Current Pharmaceutical Biotechnology - Volume 11, Issue 2, 2010

A functional protein must be in its specific three dimensional native structure. All information to reach to the native state is ciphered in its amino acid sequence. However the milieu of a cell as well as stress factors presents challenges for folding to native state [1-3]. Several stress factors i.e. temperature elevation, pH, salinity and oxygen concentration alteration, ageing may influence cells and protein folding. Fortunately, heat shock proteins (Hsps) help misfolded or unfolded proteins for proper folding. Protein quality check provides protein homeostasis and Hsps play essential role during these biochemical processes [4,5]. If Hsp cannot help substrate protein then it send the substrate to lysozyme for degradation. Uncontrolled protein folding may lead aggregation and eventually several diseases including Huntington, Alzheimer, Parkinson, Creutzfeldt-Jakob, cystic fibrosis, Gaucher and other polyglutamine neurodegenerative diseases [6-8]. Several different types of heat shock proteins or combination of these proteins have been employed as therapeutic agent since stress factors increase levels of denatured proteins. This theme issue focuses on treatment of neurodegenerative and metabolic diseases through heat shock proteins [3,7,8]. The first paper gives a brief summary on major Hsp families Hsp70, Hsp40, Hsp90, Hsp100, Hsp60, nucleotide exchange factors and small Hsps. The paper by Dr. Soti reports an interesting topic. The paper presents diet and metabolic stress related heat shock response and treatment. Small Hsps (sHsps) are the least popular group among Hsp family. Like other Hsps, sHsps confer thermotolerence to proteins in cellular extracts. The most distinguishing property of Hsps is their ATP-independent function as molecular chaperones [1]. Dr. Laskowska presents properties and diversity of sHsps along with their roles in cancer, neurodegenerative and protein folding diseases. The biggest problem in cellular milieu is macromolecular crowding. Protein-protein interaction in this environment may lead to aggregation. The process first forms small seeds and small seeds eventually forms fibers [4,5]. Aggregation of different types of protein cause various neurodegenerative diseases. Hsps prevent aggregation and solubilise aggregates, therefore Hsps have potential roles as suppressors and therapeutic agent [3-5]. Dr. Arawaka use alpha-synuclein as model to explain Hsps roles in neurodegenerative diseases. The famous Trojan horse tale provided a unique idea for researchers for cell-penetrating peptide technology. The technology of combining Hsps action with cell-penetration applied to several biochemical process, i.e apoptosis, neurodegenerative diseases [3]. A contemporary approach of these applications provided by Dr. Dietz. By the same Trojan analogy cell walls serve as rampart and the only way for cell to communicate outside environment is by means of special gates; ion-channels. Therefore, cell signaling cascades via these channels may help our understanding of diseases. Dr. Schneider reviewed role of Hsp interactions with the channels and their potential therapeutic consequences. Protein homeostasis depends on a fine equilibrium between protein synthesis and protein degradation. Heat shock proteins play essential roles in substrate protein degradation. At the later stage of life protein degradation function decreases. As a result of wasted protein and misfolded protein accumulation, protein aggregation leads neurodegenerative diseases [5-8]. Dr. Lee gathered Hsp roles in degradation pathways associated with neurodegenerative diseases. Proteins are essential tools for an organism function therefore protein homeostasis is essential for metabolism continuity. Since Hsp help nascent protein and misfolded protein folding to reach their functional three dimensional state, an increase in Hsp concentration may prevent protein aggregation and solubilise aggregates [7,8]. One strategy to increase Hsp concentration is induction. This strategy used as therapeutic approach for neurodegenerative diseases and Dr. Nagai gathered information for the polyglutamine neurodegenerative diseases. Similarly, Dr. Wyttenbach investigates Hsps as drug targets for chronic neurodegeneration. Hsp modulation, drug delivery and side effects were discussed in detail. Currently, therapeutic use of Hsps as molecular chaperones to cure neurodegenerative disease is at the earlier stage however researchers give promising results for future efforts.

Molecular chaperones and the heat shock response guard and modulate protein conformation, protect proteins from misfolding and aggregation, and maintain signalling and organellar networks. Overnutrition and the metabolic syndrome represent a pro-aging condition, and dietary restriction is the most robust environmental intervention that induces longevity from yeast to mammals. In recent years a considerable effort has been made to elucidate the signaling pathways involved in metabolic signaling. Here we review the current understanding on the connection between metabolic stress, dietary restriction and the heat shock response and highlight results showing chaperone induction as a promising therapeutic strategy to promote healthy aging and to prevent metabolic disorders.

Small heat shock proteins (sHsps) are molecular chaperones ubiquitously distributed in numerous species, from bacteria to humans. A conserved C-terminal “α-crystallin” domain organized in a β-sheet sandwich and oligomeric structure are common features of sHsps. sHsps protect cells against many kinds of stresses including heat shock, oxidative and osmotic stress. sHsps recognize unfolded proteins, prevent their irreversible aggregation and facilitate refolding of bound substrates in cooperation with ATP-dependent molecular chaperones (Hsp70/Hsp40). Mammalian sHsps (HSPBs) are multifunctional proteins involved in many cellular processes including those which are not directly related to protein folding and aggregation. HSPBs participate in cell development and cancerogenesis, regulate apoptosis and control cytoskeletal architecture. Recent data revealed that HSPBs also play an important role in membrane stabilization. Mutation in HSPB genes have been identified, which are responsible for the development of cataract, desmin related myopathy and neuropathies. HSPBs are often found as components of protein aggregates associated with protein-misfolding disorders, such as Parkinson's, Alzheimer's, Alexander's and prion diseases. It is supposed that the presence of HSPBs in intra- or extracellular protein deposits is a consequence of the chaperone activity of HSPBs, however more studies are needed to reveal the exact function of HSPBs during the formation (or removal) of disease-related aggregates.

The most characteristic feature of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease, is the occurrence of extra- or intracellular fibrillar aggregates containing misfolded proteins with beta-sheet conformation. These aggregates are composed of distinct proteins in each neurodegenerative disease. However, mutations in genes encoding major constituents of aggregates, such as Abeta, tau, alpha-synuclein, SOD1 and huntingtin, have been identified to causally associate with familial forms of the diseases. Biochemical studies demonstrate that these mutant and some wild-type proteins tend to be misfolded or form aggregates. It has been proposed that these diseases are caused by a common mechanism involving misfolded proteins that trigger a toxic cascade leading to neuronal degeneration. This hypothesis is the basis of the therapeutic potential of heat shock proteins (HSPs), which prevent protein misfolding and aggregation. Transgenic animal models of the diseases have demonstrated that induction or overexpression of HSPs can suppress neuronal dysfunction and degeneration. Do the results promise clinical success for HSP-based therapy in neurodegenerative diseases? Recent findings regarding the pathogenic species generated during fibril formation have highlighted some of the beneficial and problematic aspects of HSP-based therapy. In this review, we focus on the pathogenic role of prefibrillar intermediates, including soluble oligomers and protofibrils, on neurodegeneration, and the relationship between prefibrillar intermediates and the proteins targeted by HSPs. We discuss in vitro and in vivo experimental data showing that HSPs counteract disease progression by acting as suppressors of toxic prefibrillar intermediates and toxic misfolded proteins in neurodegenerative diseases.

Cell-penetrating peptides (CPP), also called protein transduction domains (PTD), membrane-permeable peptides (MPP), or Trojan horse peptides, have been used in many different research areas. The delivery of heat shock proteins (Hsp) using CPP has been applied in models for apoptosis, necrosis, oxidative stress, neurodegenerative diseases, stroke, cystic fibrosis, smooth muscle relaxation, myocardial injury, scar formation, and others. This review summarizes the accomplishments of the field over the last years and discusses why Hsp are particularly suitable for CPP-mediated delivery.

Screening for protein interaction partners of ion channels helps to elucidate signaling cascades to cellular targets and processes for a better understanding of the origin of diseases. Most important are the cytosolic segments of membrane- bound voltage- and ligand-gated ion channels or from ion channel regulators, which may connect to specific signaling complexes. So far, not much is known about those interactions. Molecular chaperones are proteins, which support the biosynthesis of proteins during maturation without being part of the final protein complex or which support the degradation of targeted proteins within the cellular protein quality control.

The homeostasis of the protein synthesis and degradation is crucial for cell survival. Most age-related neurodegenerative diseases are characterized by accumulation of aberrant protein aggregates in affected brain regions. The principal routes of intracellular protein metabolism are the ubiquitin proteasome system (UPS) and the autophagy-lysosome pathway (ALP). They collaborate to degrade wasted proteins and interact each other to cope with the pathological conditions, in which molecular chaperones play collective roles by assisting the protein targeting to the proteasome or autophagy. It is known that intracellular protein degradation functions are decreased with aging in many tissues and organs. Failure to perform their functions could underlie the inability of cells to adapt to stress conditions, lead to accelerated course of misfolding protein deposit and the inclusion body formation, and eventually result in neurodegeneration.One of the functions of the molecular chaperones is to help the new synthesized or the misfolding toxic proteins fold to their native and nontoxic formation. In this review, we analyze the recent perceptions and findings of molecular chaperones biology in the two degradation pathways and their pathological attribution in several neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and others. It is worthy noticing that some of the heat shock proteins (HSPs) can not only block the protein aggregation in the early stages, but also have promising effect on attenuating the formation of fibrils. Further more, when the degradation pathways are too weak to degrade all the toxic soluble proteins, molecular chaperones can also help to sequenstrate the toxic proteins into inclusion bodies. Therefore, the study of HSPs might shed new light on not only the mechanisms of protein synthesis and degradaton, but also the possible therapeutic targets of fibril formation associating diseases.

Protein misfolding and aggregation in the brain have been implicated as a common molecular pathogenesis of various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and the polyglutamine (polyQ) diseases. The polyQ diseases are a group of nine hereditary neurodegenerative diseases, including Huntington's disease (HD) and various types of spinocerebellar ataxia (SCA), which are caused by abnormal expansions of the polyQ stretch (> 35-40 repeats) in unrelated disease-causative proteins. The expanded polyQ stretch is thought to trigger misfolding of these proteins, leading to their aggregation and accumulation as inclusion bodies in affected neurons, eventually resulting in neurodegeneration. Misfolding and aggregation of the polyQ protein are the most ideal therapeutic targets since they are the most upstream events in the pathogenic cascade, and therefore, therapeutic approaches using molecular chaperones, which prevent protein misfolding and assist the refolding of misfolded proteins, are being extensively investigated. Indeed, a variety of molecular chaperones such as Hsp70 and Hsp40 have been demonstrated to exert therapeutic effects against various experimental models of the polyQ diseases. Furthermore, toward developing pharmacological therapies, small chemical activators of heat shock transcription factor 1 (HSF1) such as geldanamycin and its derivative 17-AAG, which induce multiple endogenous molecular chaperones, have been proven to be effective not only in polyQ disease models, but also in other neurodegenerative disease models. We hope that brainpermeable molecular chaperone inducers will be developed as drugs against a wide range of neurodegenerative diseases in the near future.

Intra- and extracellular protein misfolding and aggregation is likely to contribute to a number of age-related central nervous system diseases (“proteinopathies”). Therefore, molecular chaperones, such as heat shock proteins (HSPs), that regulate protein folding, misfolding and adaption to cellular stress are emerging as therapeutic targets. Here we review the current knowledge of HSP-modulating drugs and discuss the opportunities and difficulties of their therapeutic use to treat proteinopathies such as Alzheimer's- and Parkinson's disease, the polyglutamine- and prion disorders and Amyotrophic Lateral Sclerosis.

Heat shock proteins (Hsps) protect protein substrates against conformational damage to promote the function of the proteins, prevent aggregation and prevent formation of toxic inclusion bodies. Protein aggregates and fibrils have been associated with neurodegenerative diseases and with inclusion bodies. High-level expression of recombinant protein for biotechnological purposes often leads to insoluble inclusion bodies. Therefore, misfolded proteins must be properly folded or must be degraded through heat shock protein action. This function protects cells against cytotoxic outcomes. In addition to their cytoprotective roles, Hsps are involved in other functions since Hsps exist in all types of cells and tissues. Therefore, several diseases are associated with alterations of these biochemical functions. This first review of the theme issue will discuss general properties of Hsps concisely along with their potential use in pharmaceutical and biotechnological applications.

We report a significant increase of a curcumin (1,7-bis[4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione) fluorescence brightness when deposited on plasmonic platforms (self assembled silver nanostructures formed on the surface of silver semitransparent film). The enhancement of fluorescence intensity is accompanied by a strong decrease in fluorescence lifetime. Simultaneously, the increased photostability of curcumin, a pigment showing strong antiinflammatory, antioxidant and antitumorigenic activity, allows long-time detection and monitoring. We believe that the use of plasmonic platforms will improve detection, delivery and imaging of curcumin.

This has reference to the recent review article entitled “Momordica balsamina; a medicinal and neutraceutical plant for health care management” which appeared in Current Pharmaceutical Biotechnology1. The article discussed medicinal aspect i.e. anti-HIV, anti-inflammatory, hypoglycaemic, anti-bacterial, anti-plasmodial anti-diarrheal, anti-oxidant and hepatoprotective properties of M. balsamina. It is a timely article, which deserves appreciation; however by addressing few shortcomings will make it an interesting peace of research work. I complement authors for bringing about information on this plant which has skipped major international attention. The authors have concluded many properties based on the scarcely available literature which warrants urgent attention. The statement “M. balsamina is “an” (should have been “a”) miracle wild herb with anti-HIV properties2. First of all reference citation is wrong; it should have been 69(6), 1209-1214. Most importantly this reference is about identification and characterization of human retrovirus and there is no mention in this article that M. balsamina has shown some anti-HIV properties. I apprehend that such conclusions would misguide the researchers working on this plant. Such studies, where identification and usage of biological component from M. balsamina can establish anti-HIV properties are highly desirable. Furthermore, some studies have been initiated in this direction, where a low molecular weight protein purified from this novel species of Momoridca possesses ribosome inactivation property [1], this activity may be explored against viruses but same requires validation before assigning a title “anti-HIV property”. The authors interpretation is hasty as reference cited in the article3 too endorses that the effect of M. balsamina on the virus adsorption process needs to be further assessed using more sensitive techniques. In the next paragraph on same page, authors have described Momordin I and Momordin II are ribosome inactivating proteins found in Momordica sp. However, literature also states that Momordin I is a compound that has been isolated from Ampelopsis radix, a chinese herb, and found to inactivate transcription factor activator protein (AP-1) [2]. Further, structure of Momordin I (extracted from the seeds of M. charantia) should have representation in the form of helices or coils or pleats in three dimensional forms rather than a planer structure as mentioned by authors (for Momordin structure see [3]. Moreover, the structure for Momordin II represented in Fig. (2B) (on page 669) is not shown in the cited reference4 as mentioned in the article, rather amino acid sequence has been provided (as given by authors as Fig. (4) in the same article on page 678). The structures mentioned in the article are of cucurbitane-type triterpenoids isolated from M. balsamina [4]. In such a scenario; authors have misinformed the readers about structures and same needs correction in the article. The authors expressed a lot of enthusiasm towards the application of M. balsamina proteins for combating HIV/ AIDS but problems associated with toxicities and bioavailability of these proteins limit potential usefulness in such therapies. A number of critical animal toxicological and human clinical studies are not mentioned as the same have not been carried. Most of the studies that have been carried so far are inconclusive and requires further authentication before advocating this plant as a “hidden gift of nature”.

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