Putative Roles and Therapeutic Potential of the Chaperone System in Amyotrophic Lateral Sclerosis and Multiple Sclerosis.

The putative pathogenic roles and therapeutic potential of the chaperone system (CS) in amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) are reviewed to provide a bibliographic and conceptual platform for launching research on the diagnostic and therapeutic applications of CS components. Various studies suggest that dysfunction of the CS contributes to the pathogenesis of ALS and MS, and here, we identify some of the implicated CS members. The physiology and pathophysiology of the CS members can be properly understood if they are studied or experimentally or clinically manipulated for diagnostic or therapeutic purposes, bearing in mind that they belong to a physiological system with multiple interacting and dynamic components, widespread throughout the body, intra- and extracellularly. Molecular chaperones, some called heat shock protein (Hsp), are the chief components of the CS, whose canonical functions are cytoprotective. However, abnormal chaperones can be etiopathogenic factors in a wide range of disorders, chaperonopathies, including ALS and MS, according to the data reviewed. Chaperones typically form teams, and these build functional networks to maintain protein homeostasis, the canonical role of the CS. However, members of the CS also display non-canonical functions unrelated to protein homeostasis. Therefore, chaperones and other members of the CS, if abnormal, may disturb not only protein synthesis, maturation, and migration but also other physiological processes. Thus, in elucidating the role of CS components in ALS and MS, one must look at protein homeostasis abnormalities and beyond, following the clues emerging from the works discussed here.

NF-kB Regulation and the Chaperone System Mediate Restorative Effects of the Probiotic Lactobacillus fermentum LF31 in the Small Intestine and Cerebellum of Mice with Ethanol-Induced Damage.

Probiotics are live microorganisms that yield health benefits when consumed, generally by improving or restoring the intestinal flora (microbiota) as part of the muco-microbiotic layer of the bowel. In this work, mice were fed with ethanol alone or in combination with the probiotic Lactobacillus fermentum (L. fermentum) for 12 weeks. The modulation of the NF-κB signaling pathway with the induction of Hsp60, Hsp90, and IkB-α by the probiotic occurred in the jejunum. L. fermentum inhibited IL-6 expression and downregulated TNF-α transcription. NF-κB inactivation concurred with the restoration of the intestinal barrier, which had been damaged by ethanol, via the production of tight junction proteins, ameliorating the ethanol-induced intestinal permeability. The beneficial effect of the probiotic on the intestine was repeated for the cerebellum, in which downregulation of glial inflammation-related markers was observed in the probiotic-fed mice. The data show that L. fermentum exerted anti-inflammatory and cytoprotective effects in both the small intestine and the cerebellum, by suppressing ethanol-induced increased intestinal permeability and curbing neuroinflammation. The results also suggest that L. fermentum could be advantageous, along with the other available means, for treating intestinal diseases caused by stressors associated with inflammation and dysbiosis.

Inflammatory Bowel Diseases: An Updated Overview on the Heat Shock Protein Involvement.

Inflammatory bowel diseases (IBDs) represent chronic idiopathic disorders, including Crohn's disease (CD) and ulcerative colitis (UC), in which one of the trigger factors is represented by aberrant immune interactions between the intestinal epithelium and the intestinal microbiota. The involvement of heat shock proteins (HSPs) as etiological and pathogenetic factors is becoming of increasing interest. HSPs were found to be differentially expressed in the intestinal tissues and sera of patients with CD and UC. It has been shown that HSPs can play a dual role in the disease, depending on the stage of progression. They can support the inflammatory and fibrosis process, but they can also act as protective factors during disease progression or before the onset of one of the worst complications of IBD, colorectal cancer. Furthermore, HSPs are able to mediate the interaction between the intestinal microbiota and intestinal epithelial cells. In this work, we discuss the involvement of HSPs in IBD considering their genetic, epigenetic, immune and molecular roles, referring to the most recent works present in the literature. With our review, we want to shed light on the importance of further exploring the role of HSPs, or even better, the role of the molecular chaperone system (CS), in IBD: various molecules of the CS including HSPs may have diagnostic, prognostic and therapeutic potential, promoting the creation of new drugs that could overcome the side-effects of the therapies currently used.

Aberrant survival of hippocampal Cajal-Retzius cells leads to memory deficits, gamma rhythmopathies and susceptibility to seizures in adult mice.

Cajal-Retzius cells (CRs) are transient neurons, disappearing almost completely in the postnatal neocortex by programmed cell death (PCD), with a percentage surviving up to adulthood in the hippocampus. Here, we evaluate CR's role in the establishment of adult neuronal and cognitive function using a mouse model preventing Bax-dependent PCD. CRs abnormal survival resulted in impairment of hippocampus-dependent memory, associated in vivo with attenuated theta oscillations and enhanced gamma activity in the dorsal CA1. At the cellular level, we observed transient changes in the number of NPY+ cells and altered CA1 pyramidal cell spine density. At the synaptic level, these changes translated into enhanced inhibitory currents in hippocampal pyramidal cells. Finally, adult mutants displayed an increased susceptibility to lethal tonic-clonic seizures in a kainate model of epilepsy. Our data reveal that aberrant survival of a small proportion of postnatal hippocampal CRs results in cognitive deficits and epilepsy-prone phenotypes in adulthood.

Photo-responsive liposomes composed of spiropyran-containing triazole-phosphatidylcholine: investigation of merocyanine-stacking effects on liposome-fiber assembly-transition.

A spiropyran-containing triazole-phosphatidylcholine (SPTPC) was synthesized through a copper-catalyzed azide alkyne cyclo-addition (CuAAC) reaction. In water, SPTPCs self-assembled and a spontaneous spiropyran-to-merocyanine (SP-to-MC) isomerization occurred, resulting in coexistence of liposomes and fibers, and switching from the spiropyran (SP) to the merocyanine (MC) isomeric structure induced a reversible transition between these molecular assemblies. Study of the self-assembly of SPTPCs and photo-induced liposome-fiber assembly-transition revealed that the presence of MC enabled additional inter-membrane interaction during self-assembly and that the MC-stacking effect was the driving force for the assembly-transition. Exposure to UV light induced switching from SP to MC, where the planar structure of MC and the confinement of MC led to enhanced MC-stacking. The effect of MC-stacking was both advantageous and disadvantageous: MC-stacking perturbed the hydrophobic phase in the bilayer membrane and facilitated the liposome-to-fiber transition, otherwise the MC-stacking retarded switching of MC to SP, and caused an incomplete recovery of MC to SP during fiber-to-liposome recovery, thus a fatigue of SP was induced by MC-stacking during the liposome-to-fiber transition cycle. To decrease the intermolecular interactions and suppress MC-stacking, photo-inert triazole-phosphatidylcholine (TPC) was incorporated to prepare two-component TPC/SPTPC-liposomes, which exhibited better recovery kinetics. The photo-adaptive behavior of TPC/SPTPC-liposomes confirmed the disturbance of bilayer membranes by inter-membrane MC-stacking and the formation of MCTPC-enriched phases in the bilayer membrane.

Human primary macrophages scavenge AuNPs and eliminate it through exosomes. A natural shuttling for nanomaterials.

The use of nanomaterials is increasing but the real risk associated with their use in humans has to be defined. In fact, nanomaterials tend to accumulate in organs over a long period of time and are slowly degraded or eliminated by the body. Exosomes are nanovesicles actively shuttle molecules, including chemical products and metals, through the body. Macrophages scavenge the body from both organic and inorganic substances, and they use to release high amounts of exosomes. We hypothesized that macrophages may have a role in eliminating nanomaterials through their exosomes. We treated human primary macrophages with 20 nm gold nanoparticles (AuNPs), analyzing the presence of AuNPs in both cells and the released exosomes by the implementation of different techniques, including SP-ICP-MS and NTA. We showed that macrophages endocytosed AuNPs and released them through exosomes. Our study on one hand provide the evidence for a new methodology in the early identification of the nanomaterials levels in exposed subjects. On the other hand we depict a way our body shuttle virtually intact nanoparticles through macrophage-released exosomes.

Scalable-manufactured randomized glass-polymer hybrid metamaterial for daytime radiative cooling.

Passive radiative cooling draws heat from surfaces and radiates it into space as infrared radiation to which the atmosphere is transparent. However, the energy density mismatch between solar irradiance and the low infrared radiation flux from a near-ambient-temperature surface requires materials that strongly emit thermal energy and barely absorb sunlight. We embedded resonant polar dielectric microspheres randomly in a polymeric matrix, resulting in a metamaterial that is fully transparent to the solar spectrum while having an infrared emissivity greater than 0.93 across the atmospheric window. When backed with a silver coating, the metamaterial shows a noontime radiative cooling power of 93 watts per square meter under direct sunshine. More critically, we demonstrated high-throughput, economical roll-to-roll manufacturing of the metamaterial, which is vital for promoting radiative cooling as a viable energy technology.

Angiotensin II dependent cardiac remodeling in the eel Anguilla anguilla involves the NOS/NO system.

Angiotensin II (AngII), the principal effector of the Renin-Angiotensin System (RAS), plays an important role in controlling mammalian cardiac morpho-functional remodelling. In the eel Anguilla anguilla, one month administration of AngII improves cardiac performance and influences the expression and localization of molecules which regulate cell growth. To deeper investigate the morpho-functional chronic influences of AngII on the eel heart and the molecular mechanisms involved, freshwater eels (A. anguilla) were intraperitoneally injected for 2 months with AngII (1 nmol g BW-1). Then the isolated hearts were subjected to morphological and western blotting analyses, and nitrite measurements. If compared to control animals, the ventricle of AngII-treated hearts showed an increase in compacta thickness, vascularization, muscle mass and fibrosis. Structural changes were paralleled by a higher expression of AT2 receptor and a negative modulation of the ERK1-2 pathway, together with a decrease in nitrite concentration, indicative of a reduced Nitric Oxide Synthase (NOS)-dependent NO production. Moreover, immunolocalization revealed, particularly on the endocardial endothelium (EE) of AngII-treated hearts, a significant reduction of phosphorylated NOS detected by peNOS antibody accompanied by an increased expression of the eNOS disabling protein NOSTRIN, and a decreased expression of the positive regulators of NOS activity, pAkt and Hsp90. On the whole, results suggest that, in the eel, AngII modulates cardiac morpho-functional plasticity by influencing the molecular mechanisms that control NOS activity and the ERK1-2 pathway.

The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence.

Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively) blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France) and cyproheptadine (1 mg/kg) could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs.

Heat shock protein 60 levels in tissue and circulating exosomes in human large bowel cancer before and after ablative surgery.

BACKGROUND: Heat shock protein 60 (Hsp60) is a chaperonin involved in tumorigenesis, but its participation in tumor development and progression is not well understood and its value as a tumor biomarker has not been fully elucidated. In the current study, the authors presented evidence supporting the theory that Hsp60 has potential as a biomarker as well as a therapeutic target in patients with large bowel cancer. METHODS: The authors studied a population of 97 subjects, including patients and controls. Immunomorphology, Western blot analysis, and quantitative real-time polymerase chain reaction were performed on tissue specimens. Exosomes were isolated from blood and characterized by electron microscopy, biochemical tests, and Western blot analysis. RESULTS: Hsp60 was found to be increased in cancerous tissue, in which it was localized in the tumor cell plasma membrane, and in the interstitium associated with cells of the immune system, in which it was associated with exosomes liberated by tumor cells and, as such, circulated in the blood. An interesting finding was that these parameters returned to normal shortly after tumor removal. CONCLUSIONS: The data from the current study suggested that Hsp60 is a good candidate for theranostics applied to patients with large bowel carcinoma and encourage similar research among patients with other tumors in which Hsp60 has been implicated.

D-amphetamine improves attention performance in adolescent Wistar, but not in SHR rats, in a two-choice visual discrimination task.

The validity of spontaneous hypertensive rat (SHR) as a model of attention deficit hyperactivity disorder (ADHD) has been explored by comparing SHR with Wistar rats in a test of attention, the two-choice visual discrimination task (2-CVDT). Animals were 4-5 weeks old during the training phase of the experiment and 6-7 weeks old during the testing phase in which they were tested with D-amphetamine, a stimulant drug used for the treatment of ADHD. As compared to Wistar, SHR showed a slightly better attention performance, a slightly lower impulsivity level, and a lower general activity during the training phase, but these differences disappeared or lessened thereafter, during the testing phase. D-amphetamine (0.5, 1 mg/kg) improved attention performance in Wistar, but not in SHR, and did not modify impulsivity and activity in the two strains. In conclusion, the present study did not demonstrate that SHR represents a valid model of ADHD, since it did not show face validity regarding the behavioral symptoms of ADHD and predictive validity regarding the effect of a compound used for the treatment of ADHD. On the other hand, this study showed that the 2-CVDT may represent a suitable tool for evaluating in adolescent Wistar rats the effect on attention of compounds intended for the treatment of ADHD.

Bergamot Reduces Plasma Lipids, Atherogenic Small Dense LDL, and Subclinical Atherosclerosis in Subjects with Moderate Hypercholesterolemia: A 6 Months Prospective Study.

BACKGROUND: Some patients experience statin-induced side effects or prefer nutraceutical approaches for the treatment of dyslipidemia. This has led to a search for alternative therapeutic approaches for dyslipidemia management. In recent studies Citrus bergamia (known as Bergamot) juice was able to reduce serum levels of lipids. Such benefit may be attributed to high amounts of flavonoids contained in Bergamot fruit juice (neoeriocitrin, neohesperidin, naringin). The aim of the present study was to fully investigate the effects of a Bergamot extract on cardio-metabolic parameters, including plasma lipids, atherogenic lipoproteins and subclinical atherosclerosis. METHODS: Eighty subjects (42 men and 38 women, mean age: 55 ± 13 years) with moderate hypercholesterolemia [e.g., with plasma LDL-cholesterol concentrations between 160 and 190 mg/dl (between 4.1 and 4.9 mmol/l)] were included. A Bergamot-derived extract (Bergavit R(®)) was given at a fixed dose daily (150 mg of flavonoids, with 16% of neoeriocitrin, 47% of neohesperidin and 37% of naringin) for 6 months. Lipoprotein subfractions were assessed by gel electrophoresis. With this methodology low density lipoprotein (LDL) subclasses are distributed as seven bands (LDL-1 and -2 as large LDL, and LDL-3 to -7 as atherogenic small, dense LDL). Subclinical atherosclerosis was assessed by carotid intima-media thickness (cIMT) using B-mode ultrasound. RESULTS: After 6 months, Bergavit R(®) reduced total cholesterol (from 6.6 ± 0.4 to 5.8 ± 1.1 mmol/l, p < 0.0001), triglycerides (from 1.8 ± 0.6 to 1.5 ± 0.9 mmol/l, p = 0.0020), and LDL-cholesterol (from 4.6 ± 0.2 to 3.7 ± 1.0 mmol/l, p < 0.0001), while HDL- cholesterol increased (from 1.3 ± 0.2 to 1.4 ± 0.4 mmol/l, p < 0.0007). In addition, a significant increase in LDL-1 (from 41.2 ± 0.2 to 49.6 ± 0.2%, p < 0.0001) was accompanied by decreased small, dense LDL-3, -4, and 5 particles (from 14.5 ± 0.1 to 9.0 ± 0.1% p < 0.0001; 3.2 ± 0.1 to 1.5 ± 0.1% p = 0.0053; 0.3 ± 0.0% to 0.1 ± 0.0% p = 0.0133, respectively). cIMT also decreased from 1.2 ± 0.4 to 0.9 ± 0.1 mm (p < 0.0001). CONCLUSION: This is the first study investigating the effects of Bergamot flavonoids supplementation on cardio-metabolic risk in dyslipidemic subjects. Bergavit R(®) (Bergamot juice extract) supplementation significantly reduced plasma lipids and improved the lipoprotein profile. cIMT was also reduced significantly over a relatively short time frame of 6 months.

Comparative analysis of Hsp10 and Hsp90 expression in healthy mucosa and adenocarcinoma of the large bowel.

BACKGROUND: Heat shock proteins (Hsps) assist other proteins in their folding and drive the degradation of defective proteins. During evolution, these proteins have also acquired other roles. Hsp10 is involved in immunomodulation and tumor progression. Hsp90 stabilizes a range of "client" proteins involved in cell signaling. The present study evaluated the expression levels of Hsp10 and Hsp90 in normal mucosa and adenocarcinoma samples of human large bowel. MATERIALS AND METHODS: Samples of normal mucosa and adenocarcinoma were collected and Reverse transcriptase-polymerase chain reaction RT-PCR, western blotting (WB) analyses, as well as immunohistochemistry were performed to evaluate the expression levels of Hsp10 and Hsp90. RESULTS: RT-PCR showed a higher gene expression of Hsp10 and Hsp90 in adenocarcinoma samples compared to healthy mucosa. WB results confirmed these findings. Immunohistochemistry revealed higher levels of Hsp10 in adenocarcinoma in both the epithelium and the lamina propria, while Hsp90 expression was higher in the adenocarcinoma samples only in the lamina propria. CONCLUSION: Hsp10 and Hsp90 may be involved in large bowel carcinogenesis.

The role of the heme oxygenase system in the metabolic syndrome.

Molecular chaperones and the heat shock response play a major role in the maintenance of cellular homeostasis under various pathological conditions. In particular, their role is to regulate protein conformation, protect proteins from misfolding and aggregation, and maintain signalling and organellarnetworks. Among variousheat shock proteins, Hsp32 also known as heme oxygenase-1 (HO-1), has demonstrated an important role in metabolic syndrome. In particular, the HO system seems to play a major role in the complex pathophysiological cascade involved in insulin resistance mechanisms, and adipocyte functions as measured by the release of important adipokynes. The aim of the present review is to point out the role of HO-1 in metabolic syndrome, and how to exploit its beneficial effects as a therapeutic strategy to prevent complicationsof andto improve insulin sensitivity.

Hsp10: anatomic distribution, functions, and involvement in human disease.

There is growing evidence that molecular chaperones/heat shock proteins are involved in the pathogenesis of a number of human diseases, known as chaperonopathies. A better molecular understanding of the pathogenetic mechanisms is essential for addressing new strategies in diagnostics, therapeutics and clinical management of chaperonopathies, including those in which Hsp10 is involved. This chaperonin has been studied for a long time as a member of the mitochondrial protein-folding machine. However, although in normal cells Hsp10 is mainly localized in the mitochondrial matrix, it has also been found during and after stress in other subcellular compartments, such as cytosol, vesicles and secretory granules, alone or in combination with other proteins. In these extramitochondrial locales, Hsp10 plays an active role in cell signalling. For example, cancer cells often show altered levels of Hsp10, compared to normal cells. Hsp10 may also be found in the extracellular space and in the bloodstream, with a possible immunomodulatory activity. This minireview focuses on some studies to date on the involvement of Hsp10 in human disease pathogenesis.

HSP-molecular chaperones in cancer biogenesis and tumor therapy: an overview.

Molecular chaperones, many of which are heat-shock proteins (HSPs), are an important class of molecules with various functions. Pathological conditions in which chaperones become etiological and/or pathogenic factors are called chaperonopathies, and are classified into by defect, by excess, and by 'mistake'. In the latter case, the chaperone is structurally and functionally normal but participates in pathways that favor disease, although in some cases the chaperone may have post-translational modifications that may lead it to change its location and function and, thus, to become pathogenic. For example, HSP-chaperones are involved in carcinogenesis in various ways, so that some forms of cancer may be considered 'chaperonopathies by mistake'. This concept suggests new strategies for anticancer therapy (chaperonotherapy), in which the primary targets or therapeutic agents are chaperones. Chaperonotherapy consists of the utilization of HSP-chaperones for treating chaperonopathies, including cancer. Negative chaperonotherapy is aimed at eliminating or blocking the action of chaperones that favor carcinogenesis or other diseases, whereas positive chaperonotherapy uses chaperones, genes or proteins, to fight against diseases, such as cancer, by stimulating the immune system or the cellular defenses against stress.

The odyssey of Hsp60 from tumor cells to other destinations includes plasma membrane-associated stages and Golgi and exosomal protein-trafficking modalities.

BACKGROUND: In a previous work we showed for the first time that human tumor cells secrete Hsp60 via exosomes, which are considered immunologically active microvesicles involved in tumor progression. This finding raised questions concerning the route followed by Hsp60 to reach the exosomes, its location in them, and whether Hsp60 can be secreted also via other mechanisms, e.g., by the Golgi. We addressed these issues in the work presented here. PRINCIPAL FINDINGS: We found that Hsp60 localizes in the tumor cell plasma membrane, is associated with lipid rafts, and ends up in the exosomal membrane. We also found evidence that Hsp60 localizes in the Golgi apparatus and its secretion is prevented by an inhibitor of this organelle. CONCLUSIONS/SIGNIFICANCE: We propose a multistage process for the translocation of Hsp60 from the inside to the outside of the cell that includes a combination of protein traffic pathways and, ultimately, presence of the chaperonin in the circulating blood. The new information presented should help in designing future strategies for research and for developing diagnostic-monitoring means useful in clinical oncology.

Brain phenotype of transgenic mice overexpressing cystathionine ß-synthase.

BACKGROUND: The cystathionine ß-synthase (CBS) gene, located on human chromosome 21q22.3, is a good candidate for playing a role in the Down Syndrome (DS) cognitive profile: it is overexpressed in the brain of individuals with DS, and it encodes a key enzyme of sulfur-containing amino acid (SAA) metabolism, a pathway important for several brain physiological processes. METHODOLOGY/PRINCIPAL FINDINGS: Here, we have studied the neural consequences of CBS overexpression in a transgenic mouse line (60.4P102D1) expressing the human CBS gene under the control of its endogenous regulatory regions. These mice displayed a ∼2-fold increase in total CBS proteins in different brain areas and a ∼1.3-fold increase in CBS activity in the cerebellum and the hippocampus. No major disturbance of SAA metabolism was observed, and the transgenic mice showed normal behavior in the rotarod and passive avoidance tests. However, we found that hippocampal synaptic plasticity is facilitated in the 60.4P102D1 line. CONCLUSION/SIGNIFICANCE: We demonstrate that CBS overexpression has functional consequences on hippocampal neuronal networks. These results shed new light on the function of the CBS gene, and raise the interesting possibility that CBS overexpression might have an advantageous effect on some cognitive functions in DS.

Changes in immunohistochemical levels and subcellular localization after therapy and correlation and colocalization with CD68 suggest a pathogenetic role of Hsp60 in ulcerative colitis.

In an earlier work, the role of heat shock protein (Hsp60) in the pathogenesis of ulcerative colitis (UC) was suggested by its significant increase in the pathological mucosa parallel with an increase in inflammatory cells. More data in this direction are reported in this work. We analyzed by immunohistochemistry biopsies of colon tissue from 2 groups of patients with UC and treated with either 5-aminosalicylic acid (5-ASA) alone or in combination with a probiotic. We looked for inflammatory markers and Hsp60. Both the treatments were effective in reducing symptoms but the group treated with both 5-ASA and probiotics showed better clinical results. Amelioration of symptoms was associated with reduction of both inflammation and Hsp60, a reduction that was most marked in the group treated with 5-ASA and probiotics. The levels of Hsp60 positively correlated with those of CD68-positive cells, and double immunofluorescence showed a high index of colocalization of the chaperonin and CD68 in lamina propria. Immunoelectron microscopy showed that Hsp60-classically a mitochondrial protein-was abundantly also present in cytosol in biopsies taken at the time of diagnosis, but not after the treatment. Our data suggest that Hsp60 is an active player in pathogenesis of UC and it can be hypothesized that the chaperonin is responsible, at least in part, for initiation and maintenance of disease.

Hsp60: molecular anatomy and role in colorectal cancer diagnosis and treatment.

Quantitative changes in Hsp60 during the development of some tumors suggest that this chaperonin plays a role in carcinogenesis. A description of the specific role(s) of Hsp60 in tumor-cell growth and proliferation is still incomplete, but it is already evident that monitoring its levels and distribution in tissues and fluids has potential for diagnosis and staging, and for assessing prognosis and response to treatment. Although Hsp60 is considered an intramitochondrial protein, it has been demonstrated in the cytosol, cell membrane, vesicles, cell surface, extracellular space, and blood. The knowledge that Hsp60 occurs at all these locations opens new avenues for basic and applied research. It is clear that elucidating the mechanisms by which the chaperonin arrives at these various locations, and characterizing its functions in each of them will provide information useful for understanding carcinogenesis and for developing diagnostic and therapeutic tools for clinical oncology. Some of these issues pertinent to colorectal cancer (CRC) are discussed in this article.