EXCLI Journal

Current update on the protective effect of epicatechin in neurodegenerative diseases

2022-05-19T09:31:53+02:00

Need to focus on inhibitory activity of benzimidazole analogues against indolamine 2,3-dioxygenase-1 (IDO-1)

2022-05-04T09:12:05+02:00

Introducing a new index for selecting genetic polymorphisms for association studies

2022-06-08T09:09:09+02:00

A revolution in health: Opportunities and challenges of the Metaverse

2022-05-02T14:14:31+02:00

What are risk factors for COVID-19 vaccine breakthrough infections in patients with previous history of bariatric surgery?

2022-05-02T15:21:04+02:00

Current update on anticancer effects of icariin

2022-03-23T08:07:53+01:00

HDAC11: A novel inflammatory biomarker in Huntington’s disease

2022-03-03T15:39:08+01:00

Poorer and more densely populated regions have lower vaccination capability against COVID-19

2022-03-16T07:25:49+01:00

Current update on the protective effect of naringin in inflammatory lung diseases

2022-02-15T11:05:32+01:00

Lithium in drinking water and suicide risk

2022-03-01T07:41:17+01:00

Toll-like receptors, innate immune system, and lung diseases

2022-02-14T09:17:45+01:00

Recent insights into the biological and pharmacological activity of lycopene

2022-02-08T08:20:15+01:00

Metabolic syndrome in childhood cancer survivors

2022-02-03T15:03:56+01:00

Preventive role of Sapindus species in different neurological and metabolic disorders

2022-01-18T07:56:46+01:00

Seroprevalence of SARS-CoV-2 antibodies in radio and television workers

2021-12-20T08:14:54+01:00

Effects of curcumin on low-density lipoprotein oxidation

2022-05-11T11:05:47+02:00

Atherosclerosis is the most frequent cause of death globally. Oxidized low-density lipoprotein (ox-LDL) has an essential role in the formation of atherosclerotic plaques and foamy macrophages. Ox-LDL increases the uptake of cholesterol by macrophages and is the major cause of blood flow disruption. Ox-LDL is produced during oxidative stress and treatment with antioxidants could inhibit the production and function of ox-LDL. Curcumin is a potent antioxidant and has a strong track record in the treatment of numerous diseases. Recent studies indicate that Curcumin exerts a lipid-lowering effect, and can modulate the formation of atherosclerotic plaque. The current review focuses upon the role of Curcumin in oxidation of LDL and foam cell formation in atherosclerotic lesions.

The association of ACE1, ACE2, TMPRSS2, IFITM3 and VDR polymorphisms with COVID-19 severity

2022-04-27T11:37:21+02:00

Genes involved in the regulation of viral recognition and its entry into a host cell have been identified as candidates for genetic association studies on COVID-19 severity. Published findings on the effects of polymorphisms within ACE1, ACE2, TMPRSS2, IFITM3 and VDR genes remained inconclusive, so we conducted a systematic review and meta-analysis in order to elucidate their potential involvement in the genetic basis underlying the severity of COVID-19 and/or an outcome of SARS-CoV-2 infection. Identification of potentially eligible studies was based on PubMed, Scopus and Web of Science database search. Relevant studies (n=29) with a total number of 8247 SARS-CoV-2-positive participants were included in qualitative synthesis, while results of 21 studies involving 5939 were pooled in meta-analysis. Minor allele I of rs1799752 located within ACE1 was identified as a protective variant against severe COVID-19, while its effect on mortality rate was opposite. Similarly, minor allele A of ACE2 polymorphism, rs2285666, was found to associate with a decreased risk of severe COVID-19 (P = 0.003, OR = 0.512, 95 % CI = 0.331-0.793). Statistical significance was also seen for the association between COVID-19 severity and rs12329760 located within TMPRSS2. Our results did not support the supposed association of rs12252 in IFITM3 and polymorphisms within VDR with disease severity. We conclude that genetic variants within ACE1, ACE2 and TMPRSS2 may be potential biomarkers of COVID-19 severity, which needs to be further confirmed in a larger set of studies.

Recent development of machine learning-based methods for the prediction of defensin family and subfamily

2022-05-02T11:59:58+02:00

Nearly all living species comprise of host defense peptides called defensins, that are crucial for innate immunity. These peptides work by activating the immune system which kills the microbes directly or indirectly, thus providing protection to the host. Thus far, numerous preclinical and clinical trials for peptide-based drugs are currently being evaluated. Although, experimental methods can help to precisely identify the defensin peptide family and subfamily, these approaches are often time-consuming and cost-ineffective. On the other hand, machine learning (ML) methods are able to effectively employ protein sequence information without the knowledge of a protein’s three-dimensional structure, thus highlighting their predictive ability for the large-scale identification. To date, several ML methods have been developed for the in silico identification of the defensin peptide family and subfamily. Therefore, summarizing the advantages and disadvantages of the existing methods is urgently needed in order to provide useful suggestions for the development and improvement of new computational models for the identification of the defensin peptide family and subfamily. With this goal in mind, we first provide a comprehensive survey on a collection of six state-of-the-art computational approaches for predicting the defensin peptide family and subfamily. Herein, we cover different important aspects, including the dataset quality, feature encoding methods, feature selection schemes, ML algorithms, cross-validation methods and web server availability/usability. Moreover, we provide our thoughts on the limitations of existing methods and future perspectives for improving the prediction performance and model interpretability. The insights and suggestions gained from this review are anticipated to serve as a valuable guidance for researchers for the development of more robust and useful predictors.

Systems redox biology in health and disease

2022-03-16T07:05:24+01:00

Living organisms need to be able to cope with environmental challenges and other stressors and mount adequate responses that are as varied as the spectrum of those challenges. Understanding how the multi-layered biological stress responses become integrated across and between different levels of organization within an organism can provide a different perspective on the nature and inter-relationship of complex systems in health and disease. We here compare two concepts which have been very influential in stress research: Selye’s ‘General Adaptation Syndrome’ and Sies’s ‘Oxidative Stress’ paradigm. We show that both can be embraced within a more general framework of ‘change and response’. The ‘Reactive Species Interactome’ allows each of these to be considered as distinct but complementary aspects of the same system, representative of roles at different levels of organization within a functional hierarchy. The versatile chemistry of sulfur - exemplified by hydrogen sulfide, glutathione and proteinous cysteine thiols - enriched by its interactions with reactive oxygen, nitrogen and sulfur species, would seem to sit at the heart of the ‘Redox Code’ and underpin the ability of complex organisms to cope with stress.

Empirical comparison and analysis of machine learning-based predictors for predicting and analyzing of thermophilic proteins

2022-02-15T09:06:03+01:00

Thermophilic proteins (TPPs) are critical for basic research and in the food industry due to their ability to maintain a thermodynamically stable fold at extremely high temperatures. Thus, the expeditious identification of novel TPPs through computational models from protein sequences is very desirable. Over the last few decades, a number of computational methods, especially machine learning (ML)-based methods, for in silico prediction of TPPs have been developed. Therefore, it is desirable to revisit these methods and summarize their advantages and disadvantages in order to further develop new computational approaches to achieve more accurate and improved prediction of TPPs. With this goal in mind, we comprehensively investigate a large collection of fourteen state-of-the-art TPP predictors in terms of their dataset size, feature encoding schemes, feature selection strategies, ML algorithms, evaluation strategies and web server/software usability. To the best of our knowledge, this article represents the first comprehensive review on the development of ML-based methods for in silico prediction of TPPs. Among these TPP predictors, they can be classified into two groups according to the interpretability of ML algorithms employed (i.e., computational black-box methods and computational white-box methods). In order to perform the comparative analysis, we conducted a comparative study on several currently available TPP predictors based on two benchmark datasets. Finally, we provide future perspectives for the design and development of new computational models for TPP prediction. We hope that this comprehensive review will facilitate researchers in selecting an appropriate TPP predictor that is the most suitable one to deal with their purposes and provide useful perspectives for the development of more effective and accurate TPP predictors.

The effect of exercise interventions on Irisin level

2022-02-10T11:31:35+01:00

Irisin is a hormone that is offered to be a hopeful remedial target in obesity and type 2 diabetes. It has received striking attention recently, whereas, the interactions between exercise training and irisin are still unclear. Therefore, this systematic review and meta-analysis investigated the impacts of exercise interventions on circulating irisin in adults. A systematic search was conducted in PubMed, CINAHL, MEDLINE, Cochrane, Google Scholar, and Scopus up to July 15, 2021. Twenty-four studies, which assessed a total of 921 participants were included and analyzed using a random-effects model to estimate weighted mean differences (MD) with 95 % confidence intervals (CI). Overall, data revealed that exercise training significantly increased circulating irisin (MD: 0.01, 95 % CI: 0.00, 0.01, p = 0.005), and declined insulin (MD: -2.09, 95 % CI: -2.81, -1.37, p < 0.00001), glucose (MD: -12.89, 95 % CI: -16.52, -9.26, p < 0.00001), and insulin resistance (MD: -0.89, 95 % CI: -1.15, -0.62, p < 0.00001). Subgroup analysis revealed that irisin raised significantly when resistance training (p = 0.04) and combined training (p = 0.002) were applied, and for the type 2 diabetes and prediabetes (p = 0.002 for both) groups. Moreover, subgroup analysis by the type of intervention demonstrated that insulin reduced when aerobic training (p < 0.00001) and combined training (p = 0.0003) were employed, but glucose and HOMA-IR reduced after all three types of exercise training. These findings demonstrate that exercise interventions may produce ameliorations in circulating irisin. Further long-term studies are required to confirm these findings.

Oxidative stress and visual system

2022-02-09T13:58:38+01:00

Different types of tissues respond differently to the action of oxidative stress. The visual system is very sensitive to oxidative action due to continuous exposure to light. In consideration of the growing interest of scientific studies towards various compounds endowed with antioxidant and anti-inflammatory properties, we performed a review of the literature focusing on the use of some antioxidant molecules for the treatment of conditions affecting the visual system. In this study, we focused on the ability of two antioxidant agents, the small molecule α-lipoic acid (ALA) and the enzyme superoxide dismutase (SOD), to influence the neurodegenerative physiological processes related to aging and oxidative stress affecting the ocular segment. The literature data report that ALA and SOD can protect against neurodegenerative effects both the optic nerve and retina and, if administered together, they are able to lower the levels of oxidative stress, thus preventing neurodegeneration and reducing the apoptotic process.

Quantitative aspects of nitric oxide production from nitrate and nitrite

2022-02-02T07:34:19+01:00

Nitric oxide (NO) is involved in many physiological and pathological processes in the human body. At least two major pathways produce NO: (1) the L-arginine-NO-oxidative pathway in which NO synthase (NOS) enzymes convert L-arginine to NO; (2) the nitrate-nitrite-NO reductive pathway in which NO is produced from the serial reduction of nitrate and nitrite. The deficiency of NO is involved in the pathophysiology of cardiometabolic disorders. Intervention with foods containing nitrate and nitrite can potentially prevent or treat some chronic diseases, including cardiovascular diseases and diabetes. A better understanding of the NO cycle would help develop effective strategies for preventing or treating the disorders in which NO homeostasis is disturbed. This review summarizes quantitative aspects of NO production, emphasizing the nitrate-nitrite-NO pathway. Available data indicates that total NO production by NOS-dependent L-arginine-NO pathway is about 1000 μmol.day^-1. Of about 1700 μmol.day^-1ingested nitrate, ~25 % is extracted by the salivary glands and of which ~20 % is converted nitrite. It means that about 5 % of ingested nitrate is converted to nitrite in the oral cavity; assuming that all produced nitrite is reduced to NO in the stomach, it can be calculated that contribution of the nitrate-nitrite-NO pathway to the whole-body NO production is about 85 μmol.day^-1(1700 ×0.05=85) or approximately 100 μmol.day^-1. The lower contribution of the nitrate-nitrite-NO pathway does not mean that this pathway has lower importance in the whole-body NO homeostasis. Even in the adequate L-arginine supply, NOS-dependent NO production is insufficient to meet all NO functions, and the nitrate-nitrite-NO pathway must provide the rest. In conclusion, the contribution of the nitrate-nitrite-NO pathway in the whole human body NO production is <10 %, and the nitrate-nitrite-NO pathway is complementary to the NOS-dependent NO production.

Evaluating the adverse outcome of subtypes of heart failure with preserved ejection fraction defined by machine learning

2022-01-10T08:37:02+01:00

The ability to distinguish clinically meaningful subtypes of heart failure with preserved ejection fraction (HFpEF) has recently been examined by machine learning techniques but studies appear to have produced discordant results. The objective of this study is to synthesize the types of HFpEF by examining their features and relating them to phenotypes with adverse prognosis. A systematic search was conducted using the search terms “Diastolic Heart Failure” OR “heart failure with preserved ejection fraction” OR “heart failure with normal ejection fraction” OR “HFpEF” AND “machine learning” OR “artificial intelligence” OR ‘computational biology’. Ten studies were identified and they varied in their prevalence of ten clinical variables: age, sex, body mass index (BMI) or obesity, hypertension, diabetes mellitus, coronary artery disease, atrial fibrillation, chronic kidney disease, chronic obstructive pulmonary disease or symptom severity (NYHA class or BNP). The clinical findings associated with the different phenotypes in > 85 % of studies were age, hypertension, atrial fibrillation, chronic kidney disease and worse symptoms severity; an adverse outcome was in 65 % to 85 % of studies identified diabetes mellitus and female sex and in less than 65 % of studies was body mass index or obesity, and coronary artery disease. COPD was a relevant factor in only 33 % of studies. Adverse clinical outcome – death or admission to hospital (for heart failure) defined phenogroups with the worst outcome. Combining the 4 studies that calculated the MAGGIC score showed a significant (p<0.05) linear relationship between MAGGIC score and outcome, using the one-year event rate. A new score based on strength of the evidence of the HFpEF studies analyzed here, using 9 variables (eliminating COPD), showed a significant (p<0.009) linear relationship with one-year event rate. Three studies examined biomarkers in detail and the ones most prominently related to outcome or consistently found in the studies were GDF15, FABP4, FGF23, sST2, renin and TNF. The dominant factors that identified phenotypes of HFpEF with adverse outcome were hypertension, atrial fibrillation, chronic kidney disease and worse symptoms severity. A new simplified score, based on clinical factors, was proposed to assess prognosis in HFpEF. Several biomarkers were consistently elevated in phenogroups with adverse outcomes and may indicate the underlying mechanism or pathophysiology specific for phenotypes with an adverse prognosis.

Molecular mechanisms linking stress and insulin resistance

2022-01-12T07:48:16+01:00

To date, there is ample evidence to support the strong relationship between stress and insulin resistance. While diabetes mellitus acts as a potent stress inducer, stress may be an upstream event for insulin resistance as well. It is widely recognized that diabetes mellitus is more prevalent among people who have a stressful lifestyle; however, the underlying mechanisms are not well understood. In the current study, we surveyed the scientific literature for possible interactions between stress and insulin resistance and found that stress can impair glucose homeostasis, working through at least six molecular pathways.

“Nano-ghosts”: Risk assessment of submicron-sized particles in food biased towards fictional “nano”

2022-01-05T15:35:02+01:00

Much confusion has been generated in the safety assessment of food-grade TiO₂ (E171) by the comingling of studies conducted on submicron-sized particles with those examining the toxicity of more minuscule counterparts. As E171 displays a nano-sized tail in its particle distribution (up to 36 % of particles with a diameter < 100 nm), it was thought that potential hazards of this food additive can be extrapolated from studies on thoroughly nanoscale formulations. This simplistic procedure may, however, overestimate the effects of the nano-sized tail of E171 because TiO₂ particles readily aggregate or agglomerate in aqueous suspensions and biological matrices. The resulting larger clusters display a reduced oral bioavailability in comparison to the same material in nano-sized dimensions. Also, even if taken up in trace amounts, the smaller particles likely remain appended to larger particles or clusters and these aggregates or conglomerates may nullify to a great extent their “nano” characteristics. The purpose of this review is, therefore, to reevaluate the literature on the toxicity of TiO₂ particles focusing on studies that are directly relevant for the assessment of E171. The purpose is not to avert a ban on the use of E171 in food, which might well be justified in light of the uncertainties associated with this additive employed solely for its colorant properties. Instead, it will be important to avoid in the future this same bias towards a fictional “nano” hazard, especially when evaluating more innovative engineered particles that confer true benefits for example by enhancing nutritional properties, quality, freshness, traceability or sustainability of food.

LOX-1: Implications in atherosclerosis and myocardial ischemia

2021-12-20T06:33:19+01:00

Understanding the pathophysiology of atherosclerosis is fundamental to the practice of cardiovascular medicine. Atherosclerosis is a multi-step cascade of accumulation of lipids and downstream changes that lead to a fibro-fatty plaque formation in the arterial intima. Multiple biochemical stimuli, cellular receptors and intra-cellular signals are implicated in this complex mechanism. Lectin-type oxidized LDL receptor-1 or LOX-1 is a type II membrane glycoprotein receptor which has emerged as an important effector of atherosclerosis. Hence, LOX-1 modification and its clinical consequences are of much interest in recent times.

Prognostic significance and therapeutic potentials of immune checkpoints in osteosarcoma

2021-10-05T12:22:23+02:00

Although there exist manifold strategies for cancer treatment, researchers are obliged to develop novel treatments based on the challenges that arise. One of these recent treatment approaches is cancer immunotherapy, which enjoys various types of strategies itself. However, one of the most significant methods, in this regard, is employing immune checkpoint proteins (ICPs). Bone sarcomas have several subtypes, with the most common ones being chordoma, chondrosarcoma, Ewing sarcoma, and osteosarcoma. Although many aggressive treatment approaches, including radiotherapy, chemotherapy, and surgical resection, have been employed over the last decades, significantly improved outcomes have not been observed for Ewing sarcoma or osteosarcoma patients. Additionally, chordoma and chdrosarcoma resist against both radiation and chemotherapy. Accordingly, elucidating how recent therapies could affect bone sarcomas is necessary. Checkpoint inhibitors have attracted great attention for the treatment of several cancer types, including bone sarcoma. Herein, the recent advances of current immune checkpoint targets, such as anti-PD-1/PD-L1 and anti-CTLA-4 blockade, for the treatment of bone sarcoma have been reviewed.

The effects of low-toxic herbicide Roundup and glyphosate on mitochondria

2021-12-14T07:06:01+01:00

The effects of pesticides on the health of non-target living organisms in agricultural areas are critically important aspects for their safe use. Their release into the environment is an inevitable aspect for predicting and evaluation of the risk of their application. Roundup, a glyphosate-based herbicide, has been designed as an effective pesticide against weeds and now is the most widely used agrochemicals around the world due to its highly specific action of the biosynthesis of certain amino acids in plants. Despite it is claimed to be low toxic for not-target organisms, due to its broad application Roundup and products of its degradation were detected in organisms of diverse animals and humans. In this review, we describe animal and human studies of general adverse effects of Roundup and its principal substance glyphosate with focus on endocrine disruption, oxidative stress and behavioral disorders. At mechanistic level, we focus on the potential toxicity of the herbicide Roundup and glyphosate as effectors of bioenergetic functions of mitochondria. Their effects on mitochondrial membrane potential and oxidative phosphorylation are among described to date critical components responsible for its toxicity. Finally, we discuss general molecular mechanisms potentially involved in the interaction between glyphosate and mitochondria which to some extent are associated with generation of reactive oxygen species.

Epidemiology and biology of early onset colorectal cancer

2021-12-08T08:24:23+01:00

Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in men or women in the United States. Average-risk screening that begins at age 50 years has reduced incidence and mortality of CRC in those over 50 years of age, whereas CRC incidence in those under age 50 years (early onset colorectal cancer (eoCRC)) has recently and dramatically increased. In this review, we summarize the recent literature including risk factors for eoCRC, differences in clinicopathologic presentation and outcomes in eoCRC, and emerging evidence regarding the molecular pathways that are altered in eoCRC compared to later onset CRC (loCRC). Epidemiologic studies of eoCRC show predominance in distal colon and rectum, and association with several modifiable risk factors, including diabetes, obesity, diet, sedentary time, alcohol consumption and smoking. Data regarding potential risk factors of prior antibiotic exposure and microbiome alterations or direct carcinogen exposure are still emerging. Aggressive clinicopathologic features of eoCRC at presentation may be due to delay in diagnosis or more aggressive tumor biology. EoCRC outcomes are similar to loCRC when matched for stage, but overall mortality is greater due to higher frequency of advanced disease at a younger presentation, with more life-years lost. There are only few molecular evaluations of eoCRC to date, with findings of potential increase in TP53 and CTNNB1 somatic mutation and decrease in APC, KRAS and BRAF somatic mutation, compared to loCRC. Other findings include LINE-1 hypomethylation, absence of microsatellite instability (MSI-H), presence of chromosomal instability (CIN) or microsatellite and chromosomal stability (MACS). These studies are only now emerging and have not yet identified a specific molecular signature defining eoCRC. Further research evaluating genetic and molecular differences as well as environmental triggers for eoCRCs should provide a clearer understanding to inform targeted screening for pre-symptomatic at-risk younger individuals.

Potential dual inhibitors of PCSK-9 and HMG-R from natural sources in cardiovascular risk management

2021-12-06T11:09:48+01:00

Atherosclerotic cardiovascular disease (ASCVD) stands amongst the leading causes of mortality worldwide and has attracted the attention of world’s leading pharmaceutical companies in order to tackle such mortalities. The low-density lipoprotein-cholesterol (LDL-C) is considered the most prominent biomarker for the assessment of ASCVD risk. Distinct inhibitors of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-R), the chief hepatic cholesterogenic enzyme, are being used since last seven decades to manage hypercholesterolemia. On the other hand, discovery and the association of proprotein convertase subtilisin/kexin type-9 (PCSK-9) with increased ASCVD risk have established PCSK-9 as a novel therapeutic target in cardiovascular medicine. PCSK-9 is well reckoned to facilitate the LDL-receptor (LDL-R) degradation and compromised LDL-C clearance leading to the arterial atherosclerotic plaque formation. The currently available HMG-R inhibitors (statins) and PCSK-9 inhibitors (siRNA, anti-sense oligonucleotides, and monoclonal antibodies) have shown great promises in achieving LDL-C lowering goals, however, their life long prescriptions have raised significant concerns. These deficits associated with the synthetic HMG-R and PCSK-9 inhibitors called for the discovery of alternative therapeutic candidates with potential dual HMG-R and PCSK-9 inhibitory activities from natural origins. Therefore, this report firstly describes the mechanistic insights into the cholesterol homeostasis through HMG-R, PCSK-9, and LDL-R functionality and then compiles the pharmacological effects of natural secondary metabolites with special emphasis on their dual HMG-R and PCSK-9 inhibitory action. In conclusion, various natural products exhibit atheroprotective effects via targeting HMG-R and PCSK-9 activities and lipoprotein metabolism, however, further clinical assessments are still warranted prior their approval for ASCVD risk management in hypercholesterolemic patients.

Large-scale comparative review and assessment of computational methods for phage virion proteins identification

2021-10-18T07:39:57+02:00

Phage virion proteins (PVPs) are effective at recognizing and binding to host cell receptors while having no deleterious effects on human or animal cells. Understanding their functional mechanisms is regarded as a critical goal that will aid in rational antibacterial drug discovery and development. Although high-throughput experimental methods for identifying PVPs are considered the gold standard for exploring crucial PVP features, these procedures are frequently time-consuming and labor-intensive. Thusfar, more than ten sequence-based predictors have been established for the in silico identification of PVPs in conjunction with traditional experimental approaches. As a result, a revised and more thorough assessment is extremely desirable. With this purpose in mind, we first conduct a thorough survey and evaluation of a vast array of 13 state-of-the-art PVP predictors. Among these PVP predictors, they can be classified into three groups according to the types of machine learning (ML) algorithms employed (i.e. traditional ML-based methods, ensemble-based methods and deep learning-based methods). Subsequently, we explored which factors are important for building more accurate and stable predictors and this included training/independent datasets, feature encoding algorithms, feature selection methods, core algorithms, performance evaluation metrics/strategies and web servers. Finally, we provide insights and future perspectives for the design and development of new and more effective computational approaches for the detection and characterization of PVPs.

Clinical presentation vs endoscopy for an early diagnosis of eosinophilic esophagitis

2022-03-23T07:47:06+01:00

Eosinophilic esophagitis (EoE) is a type-2 mediated, chronic inflammatory disease showing an increase of both incidence and prevalence. Early diagnosis is mandatory, to prevent fibrostenotic complication of the disease. Due to the low sensitivity of the classic endoscopic features of the disease, a strong clinical suspicion should drive the decision to collect mucosal biopsies of the esophagus. We describe the case of an atopic patient suffering from dysphagia with normal esophageal mucosa and frank histological hallmarks of the disease.

Use of intranasal esketamine in a girl with treatment-resistant depression and autism spectrum disorders

2022-02-08T07:16:42+01:00

Major depression is a common comorbidity in autism spectrum disorder (ASD), often difficult to identify and to treat. Autistic subjects are more at risk for suicidal thoughts and behaviors compared to typically developing peers. Unfortunately, ASD individuals are more frequently treatment-resistant and often show side-effects which reduce efficacy. Intranasal esketamine has been recently approved as an add-on medication for treatment-resistant depression (TRD), but it has never been used in ASD with comorbid major depression. Of note, a pilot study of intranasal ketamine has shown no effect on social withdrawal in ASD without depression. The present case report describes the first girl with ASD and comorbid TRD treated with intranasal esketamine.

Tryptophan recovery index as a new biomarker for fitness

2022-06-09T10:11:01+02:00

The maximal oxygen uptake (VO₂max) and maximal power output (P_max) are commonly used parameters to evaluate the endurance fitness status. A connection between exercise and the kynurenine pathway (KP), which describes the metabolism of unused tryptophan, has already been reported. However, a potential association of the KP with endurance fitness levels remains unknown. In this study, adolescent competitive athletes performed an exhaustive incremental exercise test. Blood samples were taken before, directly after, and 30 minutes after the end of exercise. Tryptophan (Trp), kynurenine (Kyn) and kynurenic acid (KA) serum levels were determined by high-performance liquid chromatography (HPLC). Forty-four male and 27 female athletes (median age: 16 years) were recruited. During exhaustive exercise tests, Trp initially declined and then increased 30 minutes after discontinuing exercise. Similar findings were observed for Kyn, whereas KA levels behaved inversely. After incremental exhaustive exercise the relative increase of Trp concentrations, termed the tryptophan-recovery-index (TRI), showed a highly significant positive correlation with VO₂max and P_max(r=0.468 and 0.491, p-values <0.001). There was a significant gender-difference with higher levels of all metabolites at all measured time points in male participants. In the present study, a highly significant correlation was found between the TRI and the maximal oxygen uptake in well-trained athletes. The implementation of TRI can therefore be suggested as a biomarker for physical fitness.

Transient receptor potential channel involvement in antinociceptive effect of citral in orofacial acute and chronic pain models

2022-06-01T07:48:37+02:00

This study aimed to test for the possible antinociceptive effect of the naturally occurring terpene citral in rodent models of acute and chronic orofacial pain and to test for the possible involvement of transient receptor potential (TRP) channels in this effect. Acute nociceptive behavior was induced in one series of experiments by administering formalin, cinnamaldehyde, menthol or capsaicin to the upper lip. Nociceptive behavior was assessed by orofacial rubbing, and the effects of pre-treatment with citral (0.1, 0.3 or 1.0 mg/Kg) or vehicle (control) were tested on the behavior. Nociceptive behavior was also induced by formalin injected into the temporomandibular joint or mustard oil injected into the masseter muscle, preceded by citral or vehicle (control) treatment. The chronic pain model involved infraorbital nerve transection (IONX) that induced mechanical hypersensitivity which was assessed by von Frey hair stimulation of the upper lip. Motor activity was also evaluated. Docking experiments were performed using TRPV1 and TRPM8 channels. Citral but not vehicle produced significant (p<0.01, ANOVA) antinociception on all the acute nociceptive behaviors, and these effects were attenuated by TRPV1 antagonist capsazepine, TRPM3 antagonist mefenamic acid and by TRPM8 desensitization, but not by ruthenium red and TRPA1 antagonist HC-030031. The IONX animals developed facial mechanical hypersensitivity that was significantly reduced by citral but not by vehicle. The docking experiments revealed that citral may interact with TRPV1 and TRPM8 channels. These results indicate the potential use of citral as an inhibitor of orofacial nociception in both acute and chronic pain states through TRPV1, TRPM3 and TRPM8 channels.

Integrated bioinformatics analysis reveals that EZH2-rich domains promote transcriptional repression in cervical cancer

2022-05-11T13:48:07+02:00

Cervical cancer is the third female cancer most common worldwide. The carcinogenic process involves an alteration of the mechanisms associated with transcription. Several studies have reported an oncogenic role of the polycomb complex subunit, EZH2. However, the role of EZH2 in cervical cancer is unknown. Hence, the objective of this study was to determine the role of EZH2 in transcriptional regulation in cervical cancer. The EZH2 expression and the methylation status of its promoter were analyzed in The Cancer Genome Atlas. The EZH2 enrichment profile was analyzed using chromatin immunoprecipitation with massively parallel DNA sequencing data provided by ENCODE project. The chromatin compartments were identified in the 4D Nucleome Data Portal. The functional annotation was examined in Enrichr. We report that EZH2 expression is increased in cervical cancer which is associated with hypomethylation of its promoter. EZH2 is enriched at promoter and distal intergenic regions. We identified that EZH2 defines chromatin domains enriched with H3K27me3 within repressive compartments in the HeLa-S3 cell line. Additionally, high EZH2 expression is associated with the repression of the senescent phenotype in cervical cancer patients. Our results suggest the participation of EZH2 in the generation of domains with a silencer function in cervical cancer, which regulate the expression of genes associated with cellular senescence.

Immunomodulatory components of Trichinella spiralis excretory-secretory products with lactose-binding specificity

2022-05-02T12:40:42+02:00

The immunomodulatory potential of Trichinella spiralis muscle larvae excretory-secretory products (ES L1) has been well documented in vitro on dendritic cells (DCs) and in animal models of autoimmune diseases. ES L1 products possess the potential to induce tolerogenic DCs and consequently trigger regulatory mechanisms that maintain immune homeostasis. The use of ES L1 as a potential treatment for various inflammatory disorders proved to be beneficial in animal models, although the precise immunomodulatory factors have not yet been identified. This study aimed at the isolation and characterization of ES L1 components that possess galectin family member properties. Galectin-1-like proteins (TsGal-1-like) were isolated from ES L1 based on the assumption of the existence of a lactose-specific carbohydrate-recognition domain and were recognized by anti-galectin-1 antibodies in Western blot. This TsGal-1-like isolate, similar to galectin-1, induced DCs with tolerogenic properties and hence, the capacity to polarize T cell response towards a regulatory type. This was reflected by a significantly increased percentage of CD4⁺CD25⁺Foxp3⁺ regulatory T cells and significantly increased expression of IL-10 and TGF-β within this cell population. Proteomic analysis of TsGal-1-like isolate by mass spectrometry identified nineteen proteins, seven with annotated function after blast analysis against a database for T. spiralis and the UniProt database. To our surprise, none of the identified proteins possesses homology with known galectin family members. Nevertheless, the isolated components of ES L1 possess certain galectin-1 properties, such as specific lactose binding and the potential to elicit a regulatory immune response, so it would be worth further investigating the structure of sugar binding within isolated proteins and its biological significance.

Plasma lncRNA profiling identified BC200 and NEAT1 lncRNAs as potential blood-based biomarkers for late-onset Alzheimer’s disease

2022-04-20T11:39:04+02:00

Long non-coding RNAs (lncRNA) play critical roles in pathogenesis of neurodegenerative diseases. Human plasma carries lncRNAs that are stable in the blood, and their disease-specific profile have made them valuable biomarkers for some diseases. This study reports screening of the plasma levels of 90 lncRNAs in patients with Alzheimer disease (AD) to find out plasma-based AD biomarkers. Total RNA was isolated from plasma samples of 50 AD and 50 matched healthy controls. The plasma samples of 10 advanced AD patients and 10 matched healthy controls were screened for expression levels of 90 lncRNAs using Human LncRNA Profiler qPCR Array Kit (SBI). Based on the profiling results, lncRNAs BC200, NDM29, NEAT1, FAS-AS1 and GAS5-AS1 were selected for further analysis in all samples and their biomarker potency was evaluated by ROC curve analysis. We further surveyed RNAseq data by in silico analysis. We found that the NEAT1 and BC200 levels in the plasma of the AD patients were significantly higher compared with the control group (P=0.0021, p= 0.02, respectively). ROC curve analysis showed that the plasma level of NEAT1 and BC200 discriminated AD patients from healthy controls with sensitivity of 72 % and 60 %, and specificity of 84 % and 91 % respectively. Moreover, NEAT1 discriminated MCI (60 % sensitivity and 91 % specificity) and advanced-AD patients from healthy controls (73 % sensitivity and 71 % specificity). Besides, plasma level of BC200 discriminated the pre-clinical subjects from healthy controls with 83 % sensitivity and 66 % specificity. A positive correlation was also observed between plasma levels of BC200 with the age patients (r = 0.34, p=0.02). In silico RNAseq data analysis showed that a total of 33 lncRNAs were up-regulated but 13 lncRNAs were down-regulated significantly in AD patients compared with the healthy controls. In conclusion, this study elucidated that the plasma levels of lncRNAs NEAT1 and BC200 might be considered as potential blood-based biomarkers for AD development and progression.

Ergonomic assessment of postal workers’ pain symptoms and musculoskeletal risks related to parcel processing activity for delivery

2022-04-12T08:35:51+02:00

The parcel delivery activity is carried out all over the world and workers in this sector have suffered from musculoskeletal disorders (MSDs) due to the strong demand for work generated by the recent increase in e-commerce. This study aimed to evaluate postal workers' pain symptoms, movements and identify MSDs risks related to the parcel processing activity for delivery, proposing preventive measures. A sample of thirty-two workers was evaluated with the application of sociodemographic and Nordic questionnaires and electrical bioimpedance. The motion capture sensors were used to evaluate right/left shoulder joints, segment C7-T1 (Cervical) and segment L5-S1 (Lumbar) of three postal workers (percentiles of anthropometric data: 5, 50, and 95) during four real work activities that are part of the parcel processing. The analyzed workers presented musculoskeletal complaints in practically all body regions, with a greater prevalence in shoulders, hands, lower back, and knees. According to the Body Mass Index (BMI), they were on average overweight (27.8 ± 3.7 kg/m²). In the movement analysis, we identified risks related to cervical protrusion, anterior trunk flexion, and shoulder flexion, in addition to repetitive movements. In some activities, the higher stature showed an increase in lumbar and cervical anterior flexion. The set of evaluations showed that the activity of processing orders for delivery offers musculoskeletal risks. We identify that ergonomic adaptations are necessary to adapt the heights of the work environment to the statures of the postal workers. Relevance to industry: The activity of processing orders for delivery is carried out practically all over the world generating jobs and income for its employees. Nonetheless, there are still situations of ergonomic disadvantage that can generate musculoskeletal risks. The findings elucidate ergonomic risks and provide useful information for future ergonomic interventions in the postal/delivery workplace environment.

Cytotoxic capability and the associated proteomic profile of cell-free coelomic fluid extracts from the edible sea cucumber Holothuria tubulosa on HepG2 liver cancer cells

2022-04-13T06:11:56+02:00

Hepatocellular carcinoma (HCC) is an aggressive cancer histotype and one of the most common types of cancer worldwide. The identification of compounds that might intervene to restrain neoplastic cell growth appears imperative due to its elevated overall mortality. The marine environment represents a reservoir rich in bioactive compounds in terms of primary and secondary metabolites produced by aquatic animals, mainly invertebrates. In the present study, we determined whether the water-soluble cell-free extract of the coelomic fluid (CFE) of the edible sea cucumber Holothuria tubulosa could play an anti-HCC role in vitro by analyzing the viability and locomotory behavior, cell cycle distribution, apoptosis and autophagy modulation, mitochondrial function and cell redox state of HepG2 HCC cells. We showed that CFE causes an early block in the cell cycle at the G₂/M phase, which is coupled to oxidative stress promotion, autophagosome depletion and mitochondrial dysfunction ultimately leading to apoptotic death. We also performed a proteomic analysis of CFE identifying a number of proteins that are seemingly responsible for anti-cancer effects. In conclusion, H. tubulosa’s CFE merits further investigation to develop novel promising anti-HCC prevention and/or treatment agents and also beneficial supplements for formulation of functional foods and food packaging material.

Transplantation of SDF-1α-loaded liver extracellular matrix repopulated with autologous cells attenuated liver fibrosis in a rat model

2022-04-20T07:16:06+02:00

Cell-based therapy and tissue engineering are promising substitutes for liver transplantation to cure end-stage liver disorders. However, the limited sources for healthy and functional cells and poor engraftment rate are main challenges to the cell-based therapy approach. On the other hand, feasibility of production and size of bioengineered tissues are primary bottlenecks in tissue engineering. Here, we induce regeneration in a rat fibrotic liver model by transplanting a natural bioengineered scaffold with a native microenvironment repopulated with autologous stem/progenitor cells. In the main experimental group, a 1 mm³ stromal derived factor-1α (SDF-1α; S) loaded scaffold from decellularized liver extracellular matrix (LEM) was transplanted (Tx) into a fibrotic liver and the endogenous stem/progenitor cells were mobilized via granulocyte colony stimulating factor (G-CSF; G) therapy. Four weeks after transplantation, changes in liver fibrosis and necrosis, efficacy of cell engraftment and differentiation, vasculogenesis, and liver function recovery were assessed in this (LEM-TxSG) group and compared to the other groups. We found significant reduction in liver fibrosis stage in the LEM-TxSG, LEM-TxS and LEM-TxG groups compared to the control (fibrotic) group. Liver necrosis grade, and alanine transaminase (ALT) and aspartate transaminase (AST) levels dramatically reduced in all experimental groups compared to the control group. However, the number of engrafted cells into the transplanted scaffold and ratio of albumin (Alb) positive cells per total incorporated cells were considerably higher in the LEM-TxSG group compared to the LEM-Tx, LEM-TxS and LEM-TxG groups. Serum Alb levels increased in the LEM-Tx, LEM-TxS, and LEM-TxG groups, and was highest in the LEM-TxSG group, which was significantly more than the fibrotic group. Small vessel formation in the LEM-TxSG group was significantly higher than the LEM-Tx and LEM-TxS groups. Totally, these findings support application of the in vivo tissue engineering approach as a possible novel therapeutic strategy for liver fibrosis.

Medical history, medication use and physical activity in adults in their eighth and ninth decade of life in the Hertfordshire Cohort Study

2022-04-11T10:15:41+02:00

While there are many known health benefits to maintained physical activity levels in late adulthood, there have been very few studies that have considered relationships between morbidity profile and physical activity in the eighth decade of life. We studied 1097 participants, 555 men and 542 women from the Hertfordshire Cohort Study, a UK community based sample. Validated questionnaire based data were used to relate self-reported physical activity (PA) levels to medical history, and medication use. Regression analyses were adjusted for age, BMI, smoker status, alcohol consumption. The mean (SD) age of participants in the study was 80.2 (2.7) years for men and 80.2 (2.6) for women. A higher proportion of men (33.7 %) than women (24 %) were in the high activity score group. 20.8 % of female participants and 22.6 % male participants reported having no comorbid disease; 10.5 % men and 8.4 % women were taking no medication. Higher number of chronic conditions was associated with lower levels of PA [men (OR 0.73, 95 % CI 0.63-0.84, p<0.001); women (OR 0.74, 95 % CI 0.64-0.86, p<0.001)] as was being prescribed a higher number of medications [men (OR 0.88, 95 % CI 0.84-0.93, p<0.001); women (OR 0.86, 95 % CI 0.82-0.91, p<0.001)]. All these associations remained robust following adjustments. Strong relationships were seen in both sexes between PA and taking medication for disorders of the central nervous system and gastrointestinal system, with relationships generally stronger in men. We have observed relationships between comorbid medical history and medication use with physical activity in a cohort of community dwelling older adults. These highlight the need to consider medical history when considering how best to optimize PA in older adults.

The “identikit” of subject with obesity and COVID-19 vaccine breakthrough

2022-03-24T10:12:40+01:00

The mRNA coronavirus disease 2019 (COVID-19) vaccines were highly effective in the prevention of symptomatic COVID-19, hospitalization, severe disease, and death. However, a minority of vaccinated individuals might become infected and experience significant morbidity. Risk factors of COVID-19 vaccine breakthrough in obesity have not been elucidated. Thus, we aimed to portray the subjects with obesity developing COVID-19 vaccine breakthrough despite vaccination. Coronavirus 2019 (COVID-19) mRNA vaccines have been highly effective in preventing symptomatic COVID-19, hospitalization, severe illness and death. However, a minority of vaccinated individuals may become infected and experience considerable morbidity. The risk factors for COVID-19 vaccine breakthrough in obesity have not been elucidated. Therefore, we aimed to depict individuals with obesity who develop COVID-19 vaccine breakthrough despite vaccination. An online questionnaire was distributed to respondents via a snowball sampling method among subjects with obesity belonging to Italian Associations for people living with obesity aged 18 years and above. Two hundred and thirty-five respondents (44.5±14 years; BMI: 33.3±7.2 kg/m²) were included in the study. COVID-19 vaccine breakthrough was noted in 34 % of respondents. A higher prevalence of grade III obesity was detected in subjects with COVID-19 vaccine breakthrough compared to subjects that did not (27.5 % vs 13.5 %; p=0.014). In addition, a significant lower prevalence of respondents that completed third dose were found in respondents with COVID-19 vaccine breakthrough compared with respondents that did not develop it (33.8 % vs 72.9 %; p<0.001). After stratifying respondents with COVID-19 vaccine breakthrough according to the completed doses of vaccine, we found that, although no differences were detected in terms of clinical manifestations of COVID-19, there was a significant higher prevalence of type 2 diabetes and hypertension in respondents that completed third doses compared to respondents that completed first and second doses. In conclusion, COVID-19 vaccine breakthrough was more common in subjects with grade III obesity. The presence of type 2 diabetes and hypertension could counteract the immune potentiating effects of vaccine booster against COVID-19.

The diaryl-imidazopyridazine anti-plasmodial compound, MMV652103, exhibits anti-breast cancer activity

2022-03-24T07:19:59+01:00

Breast cancer is the most common malignancy in women worldwide and it remains a global health burden, in part, due to poor response and tolerance to current therapeutics. Drug repurposing, which seeks to identify new indications for existing and investigational drugs, has become an exciting strategy to address these challenges. Here we describe the anti-breast cancer activity of a diaryl-imidazopyridazine compound, MMV652103, which was previously identified for its anti-plasmodial activity. We demonstrate that MMV652103 potently inhibits the oncogenic PI4KB and PIK3C2G lipid kinases, is selectively cytotoxic to MCF7 and T47D estrogen receptor positive breast cancer cells and inhibits their ability to survive and migrate. The underlying mechanisms involved included the induction of reactive oxygen species and activation of the DNA damage and p38 MAPK stress signaling pathways. This was associated with a G1 cell cycle arrest and an increase in levels of the cyclin-dependent kinase inhibitor p21 and activation of apoptotic and autophagic cell death pathways. Lastly, MMV652103 significantly reduced the weight and metastases of MCF7 induced tumors in an in vivo chick embryo model and displayed a favorable safety profile. These findings position MMV652103 as a promising chemotherapeutic in the treatment of oestrogen receptor positive breast cancers.

Analyzing the interaction of human ACE2 and RBD of spike protein of SARS-CoV-2 in perspective of Omicron variant

2022-02-23T15:59:37+01:00

The newly identified Omicron (B.1.1.529) variant of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has steered concerns across the world due to the possession of a large number of mutations leading to high infectivity and vaccine escape potential. The Omicron variant houses 32 mutations in spike (S) protein alone. The viral infectivity is determined mainly by the ability of S protein Receptor Binding Domain (RBD) to bind to the human Angiotensin I Converting Enzyme 2 (hACE2) receptor. In this paper, the interaction of the RBDs of SARS-CoV-2 variants with hACE2 was analyzed by using protein-protein docking and compared with the novel Omicron variant. Our findings reveal that the Omicron RBD interacts strongly with hACE2 receptor via unique amino acid residues as compared to the Wuhan and many other variants. However, the interacting residues of RBD are found to be the same in Lamda (C.37) variant. This unique binding of Omicron RBD with hACE2 suggests an increased potential of infectivity and vaccine evasion potential of the new variant. The evolutionary drive of the SARS-CoV-2 may not be exclusively driven by RBD variants but surely provides for the platform for emergence of new variants.

Low-toxic herbicides Roundup and Atrazine disturb free radical processes in Daphnia in environmentally relevant concentrations

2022-02-14T09:27:20+01:00

The use of glyphosate-based Roundup and triazine herbicide Atrazine has increased markedly in last decades. Thus, it is important to evaluate toxic effects of these herbicides to non-targeted organisms such as zooplankton to understand their safety toward aquatic ecosystems. In the current study, we performed Daphnia toxicity tests based on lethality to identify LC₅₀ that provides acute aquatic toxicity classification criteria. LC₅₀ for Roundup exposure for 24 hours was found to be 0.022 mg/L and 48 hours - 0.0008 mg/L. Atrazine showed LC₅₀ at concentrations of 40 mg/L and 7 mg/L for 24 and 48 hours, respectively. We demonstrated that exposure to ecologically relevant concentrations of Roundup or Atrazine decreases lipid peroxidation and protein thiol levels, however caused increase in carbonyl protein and low-molecular-weight thiols content. Moreover, the herbicide treatments caused increase of superoxide dismutase activity. Our data suggest that at very low concentrations Roundup and Atrazine disturb free radical processes in D. magna.

Analysis of hematological parameters in rheumatoid arthritis patients receiving biological therapy

2022-02-21T07:58:18+01:00

Administration of biological therapy (BT) in rheumatoid arthritis (RA) patients is often associated with hematological complications, which result in switching among therapies. Thus, there is an instant need for suitable screening parameters that will help to individualize the therapy and minimize the onset of adverse effects. We analyzed the hematological profile of 99 RA patients receiving TNFα (Adalimumab - ADA, Golimumab - GOL, Etanercept - ETA) or IL-6 receptor (Tocilizumab - TCZ) inhibitors in order to find possible indicators to improve personalization of RA therapy. BTs significantly affect the levels of observed hematological parameters. In contrast to TNF-α inhibitors, TCZ normalized almost all monitored hematological parameters to values of healthy donors. Only GOL from the TNF-α inhibitors studied, was able to normalize neutrophil counts, as well as platelet indicators. Importantly, effects on the blood parameters (e.g. lymphocytes or platelet count) differ even within the same therapeutic group (anti-TNFα). Variable effects of individual biological agents in RA treatment point to importance to evaluate the patient’s hematological profile to improve the selection of suitable BT. It will help to personalize the administration of BT and prevent unnecessary switching from an effective therapy just because of provocation of avoidable hematological complications.

Hypoxia-inducible factor (HIF)-3α2 serves as an endothelial cell fate executor during chronic hypoxia

2022-02-07T10:20:46+01:00

The adaptive response to hypoxia involves the transcriptional induction of three transcription factors called hypoxia inducible factor alpha 1, 2 and 3 (HIF-1α, HIF-2α, and HIF-3α) which dimerize with constitutively expressed beta chains that together form the HIF-1, -2 and -3 transcription factors. During normoxic conditions, the alpha chain is expressed at low levels since its stability is regulated by prolyl-hydroxylation that promotes subsequent ubiquitination and degradation. During hypoxic conditions, however, the prolyl hydroxylases are less active, and the alpha chain accumulates through elevated protein stability and the elevated induction of expression. Two of the three HIFs isoforms present in mammals, HIF-1 and HIF-2, are well characterized and have overlapping functions that promote cell survival, whereas HIF-3’s role remains less clear. The HIF-3 response is complicated because the HIF3A gene can utilize different promotors and alternate splicing sites that result in a number of different HIF-3α isoforms. Here, using human umbilical vein endothelial cells (HUVECs), we demonstrate that one of the isoforms of HIF-3α, isoform 2 (HIF-3α2) accumulates at a late stage of hypoxia and induces the expression of DNA damage inducible transcript 3 (DDIT4), a gene known to promote apoptosis. We also demonstrate that caspase 3/7 activity is elevated, supporting that the role of the HIF-3α2 isoform is to promote apoptosis. Furthermore, we provide evidence that HIF-3α2 is also expressed in seven other primary endothelial cell types, suggesting that this may be a common feature of HIF-3α2 in endothelial cells.

IKBKE-driven TPL2 and MEK1 phosphorylations sustain constitutive ERK1/2 activation in tumor cells

2022-02-14T08:11:33+01:00

IKBKE have been associated with numerous cancers. As a result, IKBKE have emerged as potential target for cancer therapy. Accumulating evidence support that IKBKE orchestrate tumor cell survival in cancers. Here we evaluated the possible link between IKBKE and ERK phosphorylation. The effects of IKBKE silencing on MAPK activation in tumor vs. normal cells were evaluated via WB and RT-PCR. Ectopically expressed IKBKE, TPL2 or MEK1 constructs were used to examine the possible interactions among them via co-IP. In vitro kinase assays were performed to understand nature of the observed interactions. In tumors, IKBKE regulates MEK/ERK constitutive activations in vitro and in vivo. IKBKE and TPL2 physically interact and this interaction leads to TPL2 phosphorylation. We describe here a novel regulatory link between IKBKE and constitutive ERK1/2 activation in tumor cells. This new circuitry may be relevant for tumor cell survival in various malignancies.

Helicobacter pylori infection and lactose intolerance increase expiratory hydrogen

2022-02-09T07:36:13+01:00

Infection with Helicobacter pylori (H.pylori) may cause dyspepsia and/or unexplained functional nonspecific, gastrointestinal complaints of the irritable bowel syndrome (IBS) spectrum. Hitherto, in H. pylori infected patients with symptoms of the IBS spectrum the occurrence of additional food intolerance/malabsorption is not evaluated. We used a retrospective analysis of charts from 548 patients who presented with gastrointestinal complaints of the irritable bowel syndrome spectrum. An enzyme-linked IgA immunosorbent assay or histologic evaluation of gastric mucosa were used to detect H. pylori infection. A hydrogen breath (H₂) test was performed to evaluate fructose malabsorption (FM) and lactose intolerance (LIT). Serum diamine oxidase value of <10 U/ml and a response to a histamine-reduced diet was used to identify histamine intolerance (HIT). We found 293 patients infected with H. pylori, within these were 58 H. pylori patients with LIT, 23 H. pylori LIT patients with FM and 46 H. pylori LIT patients with HIT. Additionally, 13 H. pylori, lactose- and histamine intolerance patients also had FM. The Kruskal Wallis test and pairwise comparison were used to analyze differences of the area under the curve of expiratory hydrogen. In lactose H₂ breath tests compared with LIT-only patients, LIT with H. pylori, LIT and H. pylori with HIT, LIT and H. pylori with FM showed significantly higher exhaled H₂ levels (p=0.022). Pairwise comparison demonstrated H. pylori infected patients with LIT exhaled more H₂ compared to LIT-only (p=0.029). H. pylori with lactose- and histamine intolerance, and H. pylori with lactose-, histamine intolerance and FM compared to H. pylori-only patients indicated a significantly higher occurrence of stomach pain during lactose H₂ breath tests (p=0.012 and p=0.005, respectively). We demonstrate that LIT patients with high expiratory H₂ levels in lactose breath tests may have H. pylori infection and possibly additional food intolerance/malabsorption. Subsequently, besides H. pylori eradication, a dietician is necessary for an individually tailored reduction- or exclusion diet of symptom triggering food components.

Molecular docking and mouse modeling suggest CMKLR1 and INSR as targets for improving PCOS phenotypes by minocycline

2022-02-07T14:33:09+01:00

Polycystic ovary syndrome (PCOS) is the most common cause of women’s infertility. Some inflammatory pathways play a pivotal role in the pathogenesis of PCOS. This study aimed to investigate the possible beneficial effects of minocycline on chemokine-like receptor 1 (CMKLR1) and Insulin Receptor (INSR) in a PCOS model. A molecular docking study was implemented using Molecular Operating Environment (MOE) software. The PCOS was induced in NMRI mice (mean body weight 14.47±0.23) by 28 days estradiol valerate injection (2 mg/kg/day). The mice were then divided into six groups (n=8 per group, mean body weight 17.77± 0.26): control (received normal saline), PCOS model, control for minocycline, minocycline treated PCOS (50 mg/kg), letrozole treated PCOS (0.5 mg/kg), and metformin-treated PCOS (300 mg/kg). Serum FSH, LH, estradiol (E2), and testosterone were detected by ELISA. The ovarian tissues were stained by hematoxylin and eosin. The CMKLR1 and INSR expression levels were determined by Real-time-PCR. The molecular docking studies showed scores of -10.92 and -9.30 kcal/mol, respectively, for minocycline with CMKLR1 and INSR. Estradiol valerate treatment led to a significant increase in E2, graffian follicle, and decrease in corpus luteum (CL) numbers (P<0.05), while minocycline treatment improved these PCOS features. The minocycline treatment significantly decreased the CMKLR1 expression and increased the INSR expression (P<0.05) while the CMKLR1 expression was increased in PCOS model. Minocycline may improve ovulation in PCOS model by returning E2 to a normal level and increasing CL number (ovulation signs). These beneficial outcomes may be related to the changes in CMKLR1 and INSR gene expression involved in glucose metabolism and inflammation.

Phlomis fruticosa L. exerts in vitro antineurodegenerative and antioxidant activities and induces prooxidant effect in glioblastoma cell line

2022-02-07T10:07:33+01:00

Despite the significant advances in drug development we are witnessing the inability of health systems to combat both neurodegenerative diseases and cancers, especially glioblastoma. Hence, natural products are comprehensively studied in order to provide novel therapeutic options. This study aimed to explore anti-neurodegenerative and anti-glioblastoma potential of extract of Phlomis fruticosa L. using in vitro model systems. It was found that the methanol extract of P. fruticosa was able to efficiently reduce activities of enzymes linked to neurodegenerative disease including acetylcholinesterase, butyrylcholinesterase and tyrosinase. Furthermore, P. fruticosa extract has shown excellent antioxidant potential, as evidenced by six different methods. Analysis of cytotoxic effect of P. fruticosa extract on A172 glioblastoma cell line revealed that the concentration of the extract necessary for 50 % inhibition of A172 growth (IC₅₀) was 710 μg/mL. The extract did not induce changes in proliferation and morphology of A172 glioblastoma cells. On the other side, production of ROS was increased in A172 cells treated with the extract. Observed cytotoxic effect of P. fruticosa extract might be based on increase in ROS generation upon treatment. Quantitative chemical analysis revealed the presence of twelve different polyphenols with the cis 3-O-caffeoylquinic acid being the most abundant. This study provided scientific evidence for further exploration of P. fruticosa as a promising natural anti-neurodegenerative therapeutic option.

Synthesis of acetamidosulfonamide derivatives with antioxidative and QSAR studies

2022-01-09T12:03:25+01:00

A series of sixteen acetamidosulfonamide derivatives (1-16) have been synthesized and investigated for their antioxidant (radical scavenging and superoxide dismutase (SOD)) and antimicrobial activities. Most compounds exhibited antioxidant activities in which compound 15 displayed the most potent radical scavenging and SOD activities. Quantitative structure-activity relationship (QSAR) has been studied using multiple linear regression. The constructed QSAR models displayed high correlation coefficient (Q²/_Loo-CV= 0.9708 and 0.8753 for RSA and SOD activities, respectively), but low root mean square error (RMSE_LOO-CV= 0.5105 and 1.3571 for RSA and SOD activities, respectively). The structure-activity relationship showed that an ethylene group connected to pyridine ring provided significant antioxidant activities. The QSAR models give insight into the rational designed of eighty new sulfonamides with various electron donating and withdrawing groups. The top five new designed sulfonamides with nitro group are potential antioxidants to be further developed for medicinal applications.

How to keep up with the analysis of classic and emerging neurotoxins: Age-resolved fitness tests in the animal model Caenorhabditis elegans

2022-01-17T10:59:11+01:00

The global chemical inventory includes neurotoxins that are mostly interrogated concerning the biological response in developing organisms. Effects of pollutants on adults receive less attention, although vulnerabilities can be expected throughout the entire life span in young, middle-aged and old individuals. We use the animal model Caenorhabditis elegans to systematically quantify neurological outcomes by application of an age-resolved method. Adult hermaphrodite worms were exposed to pollutants or non-chemical stressors such as temperature in liquid culture on microtiter plates and locomotion fitness was analyzed in a whole-life approach. Cultivation at 15, 20 or 25 °C showed that worms held at 15 °C displayed an enhanced level of fitness concerning swimming movements until middle age (11-days-old) and then a decline. In contrast, C. elegans cultivated at ≥ 20 °C continually reduced their swimming movements with increasing age. Here, we provide a step-by-step protocol to investigate the health span of adult C. elegans that may serve as a platform for automation and data collection. Consistent with this, more neurotoxins can be investigated with respect to vulnerable age-groups as well as contributing non-chemical environmental factors such as temperature.

Ultrasound–guided posterior quadratus lumborum block for postoperative pain control after minimally invasive radical prostatectomy

2022-01-13T09:47:01+01:00

A minimally invasive approach to radical prostatectomy offers improved ambulation and discharge times. Postoperative pain control is one of the key factors that facilitates rapid recovery. With the aim to assure adequate analgesia and minimize the use of opioids, application of truncal nerve blocks has been proposed in a number of endoscopic procedures. The aim of this double-blind, placebo-controlled study was to evaluate the efficacy of bilateral posterior quadratus lumborum block (pQLB) in alleviating pain and reducing postoperative opioid demand in patients following endoscopic extraperitoneal and laparoscopic prostatectomy. We enrolled 50 patients who were diagnosed with prostate cancer and scheduled for prostatectomy. They were randomized to receive preoperative, ultrasound-guided pQLB with the use of either 30 ml of 0.375 % ropivacaine (ropivacaine group) or 30 ml of 0.9 % NaCl (placebo group). Our primary endpoint was opioid consumption in the first 24 hours after surgery. Secondary endpoints were pain intensity at predefined timepoints and the incidence of nausea and vomiting and pruritus. No differences were detected between the ropivacaine and placebo groups in intravenous oxycodone consumption during the first 24 hours after surgery. Similarly, there were no differences in pain intensity at any of the timepoints assessed. The rate of nausea and vomiting was equal in both groups and pruritus was not observed. Application of bilateral pQLB does not reduce opioid consumption after minimally invasive prostatectomy.

Pupil size as an indicator of cognitive activity in mild Alzheimer’s disease

2022-01-09T11:54:04+01:00

It is well established that pupil activity indexes cognitive processing. For instance, research has consistently demonstrated that the pupil reacts to working memory span task performance. However, little is known about pupil reaction to cognitive processing in Alzheimer’s Disease (AD). We thus investigated whether span tasks can modulate pupil size in patients with AD. We invited 24 patients with AD and 24 healthy older adults to perform backward and forward spans, as well as to count aloud in a control condition, while their pupil activity was recorded with eye tracking glasses. In patients with AD, analysis demonstrated larger pupil size during backward spans (M = 2.12, SD = .39) than during forward spans (M = 1.98, SD = .36) [t(23) = 3.22, p = .004], larger pupil size during forward spans than during counting (M = 1.67, SD = .33) [t(23) = 4.75, p < .001], as well as larger pupil size during backward spans than during counting [t(23) = 10.60, p < .001]. In control participants, analysis demonstrated larger pupil size during backward spans (M = 3.36, SD = .49) than during forward spans (M = 2.85, SD = .68) [t(23) = 5.82, p < .001], larger pupil size during forward spans than during counting (M = 2.09, SD = .62) [t(23) = 5.42, < .001], as well as larger pupil size during backward spans than during counting [t(23) = 9.70, p < .001]. Results also demonstrated a significant interaction effect between groups and conditions [F(2,92) = 16.63, p < .001]; in other words, patients with AD have shown fewer variations on the pupil size across the conditions compared to the control participants. The larger pupil size during backward spans, compared with forward spans or counting, can be attributed to the high cognitive load of backward spans. The modulation of pupil size, as observed across backward/forward spans and counting, can possibly be attributed to sympathetic/adrenergic and parasympathetic/cholinergic activities. Our study demonstrates the value of pupillometry as a potential biomarker of cognitive processing in AD.

Inconsistent eating time is associated with obesity

2022-01-03T07:03:54+01:00

Obesity is characterized by an accumulation of redundant body fat linked to metabolic dysregulation and low-grade systemic inflammation. Lifestyle choices are imperative determining factors of obesity. The contemporary lifestyle is associated with behaviors that disrupt circadian rhythms, impacting metabolic homeostasis. Our animal and human studies suggest that circadian phenotypes could be related to the risk of metabolic dysregulation and obesity. The purpose of this study is to examine the role of inconsistent eating habits on body weight in adults. Individuals who presented for colon cancer screening were enrolled. Subjects received structured questionnaires to capture 7-day eating and sleeping times in a week prospectively. Bodyweight and height were extracted from medical records, and Body Mass Index (BMI) was calculated. Inconsistent eating times were defined as an average difference of >2 hours between the largest meal on weekdays and weekends. Forty-nine of the 61 (80.3 %) individuals enrolled in the study completed the questionnaires. The mean age and standard deviation (SD) were 60.8 (7.9), and 27 (55.1 %) were male. Subjects with inconsistent eating times had a significantly higher BMI (33.8 ± 3.6 SD, n = 9) than subjects who did not (27.5 ± 6.5 SD, n = 40; p = 0.001). The highest BMI was observed in subjects who ate inconsistently and late (35.8 ± 4.6 SD). In this cross-sectional study, time of eating habits was associated with BMI. Controlled cohort studies are needed to determine the potential link between eating time and the risk of obesity in the long term.

Enhancing the efficacy of albendazole for liver cancer treatment using mesoporous silica nanoparticles

2021-12-16T07:10:15+01:00

The present study aimed to synthesize albendazole (ABZ)-loaded Mobil Composition of Matter No. 41 (MCM-41 NPs) to increase the efficacy of the drug against liver cancer. ABZ was loaded into MCM-41 NPs, and after in vitro characterization, such as size, size distribution, zeta potential, morphology, chemical composition, thermal profile, drug release, surface and pore volume, and pore size, their biological effects were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) cell migration assays. The results demonstrated that monodispersed and spherical NPs with a size of 220 ± 11.5 and 293 ± 8.7 nm, for MCM-41 NPs and ABZ-loaded MCM-41 NPs, respectively, and drug loading efficiency of 30 % were synthesized. ABZ was loaded physically into MCM-41 NPs, leading to a decrease in surface volume, pore size, and pore volume. Also, MCM-41 NPs could increase the cytotoxicity effects of ABZ by 2.9-fold (IC₅₀ = 23 and 7.9 µM for ABZ and ABZ-loaded MCM-41 NPs, respectively). In addition, both ABZ and ABZ-loaded MCM-41 NPs could restrain the cell migration by 12 %. Overall, the results of the present study suggest evaluating the potency of MCM-41 NPs, as a potent nanoplatform, for ABZ delivery in vivo environment.

Preclinical safety profile of a liver-localized mitochondrial uncoupler

2021-12-20T06:32:40+01:00

Mitochondrial uncouplers (mUncouplers) are known to exhibit a variety of toxic effects in animals. Here we report a safety profile of an mUncoupler, OPC-163493, recently synthesized at Otsuka Pharmaceutical Co, Ltd, and its development as a therapeutic agent for treating diabetes. To understand the acute and subchronic toxicity of OPC-163493, single and repeated oral dose studies in rats, dogs, and monkeys were performed. In the rat studies, rigor mortis and increased body temperatures were observed in the high dose group. Focal necrosis, fatty change, and granular eosinophilic cytoplasm of the hepatocytes were also observed in the high dose group. In the dog studies, gastrointestinal manifestations were observed with decreased body weight and decreased food consumption in the high dose group. Necrotizing arteritis was observed in multiple organs as well as meningitis with hemorrhage in the brain. In the monkey studies, vomiting, decreased food consumption, and decreased locomotor activity were observed in the high dose group. Degeneration of the proximal convoluted tubules and the straight tubular epithelium, regeneration of the proximal tubular epithelium, and degeneration of the collecting tubular epithelium were observed. The target organs of OPC-163493 were liver, blood vessels, and kidney in rats, dogs, and monkeys, respectively. In rats, dogs, and monkeys, safety ratios were 100:1, 13:1, and 20:1, respectively, in terms of total exposure (AUC_24h). These safety ratios showed clear separation between exposure to OPC-163493 in animals at NOAEL and the exposure at the effective dose in ZDF rats. This information should contribute to the drug development of new and effective mUncoupler candidates.

Cyclophosphamide and epirubicin induce high apoptosis in microglia cells while epirubicin provokes DNA damage and microglial activation at sub-lethal concentrations

2021-12-13T08:20:20+01:00

Chemotherapy Related Cognitive Impairment (CRCI), also called chemobrain, diminishes cancer patient’s life quality. Breast cancer (BC) patients have been described to be importantly affected, however, the mechanism leading to CRCI has not been fully elucidated. Recent research proposes microglia as the main architect of CRCI, thus dysregulations in these cells could trigger CRCI. The aim of this research was to evaluate the effects of two drugs commonly used against breast cancer, cyclophosphamide (CTX) and epirubicin (EPI), on the microglia cell line SIM-A9, using the BC cell line, 4T1, as a control. Our results show that CTX and EPI decrease microglia-cell viability and increase cell death on a concentration-dependent manner, being 5 and 2 times more cytotoxic to microglia cell line than to breast cancer 4T1cells, respectively. Both chemotherapies induce cell cycle arrest and a significant increase in p53, p16 and γ-H2AX in breast cancer and microglia cells. Furthermore, mitochondrial membrane potential (ΔΨm) diminishes as cell death increases, and both chemotherapies induce reactive oxygen species (ROS) production on SIM-A9 and 4T1. Moreover, caspase activation increases with treatments and its pharmacological blockade inhibits CTX and EPI induced-cell death. Finally, low concentrations of CTX and EPI induce γ-H2AX, and EPI induces cytokine release, NO production and Iba-1 overexpression. These findings indicate that microglia cells are more sensitive to CTX and EPI than BC cells and undergo DNA damage and cell cycle arrest at very low concentrations, moreover EPI induces microglia activation and a pro-inflammatory profile.

Continous, non-invasive monitoring of oxygen consumption in a parallelized microfluidic in vitro system provides novel insight into the response to nutrients and drugs of primary human hepatocytes

2021-11-22T11:59:01+01:00

Oxygen plays a fundamental role in cellular energy metabolism, differentiation and cell biology in general. Consequently, in vitro oxygen sensing can be used to assess cell vitality and detect specific mechanisms of toxicity. In 2D in vitro models currently used, the oxygen supply provided by diffusion is generally too low, especially for cells having a high oxygen demand. In organ-on-chip systems, a more physiologic oxygen supply can be generated by establishing unidirectional perfusion. We established oxygen sensors in an easy-to-use and parallelized organ-on-chip system. We demonstrated the applicability of this system by analyzing the influence of fructose (40 mM, 80 mM), ammonium chloride (100 mM) and Na-diclofenac (50 µM, 150 µM, 450 µM, 1500 µM) on primary human hepatocytes (PHH). Fructose treatment for two hours showed an immediate drop of oxygen consumption (OC) with subsequent increase to nearly initial levels. Treatment with 80 mM glucose, 20 mM lactate or 20 mM glycerol did not result in any changes in OC which demonstrates a specific effect of fructose. Application of ammonium chloride for two hours did not show any immediate effects on OC, but qualitatively changed the cellular response to FCCP treatment. Na-diclofenac treatment for 24 hours led to a decrease of the maximal respiration and reserve capacity. We also demonstrated the stability of our system by repeatedly treating cells with 40 mM fructose, which led to similar cell responses on the same day as well as on subsequent days. In conclusion, our system enables in depth analysis of cellular respiration after substrate treatment in an unidirectional perfused organ-on-chip system.

in an unidirectional perfused organ-on-chip system.

Hypermethylation of RAD9A intron 2 in childhood cancer patients, leukemia and tumor cell lines suggest a role for oncogenic transformation

2021-12-09T12:51:57+01:00

Most childhood cancers occur sporadically and cannot be explained by an inherited mutation or an unhealthy lifestyle. However, risk factors might trigger the oncogenic transformation of cells. Among other regulatory signals, hypermethylation of RAD9A intron 2 is responsible for the increased expression of RAD9A protein, which may play a role in oncogenic transformation. Here, we analyzed the RAD9A intron 2 methylation in primary fibroblasts of 20 patients with primary cancer in childhood and second primary cancer (2N) later in life, 20 matched patients with only one primary cancer in childhood (1N) and 20 matched cancer-free controls (0N), using bisulfite pyrosequencing and deep bisulfite sequencing (DBS). Four 1N patients and one 2N patient displayed elevated mean methylation levels (³10 %) of RAD9A. DBS revealed ³2 % hypermethylated alleles of RAD9A, indicative for constitutive mosaic epimutations. Bone marrow samples of NHL and AML tumor patients (n=74), EBV (Epstein Barr Virus) lymphoblasts (n=6), tumor cell lines (n=5) and FaDu subclones (n=13) were analyzed to substantiate our findings. We find a broad spectrum of tumor entities with an aberrant methylation of RAD9A. We detected a significant difference in mean methylation of RAD9A for NHL versus AML patients (p ≤0.025). Molecular karyotyping of AML samples during therapy with hypermethylated RAD9A showed an evolving duplication of 1.8 kb on Chr16p13.3 including the PKD1 gene. Radiation, colony formation assays, cell proliferation, PCR and molecular karyotyping SNP-array experiments using generated FaDu subclones suggest that hypermethylation of RAD9A intron 2 is associated with genomic imbalances in regions with tumor-relevant genes and survival of the cells. In conclusion, this is the very first study of RAD9A intron 2 methylation in childhood cancer and Leukemia. RAD9A epimutations may have an impact on leukemia and tumorigenesis and can potentially serve as a biomarker.

Prevalence and predictors of adequate treatment of overt hypothyroidism – a population-based study

2021-12-07T10:28:17+01:00

The aim of this study is to evaluate the adequacy of treatment, and to identify factors influencing treatment of hypothyroidism. Patients newly diagnosed with overt hypothyroidism (n=345) were identified via a register linked to a laboratory database. In selected periods with staff available, 165 patients were invited, and 113 (68.5 %) accepted participating in a comprehensive program including blood tests and completion of questionnaires. We performed a longitudinal follow-up on thyroid function tests 10 years after the diagnosis. Time to reach a serum TSH level of 0.2-10 mU/L (termed as clinically acceptable) and biochemical normalization (TSH: 0.2-5.0 mU/L), respectively, were analyzed using Kaplan Meier survival analysis. Predictors for longer duration to reach the normal TSH range were identified using cox proportional hazards regression. Only 67.7 % of the patients were in the euthyroid range on the long term after diagnosis of overt hypothyroidism (2 years: 59.4 %; 10 years: 67.7 %). Median time to the first normal TSH was 8.9 months (95 % CI: 7.6-10.2 months). The factors associated with longer duration until normalization of TSH after multivariate analysis were age (HR 0.79 per 10 years; 95 % CI: 0.66-0.94; P = <0.01), smoking (HR 0.47; 95 % CI: 0.26-0.83; P = <0.01), serum TSH at diagnosis (HR 0.96 per 10 mU/L; 95 % CI: 0.93-0.99; P = 0.02) and BMI (HR 0.96 per kg/m²; 95 % CI: 0.91-0.99; P = 0.03). A considerable number of hypothyroid patients remained inadequately treated. When treating hypothyroid patients, special attention should be addressed to those patients who never or lately obtain euthyroid status.

The COVID-19 vaccination acceptance/hesitancy rate and its determinants among healthcare workers of 91 Countries

2021-12-13T08:26:53+01:00

The aim of this study was to investigate the COVID-19 vaccination acceptance rate and its determinants among healthcare workers in a multicenter study. This was a cross-sectional multi-center survey conducted from February 5 to April 29, 2021. The questionnaire consisted of 26 items in 6 subscales. The English version of the questionnaire was translated into seven languages and distributed through Google Forms using snowball sampling; a colleague in each country was responsible for the forward and backward translation, and also the distribution of the questionnaire. A forward stepwise logistic regression was utilized to explore the variables and questionnaire factors tied to the intention to COVID-19 vaccination. 4630 participants from 91 countries completed the questionnaire. According to the United Nations Development Program 2020, 43.6 % of participants were from low Human Development Index (HDI) regions, 48.3 % high and very high, and 8.1 % from medium. The overall vaccination hesitancy rate was 37 %. Three out of six factors of the questionnaire were significantly related to intention to the vaccination. While ‘Perceived benefits of the COVID-19 vaccination’ (OR: 3.82, p-value<0.001) and ‘Prosocial norms’ (OR: 5.18, p-value<0.001) were associated with vaccination acceptance, ‘The vaccine safety/cost concerns’ with OR: 3.52, p-value<0.001 was tied to vaccination hesitancy. Medical doctors and pharmacists were more willing to take the vaccine in comparison to others. Importantly, HDI with OR: 12.28, 95 % CI: 6.10-24.72 was a strong positive determinant of COVID-19 vaccination acceptance. This study highlighted the vaccination hesitancy rate of 37 % in our sample among HCWs. Increasing awareness regarding vaccination benefits, confronting the misinformation, and strengthening the prosocial norms would be the primary domains for maximizing the vaccination coverage. The study also showed that the HDI is strongly associated with the vaccination acceptance/hesitancy, in a way that those living in low HDI contexts are more hesitant to receive the vaccine.

Feeding to satiation induces mild oxidative/carbonyl stress in the brain of young mice

2021-11-22T11:15:31+01:00

Intermittent fasting as a dietary intervention can prevent overweight and obesity in adult organisms. Nevertheless, information regarding consequences of intermittent fasting for redox status and reactive metabolite-mediated processes that are crucial for the normal functioning of organisms is limited. Since the information on effects of intermittent fasting on parameters of oxidative/carbonyl stress in the brains of young mice was absent, the present study addressed these questions using an every-other-day fasting (EODF) protocol. The levels of carbonyl proteins were ~28 %, 22 % and 18 % lower in the cerebral cortex of EODF males and females and middle parts of the brain of EODF males, respectively, as compared to their ad libitum fed counterparts. Lipid peroxides and α-dicarbonyl compounds were lower only in the cortex and medulla part of EODF male brain. The EODF regimen resulted in higher total non-specific antioxidant capacity in different parts of male brain and a tendency to be higher this parameter in females. At the same time, EODF regimen had no effect on the activities of the defensive antioxidant enzymes, namely superoxide dismutase, catalase, glutathione-S-transferase, glutathione peroxidase, glyoxylase 1 and glucose-6-phosphate dehydrogenase in the cortex of both sexes, but even decreased activities of these enzymes in medulla and middle part of the brain. In general, the results suggest that in the brain of young mice ad libitum feeding induces mild oxidative/carbonyl stress which may be partially alleviated by the EODF regimen. The effect of EODF regimen is more pronounced in the medulla part than in the cortex.

Risk factors, time to onset and recurrence of delirium in a mixed medical-surgical ICU population

2021-11-22T11:21:09+01:00

A retrospective secondary analysis of 4,200 patients was collected from two academic medical centers. Delirium was assessed using the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) in all patients. Univariate and multivariate Cox models, logistic regression analysis, and Chi-square Automatic Interaction Detector (CHAID) decision tree modeling were used to explore delirium risk factors. Increased delirium risk was associated with exposed only to artificial light (AL) hazard ratio (HR) 1.84 (95 % CI: 1.66-2.044, P<0.001), physical restraint application 1.11 (95 % CI: 1.001-1.226, P=0.049), and high nursing care requirements (>8 hours per 8-hour shift) 1.18 (95 % CI: 1.048-1.338, P=0.007). Delirium incidence was inversely associated with greater family engagement 0.092 (95 % CI: 0.014-0.596, P=0.012), low staff burnout and anticipated turnover scores 0.093 (95 % CI: 0.014-0.600, P=0.013), non-ICU length-of-stay (LOS)<15 days 0.725 (95 % CI: 0.655-0.804, P<0.001), and ICU LOS ≤15 days 0.509 (95 % CI: 0.456-0.567, P<0.001). CHAID modeling indicated that AL exposure and age <65 years were associated with a high risk of delirium incidence, whereas SOFA score ≤11, APACHE IV score >15 and natural light (NL) exposure were associated with moderate risk, and female sex was associated with low risk. More rapid time to delirium onset correlated with baseline sleep disturbance (P=0.049), high nursing care requirements (P=0.019), and prolonged ICU and non-ICU hospital LOS (P<0.001). Delirium recurrence correlated with age >65 years (HR 2.198; 95 % CI: 1.101-4.388, P=0.026) and high nursing care requirements (HR 1.978, 95 % CI: 1.096-3.569), with CHAID modeling identifying AL exposure (P<0.001) and age >65 years (P=0.032) as predictive variables. Development of ICU delirium correlated with application of physical restraints, high nursing care requirements, prolonged ICU and non-ICU LOS, exposure exclusively to AL (rather than natural), less family engagement, and greater staff burnout and anticipated turnover scores. ICU delirium occurred more rapidly in patients with baseline sleep disturbance, and recurrence correlated with the presence of delirium on ICU admission, exclusive AL exposure, and high nursing care requirements.

Sex-specific differences in trimethylamine N-oxide (TMAO) concentrations before and after cardiac rehabilitation in acute myocardial infarction patients

2021-11-17T13:09:52+01:00

Trimethylamine N-oxide (TMAO) is a biomarker of cardiovascular risk and may enhance the progression of atherosclerosis. The aim of the study was to determine whether there are sex-specific differences in TMAO concentrations before and after cardiac rehabilitation in acute myocardial infarction (AMI) patients. A total of 56 participants [45/56 (80.4 %) males, 11/56 (19.6 %) females] were drawn from AMI inpatients hospitalized at the Division of Cardiology, Medical University of Graz, Austria. For the assessment of TMAO, serum samples were collected within the first day after hospital admission due to AMI and at the start and end of cardiac rehabilitation. Shortly after hospital admission due to AMI, females had significantly higher TMAO blood concentrations than males. These initially high TMAO levels remained almost unchanged in the female AMI patients until the start of cardiac rehabilitation and only reached the lower TMAO concentrations observed in the male patients after rehabilitation [female patients: TMAO (acute myocardial infarction) = 5.93 μmol/L (SE = 1.835); TMAO (start of rehabilitation) = 5.68 μmol/L (SE = 1.217); TMAO (end of rehabilitation) = 3.89 μmol/L (SE = 0.554); male patients: TMAO (acute myocardial infarction) = 3.02 μmol/L (SE = 0.255), TMAO (start of rehabilitation) = 3.91 μmol/L (SE = 0.346), TMAO (end of rehabilitation) = 4.04 μmol/L (SE = 0.363)]. After AMI, women might be at higher cardiovascular risk due to persistently higher levels of TMAO. High TMAO levels in women might decrease after cardiac rehabilitation due to cardiac rehabilitation-associated lifestyle modifications. These lifestyle modifications after AMI might also prevent increases in TMAO concentrations in men.