■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

Peptides and proteins have been found to possess an inherent tendency to convert from their native functional states into intractable amyloid aggregates. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidoses. In this review, we describe this field of science with particular reference to the advances that have been made over the last decade in our understanding of its fundamental nature and consequences. We list the proteins that are known to be deposited as amyloid or other types of aggregates in human tissues and the disorders with which they are associated, as well as the proteins that exploit the amyloid motif to play specific functional roles in humans. In addition, we summarize the genetic factors that have provided insight into the mechanisms of disease onset. We describe recent advances in our knowledge of the structures of amyloid fibrils and their oligomeric precursors a...

Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade

Nanoscale materials are increasingly found in consumer goods, electronics, and pharmaceuticals. While these particles interact with the body in myriad ways, their beneficial and/or deleterious effects ultimately arise from interactions at the cellular and subcellular level. Nanoparticles (NPs) can modulate cell fate, induce or prevent mutations, initiate cell–cell communication, and modulate cell structure in a manner dictated largely by phenomena at the nano–bio interface. Recent advances in chemical synthesis have yielded new nanoscale materials with precisely defined biochemical features, and emerging analytical techniques have shed light on nuanced and context-dependent nano-bio interactions within cells. In this review, we provide an objective and comprehensive account of our current understanding of the cellular uptake of NPs and the underlying parameters controlling the nano-cellular interactions, along with the available analytical techniques to follow and track these processes.

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Cellular uptake of nanoparticles: journey inside the cell.

With more than 20 molecules in clinical use, monoclonal antibodies have finally come of age as therapeutics, generating a market value of $11 billion in 2004, expected to reach $26 billion by 2010. While delivering interesting results in the treatment of several major diseases including autoimmune, cardiovascular and infectious diseases, cancer and inflammation, clinical trials and research are generating a wealth of useful information, for instance about associations of clinical responses with Fc receptor polymorphisms and the infiltration and recruitment of effector cells into targeted tissues. Some functional limitations of therapeutic antibodies have come to light such as inadequate pharmacokinetics and tissue accessibility as well as impaired interactions with the immune system, and these deficiencies point to areas where additional research is needed. This review aims at giving an overview of the current state of the art and describes the most promising avenues that are being followed to create the next generation of antibody-based therapeutic agents.

This article is part of a themed section on Vector Design and Drug Delivery. For a list of all articles in this section see the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009

/pdf/therapeutic-antibodies-successes-limitations-and-hopes-for-4lscgwg4z1.pdf

Therapeutic antibodies: successes, limitations and hopes for the future.

Environmental exposure to microplastics: An overview on possible human health effects

Bovine seminal ribonuclease, the only dimeric ribonuclease described thus far, is found to exist in two different quaternary structure forms. In one, the N-terminal segment (residues 1-17) of each subunit is interchanged with the remaining segment of the other subunit, whereas in the second, such interchange does not occur. Functionally, they differ in that the catalytic activity of the form with interchange can be modulated by the substrate, whereas the noninterchange form exhibits no cooperativity. Each form can convert into the other, up to an equilibrium ratio, which is that found for the isolated protein. The results of refolding experiments of unfolded protein chains suggest that also in vivo the form lacking interchange may be produced first and is then partially transformed into the other dimeric form until equilibrium is reached. Although the implications of these findings may not be immediately apparent, they are intriguing and may have an impact on the unusual noncatalytic actions of the protein, such as its selective cytotoxicity toward tumor cells, activated T cells, and differentiated male germ cells.

https://www.pnas.org/content/pnas/89/5/1870.full.pdf

The dual-mode quaternary structure of seminal RNase.

Seminal RNase: a unique member of the ribonuclease superfamily

Selective deamidation of ribonuclease A. Isolation and characterization of the resulting isoaspartyl and aspartyl derivatives.

We report the preparation and characterization of a novel, fully human antitumor immunoRNase (IR). The IR, a human RNase and fusion protein made up of a human single chain variable fragment (scFv), is directed to the ErbB-2 receptor and overexpressed in many carcinomas. The anti-ErbB-2 IR, named hERB-hRNase, retains the enzymatic activity of the wild-type enzyme (human pancreatic RNase) and specifically binds to ErbB-2-positive cells with the high affinity (K(d) = 4.5 nm) of the parental scFv. hERB-hRNase behaves as an immunoprotoxin and on internalization by target cells becomes selectively cytotoxic in a dose-dependent manner at nanomolar concentrations. Administered in five doses of 1.5 mg/kg to mice bearing an ErbB-2-positive tumor, hERB-hRNase induced a dramatic reduction in tumor volume. hERB-hRNase is the first fully human antitumor IR produced thus far, with a high potential as a poorly immunogenic human drug devoid of nonspecific toxicity, directed against ErbB-2-positive malignancies.

/pdf/a-fully-human-antitumor-immunornase-selective-for-erbb-2-2izczcaypj.pdf

A Fully Human Antitumor ImmunoRNase Selective for ErbB-2-Positive Carcinomas

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2894%2901450-F

Renata Piccoli

Papers

The dual-mode quaternary structure of seminal RNase.

Seminal RNase: a unique member of the ribonuclease superfamily

Selective deamidation of ribonuclease A. Isolation and characterization of the resulting isoaspartyl and aspartyl derivatives.

A Fully Human Antitumor ImmunoRNase Selective for ErbB-2-Positive Carcinomas

The antitumor action of seminal ribonuclease and its quaternary conformations