and sterile inflammation. Clinical studies are still to come.

Areas covered: We here summarize recent advances regarding pathways for extracellular HMGB1 release, receptor usage, and functional consequences of post-translational modifications. The review also addresses results of preclinical HMGB1-targeted therapy studies in multiple inflammatory conditions and outlines the current status of emerging clinical HMGB1-specific antagonists.

Expert opinion: Blocking excessive amounts of extracellular HMGB1, particularly the disulfide isoform, offers an attractive clinical opportunity to ameliorate systemic inflammatory diseases. Therapeutic interventions to regulate intracellular HMGB1 biology must still await a deeper understanding of intracellular HMGB1 functions. Future work is needed to create more robust assays to evaluate functional bioactivity of HMGB1 antagonists. Forthcoming clinical studies would also greatly benefit from a development of antibody-based assays to quantify HMGB1 redox isoforms, presently assessed by mass spectrometry methods.     

Potential neuroprotective role of astroglial exosomes against smoking-induced oxidative stress and HIV-1 replication in the central nervous system

Introduction: HIV-1-infected smokers are at risk of oxidative damage to neuronal cells in the central nervous system by both HIV-1 and cigarette smoke. Since neurons have a weak antioxidant defense system, they mostly depend on glial cells, particularly astrocytes, for protection against oxidative damage and neurotoxicity. Astrocytes augment the neuronal antioxidant system by supplying cysteine-containing products for glutathione synthesis, antioxidant enzymes such as SOD and catalase, glucose for antioxidant regeneration via the pentose-phosphate pathway, and by recycling of ascorbic acid.

Areas covered: The transport of antioxidants and energy substrates from astrocytes to neurons could possibly occur via extracellular nanovesicles called exosomes. This review highlights the neuroprotective potential of exosomes derived from astrocytes against smoking-induced oxidative stress, HIV-1 replication, and subsequent neurotoxicity observed in HIV-1-positive smokers.

Expert opinion: During stress conditions, the antioxidants released from astrocytes either via extracellular fluid or exosomes to neurons may not be sufficient to provide neuroprotection. Therefore, we put forward a novel strategy to combat oxidative stress in the central nervous system, using synthetically developed exosomes loaded with antioxidants such as glutathione and the anti-aging protein Klotho.     

Pulmonary delivery of polyplexes for combined PAI-1 gene silencing and CXCR4 inhibition to treat lung fibrosis

This report describes the development of polyplexes based on CXCR4-inhibiting poly(ethylenimine) derivative (PEI-C) for pulmonary delivery of siRNA to silence plasminogen activator inhibitor-1 (siPAI-1) as a new combination treatment of pulmonary fibrosis (PF). Safety and delivery efficacy of the PEI-C/siPAI-1 polyplexes was investigated in vitro in primary lung fibroblasts isolated from mice with bleomycin-induced PF. Biodistribution analysis following intratracheal administration of fluorescently labeled polyplexes showed prolonged retention in the lungs. Treatment of mice with bleomycin-induced PF using the PEI-C/siPAI-1 polyplexes resulted in a significant down-regulation of the PAI-1 expression and decreased collagen deposition in the lung. The results of this study provide first evidence of the potential benefits of combined inhibition of CXCR4 and PAI-1 in the pulmonary treatment of PF.     

Neuroprotective effect of gold nanoparticles composites in Parkinson's disease model

Parkinson’s disease (PD) is second most common neurodegenerative disorder worldwide. Although drugs and surgery can relieve the symptoms of PD, these therapies are incapable of fundamentally treating the disease. For PD patients, over-expression of α-synuclein (SNCA) leads to the death of dopaminergic neurons. This process can be prevented by suppressing SNCA over-expression through RNA interference. Here, we successfully synthesized gold nanoparticles (GNP) composites (CTS@GNP-pDNA-NGF) via the combination of electrostatic adsorption and photochemical immobilization, which could load plasmid DNA (pDNA) and target specific cell types. GNP was transfected into cells via endocytosis to inhibiting the apoptosis of PC12 cells and dopaminergic neurons. Simultaneously, GNP composites are also used in PD models in vivo, and it can successfully cross the blood-brain barrier by contents of GNP in the mice brain. In general, all the works demonstrated that GNP composites have good therapeutic effects for PD models in vitro and in vivo.     

The utility of next generation sequencing in the correct diagnosis of congenital hypochloremic hypokalemic metabolic alkalosis

Persistent hypokalemic hypochloremic metabolic alkalosis represents a heterogeneous group of genetic disorders of which the most common is Bartter syndrome (BS). BS is an inherited renal tubulopathy caused by defective salt reabsorption in the thick ascending loop of Henle, which results in persistent hypokalemic hypochloremic metabolic alkalosis. Here we report a 10-year-old girl of a consanguineous family. She presented prenatally with severe polyhydramnios and distended bowel loops. Thereafter, she displayed failure to thrive and had recurrent admissions due to dehydration episodes associated with diarrhea, and characterized by hypokalemia, hypochloremia and metabolic alkalosis. BS was considered her working diagnosis for several years despite negative genetic analysis of the known genes associated with BS. Whole exome sequencing identified a novel homozygous c.1652delT deleterious frameshift mutation in the SLC26A3 gene, which confirmed the diagnosis of congenital chloride diarrhea (CCD), a rare autosomal recessive disease that mimics biochemically BS. A review of twelve additional reported cases of CCD that were initially misdiagnosed as BS, emphasizes CCD in the differential diagnosis of BS, and highlights the clinical discrepancies between these two entities. Taken together, our report further emphasizes the typical clinical features of CCD, and the importance of next generation sequencing in the diagnosis of syndromes with genetic heterogeneity. We suggest including SLC26A3 in the extended BS targeted gene panels.     

Sex chromosomes-linked single-gene disorders involved in human infertility

Human infertility is a healthcare problem that has a worldwide impact. Genetic causes of human infertility include chromosomal aneuploidies and rearrangements and single-gene defects. The sex chromosomes (X and Y) are critical players in human fertility since they contain several genes essential for sex determination and reproductive traits for both men and women. This paper provides a review of the most common sex chromosomes-linked single-gene disorders involved in human infertility and their corresponding phenotypes. In addition to the Y-linked SRY gene, which mutations may cause XY gonadal dysgenesis and sex reversal, the deletions of genes present in AZF regions of the Y chromosome (DAZ, RBMY, DBY and USP9Y genes) are implicated in varying degrees of spermatogenic dysfunction. Furthermore, a list of X-linked genes (KAL1, NR0B1, AR, TEX11, FMR1, PGRMC1, BMP15 and POF1 and 2 regions genes (XPNPEP2, POF1B, DACH2, CHM and DIAPH2)) were reported to have critical roles in pubertal and reproductive deficiencies in humans, affecting only men, only women or both sexes. Mutations in these genes may be transmitted to the offspring by a dominant or a recessive inheritance.