Loss of Function of Mutant IDS Due to Endoplasmic Reticulum-Associated Degradation: New Therapeutic Opportunities for Mucopolysaccharidosis Type II

Mucopolysaccharidosis type II (MPS II) results from the dysfunction of a lysosomal enzyme, iduronate-2-sulfatase (IDS). Dysfunction of IDS triggers the lysosomal accumulation of its substrates, glycosaminoglycans, leading to mental retardation and systemic symptoms including skeletal deformities and valvular heart disease. Most patients with severe types of MPS II die before the age of 20. The administration of recombinant IDS and transplantation of hematopoietic stem cells are performed as therapies for MPS II. However, these therapies either cannot improve functions of the central nervous system or cause severe side effects, respectively. To date, 729 pathogenetic variants in the IDS gene have been reported. Most of these potentially cause misfolding of the encoded IDS protein. The misfolded IDS mutants accumulate in the endoplasmic reticulum (ER), followed by degradation via ER-associated degradation (ERAD). Inhibition of the ERAD pathway or refolding of IDS mutants by a molecular chaperone enables recovery of the lysosomal localization and enzyme activity of IDS mutants. In this review, we explain the IDS structure and mechanism of activation, and current findings about the mechanism of degradation-dependent loss of function caused by pathogenetic IDS mutation. We also provide a potential therapeutic approach for MPS II based on this loss-of-function mechanism.

Studies on forced degradation and solid state stability of tenofovir disoproxil orotate

In order to develop a stability regulatory system for drug substances and degraded products, a forced degradation study is an essential part in the design of the method. As per ICH Guidelines Q1A in 1993, it was established as an essential requirement for the regulatory system to assess the stability of drugs and their degradation products under the degradation studies by force. These analytical methods are helpful in the development of stability, indicating the method by conducting the studies on forced degradation with their mechanism of degradation. Drug products by degradation and new drug substance by forced degradation conditions are more severe than a demonstration of specificity of stability indicating methods. The analytical method development is facilitated by those techniques for better understanding of (API) active pharmaceutical ingredients and (DP) drug products stability.

Unlocking the potential of biosynthesized zinc oxide nanoparticles for degradation of synthetic organic dyes as wastewater pollutants

The azo dyes released into water from different industries are accumulating in the water bodies and bioaccumulating within living systems thereby affecting environmental health. This is a major concern in developing countries where stringent regulations are not followed for the discharge of industrial waste into water bodies. This has led to the accumulation of various pollutants including dyes. As these developing countries also face acute water shortages and due to the lack of cost-effective systems to remove these pollutants, it is essential to remove these toxic dyes from water bodies, eradicate dyes, or generate fewer toxic derivatives. The photocatalysis mechanism of degradation of azo dyes has gained importance due to its eco-friendly and non-toxic roles in the environment. The zinc nanoparticles act as photocatalysts in combination with plant extracts. Plant-based nanoparticles over the years have shown the potential to degrade dyes efficiently. This is carried out by adjusting the dye and nanoparticle concentrations and combinations of nanoparticles. Our review article considers increasing the efficiency of degradation of dyes using Zinc oxide (ZnO) nanoparticles and understanding the photocatalytic mechanisms in the degradation of dyes and the toxic effects of these dyes and nanoparticles in different tropic levels.

Preparation of Non-polluting Tb-Doped Mesoporous Carbon Nitride Photocatalyst and Study on the Efficacy and Mechanism of Degradation of Antibiotics in Water

Given that the biological treatment of antibiotic wastewater can easily induce resistant bacteria, the photocatalytic degradation of antibiotics is considered a better method for treating antibiotic wastewater. Therefore, the ability to remove Tylosin (TYL) and Tetracycline (TC) in aqueous solution using rare earth element Tb-doped g-C3N4 under simulated natural solar radiation was investigated. A series of rare earth Tb3+ doped mesoporous g-C3N4 were successfully prepared by nitric acid treatment and Tb(NO3)3·5H2O samples showed significantly higher degradation efficiency for TYL and TC than pure g-C3N4. Leaching toxicity experiments were carried out on the catalyst using chard seeds and demonstrated negligible toxicity of the leachate from the catalyst. The structure, elemental state, optical properties, morphology and photogenerated carrier separation of the prepared xTCN catalysts were characterized by XRD, XPS, UV-Vis DRS, TEM and PL. The results showed that Tb doping enhanced the photocatalytic activity of the g-C3N4 catalyst by narrowing the band gap while improving the light-trapping ability; The separation and transport rate of photogenerated carriers were significantly increased after Tb doping. Finally, a simple, efficient and non-polluting Tb-doped carbon nitride photocatalyst is successfully developed in this paper.

Analysis of Factors Influencing Plant–Microbe Combined Remediation of Soil Contaminated by Polycyclic Aromatic Hydrocarbons

Polycyclic aromatic hydrocarbons (PAHs) are frequently detected in soil. Their biological toxicity and carcinogenic, teratogenic, and mutagenic effects pose a great threat to the ecological environment and human health. Firstly, the sources, physicochemical properties, and environmental hazards of PAHs are reviewed in this paper, and then their pollution status and different methods for their detection in soil are described in detail. The remediation technologies to treat pollution in the field and farmland are compared, and the technical status and factors influencing phytomicrobial remediation of PAHs in contaminated soil are evaluated in the most comprehensive way. The mechanisms of phytomicrobial remediation of PAHs-contaminated soil under different conditions are innovatively discussed. Additionally, the regulation mechanism of enzymes involved in plant and microbial degradation of PAHs in soils is studied. This is the first study on the regulation mechanism of degradation enzyme in a PAHs review. The aim of this paper is to review the pollution status, remediation technologies, mechanisms, and biodegradation actions of PAHs in soil. This review creatively provides reliable technical support for strengthening soil remediation and environmental management.

Autophagy Markers p62, LC3II and Beclin1 Correlate with Clark Levels in Melanoma Tumors

BackgroundThe prognosis of melanoma depends on early diagnosis and timely treatment. Autophagy as a mechanism of degradation/recycling of cellular debris, has potential to be evaluated as prognostic biomarker in current research. MethodsIn this study, ATG5 and Beclin 1 gene expression in different Clark levels of melanoma were evaluated in a retrospective study of 10 years in the cancer institute of Tehran, Iran. The autophagy activity and the correlation with clinicopathological data were also investigated in a tissue microarray series of 52 melanomas after immunohistochemical staining for the autophagy-associated proteins p62, LC3II and Beclin1. The possibility of autophagy biomarkers were assessed by ROC curve analysis.ResultsThe patterns of ATG5 and Beclin1 gene expression are different. While ATG5 was increased in the early stage and then decreased as the stage was progressed in comparison to tumor margin, the Beclin1 expression was decreased and not altered during tumor progression. However, Beclin1 expression at the protein level was increased with tumor progression. The expression of LC3II was also raised while the p62 levels were declined as the tumor progressed, suggesting an increased autophagy activity in melanoma patients. Melanoma ulceration was positively correlated with Beclin 1 and LC3II expression and inversely correlated with p62 (p<0.05). Autophagy markers expression did not significantly correlate with melanoma mitotic rate and thickness. ConclusionsAutophagy is a potential prognostic factor in the early stage of melanoma and could be considered as a therapeutic target.