Mitochondria dysfunction induced by decyl-TPP mitochondriotropic antioxidant based on caffeic acid AntiOxCIN6 sensitizes cisplatin lung anticancer therapy due to a remodeling of energy metabolism.

The pharmacological interest in mitochondria is very relevant since these crucial organelles are involved in the pathogenesis of multiple diseases, such as cancer. In order to modulate cellular redox/oxidative balance and enhance mitochondrial function, numerous polyphenolic derivatives targeting mitochondria have been developed. Still, due to the drug resistance emergence in several cancer therapies, significant efforts are being made to develop drugs that combine the induction of mitochondrial metabolic reprogramming with the ability to generate reactive oxygen species, taking into consideration the varying metabolic profiles of different cell types. We previously developed a mitochondria-targeted antioxidant (AntiOxCIN6) by linking caffeic acid to lipophilic triphenylphosphonium cation through a 10-carbon aliphatic chain. The antioxidant activity of AntiOxCIN6 has been documented but how the mitochondriotropic compound impact energy metabolism of both normal and cancer cells remains unknown. We demonstrated that AntiOxCIN6 increased antioxidant defense system in HepG2 cells, although ROS clearance was ineffective. Consequently, AntiOxCIN6 significantly decreased mitochondrial function and morphology, culminating in a decreased capacity in complex I-driven ATP production without affecting cell viability. These alterations were accompanied by an increase in glycolytic fluxes. Additionally, we demonstrate that AntiOxCIN6 sensitized A549 adenocarcinoma cells for CIS-induced apoptotic cell death, while AntiOxCIN6 appears to cause metabolic changes or a redox pre-conditioning on lung MRC-5 fibroblasts, conferring protection against cisplatin. We propose that length and hydrophobicity of the C10-TPP+ alkyl linker play a significant role in inducing mitochondrial and cellular toxicity, while the presence of the antioxidant caffeic acid appears to be responsible for activating cytoprotective pathways.

Nurturing through Nutrition: Exploring the Role of Antioxidants in Maternal Diet during Pregnancy to Mitigate Developmental Programming of Chronic Diseases.

Chronic diseases represent one of the major causes of death worldwide. It has been suggested that pregnancy-related conditions, such as gestational diabetes mellitus (GDM), maternal obesity (MO), and intra-uterine growth restriction (IUGR) induce an adverse intrauterine environment, increasing the offspring's predisposition to chronic diseases later in life. Research has suggested that mitochondrial function and oxidative stress may play a role in the developmental programming of chronic diseases. Having this in mind, in this review, we include evidence that mitochondrial dysfunction and oxidative stress are mechanisms by which GDM, MO, and IUGR program the offspring to chronic diseases. In this specific context, we explore the promising advantages of maternal antioxidant supplementation using compounds such as resveratrol, curcumin, N-acetylcysteine (NAC), and Mitoquinone (MitoQ) in addressing the metabolic dysfunction and oxidative stress associated with GDM, MO, and IUGR in fetoplacental and offspring metabolic health. This approach holds potential to mitigate developmental programming-related risk of chronic diseases, serving as a probable intervention for disease prevention.

From Non-Alcoholic Fatty Liver to Hepatocellular Carcinoma: A Story of (Mal)Adapted Mitochondria.

Non-alcoholic fatty liver disease (NAFLD) is a global pandemic affecting 25% of the world's population and is a serious health and economic concern worldwide. NAFLD is mainly the result of unhealthy dietary habits combined with sedentary lifestyle, although some genetic contributions to NAFLD have been documented. NAFLD is characterized by the excessive accumulation of triglycerides (TGs) in hepatocytes and encompasses a spectrum of chronic liver abnormalities, ranging from simple steatosis (NAFL) to steatohepatitis (NASH), significant liver fibrosis, cirrhosis, and hepatocellular carcinoma. Although the molecular mechanisms that cause the progression of steatosis to severe liver damage are not fully understood, metabolic-dysfunction-associated fatty liver disease is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Mitochondria are highly dynamic organelles that undergo functional and structural adaptations to meet the metabolic requirements of the cell. Alterations in nutrient availability or cellular energy needs can modify mitochondria formation through biogenesis or the opposite processes of fission and fusion and fragmentation. In NAFL, simple steatosis can be seen as an adaptive response to storing lipotoxic free fatty acids (FFAs) as inert TGs due to chronic perturbation in lipid metabolism and lipotoxic insults. However, when liver hepatocytes' adaptive mechanisms are overburdened, lipotoxicity occurs, contributing to reactive oxygen species (ROS) formation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress. Impaired mitochondrial fatty acid oxidation, reduction in mitochondrial quality, and disrupted mitochondrial function are associated with a decrease in the energy levels and impaired redox balance and negatively affect mitochondria hepatocyte tolerance towards damaging hits. However, the sequence of events underlying mitochondrial failure from steatosis to hepatocarcinoma is still yet to be fully clarified. This review provides an overview of our understanding of mitochondrial adaptation in initial NAFLD stages and highlights how hepatic mitochondrial dysfunction and heterogeneity contribute to disease pathophysiology progression, from steatosis to hepatocellular carcinoma. Improving our understanding of different aspects of hepatocytes' mitochondrial physiology in the context of disease development and progression is crucial to improving diagnosis, management, and therapy of NAFLD/NASH.

Innovative moments in recovered cases treated with the unified protocol for transdiagnostic treatment of emotional disorders.

OBJECTIVE: Innovative moments (IMs) are moments in which the previous problematic pattern of meaning is challenged. Studies have shown that IMs are associated with good psychotherapy outcomes. A three-level hierarchy of IMs was observed in recent studies, with level 1 IMs being more elementary and levels 2 and 3 being more complex and associated with treatment success. However, studies with manualized protocol treatments are thus far lacking. This study analyzed the longitudinal progression of IMs in the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) and explored its associations with changes in psychological distress. METHODS: Data were collected from a Portuguese university-based outpatient clinic and included 18 cases with positive outcomes. Nine sessions of each case were coded with the IM coding system (N=162). RESULTS: Multilevel analyses showed a significant increase in all IM levels across treatments. The decrease in psychological distress predicted an increase in level 2 IMs in the same session. CONCLUSION: The evolution of IMs is similar to what was found previously in other studies. Contrary to what was found in previous studies, IMs did not predict outcomes in the following session, whereas the reduction in psychological distress predicted the emergence of level 2 IMs.

Reviewing working memory training gains in healthy older adults: A meta-analytic review of transfer for cognitive outcomes.

The objective of this meta-analytic review was to systematically assess the effects of working memory training on healthy older adults. We identified 552 entries, of which 27 experiments met our inclusion criteria. The final database included 1130 participants. Near- and far-transfer effects were analysed with measures of short-term memory, working memory, and reasoning. Small significant and long-lasting transfer gains were observed in working memory tasks. Effects on reasoning was very small and only marginally significant. The effects of working memory training on both near and far transfer in older adults were moderated by the type of training tasks; the adopted outcome measures; the training duration; and the total number of training hours. In this review, we provide an updated review of the literature in the field by carrying out a robust multi-level meta-analysis focused exclusively on working memory training in healthy older adults. Recommendations for future research are suggested.

Relational schemas as mediators of innovative moments in symptom improvement in major depression.

OBJECTIVES: Innovative moments (IMs) are exceptions to the maladaptive framework of meaning that typically motivates clients to seek psychotherapy, and previous studies have shown that IMs are associated with psychotherapy outcomes. While IMs are exceptions that occur at the level of the therapeutic conversation, relational schemas are more stable patterns, and their increased flexibility may facilitate change during psychotherapy. With this in mind, we tested the hypothesis that IMs contribute to outcomes by improving the flexibility of relational schemas. METHOD: The Core Conflictual Relationship Theme (CCRT) was used to assess relational schemas. IMs were evaluated using the Innovative Moments Coding System. The sample included 22 clients diagnosed with major depressive disorder. The flexibility of the three components of the CCRT (Wishes, responses of the self (RS), and responses of others (RO)) were tested as mediators between IMs and outcomes. RESULTS: The flexibility of the RS was a mediator between IMs and outcomes, but Wishes and RO were not. CONCLUSION: These findings align with previous research showing that RS is the component most open to change, whereas the other components seem less sensitive to change during brief therapy. Clinical or methodological significance of this article: This study shows the mediation role of relational schemas in the association between in-session events (innovative moments (IMs)) and the symptoms improvement. It contributes to the literature that emphasizes the importance of relational schemas in psychotherapy by using a mediation model, which has rarely been tested.

Reconceptualization innovative moments as a predictor of symptomatology improvement in treatment for depression.

OBJECTIVES: In previous studies, reconceptualization innovative moments were associated with successful psychotherapy. Reconceptualization has two components-(a) a positive temporal contrast between the past self and the present self (contrasting self [CS]) and (b) a description of how and/or why this change has occurred (change process [CP])-from the perspective of the client. The aim of this study is to analyse if CS and CP have the same association with outcomes as reconceptualization. METHOD: Sixteen cases of clients with major depression (305 sessions) were analysed. Longitudinal regression models were used to explore if proportions of CS, CP, and reconceptualization predicted outcome measures and if outcome measures predicted CS, CP, and reconceptualization. RESULTS: Reconceptualization is less frequent than CS and CP taken separately, but reconceptualization was a better predictor of treatment outcomes than were its separate components. Moreover, symptom improvement did not predict reconceptualization. CONCLUSION: The construction of new meanings is important in improving depressive symptomatology. Psychotherapists can elicit these new meanings in their regular practice by posing questions that may help clients to conceptualize what is changing in themselves (CS) and questions of how this change is occurring (CP). The construction of an integrative account of these new meanings is associated with psychotherapeutic gains, and thus, reconceptualizing change could improve symptoms of depression.