Cognitive inhibition deficit in long COVID-19: An exploratory study.

Background and objectives: An increasing number of research studies point toward the importance and prevalence of long-term neurocognitive symptoms following infection with COVID-19. Our objectives were to capture the prevalence of cognitive impairments from 1 to 16 months post-COVID-19 infection, assess the changes in neuropsychological functions over time, and identify factors that can predict long-term deficits in cognition. Methodology: A cross-sectional research design was adopted to compare four sub-samples recruited over a 16-month timeframe (1-4, 5-8, 9-12, and 13-16 months). Phone interviews were conducted at least 6 weeks after being infected by COVID-19. Sociodemographic and clinical questionnaires were administered followed by standardized neurocognitive and psychological tests and health questionnaires screening cognitive symptoms, anxiety, depression, fatigue, and autonomy. Results: Regarding general health questionnaires, 55.2% of the 134 participants had symptoms of psychiatric illness, while 21.6% of patients had moderate-to-severe anxiety or depression. Cognitive efficiency was diminished in 19.4% of our population. Executive dysfunction was screened in 56% of patients, and an impairment of cognitive flexibility and inhibition was revealed in 38.8%. Depression, hospital or intensive care unit (ICU) admission, and the duration of hospital or ICU stay were associated with an inhibition deficit. The duration elapsed from the initial infection, and the neurocognitive assessment was not associated with a decrease in inhibition deficit. The prevalence of cognitive impairments, other than inhibition deficit, tended to decrease during the study period. Discussion: This study supports the extensive literature on the cognitive and neuropsychiatric sequelae of COVID-19 and highlights long-lasting inhibition deficits, while other cognitive functions seemed to improve over time. The severity of infection could interact as a catalyst in the complex interplay between depression and executive functions. The absence of a relation between inhibition deficits and sociodemographic or medical factors reinforces the need for cognitive screening in all COVID-19 patients. Future research should focus on inhibition deficits longitudinally to assess the progression of this impairment.

Identifying harm reduction strategies for alcohol and drug-use in inpatient care settings and emergency departments: a scoping review protocol.

INTRODUCTION: People who use alcohol and/or drugs (PWUAD) are at high risk of medical complications, frequent hospitalisation and drug-related death following discharge from inpatient settings and emergency departments (EDs). Harm reduction strategies implemented in these settings may mitigate negative health outcomes for PWUAD. However, the scope of harm reduction strategies used globally within inpatient settings and EDs is unknown. The objective of this review is to identify and synthesise reported harm reduction strategies that have been implemented across inpatient settings and EDs for PWUAD. METHODS AND ANALYSIS: This review will include studies from any country and health service reporting on harm reduction strategies implemented in inpatient settings or EDs. The population of interest includes people of any race, gender and age identifying as PWUAD, or individuals who provided care to PWUAD. Studies which describe implementation strategies and barriers and enablers to implementation will be included. Studies published in English, or those available for English translation will be included. The following databases will be searched: MEDLINE All (Ovid), Embase (Elsevier Embase.com), CINAHL with Full Text (EBSCOhost), PsycINFO (EBSCOhost) and SCOPUS (Elsevier Scopus.com). A grey literature search will be conducted. There will be no date restrictions on the search. Titles, abstracts and full texts will be screened in duplicate. Data will be extracted using a standardised form. The results will be reported using the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for scoping reviews. ETHICS AND DISSEMINATION: Scoping reviews do not require ethical approval. Patient partners with lived experience and relevant knowledge users will be engaged as research team members throughout all phases of the research process. A report detailing context, methodology and findings from this review will be disseminated to knowledge users and relevant community stakeholders. This review will be submitted for publication to a relevant peer-reviewed journal.

Strategies for Research, Practice, and Policy for Autism in Later Life: A Report from a Think Tank on Aging and Autism.

Over the past decade, there has been a growing interest in adults on the autistic spectrum, and more recently, the challenges related to aging in this population. A two-day Think Tank meeting, focused on aging in autism, was convened amongst international leaders in the field of autism research and practice. This meeting included a series of presentations addressing the current status of aging research, followed by discussions regarding priorities going forward. Attendees shared their thoughts and concerns regarding community services, government policies, societal perspectives and physical and mental health. The goal of these discussions was to consider systematic approaches aimed at providing meaningful supports that can ensure a quality of life for seniors on the autism spectrum.

The Associations Between Clinical, Social, Financial Factors and Unmet Needs of Autistic Adults: Results from an Observational Study.

Background: Autism is a developmental disability that affects how individuals experience the world. Each Autistic individual experiences Autism in their own way, meaning that the level and type of assistance in their everyday lives vary widely. A shortage of programs and services tailored to Autistic adults exists worldwide, and the current gap between needs and services is likely to worsen as the growing number of Autistic children being diagnosed reach adulthood. This research sought to determine priorities in terms of health and social service needs of Autistic adults and to examine factors influencing whether or not these services were being received. Methods: Through a multistakeholder approach, researchers and Autistic adults codeveloped the Maritime Provinces Needs Assessment Survey and collected data from August 2017 to February 2018. The research team engaged Autistic adult partners, including one that was project colead, as full partners. We recruited survey respondents from three Maritime Provinces using mainly social media and local Autism networks. We used Poisson regression analyses to identify factors most strongly associated with the number of unmet needs reported by Autistic adults. Results: In total, 260 respondents completed the needs assessment survey: 77 self-reporting Autistic adults (aged 19-55 years), 87 Autistic adults (aged 18-63 years) whose information was provided by a proxy respondent, and 96 professionals working in the field of Autism. Autistic adults reported a mean of 2.1 ± 1.5 (self-reported) and 2.8 ± 2.1 (proxy-reported) services wanted but not received. The number of mental health and neurodevelopmental conditions, unemployment, and perception that government support is insufficient were positively related to unmet needs. Conclusions: Overall, the results of this study highlight considerable gaps among the support needs of Autistic adults. The identification of factors associated with a higher number of unmet needs helps identify potential subgroups requiring more attention. Lay summary: Why was this study done?: There is currently a shortage of programs and services for Autistic adults. Little is known about which services are most important to Autistic adults and which factors are associated with not receiving them.What was the purpose of this study?: Our goals were (1) to determine the service need priorities of Autistic adults and (2) to examine factors associated with unmet needs.What did the researchers do?: The researchers invited health professionals, service providers, policy makers, Autism advocates, as well as Autistic adults and caregivers of Autistic adults to participate as part of the project team. In the early phases of the project, we named an Autistic adult colead of the project. In doing so, we acknowledged that conducting relevant research on the Autistic adult community implies not only hearing their voices and concerns, but also providing an opportunity for equal say on the research itself.We adapted previously used surveys to align them with our objectives of focusing only on Autistic adults. We launched the survey online and promoted it using various media and community channels, many of them direct suggestions from Autistic adult team members. We made paper copies available and provided a phone number for those who needed support filling out the survey.What were the results of the study?: More than 25% of Autistic adults identified 12 different services as priority needs.Autistic adults who (1) reported more mental health and neurodevelopmental conditions, (2) perceived their mental health as poor, or (3) felt that government support was insufficient were at greater risk of having unmet needs.What do these findings add to what was already known?: Similar to previous studies, we found that the service needs of Autistic adults are varied, and that many are not receiving the services they consider a priority. Our study also went one step further by identifying factors that are associated with a higher number of unmet needs.What are potential weaknesses in the study?: Our sample does not necessarily reflect the Autistic adult community as a whole, since we were unable to guarantee that hard-to-reach segments had access to our survey. In addition, we are unable to know how our results may change over time, as our survey was filled out on one occasion only. Finally, we did not measure Autistic traits and therefore are unable to estimate how different types of traits are associated with certain needs.How will these findings help autistic adults now or in the future?: Our results may help bring attention to subgroups of Autistic adults who need more help receiving the services they require.

"We are the stakeholders with the most at stake": scientific and autism community co-researchers reflect on their collaborative experience in the CONNECT project.

BACKGROUND: Little research describes the everyday challenges and needs of autistic adults. In order to fill this data gap, the CONtiNuity of carE and support for autistiC adulTs (CONNECT) project set out to learn about the health and well-being of autistic adults as well as their service and support needs. To do so, CONNECT welcomed autistic adults and caregivers of autistic adults as members of the research team, alongside researchers, policy-makers, service providers and health professionals. Autistic adults were involved in every stage of the research project and participated in team meetings held several times a year as well as in numerous email exchanges. METHODS: Two feedback questionnaires were designed for this study: one for the scientific co-researchers and one for the autism community co-researchers (the project's "patient partners"). Although the surveys varied from one another, they probed respondents to provide critical and constructive comments on issues that were central to their engagement in CONNECT. Four scientific co-researchers and four autism community co-researchers filled out the questionnaires. A comparative analysis was carried out on the responses provided to the open- and closed-ended survey questions as well as on complimentary data collected from the team's documents. RESULTS: CONNECT was seen as a positive experience for both groups. Highlights included: helping tailor and design research and its relevant materials to better suit the needs of the autistic community; establishing relationships and creating long-lasting friendships with other autistic adults; gaining a better understanding of the research process; and forging new connections with regional, national and international stakeholders. Areas for improvement include: establishing clear roles, responsibilities and expectations from the start; outlining a strategy to address unforeseen changes in project leadership; and creating a platform allowing for the involvement and participation of a more representative sample of adults on the autism spectrum. CONCLUSIONS: While not without its challenges, CONNECT demonstrates that a collaborative multi-stakeholder approach engaging autistic adults can be an effective model for conducting research on adult autism. Autistic adults and their caregivers can make the research process more open and accessible and make its outputs more relevant, useful and meaningful to the wider autistic adult community.

Comparing the Effect of Combining Exercise with Rosuvastatin versus Atorvastatin on Lipid Profile and Functional Capacity: A Retrospective Cohort Study.

BACKGROUND: Statins and exercise are recommended for managing hypercholesterolemia. However, statin types may vary in their interaction with exercise. We compared rosuvastatin versus atorvastatin combination with exercise on lipid profile and functional capacity. METHODS: A retrospective cohort study using data from a 12-week cardiovascular rehabilitation program between 2014 and 2016. Statin use was determined through prescriptions, and the average exercise minutes/week were computed from exercise logs. The outcomes were changes in total cholesterol, low- and high-density lipoproteins (LDL and HDL), triglycerides, and functional capacity (6-minute walk test (6MWT)). Directed acyclic graphs were used to identify potential confounders, accounted for using multiple linear regression modeling. RESULTS: The cohort included 282 patients from 106 atorvastatin and 176 rosuvastatin users. The average exercise minutes/week was 109.4 ± 66.1 among atorvastatin and 106.7 ± 49.1 among rosuvastatin users. Interaction models suggested that a higher number of exercise minutes/week were more favorable among atorvastatin users on total cholesterol and LDL (0.004, 95% CI: 0.001, 0.008 and 0.004, 95% CI: 0.001, 0.007, respectively) but did not reach significance for HDL and triglycerides. Rosuvastatin use was associated with greater increases in 6MWT; however, we observed no between-group differences in interaction estimates by the type of statin used. CONCLUSION: Rosuvastatin use could blunt the beneficial effect of exercise on LDL and total cholesterol compared to atorvastatin. No significant differences were observed in triglycerides, HDL, and functional capacity levels. Additional studies are warranted with randomized treatments and larger samples. Healthcare providers should continue prescribing statins alongside recommending exercise modalities, with a careful follow-up for rosuvastatin users.

HEALTH ASSESSMENT OF WILD LOWLAND TAPIRS (TAPIRUS TERRESTRIS) IN THE HIGHLY THREATENED CERRADO BIOME, BRAZIL.

Over 2 yr, we assessed the health of 35 lowland tapirs (Tapirus terrestris) in the Brazilian Cerrado (CE) biome, an area that is highly affected by human activities. This involved physical examinations, hematology and blood biochemistry, urinalysis, fecal parasitologic evaluation, microbial profiling of anatomic cavities and lesions, and serologic surveys for evidence of infectious agents. Research methods closely resembled those used in previous tapir health assessments in the Atlantic Forest (AF) and Pantanal (PA) biomes, allowing for a comparison among the three populations. Although not reaching statistical significance (P>0.05), tapirs from the CE exhibited poorer body and skin condition as compared to animals from the AF and PA. Furthermore, there were higher prevalences of dental problems and traumatic lesions as compared to those from the AF and PA. Eight of the 12 hematologic parameters evaluated and 17 of the 30 biochemical parameters differed significantly (P<0.05) between the tapirs from CE and those from the AF and PA. We isolated 24 different microbiologic strains from swabs of anatomic cavities and dermal lesions, of which five taxa had not previously been found in the AF or PA. We detected serum antibodies to Leptospira interrogans, bluetongue virus, and porcine parvovirus. Overall, our results suggested that tapirs from the CE exhibited more health abnormalities than tapirs in the AF and PA, possibly due to a greater exposure to environmental disturbances in the area.

Phylogenetics, patterns of genetic variation and population dynamics of Trypanosoma terrestris support both coevolution and ecological host-fitting as processes driving trypanosome evolution.

BACKGROUND: A considerable amount of evidence has favored ecological host-fitting, rather than coevolution, as the main mechanism responsible for trypanosome divergence. Nevertheless, beyond the study of human pathogenic trypanosomes, the genetic basis of host specificity among trypanosomes isolated from forest-inhabiting hosts remains largely unknown. METHODS: To test possible scenarios on ecological host-fitting and coevolution, we combined a host capture recapture strategy with parasite genetic data and studied the genetic variation, population dynamics and phylogenetic relationships of Trypanosoma terrestris, a recently described trypanosome species isolated from lowland tapirs in the Brazilian Pantanal and Atlantic Forest biomes. RESULTS: We made inferences of T. terrestris population structure at three possible sources of genetic variation: geography, tapir hosts and 'putative' vectors. We found evidence of a bottleneck affecting the contemporary patterns of parasite genetic structure, resulting in little genetic diversity and no evidence of genetic structure among hosts or biomes. Despite this, a strongly divergent haplotype was recorded at a microgeographical scale in the landscape of Nhecolândia in the Pantanal. However, although tapirs are promoting the dispersion of the parasites through the landscape, neither geographical barriers nor tapir hosts were involved in the isolation of this haplotype. Taken together, these findings suggest that either host-switching promoted by putative vectors or declining tapir population densities are influencing the current parasite population dynamics and genetic structure. Similarly, phylogenetic analyses revealed that T. terrestris is strongly linked to the evolutionary history of its perissodactyl hosts, suggesting a coevolving scenario between Perissodactyla and their trypanosomes. Additionally, T. terrestris and T. grayi are closely related, further indicating that host-switching is a common feature promoting trypanosome evolution. CONCLUSIONS: This study provides two lines of evidence, both micro- and macroevolutionary, suggesting that both host-switching by ecological fitting and coevolution are two important and non-mutually-exclusive processes driving the evolution of trypanosomes. In line with other parasite systems, our results support that even in the face of host specialization and coevolution, host-switching may be common and is an important determinant of parasite diversification.

Incidence and risk factors for anastomotic bleeding in lower gastrointestinal surgery.

OBJECTIVE: Although major anastomotic bleeding after lower gastrointestinal surgery is considered rare, it can be life-threatening if not properly managed. The objective of this study was to assess the incidence of postoperative lower gastrointestinal intraluminal bleeding and to identify its potential risk factors. This retrospective cohort study used data from charts of 314 patients who underwent digestive surgery of the colon or small intestine. Details are reported for their sociodemographic data, surgical approach, comorbidities, timing and presentation of intraluminal bleeding events, bleeding diagnosis, treatment strategies, hospital length of stay, and clinical complications. RESULTS: A total of 7 patients (2.3%) experienced intraluminal bleeding in the postoperative period. The average length of hospital stay before discharge was 12 days (median = 13 days). Patients with intraluminal bleeding had a significantly higher percentage of coronary artery diseases compared to patients without intraluminal bleeding (P value = .04), as well as having a cancer diagnosis (P value = .02). The clinical complications that were more likely in patients with intraluminal bleeding included requiring blood transfusions (P value = .01), reduction in hemoglobin (P value = .001), cardiac ischemia (P value = .02), and atrial fibrillations (P value = .02).

Approaches to considering sex and gender in continuous professional development for health and social care professionals: An emerging paradigm.

Consideration of sex and gender in research and clinical practice is necessary to redress health inequities and reduce knowledge gaps. As all health professionals must maintain and update their skills throughout their career, developing innovative continuing professional education programs that integrate sex and gender issues holds great promise for reducing these gaps. This article proposes new approaches to partnership, team development, pedagogical theory, content development, evaluation and data management that will advance the integration of sex and gender in continuing professional development (CPD). Our perspectives build on an intersectoral and interprofessional research team that includes several perspectives, including those of CPD, health systems, knowledge translation and sex and gender.

Redox mechanism of levobupivacaine cytostatic effect on human prostate cancer cells.

Anti-cancer effects of local anesthetics have been reported but the mode of action remains elusive. Here, we examined the bioenergetic and REDOX impact of levobupivacaine on human prostate cancer cells (DU145) and corresponding non-cancer primary human prostate cells (BHP). Levobupivacaine induced a combined inhibition of glycolysis and oxidative phosphorylation in cancer cells, resulting in a reduced cellular ATP production and consecutive bioenergetic crisis, along with reactive oxygen species generation. The dose-dependent inhibition of respiratory chain complex I activity by levobupivacaine explained the alteration of mitochondrial energy fluxes. Furthermore, the potency of levobupivacaine varied with glucose and oxygen availability as well as the cellular energy demand, in accordance with a bioenergetic anti-cancer mechanism. The levobupivacaine-induced bioenergetic crisis triggered cytostasis in prostate cancer cells as evidenced by a S-phase cell cycle arrest, without apoptosis induction. In DU145 cells, levobupivacaine also triggered the induction of autophagy and blockade of this process potentialized the anti-cancer effect of the local anesthetic. Therefore, our findings provide a better characterization of the REDOX mechanisms underpinning the anti-effect of levobupivacaine against human prostate cancer cells.

Avoidance of the vaginal incision site for mesh placement in vaginal wall prolapse surgery: A prospective study.

OBJECTIVE: To evaluate efficacy of a minimal surface area, vaginally-installed polypropylene tape (VPT), avoiding insertion on the incision line to treat an anterior, posterior or anteroposterior vaginal wall prolapse. STUDY DESIGN: Patients with an anterior, posterior or anteroposterior vaginal wall prolapse waiting for surgical treatment were included in the study. Primary outcome was the incidence of prolapse recurrence reported with combined outcome measures and was reported with Kaplan-Meier cumulative incidence. Secondary outcomes were operative complications, adverse events, urinary, colorectal and sexual functions as well as quality of life. Participation in the study involved up to 8 visits over 5 years. At each visit, patients used a self-reported questionnaire to report symptoms related to pain, urinary, colorectal, sexual functions, and quality of life. A physical examination was also performed. Paired t-tests were used to investigate change in POP-Q and quality of life measurements since baseline. RESULTS: 71 patients underwent the procedure and were followed-up for an average (standard deviation) of 32.5 (18.7) months. Only 2 (2.8%) women experienced a recurrence of their pelvic organ prolapse. Only one case of erosion and no case of persistent pain have been recorded up to 5 years post-surgery. Quality of life was improved and then sustained throughout the follow-up period (p<0.01). CONCLUSION: This VPT surgical procedure is safe and has a high level of efficacy to treat anterior, posterior or anteroposterior vaginal wall prolapse. It is also associated with improvements in quality of life of patients which are sustained for many years.

Rheb regulates mitophagy induced by mitochondrial energetic status.

Mitophagy has been recently described as a mechanism of elimination of damaged organelles. Although the regulation of the amount of mitochondria is a core issue concerning cellular energy homeostasis, the relationship between mitochondrial degradation and energetic activity has not yet been considered. Here, we report that the stimulation of mitochondrial oxidative phosphorylation enhances mitochondrial renewal by increasing its degradation rate. Upon high oxidative phosphorylation activity, we found that the small GTPase Rheb is recruited to the mitochondrial outer membrane. This mitochondrial localization of Rheb promotes mitophagy through a physical interaction with the mitochondrial autophagic receptor Nix and the autophagosomal protein LC3-II. Thus, Rheb-dependent mitophagy contributes to the maintenance of optimal mitochondrial energy production. Our data suggest that mitochondrial degradation contributes to a bulk renewal of the organelle in order to prevent mitochondrial aging and to maintain the efficiency of oxidative phosphorylation.

Mitoplasticity: adaptation biology of the mitochondrion to the cellular redox state in physiology and carcinogenesis.

Adaptation and transformation biology of the mitochondrion to redox status is an emerging domain of physiology and pathophysiology. Mitochondrial adaptations occur in response to accidental changes in cellular energy demand or supply while mitochondrial transformations are a part of greater program of cell metamorphosis. The possible role of mitochondrial adaptations and transformations in pathogenesis remains unexplored, and it has become critical to decipher the stimuli and the underlying molecular pathways. Immediate activation of mitochondrial function was described during acute exercise, respiratory chain injury, Endoplasmic Reticulum stress, genotoxic stress, or environmental toxic insults. Delayed adaptations of mitochondrial form, composition, and functions were evidenced for persistent changes in redox status as observed in endurance training, in fibroblasts grown in presence of respiratory chain inhibitors or in absence of glucose, in the smooth muscle of patients with severe asthma, or in the skeletal muscle of patients with a mitochondrial disease. Besides, mitochondrial transformations were observed in the course of human cell differentiation, during immune response activation, or in cells undergoing carcinogenesis. Little is known on the signals and downstream pathways that govern mitochondrial adaptations and transformations. Few adaptative loops, including redox sensors, kinases, and transcription factors were deciphered, but their implication in physiology and pathology remains elusive. Mitoplasticity could play a protective role against aging, diabetes, cancer, or neurodegenerative diseases. Research on adaptation and transformation could allow the design of innovative therapies, notably in cancer.

Rationale for mitochondria-targeting strategies in cancer bioenergetic therapies.

In the 1920s, Otto Warburg first hypothesized that mitochondrial impairment is a leading cause of cancer although he recognized the existence of oxidative tumors. Likewise, Weinhouse and others in the 50s found that deficient mitochondrial respiration is not an obligatory feature of cancer and Peter Vaupel suggested in the 1990s that tumor oxygenation rather than OXPHOS capacity was the limiting factor of mitochondrial energy production in cancer. Recent studies now clearly indicate that mitochondria are highly functional in mice tumors and the field of oncobioenergetic identified MYC, Oct1 and RAS as pro-OXPHOS oncogenes. In addition, cancer cells adaptation to aglycemia, metabolic symbiosis between hypoxic and non-hypoxic tumor regions as well the reverse Warburg hypothesis support the crucial role of mitochondria in the survival of a subclass of tumors. Therefore, mitochondria are now considered as potential targets for anti-cancer therapy and tentative strategies including a bioenergetic profile characterization of the tumor and the subsequent adapted bioenergetic modulation could be considered for cancer killing. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.

Preservation of NADH ubiquinone-oxidoreductase activity by Src kinase-mediated phosphorylation of NDUFB10.

The tyrosine kinase Src is upregulated in several cancer cells. In such cells, there is a metabolic reprogramming elevating aerobic glycolysis that seems partly dependent on Src activation. Src kinase was recently shown to be targeted to mitochondria where it modulates mitochondrial bioenergetics in non-proliferative tissues and cells. The main goal of our study was to determine if increased Src kinase activity could also influence mitochondrial metabolism in cancer cells (143B and DU145 cells). We have shown that 143B and DU145 cells produce most of the ATP through glycolysis but also that the inhibition of OXPHOS led to a significant decrease in proliferation which was not due to a decrease in the total ATP levels. These results indicate that a more important role for mitochondria in cancer cells could be ensuring mitochondrial functions other than ATP production. This study is the first to show a putative influence of intramitochondrial Src kinase on oxidative phosphorylation in cancer cells. Indeed, we have shown that Src kinase inhibition led to a decrease in mitochondrial respiration via a specific decrease in complex I activities (NADH-ubiquinone oxidoreductase). This decrease is associated with a lower phosphorylation of the complex I subunit NDUFB10. These results suggest that the preservation of complex I function by mitochondrial Src kinase could be important in the development of the overall phenotype of cancer.

Antiproliferative activity of levobupivacaine and aminoimidazole carboxamide ribonucleotide on human cancer cells of variable bioenergetic profile.

We assessed the impact of ten mitoactive drugs on the viability and the proliferation of human cancer cells of variable origin and bioenergetics. A validated chemotherapeutic drug, doxorubicin, was used as a gold-standard for comparison. We also looked at the effect of these drugs on Rho(0) cells and on embryonic fibroblasts, both of which rely mainly on glycolysis to generate the vital ATP. The statistical analysis of the area under the curves revealed a cell-type specific response to mitodopant and mitotoxic compounds, in correlation with the contribution of glycolysis to cellular ATP synthesis. These findings indicate that the bioenergetic state of the cell determines in part the impact of mitodopants and mitotoxics on cancer cells viability.

AICAR inhibits cancer cell growth and triggers cell-type distinct effects on OXPHOS biogenesis, oxidative stress and Akt activation.

The AMP-activated protein kinase agonist AICAR mimics a low intracellular energy state and inhibits the proliferation of cancer cells by different mechanisms, which may depend on the bioenergetic signature of these cells. AICAR can also stimulate mitochondrial biogenesis in myoblasts, neurons and HeLa cells. Yet, whether the reactivation of oxidative phosphorylation biogenesis by AICAR contributes to the growth arrest of cancer cells remains undetermined. To investigate this possibility, we looked at the impact of 24- and 48-hour treatments with 750 µM AICAR on human cancer cell lines (HeLa, DU145, and HEPG2), non-cancer cells (EM64, FM14, and HLF), embryonic cells (MRC5) and Rho(0) cells. We determined the bioenergetic profile of these cells and assessed the effect of AICAR on oxidative phosphorylation biogeneis, cell viability and cell proliferation, ROS generation, mitochondrial membrane potential and apoptosis induction. We also followed possible changes in metabolic regulators such as Akt and Hif1-α stabilization which might participate to the anti-proliferative effect of AICAR. Our results demonstrated a strong and cancer-specific anti-growth effect of AICAR that may be explained by three different modes according to cell type: the first mode included stimulation of the mitochondrial apoptotic pathway however with compensatory activation of Akt and upregulation of oxidative phosphorylation. In the second mode of action of AICAR Akt phosphorylation was reduced. In the third mode of action, apoptosis was activated by different pathways. The sensitivity to AICAR was higher in cells with a low steady-state ATP content and a high proliferation rate.