Chapter 1 Transmissible Spongiform Encephalopathy: from the High Middle Ages to Daniel Carlton Gajdusek Paul Brown Chapter 2 The Rich Chemistry of the Copper and Zinc Sites in Cellular Prion Protein Glenn L. Millhauser Chapter 3 Role of Cellular Prion Protein in the Amyloid-ss Oligomer Pathophysiology of Alzheimer's Disease Adam C. Kaufman, Stephen M. Strittmatter Chapter 4 Cellular Prion Protein and Cancers Wei Xin, Man-sun Sy, Chaoyang Li Chapter 5 Insoluble Cellular Prion Protein Wen-Quan Zou Chapter 6 Protein Misfolding Cyclic Amplification Fabio Moda, Sandra Pritzkow, Claudio Soto Chapter 7 Cofactor Involvement in Prion Propagation Surachai Supattapone, Michael B. Miller Chapter 8 Prion Protein Conversion and Lipids Jiyan Ma Chapter 9 New Perspectives on Prion Conversion: Introducing a Mechanism of Deformed Templating Ilia V. Baskakov Chapter 10 Infectious and Pathogenic Forms of Prion Protein Emiliano Biasini, David A. Harris Chapter 11 Cellular Mechanisms of Propagation and Clearance Hermann M. Schatzl Chapter 12 Molecular Mechanisms Encoding Quantitative and Qualitative Traits of Prion Strains Jiri G. Safar Chapter 13 Modeling the Cell Biology of Prions Richard Rubenstein, Robert B. Petersen Chapter 14 Prion Strain Interference Charles R. Schutt, Ronald A. Shikiya, Jason C. Bartz Chapter 15 Introduction to Yeast and Fungal Prions Reed B. Wickner Chapter 16 Yeast Prions are Pathogenic, in-register Parallel Amyloids Reed B. Wickner, Herman K. Edskes, David A. Bateman, Amy C. Kelly, Anton Gorkovskiy

Physiology and pathophysiology

Acute kidney injury (AKI) is a global health challenge of vast proportions, as approx. 13.3% of people worldwide are affected annually. The pathophysiology of AKI is very complex, but its main causes are sepsis, ischemia, and nephrotoxicity. Nephrotoxicity is mainly associated with the use of drugs. Drug-induced AKI accounts for 19–26% of all hospitalized cases. Drug-induced nephrotoxicity develops according to one of the three mechanisms: (1) proximal tubular injury and acute tubular necrosis (ATN) (a dose-dependent mechanism), where the cause is related to apical contact with drugs or their metabolites, the transport of drugs and their metabolites from the apical surface, and the secretion of drugs from the basolateral surface into the tubular lumen; (2) tubular obstruction by crystals or casts containing drugs and their metabolites (a dose-dependent mechanism); (3) interstitial nephritis induced by drugs and their metabolites (a dose-independent mechanism). In this article, the mechanisms of the individual types of injury will be described. Specific groups of drugs will be linked to specific injuries. Additionally, the risk factors for the development of AKI and the methods for preventing and/or treating the condition will be discussed.

The Mechanism of Drug Nephrotoxicity and the Methods for Preventing Kidney Damage

This contribution presents the biosynthesis, physiochemical properties, toxicity and photocatalytic activity of biogenic CeO2 NPs using, for the first time, marine oyster extract as an effective and rich source of bioreducing and capping/stabilizing agents in a one-pot recipe. CeO2 NPs formation was initially confirmed through the color change from light green to pale yellow and subsequently, their corresponding absorption peak was spectroscopically determined at 310 nm with an optical band-gap of 4.67 eV using the DR-UV technique. Further, XRD and Raman analyses indicated that nanoceria possessed face-centered cubic arrangements without any impurities, having an average crystallite size of 10 nm. TEM and SEM results revealed that biogenic CeO2 NPs was approximately spherical in shape with a median particle size of 15 ± 1 nm. The presence of various bioorganic substances on the surface of nanoparticles was deduced by FTIR and TGA results. It is found that marine-based nanoceria shows no cytotoxic effect on the normal cell, thus indicating their enhanced biocompatibility and biosafety to living organisms. Environmentally, due to energy band gap, visible light-activated CeO2 nanocatalyst revealed superior photocatalytic performance on degradation of methylene blue pollutant with removal rate of 99%. Owing to the simplicity, cost-effectiveness, and environmentally friendly nature, this novel marine biosynthetic route paves the way for prospective applications of nanoparticles in various areas.

Enhanced sunlight photocatalytic activity and biosafety of marine-driven synthesized cerium oxide nanoparticles.

Nanozymes are nanomaterials with similar catalytic activities to natural enzymes. Compared with natural enzymes, they have numerous advantages, including higher physiochemical stability, versatility, and suitability for mass production. In the past decade, the synthesis of nanozymes and their catalytic mechanisms have advanced beyond the simple replacement of natural enzymes, allowing for fascinating applications in various fields such as biosensing and disease treatment. In particular, the exploration of nanozymes as powerful toolkits in diagnostic viral testing and antiviral therapy has attracted growing attention. It can address the great challenges faced by current natural enzyme-based viral testing technologies, such as high cost and storage difficulties. Therefore, nanozyme can provide a novel nanozyme-based antiviral therapeutic regime with broader availability and generalizability that are keys to fighting a pandemic such as COVID-19. Herein, we provide a timely review of the state-of-the-art nanozymes regarding their catalytic activities, as well as a focused discussion on recent research into the use of nanozymes in viral testing and therapy. The remaining challenges and future perspectives will also be outlined. Ultimately, this review will inform readers of the current knowledge of nanozymes and inspire more innovative studies to push forward the frontier of this field. 

Exploration of nanozymes in viral diagnosis and therapy

CeO2 with the reversible Ce3+/Ce4+ redox pair exhibits multiple enzyme-like catalytic performance, which has been recognized as a promising nanozyme with potentials for disease diagnosis and treatments. Tailorable surface physicochemical properties of various CeO2 catalysts with controllable sizes, morphologies, and surface states enable a rich surface chemistry for their interactions with various molecules and species, thus delivering a wide variety of catalytic behaviors under different conditions. Despite the significant progress made in developing CeO2-based nanozymes and their explorations for practical applications, their catalytic activity and specificity are still uncompetitive to their counterparts of natural enzymes under physiological environments. With the attempt to provide the insights on the rational design of highly performed CeO2 nanozymes, this review focuses on the recent explorations on the catalytic mechanisms of CeO2 with multiple enzyme-like performance. Given the detailed discussion and proposed perspectives, we hope this review can raise more interest and stimulate more efforts on this multi-disciplinary field. 

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Insights on catalytic mechanism of CeO2 as multiple nanozymes

Acute kidney injury (AKI) is a prevalent and lethal adverse event that severely affects cancer patients receiving chemotherapy. It is correlated with the collateral damage to renal cells caused by reactive oxygen species (ROS). Currently, ROS management is a practical strategy that can reduce the risk of chemotherapy-related AKI, but at the cost of chemotherapeutic efficacy. Herein, we report catalytic activity tunable ceria nanoparticles (CNPs) that can prevent chemotherapy-induced AKI without interference with chemotherapeutic agents. Specifically, in the renal cortex, CNPs exhibit catalytic activity that decomposes hydrogen peroxide, and subsequently regulate the ROS-involved genes by activating the Nrf2/Keap1 signaling pathway. These restore the redox homeostasis for the protection of kidney tubules. Under an acidic tumor microenvironment, CNPs become inert due to the excessive H+ that disrupts the re-exposure of active catalytic sites, allowing a buildup of chemotherapy-mediated ROS generation to kill cancer cells. As ROS-modulating agents, CNPs incorporated with context-dependent catalytic activity, hold a great potential for clinical prevention and treatment of AKI in cancer patients. Reactive oxygen species management is a practical strategy that can reduce the risk of chemotherapy-induced acute kidney injury, but at the cost of chemotherapeutic efficacy. Here the authors report catalytic activity tunable ceria nanoparticles as context-dependent reactive oxygen species scavengers, which can prevent chemotherapy-induced acute kidney injury without interfering with chemotherapeutic agents.

/pdf/catalytic-activity-tunable-ceria-nanoparticles-prevent-8srrggqn4e.pdf

Catalytic activity tunable ceria nanoparticles prevent chemotherapy-induced acute kidney injury without interference with chemotherapeutics.

Cisplatin is a clinically advanced and highly effective anticancer drug used in the treatment of a wide variety of malignancies, such as head and neck, lung, testis, ovary, breast cancer, etc. However, it has only a limited use in clinical practice due to its severe adverse effects, particularly nephrotoxicity; 20%-35% of patients develop acute kidney injury (AKI) after cisplatin administration. The nephrotoxic effect of cisplatin is cumulative and dose dependent and often necessitates dose reduction or withdrawal. Recurrent episodes of AKI result in impaired renal tubular function and acute renal failure, chronic kidney disease, uremia, and hypertensive nephropathy. The pathophysiology of cisplatin-induced AKI involves proximal tubular injury, apoptosis, oxidative stress, inflammation, and vascular injury in the kidneys. At present, there are no effective drugs or methods for cisplatin-induced kidney injury. Recent in vitro and in vivo studies show that numerous natural products (flavonoids, saponins, alkaloids, polysaccharide, phenylpropanoids, etc.) have specific antioxidant, anti-inflammatory, and anti-apoptotic properties that regulate the pathways associated with cisplatin-induced kidney damage. In this review we describe the molecular mechanisms of cisplatin-induced nephrotoxicity and summarize recent findings in the field of natural products that undermine these mechanisms to protect against cisplatin-induced kidney damage and provide potential strategies for AKI treatment.

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Natural products: potential treatments for cisplatin-induced nephrotoxicity.

Optineurin (OPTN) has important functions in diverse biological processes and diseases, but its effect on dendritic cell (DC) differentiation and functionality remains elusive. Here we show that OPTN is upregulated in human and mouse DC maturation, and that deletion of Optn in mice via CD11c-Cre attenuates DC maturation and impairs the priming of CD4+ T cells, thus ameliorating autoimmune symptoms such as experimental autoimmune encephalomyelitis (EAE). Mechanistically, OPTN binds to the JH1 domain of JAK2 and inhibits JAK2 dimerization and phosphorylation, thereby preventing JAK2-STAT3 interaction and inhibiting STAT3 phosphorylation to suppress downstream transcription of IL-10. Without such a negative regulation, Optn-deficient DCs eventually induce an IL-10/JAK2/STAT3/IL-10 positive feedback loop to suppress DC maturation. Finally, the natural product, Saikosaponin D, is identified as an OPTN inhibitor, effectively inhibiting the immune-stimulatory function of DCs and the disease progression of EAE in mice. Our findings thus highlight a pivotal function of OPTN for the regulation of DC functions and autoimmune disorders.

/pdf/optineurin-modulates-the-maturation-of-dendritic-cells-to-2jf4yv6gcw.pdf

Optineurin modulates the maturation of dendritic cells to regulate autoimmunity through JAK2-STAT3 signaling.

Platinum (Pt) resistance in cancer almost inevitably occurs during clinical Pt-based chemotherapy. The spontaneous nucleotide-excision repair of cancer cells is a representative process that leads to Pt resistance, which involves the local DNA bending to facilitate the recruitment of nucleotide-excision repair proteins and subsequent elimination of Pt-DNA adducts. By exploiting the structural vulnerability of this process, we herein report a nuclease-mimetic Pt nanozyme that can target cancer cell nuclei and induce concurrent DNA platination and oxidative cleavage to overcome Pt drug resistance. We show that the Pt nanozyme, unlike cisplatin and conventional Pt nanoparticles, specifically induces the nanozyme-catalyzed cleavage of the formed Pt-DNA adducts by generating in situ reactive oxygen species, which impairs the damage recognition factors-induced DNA bending prerequisite for nucleotide-excision repair. The recruitment of downstream effectors of nucleotide-excision repair to DNA lesion sites, including xeroderma pigmentosum groups A and F, is disrupted by the Pt nanozyme in cisplatin-resistant cancer cells, allowing excessive accumulation of the Pt-DNA adducts for highly efficient cancer therapy. Our study highlights the potential benefits of applying enzymatic activities to the use of the Pt nanomedicines, providing a paradigm shift in DNA damaging chemotherapy. 

/pdf/a-nuclease-mimetic-platinum-nanozyme-induces-concurrent-dna-1h5n74ut.pdf

A nuclease-mimetic platinum nanozyme induces concurrent DNA platination and oxidative cleavage to overcome cancer drug resistance

The invention provides application of optineurin protein in preparing acute hepatic damage diagnosis and treatment products. Experiments prove that the OPTN (optineurin) protein is increased in protein in acute hepatic damage tissues and relieves polarization of macrophages through autophagy to release acute hepatic damage, and accordingly acute hepatic damage can be relieved by expressing the OPTN protein or applying bavachinin. Therefore, the OPTN protein can serve as a specific marker protein for diagnosis and drug therapy of acute hepatic damage, and through the agonist of the bavachinin and overexpression viruses, effectively treats acute hepatic damage to achieve more accurate and quicker diagnosis and treatment of acute hepatic damage. The optineurin protein provides a new therapeutic target and an effective new drug for treating acute hepatic damage.

Chunyan Fang

Papers

Catalytic activity tunable ceria nanoparticles prevent chemotherapy-induced acute kidney injury without interference with chemotherapeutics.

Natural products: potential treatments for cisplatin-induced nephrotoxicity.

Optineurin modulates the maturation of dendritic cells to regulate autoimmunity through JAK2-STAT3 signaling.

A nuclease-mimetic platinum nanozyme induces concurrent DNA platination and oxidative cleavage to overcome cancer drug resistance

Application of optineurin protein in preparing acute hepatic damage diagnosis and treatment products