Inflammation as common link to progressive neurological diseases.

Life expectancy has increased immensely over the past decades, bringing new challenges to the health systems as advanced age increases the predisposition for many diseases. One of those is the burden of neurologic disorders. While many hypotheses have been placed to explain aging mechanisms, it has been widely accepted that the increasing pro-inflammatory status with advanced age or "inflammaging" is a main determinant of biological aging. Furthermore, inflammaging is at the cornerstone of many age-related diseases and its involvement in neurologic disorders is an exciting hypothesis. Indeed, aging and neurologic disorders development in the elderly seem to share some basic pathways that fundamentally converge on inflammation. Peripheral inflammation significantly influences brain function and contributes to the development of neurological disorders, including Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Understanding the role of inflammation in the pathogenesis of progressive neurological diseases is of crucial importance for developing effective treatments and interventions that can slow down or prevent disease progression, therefore, decreasing its social and economic burden.

Autophagy (but not metabolism) is a key event in mitoxantrone-induced cytotoxicity in differentiated AC16 cardiac cells.

Mitoxantrone (MTX) is an antineoplastic agent used to treat advanced breast cancer, prostate cancer, acute leukemia, lymphoma and multiple sclerosis. Although it is known to cause cumulative dose-related cardiotoxicity, the underlying mechanisms are still poorly understood. This study aims to compare the cardiotoxicity of MTX and its' pharmacologically active metabolite naphthoquinoxaline (NAPHT) in an in vitro cardiac model, human-differentiated AC16 cells, and determine the role of metabolism in the cardiotoxic effects. Concentration-dependent cytotoxicity was observed after MTX exposure, affecting mitochondrial function and lysosome uptake. On the other hand, the metabolite NAPHT only caused concentration-dependent cytotoxicity in the MTT reduction assay. When assessing the effect of different inhibitors/inducers of metabolism, it was observed that metyrapone (a cytochrome P450 inhibitor) and phenobarbital (a cytochrome P450 inducer) slightly increased MTX cytotoxicity, while 1-aminobenzotriazole (a suicide cytochrome P450 inhibitor) decreased fairly the MTX-triggered cytotoxicity in differentiated AC16 cells. When focusing in autophagy, the mTOR inhibitor rapamycin and the autophagy inhibitor 3-methyladenine exacerbated the cytotoxicity caused by MTX and NAPHT, while the autophagy blocker, chloroquine, partially reduced the cytotoxicity of MTX. In addition, we observed a decrease in p62, beclin-1, and ATG5 levels and an increase in LC3-II levels in MTX-incubated cells. In conclusion, in our in vitro model, neither metabolism nor exogenously given NAPHT are major contributors to MTX toxicity as seen by the residual influence of metabolism modulators used on the observed cytotoxicity and by NAPHT's low cytotoxicity profile. Conversely, autophagy is involved in MTX-induced cytotoxicity and MTX seems to act as an autophagy inducer, possibly through p62/LC3-II involvement.

The role of inflammation and antioxidant defenses in the cardiotoxicity of doxorubicin in elderly CD-1 male mice.

Doxorubicin (DOX) is a potent chemotherapeutic agent used against several cancer types. However, due to its cardiotoxic adverse effects, the use of this drug may be also life-threatening. Although most cancer patients are elderly, they are poorly represented and evaluated in pre-clinical and clinical studies. Considering this, the present work aims to evaluate inflammation and oxidative stress as the main mechanisms of DOX-induced cardiotoxicity, in an innovative approach using an experimental model constituted of elderly animals treated with a clinically relevant human cumulative dose of DOX. Elderly (18-20 months) CD-1 male mice received biweekly DOX administrations, for 3 weeks, to reach a cumulative dose of 9.0 mg/kg. One week (1W) or two months (2 M) after the last DOX administration, the heart was collected to determine both drug's short and longer cardiac adverse effects. The obtained results showed that DOX causes cardiac histological damage and fibrosis at both time points. In the 1W-DOX group, the number of nuclear factor kappa B (NF-κB) p65 immunopositive cells increased and a trend toward increased NF-κB p65 expression was seen. An increase of inducible nitric oxide synthase (iNOS) and interleukin (IL)-33 and a trend toward increased IL-6 and B-cell lymphoma-2-associated X (Bax) expression were seen after DOX. In the same group, a decrease in IL-1ß, p62, and microtubule-associated protein 1A/1B-light chain 3 (LC3)-I, p38 mitogen-activated protein kinase (MAPK) expression was observed. Contrariwise, the animals sacrificed 2 M after DOX showed a significant increase in glutathione peroxidase 1 and Bax expression with persistent cardiac damage and fibrosis, while carbonylated proteins, erythroid-2-related factor 2 (Nrf2), NF-κB p65, myeloperoxidase, LC3-I, and LC3-II expression decreased. In conclusion, our study demonstrated that in an elderly mouse population, DOX induces cardiac inflammation, autophagy, and apoptosis in the heart in the short term. When kept for a longer period, oxidative-stress-linked pathways remained altered, as well as autophagy markers and tissue damage after DOX treatment, emphasizing the need for continuous post-treatment cardiac monitoring.

Biodistribution and intestinal inflammatory response following voluntary oral intake of silver nanoparticles by C57BL/6J mice.

Silver nanoparticles (AgNP) are among the most widely commercialized nanomaterials globally, with applications in medicine and the food industry. Consequently, the increased use of AgNP in the food industry has led to an unavoidable rise  in human exposure to these nanoparticles. Their widespread use raises concerns about potential hazards to human health, specifically their intestinal pro-inflammatory effects. Thus, the main objective of this study was to evaluate the biological effects of two subacute doses of 5 nm polyvinylpyrrolidone (PVP)-AgNP in C57BL/6J mice. One mg/kg body weight or 10 mg/kg bw was provided once a day for 14 days, using a new technology (HaPILLness) that allows voluntary, stress-free, and accurate oral dosing. It was observed that after oral ingestion, while AgNP is biodistributed throughout the entire organism, most of the ingested dose is excreted in the feces. The passage and accumulation of AgNP throughout the intestine instigated a prominent inflammatory response, marked by significant histological, vascular, and cellular transformations. This response was driven by the activation of the nuclear factor-кB (NF-кB) inflammatory pathway, ultimately leading to the generation of multiple cytokines and chemokines.

A Clinically Relevant Dosage of Mitoxantrone Disrupts the Glutathione and Lipid Metabolic Pathways of the CD-1 Mice Brain: A Metabolomics Study.

Long-term cognitive dysfunction, or "chemobrain", has been observed in cancer patients treated with chemotherapy. Mitoxantrone (MTX) is a topoisomerase II inhibitor that binds and intercalates with DNA, being used in the treatment of several cancers and multiple sclerosis. Although MTX can induce chemobrain, its neurotoxic mechanisms are poorly studied. This work aimed to identify the adverse outcome pathways (AOPs) activated in the brain upon the use of a clinically relevant cumulative dose of MTX. Three-month-old male CD-1 mice were given a biweekly intraperitoneal administration of MTX over the course of three weeks until reaching a total cumulative dose of 6 mg/kg. Controls were given sterile saline in the same schedule. Two weeks after the last administration, the mice were euthanized and their brains removed. The left brain hemisphere was used for targeted profiling of the metabolism of glutathione and the right hemisphere for an untargeted metabolomics approach. The obtained results revealed that MTX treatment reduced the availability of cysteine (Cys), cysteinylglycine (CysGly), and reduced glutathione (GSH) suggesting that MTX disrupts glutathione metabolism. The untargeted approach revealed metabolic circuits of phosphatidylethanolamine, catecholamines, unsaturated fatty acids biosynthesis, and glycerolipids as relevant players in AOPs of MTX in our in vivo model. As far as we know, our study was the first to perform such a broad profiling study on pathways that could put patients given MTX at risk of cognitive deficits.

Four decades of chemotherapy-induced cognitive dysfunction: comprehensive review of clinical, animal and in vitro studies, and insights of key initiating events.

Cognitive dysfunction has been one of the most reported and studied adverse effects of cancer treatment, but, for many years, it was overlooked by the medical community. Nevertheless, the medical and scientific communities have now recognized that the cognitive deficits caused by chemotherapy have a strong impact on the morbidity of cancer treated patients. In fact, chemotherapy-induced cognitive dysfunction or 'chemobrain'  (also named also chemofog) is at present a well-recognized effect of chemotherapy that could affect up to 78% of treated patients. Nonetheless, its underlying neurotoxic mechanism is still not fully elucidated. Therefore, this work aimed to provide a comprehensive review using PubMed as a database to assess the studies published on the field and, therefore, highlight the clinical manifestations of chemobrain and the putative neurotoxicity mechanisms.In the last two decades, a great number of papers was published on the topic, mainly with clinical observations. Chemotherapy-treated patients showed that the cognitive domains most often impaired were verbal memory, psychomotor function, visual memory, visuospatial and verbal learning, memory function and attention. Chemotherapy alters the brain's metabolism, white and grey matter and functional connectivity of brain areas. Several mechanisms have been proposed to cause chemobrain but increase of proinflammatory cytokines with oxidative stress seem more relevant, not excluding the action on neurotransmission and cellular death or impaired hippocampal neurogenesis. The interplay between these mechanisms and susceptible factors makes the clinical management of chemobrain even more difficult. New studies, mainly referring to the underlying mechanisms of chemobrain and protective measures, are important in the future, as it is expected that chemobrain will have more clinical impact in the coming years, since the number of cancer survivors is steadily increasing.

Cardiotoxicity of cyclophosphamide's metabolites: an in vitro metabolomics approach in AC16 human cardiomyocytes.

Cyclophosphamide is a widely used anticancer and immunosuppressive prodrug that unfortunately causes severe adverse effects, including cardiotoxicity. Although the exact cardiotoxic mechanisms are not completely understood, a link between cyclophosphamide's pharmacologically active metabolites, namely 4-hydroxycyclophosphamide and acrolein, and the toxicity observed after the administration of high doses of the prodrug is likely. Therefore, the objective of this study is to shed light on the cardiotoxic mechanisms of cyclophosphamide and its main biotransformation products, through classic and metabolomics studies. Human cardiac proliferative and differentiated AC16 cells were exposed to several concentrations of the three compounds, determining their basic cytotoxic profile and preparing the next study, using subtoxic and toxic concentrations for morphological and biochemical studies. Finally, metabolomics studies were applied to cardiac cells exposed to subtoxic concentrations of the aforementioned compounds to determine early markers of damage. The cytotoxicity, morphological and biochemical assays showed that 4-hydroxycyclophosphamide and acrolein induced marked cardiotoxicity at µM concentrations (lower than 5 µM), being significantly lower than the ones observed for cyclophosphamide (higher than 2500 µM). Acrolein led to increased levels of ATP and total glutathione on proliferative cells at 25 µM, while no meaningful changes were observed in differentiated cells. Higher levels of carbohydrates and decreased levels of fatty acids and monoacylglycerols indicated a metabolic cardiac shift after exposure to cyclophosphamide's metabolites, as well as a compromise of precursor amino acids used in the synthesis of glutathione, seen in proliferative cells' metabolome. Overall, differences in cytotoxic mechanisms were observed for the two different cellular states used and for the three molecules, which should be taken into consideration in the study of cyclophosphamide cardiotoxic mechanisms.

Chemobrain: mitoxantrone-induced oxidative stress, apoptotic and autophagic neuronal death in adult CD-1 mice.

Mitoxantrone (MTX) is a topoisomerase II inhibitor used to treat a wide range of tumors and multiple sclerosis but associated with potential neurotoxic effects mediated by hitherto poorly understood mechanisms. In adult male CD-1 mice, the underlying neurotoxic pathways of a clinically relevant cumulative dose of 6 mg/kg MTX was evaluated after biweekly administration for 3 weeks and sacrifice 1 week after the last administration was undertaken. Oxidative stress, neuronal damage, apoptosis, and autophagy were analyzed in whole brain, while coronal brain sections were used for a closer look in the hippocampal formation (HF) and the prefrontal cortex (PFC), as these areas have been signaled out as the most affected in 'chemobrain'. In the whole brain, MTX-induced redox imbalance shown as increased endothelial nitric oxide synthase and reduced manganese superoxide dismutase expression, as well as a tendency to a decrease in glutathione levels. MTX also caused diminished ATP synthase ß expression, increased autophagic protein LC3 II and tended to decrease p62 expression. Postsynaptic density protein 95 expression decreased in the whole brain, while hyperphosphorylation of Tau was seen in PFC. A reduction in volume was observed in the dentate gyrus (DG) and CA1 region of the HF, while GFAP-ir astrocytes increased in all regions of the HF except in the DG. Apoptotic marker Bax increased in the PFC and in the CA3 region, whereas p53 decreased in all brain areas evaluated. MTX causes damage in the brain of adult CD-1 mice in a clinically relevant cumulative dose in areas involved in memory and cognition.

Factors contributing to the mental health outcomes of carers during the transition of their family member to residential aged care: a systematic search and narrative review.

OBJECTIVES: The transition of an older family member into a residential aged care facility (RACF) is often challenging for both the person being admitted and their family carer. This review aimed to identify the protective and contributing factors to adverse mental health outcomes among family carers following the decision to move a family member to a RACF. METHOD: A search of CINAHL, PubMed and PsycINFO was conducted for empirical papers published in English between 2004 and 2019, exploring the mental health or quality of life (QoL) of family carers of those recently admitted, or considering admission, to a RACF. Articles were reviewed by two authors for inclusion. RESULTS: Twenty-three studies met the inclusion criteria. Pre-existing depressive symptoms and poor subjective health were related to adverse mental health outcomes following admission. Information from the facility, support to change roles, and factors related to carer's health and demographics, were associated with changes in the mental health outcomes of carers during the transition of their relative to a RACF. Key protective factors of carer's mental health outcomes following the transition of their relative to a RACF are flow and transparency of information between carer and the facility staff, and staff efforts to involve carers in providing emotional support to their relative, in monitoring care, and advocating for their quality of life. CONCLUSION: There is evidence to suggest factors such lack of flow and transparency of information between carer and the facility staff may predispose carers to poor mental health and QoL following the transition of a relative to a RACF. Key protective factors of carer's mental health following admission are staff efforts to involve carers in providing emotional support to their relative, in monitoring care, and advocating for their quality of life. This review also indicates that the combination of factors that puts family carers more at risk of poor mental health and lower quality of life throughout the transition period. Policy and practice should follow recommendations that consider a combination of the above factors when addressing the needs of family carers before and after admission of an older person to RACF.

Flavonoids as antiobesity agents: A review.

Obesity is a global health problem that affects all age groups in both developing and developed countries. In recent years, the prevalence of overweight and obesity has reached pandemic levels, resulting in a dramatic increase in the incidence of various comorbidities, such as cardiovascular diseases, type 2 diabetes, and cancer, consequently leading to massive health and socioeconomic burdens. Together with lifestyle changes, antiobesity pharmacotherapy is gaining momentum as an adjunctive treatment. However, the available pharmacological approaches have limited use owing to either significant adverse effects or low efficacy. Over the years, natural products have been an important source of lead compounds for drug discovery. Among these, flavonoids are associated with important biological effects and health-promoting activities. In this review, we discuss the modulatory effects of flavonoids on obesity and their potential mechanisms of action. The literature strongly suggests that most common flavonoids demonstrate a pronounced effect on obesity as shown by their ability to lower body weight, fat mass, and plasma triglycerides/cholesterol, both in in vitro and in vivo models. The impact of flavonoids on obesity can be observed through different mechanisms: reducing food intake and fat absorption, increasing energy expenditure, modulating lipid metabolism, or regulating gut microbiota profile. A better understanding of the known antiobesity mechanisms of flavonoids will enable their potential use to treat this medical condition. Therefore, this review focuses on the putative biological mechanisms through which flavonoids may prevent or treat obesity and highlights new perspectives on future pharmacological use.

An updated review on synthetic cathinones.

Cathinone, the main psychoactive compound found in the plant Catha edulis Forsk. (khat), is a ß-keto analogue of amphetamine, sharing not only the phenethylamine structure, but also the amphetamine-like stimulant effects. Synthetic cathinones are derivatives of the naturally occurring cathinone that largely entered the recreational drug market at the end of 2000s. The former "legal status", impressive marketing strategies and their commercial availability, either in the so-called "smartshops" or via the Internet, prompted their large spread, contributing to their increasing popularity in the following years. As their popularity increased, the risks posed for public health became clear, with several reports of intoxications and deaths involving these substances appearing both in the social media and scientific literature. The regulatory measures introduced thereafter to halt these trending drugs of abuse have proved to be of low impact, as a continuous emergence of new non-controlled derivatives keep appearing to replace those prohibited. Users resort to synthetic cathinones due to their psychostimulant properties but are often unaware of the dangers they may incur when using these substances. Therefore, studies aimed at unveiling the pharmacological and toxicological properties of these substances are imperative, as they will provide increased expertise to the clinicians that face this problem on a daily basis. The present work provides a comprehensive review on history and legal status, chemistry, pharmacokinetics, pharmacodynamics, adverse effects and lethality in humans, as well as on the current knowledge of the neurotoxic mechanisms of synthetic cathinones.

In vivo toxicometabolomics reveals multi-organ and urine metabolic changes in mice upon acute exposure to human-relevant doses of 3,4-methylenedioxypyrovalerone (MDPV).

3,4-Methylenedioxypyrovalerone (MDPV) is consumed worldwide, despite its potential to cause toxicity in several organs and even death. There is a recognized need to clarify the biological pathways through which MDPV elicits general and target-organ toxicity. In this work, a comprehensive untargeted GC-MS-based metabolomics analysis was performed, aiming to detect metabolic changes in putative target organs (brain, heart, kidneys and liver) but also in urine of mice after acute exposure to human-relevant doses of MDPV. Male CD-1 mice received binge intraperitoneal administrations of saline or MDPV (2.5 mg/kg or 5 mg/kg) every 2 h, for a total of three injections. Twenty-four hours after the first administration, target organs, urine and blood samples were collected for metabolomics, biochemical and histological analysis. Hepatic and renal tissues of MDPV-treated mice showed moderate histopathological changes but no significant differences were found in plasma and tissue biochemical markers of organ injury. In contrast, the multivariate analysis significantly discriminated the organs and urine of MDPV-treated mice from the control (except for the lowest dose in the brain), allowing the identification of a panoply of metabolites. Those levels were significantly deviated in relation to physiological conditions and showed an organ specific response towards the drug. Kidneys and liver showed the greatest metabolic changes. Metabolites related with energetic metabolism, antioxidant defenses and inflammatory response were significantly changed in the liver of MDPV-dosed animals, while the kidneys seem to have developed an adaptive response against oxidative stress caused by MDPV. On the other hand, the dysregulation of metabolites that contribute to metabolic acidosis was also observed in this organ. The heart showed an increase of fatty acid biosynthesis, possibly as an adaptation to maintain the cardiac energy homeostasis. In the brain, changes in 3-hydroxybutyric acid levels may reflect the activation of a neurotoxic pathway. However, the increase in metabolites with neuroprotective properties seems to counteract this change. Metabolic profiling of urine from MDPV-treated mice suggested that glutathione-dependent antioxidant pathways may be particularly involved in the compensatory mechanism to counteract oxidative stress induced by MDPV. Overall, this study reports, for the first time, the metabolic profile of liver, kidneys, heart, brain, and urine of MDPV-dosed mice, providing unique insights into the biological pathways of toxicity. Our findings also underline the value of toxicometabolomics as a robust and sensitive tool for detecting adaptive/toxic cellular responses upon exposure to a physiologically relevant dose of a toxic agent, earlier than conventional toxicity tests.

The Secretome of Human Neonatal Mesenchymal Stem Cells Modulates Doxorubicin-Induced Cytotoxicity: Impact in Non-Tumor Cells.

Doxorubicin (Dox) is one of the most widely used treatments for breast cancer, although limited by the well-documented cardiotoxicity and other off-target effects. Mesenchymal stem cell (MSC) secretome has shown immunomodulatory and regenerative properties, further potentiated under 3D conditions. This work aimed to uncover the effect of the MSC-derived secretome from 3D (CM3D) or 2D (CM2D) cultures, in human malignant breast cells (MDA-MB-231), non-tumor breast epithelial cells (MCF10A) and differentiated AC16 cardiomyocytes, co-treated with Dox. A comprehensive proteomic analysis of CM3D/CM2D was also performed to unravel the underlying mechanism. CM3D/CM2D co-incubation with Dox revealed no significant differences in MDA-MB-231 viability when compared to Dox alone, whereas MCF10A and AC16 viability was consistently improved in Dox+CM3D-treated cells. Moreover, neither CM2D nor CM3D affected Dox anti-migratory and anti-invasive effects in MDA-MB-231. Notably, Ge-LC-MS/MS proteomic analysis revealed that CM3D displayed protective features that might be linked to the regulation of cell proliferation (CAPN1, CST1, LAMC2, RANBP3), migration (CCN3, MMP8, PDCD5), invasion (TIMP1/2), oxidative stress (COX6B1, AIFM1, CD9, GSR) and inflammation (CCN3, ANXA5, CDH13, GDF15). Overall, CM3D decreased Dox-induced cytotoxicity in non-tumor cells, without compromising Dox chemotherapeutic profile in malignant cells, suggesting its potential use as a chemotherapy adjuvant to reduce off-target side effects.

Adverse outcome pathways induced by 3,4-dimethylmethcathinone and 4-methylmethcathinone in differentiated human SH-SY5Y neuronal cells.

Cathinones (ß-keto amphetamines), widely abused in recreational settings, have been shown similar or even worse toxicological profile than classical amphetamines. In the present study, the cytotoxicity of two ß-keto amphetamines [3,4-dimethylmethcathinone (3,4-DMMC) and 4-methylmethcathinone (4-MMC)], was evaluated in differentiated dopaminergic SH-SY5Y cells in comparison to methamphetamine (METH). MTT reduction and NR uptake assays revealed that both cathinones and METH induced cytotoxicity in a concentration- and time-dependent manner. Pre-treatment with trolox (antioxidant) partially prevented the cytotoxicity induced by all tested drugs, while N-acetyl-L-cysteine (NAC; antioxidant and glutathione precursor) and GBR 12909 (dopamine transporter inhibitor) partially prevented the cytotoxicity induced by cathinones, as evaluated by the MTT reduction assay. Unlike METH, cathinones induced oxidative stress evidenced by the increase on intracellular levels of reactive oxygen species (ROS), and also by the decrease of intracellular glutathione levels. Trolox prevented, partially but significantly, the ROS generation elicited by cathinones, while NAC inhibited it completely. All tested drugs induced mitochondrial dysfunction, since they led to mitochondrial membrane depolarization and to intracellular ATP depletion. Activation of caspase-3, indicative of apoptosis, was seen both for cathinones and METH, and confirmed by annexin V and propidium iodide positive staining. Autophagy was also activated by all drugs tested. Pre-incubation with bafilomycin A1, an inhibitor of the vacuolar H+-ATPase, only protected against the cytotoxicity induced by METH, which indicates dissimilar toxicological pathways for the tested drugs. In conclusion, the mitochondrial impairment and oxidative stress observed for the tested cathinones may be key factors for their neurotoxicity, but different outcome pathways seem to be involved in the adverse effects, when compared to METH.

Correction to: In vitro mechanistic studies on α-amanitin and its putative antidotes.

In the original publication of the article.

In vitro mechanistic studies on α-amanitin and its putative antidotes.

α-Amanitin plays a key role in Amanita phalloides intoxications. The liver is a major target of α-amanitin toxicity, and while RNA polymerase II (RNA Pol II) transcription inhibition is a well-acknowledged mechanism of α-amanitin toxicity, other possible toxicological pathways remain to be elucidated. This study aimed to assess the mechanisms of α-amanitin hepatotoxicity in HepG2 cells. The putative protective effects of postulated antidotes were also tested in this cell model and in permeabilized HeLa cells. α-Amanitin (0.1-20 µM) displayed time- and concentration-dependent cytotoxicity, when evaluated through the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction and neutral red uptake assays. Additionally, α-amanitin decreased nascent RNA synthesis in a concentration- and time-dependent manner. While α-amanitin did not induce changes in mitochondrial membrane potential, it caused a significant increase in intracellular ATP levels, which was not prevented by incubation with oligomycin, an ATP synthetase inhibitor. Concerning the cell redox status, α-amanitin did not increase reactive species production, but caused a significant increase in total and reduced glutathione, which was abolished by pre-incubation with the inhibitor of gamma-glutamylcysteine synthase, buthionine sulfoximine. None of the tested antidotes [N-acetyl cysteine, silibinin, benzylpenicillin, and polymyxin B (PolB)] conferred any protection against α-amanitin-induced cytotoxicity in HepG2 cells or reversed the inhibition of nascent RNA caused by the toxin in permeabilized HeLa cells. Still, PolB interfered with RNA Pol II activity at high concentrations, though not impacting on α-amanitin observed cytotoxicity. New hepatotoxic mechanisms of α-amanitin were described herein, but the lack of protection observed in clinically used antidotes may reflect the lack of knowledge on their true protection mechanisms and may explain their relatively low clinical efficacy.

Mitoxantrone impairs proteasome activity and prompts early energetic and proteomic changes in HL-1 cardiomyocytes at clinically relevant concentrations.

Mitoxantrone (MTX) is used to treat several types of cancers and to improve neurological disability in multiple sclerosis. Unfortunately, cardiotoxicity is a severe and common adverse effect in MTX-treated patients. Herein, we aimed to study early and late mechanisms of MTX-induced cardiotoxicity using murine HL-1 cardiomyocytes. Cells were exposed to MTX (0.1, 1 or 10 µM) during short (2, 4, 6, or 12 h) or longer incubation periods (24 or 48 h). At earlier time points, (6 and 12 h) cytotoxicity was already observed for 1 and 10 µM MTX. Proteomic analysis of total protein extracts found 14 proteins with higher expression and 26 with lower expression in the cells exposed for 12 h to MTX (pH gradients 4-7 and 6-11). Of note, the expression of the regulatory protein 14-3-3 protein epsilon was increased by a factor of two and three, after exposure to 1 and 10 µM MTX, respectively. At earlier time-points, 10 µM MTX increased intracellular ATP levels, while decreasing media lactate levels. At later stages (24 and 48 h), MTX-induced cytotoxicity was concentration and time-dependent, according to the MTT reduction and lactate dehydrogenase leakage assays, while caspase-9, -8 and -3 activities increased at 24 h. Regarding cellular redox status, total glutathione increased in 1 µM MTX (24 h), and that increase was dependent on gamma-glutamylcysteine synthetase activity. Meanwhile, for both 1 and 10 µM MTX, oxidized glutathione was significantly higher than control at 48 h. Moreover, MTX was able to significantly decrease proteasomal chymotrypsin-like activity in a concentration and time-independent manner. In summary, MTX significantly altered proteomic, energetic and oxidative stress homeostasis in cardiomyocytes at clinically relevant concentrations and our data clearly demonstrate that MTX causes early cardiotoxicity that needs further study.

A cluster randomised trial of the program to enhance adjustment to residential living (PEARL): a novel psychological intervention to reduce depression in newly admitted aged care residents.

BACKGROUND: Depression rates are high in residential aged care (RAC) facilities, with newly admitted residents at particular risk. New approaches to address depression in this population are urgently required, particularly psychological interventions suitable for widespread use across the RAC sector. The Program to Enhance Adjustment to Residential Living (PEARL) is a brief intervention, designed to provide individually tailored care approaches to meet the psychological needs of newly admitted residents, delivered in collaboration with facility staff. METHODS: PEARL will be evaluated using a cluster randomised controlled design, comparing outcomes for residents who participate in the intervention with those residing in care as usual control facilities. Participants are RAC residents aged 60 years or above, with normal cognition or mild-moderate cognitive impairment, who relocated to the facility within the previous 4 weeks. The primary outcomes are depressive symptoms and disorders, with secondary outcomes including anxiety, stress, quality of life, adjustment to RAC, and functional dependence, analysed on an intention to treat basis using multilevel modelling. DISCUSSION: PEARL is an intervention based on self-determination theory, designed to reduce depression in newly admitted residents by tailoring day to day care to meet their psychological needs. This simple psychological approach offers an alternative care model to the current over-reliance of antidepressant medications. TRIAL REGISTRATION: ACTRN12616001726448; Registered 16 December 2016 with the Australian New Zealand Clinical Trials Registry.

The Impact of a Dairy Milk Recovery Beverage on Bacterially Stimulated Neutrophil Function and Gastrointestinal Tolerance in Response to Hypohydration Inducing Exercise Stress.

The study aimed to determine the impact of a dairy milk recovery beverage immediately after endurance exercise on leukocyte trafficking, neutrophil function, and gastrointestinal tolerance markers during recovery. Male runners (N = 11) completed two feeding trials in randomized order, after 2 hr of running at 70% V˙O2max, fluid restricted, in temperate conditions (25 °C, 43% relative humidity). Immediately postexercise, the participants received a chocolate-flavored dairy milk beverage equating to 1.2 g/kg body mass carbohydrate and 0.4 g/kg body mass protein in one trial, and water volume equivalent in another trial. Venous blood and breath samples were collected preexercise, postexercise, and during recovery to determine the leukocyte counts, plasma intestinal fatty acid binding protein, and cortisol concentrations, as well as breath H2. In addition, 1,000 µl of whole blood was incubated with 1 µg/ml Escherichia coli lipopolysaccharide for 1 hr at 37 °C to determine the stimulated plasma elastase concentration. Gastrointestinal symptoms and feeding tolerance markers were measured preexercise, every 15 min during exercise, and hourly postexercise for 3 hr. The postexercise leukocyte (mean [95% confidence interval]: 12.7 [11.6, 14.0] × 109/L [main effect of time, MEOT]; p < .001) and neutrophil (10.2 [9.1, 11.5] × 109/L; p < .001) counts, as well as the plasma intestinal fatty acid binding protein (470 pg/ml; +120%; p = .012) and cortisol (236 nMol/L; +71%; p = .006) concentrations, were similar throughout recovery for both trials. No significant difference in breath H2 and gastrointestinal symptoms was observed between trials. The total (Trial × Time, p = .025) and per cell (Trial × Time, p = .001) bacterially stimulated neutrophil elastase release was greater for the chocolate-flavored dairy milk recovery beverage (+360% and +28%, respectively) in recovery, compared with the water trial (+85% and -38%, respectively). Chocolate-flavored dairy milk recovery beverage consumption immediately after exercise prevents the decrease in neutrophil function during the recovery period, and it does not account for substantial malabsorption or gastrointestinal symptoms over a water volume equivalent.

Communication changes with laryngectomy and impact on quality of life: a review.

PURPOSE: Patients with throat cancer at later stages often undergo total laryngectomy, a procedure that removes the larynx (voice box) and directly impacts the patient's ability to produce natural voice and communication. This narrative review aimed to explore how changes to communication following laryngectomy may impact quality of life (QoL) for patients. METHODS: Literature searches were conducted using CINAHL, MEDLINE and PsychInfo databases for studies published between 2007 and 2018. The search terms (and derivatives) of laryngectomy AND communication AND quality of life were used. A synthesis and appraisal of the studies was conducted. RESULTS: Twelve studies met the inclusion criteria and were included in this review. The two main themes identified relating to changes in communication and impact on QoL were changes in communication competency (immediate changes and communication option used) and adaptation to change (e.g. self-related factors and relationships with others). Regardless of the type of communication option used, participants in all studies reported negative changes in their communication competency and QoL post-laryngectomy. Voice-related factors and aesthetics of the communication option used were noted to influence self-ratings of QoL for the participants, rather than how well others understood them. Participants using tracheoesophageal speech (TES) consistently showed the highest self-reported QoL across the majority of studies. A model incorporating the findings from this review has been proposed which outlines how changes in communication post-laryngectomy may lead to an impact on QoL. Here, the factors of changes in communication competency, self-perception and social engagement impact each other and are also influenced by adaptation to change. CONCLUSION: This review has highlighted the complex nature of changes faced by patients following laryngectomy in relation to communication and QoL. The model linking communication changes to QoL may become a useful tool for researchers and clinicians in supporting the management of patients post-laryngectomy.