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.     

<Emphasis Type="Italic">In Vitro</Emphasis>-<Emphasis Type="Italic">In Vivo</Emphasis> Dose Response of Ursolic Acid,Sulforaphane, PEITC,and Curcumin in Cancer Prevention

According to the National Center of Health Statistics, cancer was the culprit of nearly 600,000 deaths in 2016 in the USA. It is by far one of the most heterogeneous diseases to treat. Treatment for metastasized cancers remains a challenge despite modern diagnostics and treatment regimens. For this reason, alternative approaches are needed. Chemoprevention using dietary phytochemicals such as triterpenoids, isothiocyanates, and curcumin in the prevention of initiation and/or progression of cancer poses a promising alternative strategy. However, significant challenges exist in the extrapolation of in vitro cell culture data to in vivo efficacy in animal models and to humans. In this review, the dose at which these phytochemicals elicit a response in vitro and in vivo of a multitude of cellular signaling pathways will be reviewed highlighting Nrf2-mediated antioxidative stress, anti-inflammation, epigenetics, cytoprotection, differentiation, and growth inhibition. The in vitro-in vivo dose response of phytochemicals can vary due, in part, to the cell line/animal model used, the assay system of the biomarker used for the readout, chemical structure of the functional analog of the phytochemical, and the source of compounds used for the treatment study. While the dose response varies across different experimental designs, the chemopreventive efficacy appears to remain and demonstrate the therapeutic potential of triterpenoids, isothiocyanates, and curcumin in cancer prevention and in health in general.     

Nano in nano: Biosynthesized gold and iron nanoclusters cargo neoplastic exosomes for cancer status biomarking

Timely detection is crucial for successful treatment of cancer. The current study describes a new approach that involves utilization of the tumor cell environment for bioimaging with in-situ biosynthesized nanoscale gold and iron probes and subsequent dissemination of Au-Fe nanoclusters from cargo exosomes within the circulatory system. We have isolated the Au-Fe cargo exosomes from the blood of the treated murine models after in situ biosyntheses from their respective pre-ionic solutions (HAuCl₄, FeCl₂), whereas Na₂SeO₃ supplementation added into Au lethal effect. The microarray data of various differentially expressed genes revealed the up-regulated tumor ablation and metal binding genes in SGC-7901 cell lines after treatment with Au-Fe-Se triplet ionic solution. The isolation of Au-Fe nanoclusters cargo exosomes (nano in nano) after secretion from deeply seated tumors may help in early diagnosis and reveal the tumor ablation status during and after the relevant treatment like radio-chemo therapies et al.     

Clinical ultrasound stimulating angiogenesis following drug-release from polymersomes on the ischemic zone for peripheral arterial occlusive disease

Peripheral Arterial Occlusive Disease (PAOD) is an aging disease that affects the quality of life of many people by its intermittent claudication and critical limb ischemia presentations. Traditional treatment and management of PAOD are asking patients to make a life change and medication with antiplatelet, statins and cilostazol, which decrease the possibility of clot formation. Our strategy has employed a magnetic Fe₃O₄-PLGA polymersome to carry the cilostazol into the ischemic area by magnetic attraction following remote-control drug release through low-energy ultrasound exposure. In the animal studies, the cilostazol-loaded Fe₃O₄-PLGA polymersomes were injected and accumulated at ischemic leg through magnetic attraction. Then, using a clinical-use ultrasound machine the leg was irradiated to forward cilostazol release from the accumulated polymersomes. Dramatically, we found an observable result of bloody flux recovery in the leg after 7?days compared to the non-treated leg that showed no evidence of the blood recovery.     

Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin C disease: A case series and literature review

Cobalamin (cbl) C disease is a rare autosomal recessive inheritance disease, which is the most common cobalamin metabolic disorder. Its clinical phenotype involves multiple systems with varying degrees of severity, where in mild cases can be asymptomatic for many years, whereas severe cases may cause death during the neonatal period. The disease is caused by mutations in the MMACHC gene located on chromosome 1p34.1 that contains 5 exons; among which, exons 1–4 have an 849 bp coding sequence that encodes a protein containing 282 amino acids. Through clinical physical examination and laboratory tests, especially blood and urine screening, we found 28 cblC pediatric patients with clinical manifestations, such as mental retardation, motor development delay, epilepsy, metabolic acidosis, vomiting and diarrhea. By Sanger sequencing, we found homozygous or compound heterozygous mutations of MMACHC in 27 of the patients, and single heterozygous mutation of MMACHC in one of them. The c.609G > A, c.658-660delAAG, c.80A > G and c.482G > A mutations accounted for 43.64% (24/55), 10.91% (6/55), 9.09% (5/55) and 7.27% (4/55) of all the mutations, respectively. This spectrum finding is basically consistent with the previously reported data in Chinese patients. The most common c.609G > A mutation may likely lead to early-onset cblC disease. In previous literature involving a large sample of Caucasian cblC cases, the mutation spectrum of MMACHC gene is almost completely different from that of the Chinese population. The most common mutations in the Caucasian population were c.271dupA, c.394C > T and c.331C > T, which account for 48.05% (542/1128), 13.65% (154/1128) and 7.36% (83/1128) of all the mutant alleles, respectively. The c.271dupA mutation and c.331C > T mutation were mainly associated with early-onset cblC in children less than 1 year old, whilst the c.394C > T mutation was mainly associated with late-onset cblC patients characterised by isolated acute nervous system abnormalities. We also analysed the cause behind the different mutation spectrum of MMACHC gene between the Chinese and Caucasian populations.     

Severe aortic valve stenosis in a 14-year-old boy with sitosterolemia

We report a 14-year-old boy finally diagnosed with sitosterolemia, presenting with severe aortic valve stenosis. Genetic analysis revealed homozygous null mutation c.1336 C > T (p.R446X) in ABCG5 gene. His cardiac ultrasound presented aortic valve stenosis and moderate aortic regurgitation. His whole aorta computed tomography angiogram scan revealed aortic stenosis superior to the aortic valve, followed by ascending aorta dilation, whereas his coronary and peripheral arteries appeared normal. His maximum total cholesterol and low-density lipoprotein-cholesterol levels dropped dramatically after diet control, and ezetimibe was prescribed for treatment. The current case indicated that sitosterolemia may be a heterogeneous disease in clinical phenotype.