Myelin pathology: Involvement of molecular chaperones and the promise of chaperonotherapy

The process of axon myelination involves various proteins including molecular chaperones. Myelin alteration is a common feature in neurological diseases due to structural and functional abnormalities of one or more myelin proteins. Genetic proteinopathies may occur either in the presence of a normal chaperoning system, which is unable to assist the defective myelin protein in its folding and migration, or due to mutations in chaperone genes, leading to functional defects in assisting myelin maturation/migration. The latter are a subgroup of genetic chaperonopathies causing demyelination. In this brief review, we describe some paradigmatic examples pertaining to the chaperonins Hsp60 (HSPD1, or HSP60, or Cpn60) and CCT (chaperonin-containing TCP-1). Our aim is to make scientists and physicians aware of the possibility and advantages of classifying patients depending on the presence or absence of a chaperonopathy. In turn, this subclassification will allow the development of novel therapeutic strategies (chaperonotherapy) by using molecular chaperones as agents or targets for treatment

Effect of Aqueous Ozone on the NF-κB System

Ozone has been proposed as an alternative oral antiseptic in dentistry, due to its antimicrobial power reported for gaseous and aqueous forms, the latter showing a high biocompatibility with mammalian cells. New therapeutic strategies for the treatment of periodontal disease and apical periodontitis should consider not only antibacterial effects, but also their influence on the host immune response. Therefore, our aim was to investigate the effect of aqueous ozone on the NF-κB system, a paradigm for inflammationassociated signaling/transcription. We showed that NF-κB activity in oral cells stimulated with TNF, and in periodontal ligament tissue from root surfaces of periodontally damaged teeth, was inhibited following incubation with ozonized medium. Under this treatment, IκBalpah proteolysis, cytokine expression, and κB-dependent transcription were prevented. Specific ozonized amino acids were shown to represent major inhibitory components of ozonized medium. In summary, our study establishes a condition under which aqueous ozone exerts inhibitory effects on the NF-κB system, suggesting that it has an antiinflammatory capacity

Chaperonopathies and Chaperonotherapy. Hsp60 as Therapeutic Target in Cancer: Potential Benefits and Risks.

In this minireview we focus on Hsp60 as a target for anticancer therapy. We discuss the new concepts of chaperonopathies and chaperonotherapy and present information on Hsp60 localization in the cell membrane of human tumor cells. We describe novel mechanisms for Hsp60 reaching the extracellular environment that involve membrane-associated stages, as well as data on anti-Hsp60 antibodies found in human sera, both in normal subjects and patients affected by autoimmune diseases. Finally, we discuss possible therapeutic applications of anti-Hsp60 antibodies in cancer treatment, evaluating also side effects on non-tumor cells. In conclusion, the way for investigating Hsp60-targeted anti-tumor therapy is open, at least for those tumors that express Hsp60 on its surface and/or secrete it outside the cell, as is the search for the molecular mechanisms involved in Hsp60 translocation from cytosol to cell membrane: elucidation of this mechanism will greatly facilitate the optimization of chaperonotherapy centered on Hsp60 with anti-tumor efficacy and minimal side effects

Nanoplastics affect moulting and faecal pellet sinking in Antarctic krill (Euphausia superba) juveniles

Plastic debris has been identified as a potential threat to Antarctic marine ecosystems, however, the impact of nanoplastics (<1 μm) is currently unexplored. Antarctic krill (Euphausia superba) is a keystone species of Southern Ocean pelagic ecosystems, which plays a central role in the Antarctic food webs and carbon (C) cycle. Krill has been shown to rapidly fragment microplastic beads through the digestive system, releasing nanoplastics with unknown toxicological effects. Here we exposed krill juveniles to carboxylic (COOH, anionic) and amino- (NH2, cationic) polystyrene nanoparticles (PS NPs) and we investigated lethal and sub-lethal endpoints after 48 h. The analysis of PS NP suspensions in Antarctic sea water (SW) media showed that PS-COOH formed large agglomerates (1043 ± 121 nm), while PS-NH2 kept their nominal size (56.8 ± 3 nm) during the exposure time. After 48 h, no mortality was found but increase in exuviae production (12.6 ± 1.3%) and reduced swimming activity were observed in juveniles exposed to PS-NH2. The microbial community composition in SW supports the release of krill moults upon PS NP exposure and stimulates further research on the pivotal role of krill in shaping Southern Ocean bacterial assemblages. The presence of fluorescent signal in krill faecal pellets (FPs) confirmed the waterborne ingestion and egestion of PS-COOH at 48 h of exposure. Changes in FP structure and properties were also associated to the incorporation of PS NPs regardless of their surface charge. The effects of PS NPs on krill FP properties were compared to Control 0 h as a reference for full FPs (plastic vs food) and Control 48 h as a reference for more empty-like FPs (plastic vs lack of food). Exposure to PS NPs led to a FP sinking rate comparable to Control 48 h, but significantly lower than Control 0 h (58.40 ± 23.60 m/d and 51.23 ± 28.60 m/d for PS-COOH and PS-NH2; 168.80 ± 74.58 m/d for Control 0 h). Considering the important role played by krill in the food web and C export in the Southern Ocean, the present study provides cues about the potential impact of nanoplastics on Antarctic pelagic ecosystems and their biogeochemical cycles

Curcumin affects HSP60 folding activity and levels in neuroblastoma cells

The fundamental challenge in fighting cancer is the development of protective agents able to interfere with the classical pathways of malignant transformation, such as extracellular matrix remodeling, epithelial\u2013mesenchymal transition and, alteration of protein homeostasis. In the tumors of the brain, proteotoxic stress represents one of the main triggering agents for cell transformation. Curcumin is a natural compound with anti-inflammatory and anti-cancer properties with promising potential for the development of therapeutic drugs for the treatment of cancer as well as neurodegenerative diseases. Among the mediators of cancer development, HSP60 is a key factor for the maintenance of protein homeostasis and cell survival. High HSP60 levels were correlated, in particular, with cancer development and progression, and for this reason, we investigated the ability of curcumin to affect HSP60 expression, localization, and post-translational modifications using a neuroblastoma cell line. We have also looked at the ability of curcumin to interfere with the HSP60/HSP10 folding machinery. The cells were treated with 6, 12.5, and 25 \ub5M of curcumin for 24 h, and the flow cytometry analysis showed that the compound induced apoptosis in a dose-dependent manner with a higher percentage of apoptotic cells at 25 \ub5M. This dose of curcumin-induced a decrease in HSP60 protein levels and an upregulation of HSP60 mRNA expression. Moreover, 25 \ub5M of curcumin reduced HSP60 ubiquitination and nitration, and the chaperonin levels were higher in the culture media compared with the untreated cells. Furthermore, curcumin at the same dose was able to favor HSP60 folding activity. The reduction of HSP60 levels, together with the increase in its folding activity and the secretion in the media led to the supposition that curcumin might interfere with cancer progression with a protective mechanism involving the chaperonin

SARS-CoV-2 in patients with cancer: possible role of mimicry of human molecules by viral proteins and the resulting anti-cancer immunity

A few reports suggest that molecular mimicry can have a role in determining the more severe and deadly forms of COVID-19, inducing endothelial damage, disseminated intravascular coagulation, and multiorgan failure. Heat shock proteins/molecular chaperones can be involved in these molecular mimicry phenomena. However, tumor cells can display on their surface heat shock proteins/molecular chaperones that are mimicked by SARS-CoV-2 molecules (including the Spike protein), similarly to what happens in other bacterial or viral infections. Since molecular mimicry between SARS-CoV-2 and tumoral proteins can elicit an immune reaction in which antibodies or cytotoxic cells produced against the virus cross-react with the tumor cells, we want to prompt clinical studies to evaluate the impact of SARS-CoV-2 infection on prognosis and follow up of various forms of tumors. These topics, including a brief historical overview, are discussed in this paper

HEAT SHOCK PROTEINS AND ULCERATIVE COLITIS: THE START OF A NEW ERA?

We read with great interest the article written by Abou El Azm and coworkers, published in the last issue of the Arab Journal of Gastroenterology [1]. In this article, the authors investigated the molecular expression of heat shock proteins (HSP) 70 and 90 in relation to the grades of inflammation and dysplasia in patients with ulcerative colitis (UC) before and after treatment. In this study, in agreement with other published studies [2–4], the authors not only found a potential role for HSP 70 and HSP 90 for assessment of the activity and prognosis of UC, but also such markers predicted the presence of dysplasia and differentiated it from reactive atypia [1]. HSP had been found not only a marker of active disease, thus considering UC as a ‘‘chaperonopathy by mistake’’, but also show a key role in the psychosocial setting in which inflammatory bowel diseases manifest themselves [5]. Furthermore, they could represent a new diagnostic tool to differentiate the different phenotypes of UC, thus allowing to tailor a targeted approach to better manage UC patients [6]. However, some unresolved issues still remain about the potential roles of HSP in both the acute and the longstanding disease. First, it should be interesting to assess the role of HSP in the infections associated to UC flares, like Clostridium difficile and Cytomegalovirus (CMV) infections. In fact, HSP could be investigated as a further marker of inflammation in case of severe and steroid-refractory disease; with regard to CMV infection, mucosal levels of HSP could differentiate when CMV plays a role of direct pathogen or when it represents merely a ‘‘silent bystander’’. Second, in longstanding UC, an integrated approach of colorectal cancer surveillance, by using the advanced endoscopic imaging together with mucosal markers, like HSP, could result in being markedly helpful, both to clinicians and pathologist. In fact, current guidelines recommend that image-enhanced endoscopy (IEE) may increase the yield of detection of dysplasia, thus representing a reasonable alternative to the random sampling of colon using standard white light [7]. The use of both IEE and new biomarkers, like HSP, predicting future occurrence of colonic neoplasia, could lead to a more centralised approach of UC patients, in which a ‘‘biomarker-based surveillance’’ might play a pivotal rol