Nitazoxanide Stimulates Autophagy and Inhibits mTORC1 Signaling and Intracellular Proliferation of Mycobacterium tuberculosis

Tuberculosis, caused by Mycobacterium tuberculosis infection, is a major cause of morbidity and mortality in the world today. M. tuberculosis hijacks the phagosome-lysosome trafficking pathway to escape clearance from infected macrophages. There is increasing evidence that manipulation of autophagy, a regulated catabolic trafficking pathway, can enhance killing of M. tuberculosis. Therefore, pharmacological agents that induce autophagy could be important in combating tuberculosis. We report that the antiprotozoal drug nitazoxanide and its active metabolite tizoxanide strongly stimulate autophagy and inhibit signaling by mTORC1, a major negative regulator of autophagy. Analysis of 16 nitazoxanide analogues reveals similar strict structural requirements for activity in autophagosome induction, EGFP-LC3 processing and mTORC1 inhibition. Nitazoxanide can inhibit M. tuberculosis proliferation in vitro. Here we show that it inhibits M. tuberculosis proliferation more potently in infected human THP-1 cells and peripheral monocytes. We identify the human quinone oxidoreductase NQO1 as a nitazoxanide target and propose, based on experiments with cells expressing NQO1 or not, that NQO1 inhibition is partly responsible for mTORC1 inhibition and enhanced autophagy. The dual action of nitazoxanide on both the bacterium and the host cell response to infection may lead to improved tuberculosis treatment

Variability and Action Mechanism of a Family of Anticomplement Proteins in Ixodes ricinus

Background: Ticks are blood feeding arachnids that characteristically take a long blood meal. They must therefore counteract host defence mechanisms such as hemostasis, inflammation and the immune response. This is achieved by expressing batteries of salivary proteins coded by multigene families. Methodology/Principal Findings: We report the in-depth analysis of a tick multigene family and describe five new anticomplement proteins in ixodes ricinus. Compared to previously described Ixodes anticomplement proteins, these segregated into a new phylogenetic group or subfamily. These proteins have a novel action mechanism as they specifically bind to properdin, leading to the inhibition of C3 convertase and the alternative complement pathway. An excess of non-synonymous over synonymous changes indicated that coding sequences had undergone diversifying selection. Diversification was not associated with structural, biochemical o, functional diversity, adaptation to host species or stage specificity but rather to differences in antigenicity. Conclusion/Significance: Anticomplement proteins from I. ricinus are the first inhibitors that specifically target a positive regulator of complement, properdin. They may provide new tools for the investigation of role of properdin in physiological and pathophysiological mechanisms. They may also be useful in disorders affecting the alternative complement pathway, Looking for and detecting the different selection pressures involved will help in understanding the evolution of multigene families and hematophagy in arthropods. © 2008 Couveur et al.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling

BackgroundMammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that relays nutrient availability signals to control numerous cellular functions including autophagy, a process of cellular self-eating activated by nutrient depletion. Addressing the therapeutic potential of modulating mTORC1 signaling and autophagy in human disease requires active chemicals with pharmacologically desirable properties.Methodology/Principal FindingsUsing an automated cell-based assay, we screened a collection of &gt;3,500 chemicals and identified three approved drugs (perhexiline, niclosamide, amiodarone) and one pharmacological reagent (rottlerin) capable of rapidly increasing autophagosome content. Biochemical assays showed that the four compounds stimulate autophagy and inhibit mTORC1 signaling in cells maintained in nutrient-rich conditions. The compounds did not inhibit mTORC2, which also contains mTOR as a catalytic subunit, suggesting that they do not inhibit mTOR catalytic activity but rather inhibit signaling to mTORC1. mTORC1 inhibition and autophagosome accumulation induced by perhexiline, niclosamide or rottlerin were rapidly reversed upon drug withdrawal whereas amiodarone inhibited mTORC1 essentially irreversibly. TSC2, a negative regulator of mTORC1, was required for inhibition of mTORC1 signaling by rottlerin but not for mTORC1 inhibition by perhexiline, niclosamide and amiodarone. Transient exposure of immortalized mouse embryo fibroblasts to these drugs was not toxic in nutrient-rich conditions but led to rapid cell death by apoptosis in starvation conditions, by a mechanism determined in large part by the tuberous sclerosis complex protein TSC2, an upstream regulator of mTORC1. By contrast, transient exposure to the mTORC1 inhibitor rapamycin caused essentially irreversible mTORC1 inhibition, sustained inhibition of cell growth and no selective cell killing in starvation.Conclusion/SignificanceThe observation that drugs already approved for human use can reversibly inhibit mTORC1 and stimulate autophagy should greatly facilitate the preclinical and clinical testing of mTORC1 inhibition for indications such as tuberous sclerosis, diabetes, cardiovascular disease and cancer.<br/

Chromosomal alterations in oligodendroglial tumors over multiple surgeries: Is progression associated with change in 1p/19q status?

10577 Background: There is morphologic and genotypic heterogeneity of oligodendroglial neoplasms. Tumors with loss of heterozygosity (LOH) of 1p and/or 19q are associated with increased chemo-sensitivity and survival. Despite treatment, rates of recurrence and malignant transformation are high. The pathogenesis of treatment-resistance is unknown. We aim to determine if tumour progression is associated with a proliferation of clonagens with retention of heterozygosity (ROH) of 1p, or if progressing tumours remain 1p/19q LOH. Methods: Between 1/1/2001 and 7/31/2006, 24 patients with oligodendroglial neoplasms, and possessing serial biopsies taken at diagnosis and at progression, were identified. Using PCR amplification of multiple microsatellite markers, a total of 53 tumour specimens were available for LOH analysis of 1p and 19q; 40 were also tested for 9p and 10q. Results: At diagnosis, the median age was 34 (24–66) years and 14 were male. Using the WHO criteria, 19 tumors were Grade II oligodendrogliomas or oligoastrocytomas, and 5 were high grade. The most common genomic status was 19q LOH (88%); 54% had 1p LOH. Of the 13 primary biopsies with 1p LOH, 11 had 19q LOH, 1 had 19q ROH, and 1 was 19q non-informative. A further 2 primaries were mixed 1p LOH/ROH, and 9 were 1p ROH. At progression, 10 of 11 patients with 1p/19q LOH had persistent co-deletion. The patient with 1p LOH and 19q ROH at diagnosis, had 1p/19q LOH at progression. Of the mixed 1p primaries, 1 was 1p ROH, and the other remained mixed LOH/ROH at progression. 8 of 9 primaries with 1p ROH remained 1p ROH. There was also little heterogeneity of 9p and 10q between primary and progressive tumours. Using Kaplain-Meier analysis, mean overall survival (OS) for the group was 102 (95% CI: 77–127) months. Mean progression-free survival was 52 (95% CI: 33–72) months. OS was not statistically significant between patients with 1p LOH and 1p ROH primary tumours. Conclusions: 91% of repeat biopsies of oligodendroglial tumors, demonstrated persistent 1p/19q LOH. Therefore, progression of 1p/19q LOH primary tumours is not due to a proliferating sub-group of chemo-resistant, 1p ROH clonagens. We propose that additional mutations contribute to this aggressive phenotype. No significant financial relationships to disclose. </jats:p

Long-term Satisfaction with CO2 Laser Treatment for Moderate to Major Rhinophyma: A Single-centre Study

Rhinophyma, a severe manifestation of rosacea, predominantly affects Caucasian males aged 50–70 and is characterized by thickening and enlargement of the nasal skin. The condition can seriously both impact cosmetic appearance and obstruct nasal breathing. While its appearance is distinct, conditions such as basal cell carcinoma can mimic it, complicating diagnosis. Treatment options for rhinophyma range from medical therapies to surgical interventions, with CO2 laser resurfacing emerging as the gold standard due to its precision and minimal blood loss. This retrospective case series evaluates the long-term efficacy and patient satisfaction of CO2 laser treatment in 11 male patients treated between 2015 and 2023 at the Karolinska University Hospital. The results revealed sustained positive outcomes, with 92% of patients reporting high satisfaction and 55% experiencing improved nasal airflow post-procedure. Despite some instances of hypopigmentation and scarring, no major side effects were reported. The study supports CO2 laser treatment as a safe and effective option for moderate to major rhinophyma in Caucasian male patients with Fitzpatrick skin types I–III. The importance of considering skin type, where extra caution must be employed when treating skin types IV–VI, should be emphasized as the treatmen

Darier disease is associated with neurodegenerative disorders and epilepsy

Darier disease (DD) is a rare monogenetic skin disorder with limited data on its potential association with neurological disorders. This study aimed to investigate the association between DD and neurological disorders, specifically Parkinson's disease, dementias, and epilepsy. Using Swedish national registers in a period spanning between 1977 and 2013, 935 individuals with DD were compared with up to 100 comparison individuals each, randomly selected from the general population based on birth year, sex, and county of residence at the time of the first diagnosis of DD. Individuals with DD had increased risks of being diagnosed with Parkinson's disease (RR 2.1, CI 1.1; 4.4), vascular dementia (RR 2.1, CI 1.0; 4.2), and epilepsy, (RR 2.5, CI 1.8; 3.5). No association of DD with other dementias were detected. This study demonstrates a new association between DD and neurodegenerative disorders and epilepsy, underlining the need for increased awareness, interdisciplinary collaboration, and further research to understand the underlying mechanisms. Early identification and management of neurological complications in DD patients could improve treatment strategies and patient outcomes. The findings also highlight the role of SERCA2 in the pathophysiology of neurological disorders, offering new targets for future research and potentials for novel treatments.</p

Training programmes in sustainable forest management in Austria, Croatia and Slovenia

Background and Purpose: During the Erasmus+ project "Cooperation for Innovative Approach in Sustainable Forest Management Training (CIA2SFM)" a study of the existing vocational education and training (VET) and lifelong learning (LLL) programmes in the field of sustainable forest management (SFM) was conducted in Austria, Croatia and Slovenia. The aim of this paper is to get an overview of and analyse SFM-related VET and LLL programmes in the study area, with an emphasis on the identification of good practice examples and providing recommendations for improvement. Materials and Methods: A combined approach of literature review, Internet search and consultations with training providers was applied in order to collect data on training programmes conducted in the period 2006-2015 in Austria, Croatia and Slovenia. The programmes were analysed based on topics, types of methods used, existence of specified learning outcomes, programme evaluation by participants and how the programme was advertised. The analysis employed basic descriptive statistics. Topics were grouped into broader themes. Only training programmes targeting private forest owners, forestry professionals, and forestry entrepreneurs were analysed. Three examples of good practice in each country were selected based on collaboratively developed criteria. Results: In Austria, Croatia and Slovenia numerous training courses related to SFM were conducted in the analysed period, predominantly addressing target groups in forestry sector and covering a variety of topics. The relative importance of themes varied among countries. In order to facilitate the knowledge uptake by participants various methods were applied. Although indoor ex-cathedra approaches prevailed, it could be recognized that there is a growth in interest for foster demonstrations in the field, organizing field trips, emphasize on practical work and combining methods and approaches in most countries. Conclusions: Even if national providers of training programmes may relate to individual needs within national forestry sectors, SFM-related training programmes should be regularly screened and updated according to international agendas and emerging issues. In order to cope with increasing uncertainty and expanding risks forest ecosystems are facing, it is an important task to open up the recent training offer to innovative forms of learning, combinations of topics and learning environments