Effects of Sodium Nitroprusside on Lipopolysaccharide-Induced Inflammation and Disruption of Blood-Brain Barrier.

In various neurodegenerative conditions, inflammation plays a significant role in disrupting the blood-brain barrier (BBB), contributing to disease progression. Nitric oxide (NO) emerges as a central regulator of vascular function, with a dual role in inflammation, acting as both a pro- and anti-inflammatory molecule. This study investigates the effects of the NO donor sodium nitroprusside (SNP) in protecting the BBB from lipopolysaccharide (LPS)-induced inflammation, using bEnd.3 endothelial cells as a model system. Additionally, Raw 264.7 macrophages were employed to assess the effects of LPS and SNP on their adhesion to a bEnd.3 cell monolayer. Our results show that LPS treatment induces oxidative stress, activates the JAK2/STAT3 pathway, and increases pro-inflammatory markers. SNP administration effectively mitigates ROS production and IL-6 expression, suggesting a potential anti-inflammatory role. However, SNP did not significantly alter the adhesion of Raw 264.7 cells to bEnd.3 cells induced by LPS, probably because it did not have any effect on ICAM-1 expression, although it reduced VCAM expression. Moreover, SNP did not prevent BBB disruption. This research provides new insights into the role of NO in BBB disruption induced by inflammation.

Post-traumatic growth in cancer survivors: What is its extent and what are important determinants? / Crecimiento postraumático en sobrevivientes de cáncer: ¿cuál es su alcance y cuáles son sus determinantes importantes?

Background/Objective: The aim was to investigate the extent and longitudinal determinants of post-traumatic growth (PTG) in cancer survivors. Methods: A sample of 1316 cancer survivors with various cancer types was examined using the EORTC QLQ-FA12 to assess fatigue, the EORTC QLQ-C30 pain items to assess pain and the Patient Health Questionnaire (PHQ-4) to assess emotional distress two years after diagnosis (t0). Additionally, patients rated how well they felt informed about fatigue at t0. PTG was assessed with the 21-item PTG-Inventory four years after diagnosis (t1) comprising the five subdimensions appreciation of life, relation to others, personal strengths, new possibilities and spiritual change. Results: Regarding the extent of PTG, most positive developments were experienced in the PTG subdimension appreciation of life whereas the subdimension spiritual change was the least pronounced domain. Fatigue, pain and emotional distress were longitudinal but non-linear predictors of long-term PTG. Additionally, poor informedness about fatigue was associated with less PTG. Conclusions: PTG can be perceived even years after a traumatic cancer event and is longitudinally associated with common cancer side effects like fatigue, emotional distress and pain. Further research into the role of individuals' informedness contributing to PTG is needed.(AU)

Dropout from exercise trials among cancer survivors-An individual patient data meta-analysis from the POLARIS study.

INTRODUCTION: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. METHODS: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. RESULTS: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI >28.4 kg/m2 , performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI >28.4 kg/m2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m2 exercising during (5.2%) or post (9.5%) treatment. CONCLUSIONS: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects.

Patterns and influencing factors of exercise attendance of breast cancer patients during neoadjuvant chemotherapy.

BACKGROUND: Performing 2-3 exercise sessions/week may relieve therapy-related side effects of breast cancer patients (BRCA) and improve their quality of life. However, attendance to the exercise sessions is often impaired. Thus, we investigated patterns and possible influencing factors of attendance to an aerobic (AT) or resistance training (RT) intervention in BRCA during neoadjuvant chemotherapy. METHODS: BRCA (N = 122) were randomly allocated to supervised AT or RT twice weekly during neoadjuvant chemotherapy (18 ± 4 weeks). Attendance was calculated individually and group-wise per training week as the percentage of the performed sessions out of the prescribed sessions. Possible influencing factors were investigated using multiple regression analyses. RESULTS: Mean individual attendance was 44.1% ± 29.3% with no significant differences between the groups. Group-wise attendance was highest in the first 6 weeks of training with ≥ 60% for AT and ≥ 50% for RT, but decreased over the course of the intervention accompanying chemotherapy. Significantly higher attendance was associated with not having vs. having nausea (ß = - 14.57; p = 0.007) and not having vs. having pain (ß = - 12.07; p = 0.12), whereas fatigue did not show any association (ß = - 0.006; p = 0.96). Having been randomized into a preferred intervention group (48.8%) showed no association with attendance. Yet, patients' rating of the exercise intervention as "good"/ "very good" (58.7%) was significantly associated with higher attendance (p = 0.01). CONCLUSION: For both exercise interventions, group-wise attendance/training week decreased during chemotherapy despite good intervention ratings. While some patients never started, others trained almost constantly twice weekly. The study revealed that patients who are nauseous or experience pain may need more support to attend more exercise sessions. Trial Registration Clinicaltrials.gov: NCT02999074 from May 6, 2016.

Cancer-related fatigue: Quality, credibility, usability, and readability of information on websites of health care institutions in Germany.

OBJECTIVES: This study aimed to portray available information on cancer-related fatigue on German health care institution websites considering the idea of patient empowerment. METHODS: Based on website quality criteria, we developed a website-rating tool comprising 18 items. Descriptive analyses, a KruskalWallis test, and corresponding post hoc tests comparing rating sum scores between institution groups were performed. RESULTS: Websites of 283 systematically compiled health care institutions were included in the rating. Cancer-related fatigue was introduced on 21.9% and detailed information was provided on 27.9% of the websites. Information material was offered on 9.2% of the websites, while fatigue treatment offers were presented on 21.6% of the websites. The rating sum scores differed between institution groups (p < 0.001), with Comprehensive Cancer Centers scoring significantly higher than the others. CONCLUSION: The rating revealed an overall sparse provision of information, with fatigue being addressed on less than half of the websites. PRACTICE IMPLICATIONS: For patients who have access to at least one introduction about fatigue, institutions need to extend their websites. Patients could further be referred to external institutions or information booklets. The naming of contact persons may help linking patients to providers.

Novel SK channel positive modulators prevent ferroptosis and excitotoxicity in neuronal cells.

Small conductance calcium-activated potassium (SK) channel activity has been proposed to play a role in the pathology of several neurological diseases. Besides regulating plasma membrane excitability, SK channel activation provides neuroprotection against ferroptotic cell death by reducing mitochondrial Ca2+ uptake and reactive oxygen species (ROS). In this study, we employed a multifaceted approach, integrating structure-based and computational techniques, to strategically design and synthesize an innovative class of potent small-molecule SK2 channel modifiers through highly efficient multicomponent reactions (MCRs). The compounds' neuroprotective activity was compared with the well-studied SK positive modulator, CyPPA. Pharmacological SK channel activation by selected compounds confers neuroprotection against ferroptosis at low nanomolar ranges compared to CyPPA, that mediates protection at micromolar concentrations, as shown by an MTT assay, real-time cell impedance measurements and propidium iodide staining (PI). These novel compounds suppress increased mitochondrial ROS and Ca2+ level induced by ferroptosis inducer RSL3. Moreover, axonal degeneration was rescued by these novel SK channel activators in primary mouse neurons and they attenuated glutamate-induced neuronal excitability, as shown via microelectrode array. Meanwhile, functional afterhyperpolarization of the novel SK2 channel modulators was validated by electrophysiological measurements showing more current change induced by the novel modulators than the reference compound, CyPPA. These data support the notion that SK2 channel activation can represent a therapeutic target for brain diseases in which ferroptosis and excitotoxicity contribute to the pathology.

Patient-physician communication about cancer-related fatigue: a survey of patient-perceived barriers.

PURPOSE: Cancer-related fatigue is a subjective, distressing, and common sequela of cancer which is often disregarded and underdiagnosed. Fatigue is assessed by self-report requiring communication between patient and physician. In this study, we investigated the patients' perspective on the patient-physician communication about fatigue. METHODS: On average five months after diagnosis 1179 cancer patients, recruited in Germany, completed a survey as part of the LIFT project. The survey included questions on sociodemographic data, fatigue, depression, fatigue management, patient-physician communication, and communication barriers. Data were analyzed descriptively and using logistic regression analyses. RESULTS: Half of the participants reported that their physician had never asked them whether they felt exhausted. Patients undergoing chemo-, radio-, or immunotherapy were more likely to be asked about fatigue, while older age and major depression decreased the likelihood. Sixty-four percent of the patients felt impeded by communication barriers. Common barriers were not knowing who to turn to for fatigue (39%), time constraints (31%), and the fear of being perceived as weak (22%). Almost half of the participants indicated that their physicians were not appreciative and did not deal adequately with fatigue-related questions. CONCLUSION: This study revealed gaps in the patient-physician communication regarding cancer-related fatigue. Contrary to guideline recommendations a minority of physicians addressed fatigue. On the other hand, cancer patients felt reluctant to bring up this topic due to structural barriers and fears. Physicians should routinely address fatigue and adopt a communication style which encourages patients to likewise state their symptoms and raise their questions. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT04921644. Registered in June 2021.

Cancer-related fatigue: Towards a more targeted approach based on classification by biomarkers and psychological factors.

Cancer-related fatigue is a frequent, burdensome and often insufficiently treated symptom. A more targeted treatment of fatigue is urgently needed. Therefore, we examined biomarkers and clinical factors to identify fatigue subtypes with potentially different pathophysiologies. The study population comprised disease-free breast cancer survivors of a German population-based case-control study who were re-assessed on average 6 (FU1, n = 1871) and 11 years (FU2, n = 1295) after diagnosis. At FU1 and FU2, we assessed fatigue with the 20-item multidimensional Fatigue Assessment Questionnaire and further factors by structured telephone-interviews. Serum samples collected at FU1 were analyzed for IL-1ß, IL-2, IL-4, IL-6, IL-10, TNF-a, GM-CSF, IL-5, VEGF-A, SAA, CRP, VCAM-1, ICAM-1, leptin, adiponectin and resistin. Exploratory cluster analyses among survivors with fatigue at FU1 and no history of depression yielded three clusters (CL1, CL2 and CL3). CL1 (n = 195) on average had high levels of TNF-α, IL1-ß, IL-6, resistin, VEGF-A and GM-CSF, and showed high BMI and pain levels. Fatigue in CL1 manifested rather in physical dimensions. Contrarily, CL2 (n = 78) was characterized by high leptin level and had highest cognitive fatigue. CL3 (n = 318) did not show any prominent characteristics. Fatigued survivors with a history of depression (n = 214) had significantly higher physical, emotional and cognitive fatigue and showed significantly less amelioration of fatigue from FU1 to FU2 than survivors without depression. In conclusion, from the broad phenotype "cancer-related fatigue" we were able to delineate subgroups characterized by biomarkers or history of depression. Future investigations may take these subtypes into account, ultimately enabling a better targeted therapy of fatigue.

Posttraumatic growth and health-related quality of life in cancer survivors: Does fatigue moderate the link?

Interest in post-traumatic growth (PTG) as a predictor of health-related quality of life (HRQoL) is currently gaining attention. However, current evidence is still inconclusive on the nature of this relationship. The first objective of this study was to investigate the relationship between PTG and global HRQoL among cancer survivors. We further investigated the moderating role of fatigue in the association between PTG and global HRQoL. In the FiX study (Fatigue in Germany - Examination of prevalence, severity, and state of screening and treatment) cancer-related fatigue (EORTC QLQ-FA12), PTG inventory and global HRQoL (EORTC QLQ-C30) were assessed four years after cancer diagnosis in 1316 cancer-free survivors (mean age = 67.28, SD = 11.05, 51.4% female). Multiple linear regression analysis and moderation analysis were performed. The results showed that PTG had a convex quadratic relationship with global HRQoL (p < 0.001). Contrary to our hypothesis, fatigue did not moderate the relationship between PTG (linear and quadratic terms) and global HRQoL, neither when considering the overall PTG score nor for any PTG subdimension. In conclusion, PTG has a convex quadratic relationship with long-term global HRQoL that was not modified by persisting fatigue. Future statistical models investigating PTG and global HRQoL should take this non-linear relationship into account. Aiming to increase PTG might contribute to, but is likely not sufficient for high levels of global HRQoL in cancer survivors in the long run.

Correlating Molar Mass, π-Conjugation, and Optical Properties of Narrowly Distributed Anionic Polythiophenes in Aqueous Solutions.

Polythiophene-based conjugated polyelectrolytes (CPE) are attracting increasing attention as sensor or interface materials in chemistry and biology. While cationic polythiophenes are better understood, limited structural information is available on their anionic counterparts. Limited access to well-defined polymers has made the study of structure-property relationships difficult and clear correlations have remained elusive. By combining controlled Kumada catalyst transfer polymerization with a polymer-analog substitution, regioregular and narrowly distributed poly(6-(thiophen-3-yl)hexane-1-sulfonate)s (PTHS) with tailored chain length are prepared. Analysis of their aqueous solution structures by small-angle neutron scattering (SANS) revealed a cylindrical conformation for all polymers tested, with a length close to the contour length of the polymer chains, while the estimated radii remain too small (<1.5 nm) for extensive π-stacking of the chains. The latter is particularly interesting as the longest polymer exhibits a concentration-independent structured absorption typical of crystalline polythiophenes. Increasing the ionic strength of the solution diminishes these features as the Coulomb repulsion between the charged repeat units is shielded, allowing the polymer to adopt a more coiled conformation. The extended π-conjugation, therefore, appears to be a key parameter for these unique optical features, which are not present in the corresponding cationic polythiophenes.

Maintenance of Aerobic or Resistance Training After an Exercise Intervention Among Breast Cancer Patients After Neoadjuvant Chemotherapy.

BACKGROUND: Exercise interventions have been shown to be beneficial for cancer patients regarding various treatment-related side effects and quality of life. For sustainable effects, patients should continue the training. Therefore, we investigated the maintenance of an exercise training in breast cancer patients, reasons for (dis)continuation, and explored possible influencing factors. METHODS: The investigation is based on a 3-arm randomized intervention trial comparing aerobic and resistance training (19 [4]) during or after neoadjuvant chemotherapy among breast cancer patients. About 2 years after breast surgery, 68 patients (age 52 [11] y) provided information about training continuation, self-reported reasons of (dis)continuation, sociodemographics, employment status, age, and body mass index. Training continuation was investigated with Kaplan-Meier analyses. RESULTS: The intervention was rated as good or very good by 88.1% of participants. Nevertheless, 52.9% discontinued the training directly, but half of them changed to different types of exercise. Reasons for discontinuation included lack of time and long travel distance to the training facility. The median continuation was 19.0 months (Q1, Q3: 5.5, 36.0) with no statistically significant difference between the intervention groups. Younger, better educated, partnered patients tended toward longer training continuation. CONCLUSIONS: The majority of patients continued exercising after the end of intervention. However, a nonnegligible number discontinued training immediately or after few months. Practical, social, and financial support for a transition to an adequate training that is affordable and feasible in the patient's daily life might foster training maintenance. Especially patients who are less educated, elderly, or living alone may need more support to continue exercising.

Novel crosstalk mechanisms between GluA3 and Epac2 in synaptic plasticity and memory in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease which accounts for the most cases of dementia worldwide. Impaired memory, including acquisition, consolidation, and retrieval, is one of the hallmarks in AD. At the cellular level, dysregulated synaptic plasticity partly due to reduced long-term potentiation (LTP) and enhanced long-term depression (LTD) underlies the memory deficits in AD. GluA3 containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are one of key receptors involved in rapid neurotransmission and synaptic plasticity. Recent studies revealed a novel form of GluA3 involved in neuronal plasticity that is dependent on cyclic adenosine monophosphate (cAMP), rather than N-methyl-d-aspartate (NMDA). However, this cAMP-dependent GluA3 pathway is specifically and significantly impaired by amyloid beta (Aß), a pathological marker of AD. cAMP is a key second messenger that plays an important role in modulating memory and synaptic plasticity. We previously reported that exchange protein directly activated by cAMP 2 (Epac2), acting as a main cAMP effector, plays a specific and time-limited role in memory retrieval. From electrophysiological perspective, Epac2 facilities the maintenance of LTP, a cellular event closely associated with memory retrieval. Additionally, Epac2 was found to be involved in the GluA3-mediated plasticity. In this review, we comprehensively summarize current knowledge regarding the specific roles of GluA3 and Epac2 in synaptic plasticity and memory, and their potential association with AD.

Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis.

Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death, that has been implicated in Alzheimer's disease and Parkinson's disease. Inhibition of cystine/glutamate antiporter could lead to mitochondrial fragmentation, mitochondrial calcium ([Ca2+]m) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨm), and ferroptotic cell death. The observation that mitochondrial dysfunction is a characteristic of ferroptosis makes preservation of mitochondrial function a potential therapeutic option for diseases associated with ferroptotic cell death. Mitochondrial calcium levels are controlled via the mitochondrial calcium uniporter (MCU), the main entry point of Ca2+ into the mitochondrial matrix. Therefore, we have hypothesized that negative modulation of MCU complex may confer protection against ferroptosis. Here we evaluated whether the known negative modulators of MCU complex, ruthenium red (RR), its derivative Ru265, mitoxantrone (MX), and MCU-i4 can prevent mitochondrial dysfunction and ferroptotic cell death. These compounds mediated protection in HT22 cells, in human dopaminergic neurons and mouse primary cortical neurons against ferroptotic cell death. Depletion of MICU1, a [Ca2+]m gatekeeper, demonstrated that MICU is protective against ferroptosis. Taken together, our results reveal that negative modulation of MCU complex represents a therapeutic option to prevent degenerative conditions, in which ferroptosis is central to the progression of these pathologies.

Unravelling the signaling power of pollutants.

Exposure to environmental pollutants contributes to diverse pathologies, including pulmonary disease, lower respiratory infections, cancer, and stroke. Pollutants' entry can occur through inhalation, traversing endothelial and epithelial barriers, and crossing the blood-brain barrier, leading to a wide distribution throughout the human body via systemic circulation. Pollutants cause cellular damage by multiple mechanisms encompassing oxidative stress, mitochondrial dysfunction, (neuro)inflammation, and protein instability/proteotoxicity. Sensing pollutants has added a new dimension to disease progression and drug failure. Understanding the molecular pathways and potential receptor binding/signaling that underpin 'sensing' could contribute to ways to combat the detrimental effects of pollutants. We highlight key points of pollutant signaling, crosstalk with receptors acting as drug targets for chronic diseases, and discuss the potential for future therapeutics.

Providing the basis for a patient-centred and effective screening for cancer-related fatigue (MERLIN study): design of a longitudinal observational study.

INTRODUCTION: Cancer-related fatigue (CRF) is a frequent and burdensome sequela of cancer and cancer therapies. It can persist from months to years and has a substantial impact on patients' quality of life and functioning. CRF is often still not adequately diagnosed and insufficiently treated. According to guideline recommendations, patients should be routinely screened for CRF from cancer diagnosis onwards. We will investigate how an effective screening should be designed regarding timing, frequency, screening type and cut-off points. METHODS AND ANALYSIS: MERLIN is a longitudinal observational study that will include 300 patients with cancer at the beginning of cancer therapy. The main study centre is the National Center for Tumour Diseases Heidelberg, Germany. Patients answer five items to shortly screen for CRF at high frequency during their therapy and at lower frequency during the post-treatment phase for 18 months. Further, CRF is assessed at wider intervals based on the Cella criteria, the Brief Fatigue Inventory impact scale, the quality of life fatigue questionnaire (QLQ-FA12) and the fatigue and cognitive items of the quality of life core questionnaire (QLQ-C30), both of the European Organisation for Research and Treatment of Cancer. Important psychological, socio-demographical or medical factors, which may exacerbate CRF are assessed. All assessments are performed online. Receiver operating curves, areas under the curve, sensitivity, specificity, positive and negative predictive values and likelihood ratios will be calculated to determine optimal short screening modalities. ETHICS AND DISSEMINATION: The study was approved by the ethics committee of the Medical Faculty of the Heidelberg University, Germany (approval number: S-336/2022). Written informed consent is obtained from all participants. The study is conducted in full conformance with the principles of the Declaration of Helsinki. Results will be published in peer-reviewed scientific journals, presented at conferences and communicated to clinical stakeholders to foster the implementation of an effective CRF management. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; registration number: NCT05448573.

Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.

Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.

The Expression of Epac2 and GluA3 in an Alzheimer's Disease Experimental Model and Postmortem Patient Samples.

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, characterized by amyloid beta (Aß) and hyperphosphorylated tau accumulation in the brain. Recent studies indicated that memory retrieval, rather than memory formation, was impaired in the early stage of AD. Our previous study reported that pharmacological activation of hippocampal Epac2 promoted memory retrieval in C57BL/6J mice. A recent study suggested that pharmacological inhibition of Epac2 prevented synaptic potentiation mediated by GluA3-containing AMPARs. In this study, we aimed to investigate proteins associated with Epac2-mediated memory in hippocampal postmortem samples of AD patients and healthy controls compared with the experimental AD model J20 and wild-type mice. Epac2 and phospho-Akt were downregulated in AD patients and J20 mice, while Epac1 and phospho-ERK1/2 were not altered. GluA3 was reduced in J20 mice and tended to decrease in AD patients. PSD95 tended to decrease in AD patients and J20. Interestingly, AKAP5 was increased in AD patients but not in J20 mice, implicating its role in tau phosphorylation. Our study points to the downregulation of hippocampal expression of proteins associated with Epac2 in AD.

The old second messenger cAMP teams up with novel cell death mechanisms: potential translational therapeutical benefit for Alzheimer's disease and Parkinson's disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent neurodegenerative disorders severely impacting life expectancy and quality of life of millions of people worldwide. AD and PD exhibit both a very distinct pathophysiological disease pattern. Intriguingly, recent researches, however, implicate that overlapping mechanisms may underlie AD and PD. In AD and PD, novel cell death mechanisms, encompassing parthanatos, netosis, lysosome-dependent cell death, senescence and ferroptosis, apparently rely on the production of reactive oxygen species, and seem to be modulated by the well-known, "old" second messenger cAMP. Signaling of cAMP via PKA and Epac promotes parthanatos and induces lysosomal cell death, while signaling of cAMP via PKA inhibits netosis and cellular senescence. Additionally, PKA protects against ferroptosis, whereas Epac1 promotes ferroptosis. Here we review the most recent insights into the overlapping mechanisms between AD and PD, with a special focus on cAMP signaling and the pharmacology of cAMP signaling pathways.

Protective effects of caffeine against palmitate-induced lipid toxicity in primary rat hepatocytes is associated with modulation of adenosine receptor A1 signaling.

BACKGROUND: Epidemiological evidence has shown an association between coffee consumption and reduced risk for chronic liver diseases, including metabolic-dysfunction-associated liver disease (MALFD). Lipotoxicity is a key cause of hepatocyte injury during MAFLD. The coffee component caffeine is known to modulate adenosine receptor signaling via the antagonism of adenosine receptors. The involvement of these receptors in the prevention of hepatic lipotoxicity has not yet been explored. The aim of this study was to explore whether caffeine protects against palmitate-induced lipotoxicity by modulating adenosine receptor signaling. METHODS: Primary hepatocytes were isolated from male rats. Hepatocytes were treated with palmitate with or without caffeine or 1,7DMX. Lipotoxicity was verified using Sytox viability staining and mitochondrial JC-10 staining. PKA activation was verified by Western blotting. Selective (ant)agonists of A1AR (DPCPX and CPA, respectively) and A2AR (istradefyline and regadenoson, respectively), the AMPK inhibitor compound C, and the Protein Kinase A (PKA) inhibitor Rp8CTP were used. Lipid accumulation was verified by ORO and BODIPY 453/50 staining. RESULTS: Caffeine and its metabolite 1,7DMX prevented palmitate-induced toxicity in hepatocytes. The A1AR antagonist DPCPX also prevented lipotoxicity, whereas both the inhibition of PKA and the A1AR agonist CPA (partially) abolished the protective effect. Caffeine and DPCPX increased lipid droplet formation only in palmitate-treated hepatocytes and decreased mitochondrial ROS production. CONCLUSIONS: The protective effect of caffeine against palmitate lipotoxicity was shown to be dependent on A1AR receptor and PKA activation. Antagonism of A1AR also protects against lipotoxicity. Targeting A1AR receptor may be a potential therapeutic intervention with which to treat MAFLD.

Longitudinal associations of bioelectrical phase angle and fatigue in breast cancer patients.

Cancer-related fatigue is commonly treated in an undifferentiated manner, because its pathophysiology is still not well understood. Therefore, we investigated if bioelectrical phase angle (PhA), a non-invasive marker of cell integrity, could help to single out specific fatigue subtypes. In a randomized controlled strength training intervention trial, PhA was measured by bioelectrical impedance analysis in 158 breast cancer patients. Fatigue was assessed with the multidimensional 20-item Fatigue Assessment Questionnaire. Multiple regression analyses considering changes in PhA and fatigue from baseline to post-intervention and ANCOVA models investigating the strength training effect on PhA were conducted. Further, explorative mediation and moderation analyses were performed. Decrease (=worsening) in PhA was significantly associated with increase in physical (P = .010) and emotional (P = .019) fatigue. These associations were markedly stronger in patients with normal BMI (interaction P = .059 and .097) and with low pre-diagnosis exercise level (interaction P = .058 and .19). Among patients with normal BMI strength training was associated with an increase in PhA (ANCOVA P = .059), but not among overweight/obese patients (interaction P = .035). Chemotherapy was a major determinant for low PhA, but PhA did not mediate the effect of chemotherapy on fatigue. In conclusion, PhA has a significant inverse association with physical and emotional fatigue. This association is moderated by BMI and previous exercise. Significant relationships of PhA were also observed with chemotherapy and strength training. Thus, PhA might be a marker that could help in the classification of subtypes of fatigue with different pathophysiology, which may require specifically tailored treatment. Further research on this is warranted.