High intensity interval training exercise-induced physiological changes and their potential influence on metabolic syndrome clinical biomarkers: a meta-analysis

Abstract: Background: Despite the current debate about the effects of high intensity interval training (HIIT), HIIT elicits big morpho-physiological benefit on Metabolic Syndrome (MetS) treatment. However, no review or meta-analysis has compared the effects of HIIT to non-exercising controls in MetS variables. The aim of this study was to determine through a systematic review, the effectiveness of HIIT on MetS clinical variables in adults. Methods: Studies had to be randomised controlled trials, lasting at least 3 weeks, and compare the effects of HIIT on at least one of the MetS clinical variables [fasting blood glucose (BG), high-density lipoprotein (HDL-C) triglyceride (TG), systolic (SBP) or diastolic blood pressure (DBP) and waist circumference (WC)] compared to a control group. The methodological quality of the studies selected was evaluated using the PEDro scale. Results: Ten articles fulfilled the selection criteria, with a mean quality score on the PEDro scale of 6.7. Compared with controls, HIIT groups showed significant and relevant reductions in BG (− 0.11 mmol/L), SBP (− 4.44 mmHg), DBP (− 3.60 mmHg), and WC (− 2.26 cm). Otherwise, a slight increase was observed in HDL-C (+ 0.02 mmol/L). HIIT did not produce any significant changes in TG (− 1.29 mmol/L). Conclusions: HIIT improves certain clinical aspects in people with MetS (BG, SBP, DBP and WC) compared to people with MetS who do not perform physical exercise. Plausible physiological changes of HIIT interventions might be related with large skeletal muscle mass implication, improvements in the vasomotor control, better baroreflex control, reduction of the total peripheral resistance, increases in excess post-exercise oxygen consumption, and changes in appetite and satiety mechanisms

The immunomodulator PSK induces in vitro cytotoxic activity in tumour cell lines via arrest of cell cycle and induction of apoptosis

Background Protein-bound polysaccharide (PSK) is derived from the CM-101 strain of the fungus Coriolus versicolor and has shown anticancer activity in vitro and in in vivo experimental models and human cancers. Several randomized clinical trials have demonstrated that PSK has great potential in adjuvant cancer therapy, with positive results in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunomodulator of biological responses. The precise molecular mechanisms responsible for its biological activity have yet to be fully elucidated.Methods The in vitro cytotoxic anti-tumour activity of PSK has been evaluated in various tumour cell lines derived from leukaemias, melanomas, fibrosarcomas and cervix, lung, pancreas and gastric cancers. Tumour cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of PSK on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in PSK-treated cells.Results PSK showed in vitro inhibition of tumour cell proliferation as measured by BrdU incorporation and viable cell count. The inhibition ranged from 22 to 84%. Inhibition mechanisms were identified as cell cycle arrest, with cell accumulation in G0/G1 phase and increase in apoptosis and caspase-3 expression. These results indicate that PSK has a direct cytotoxic activity in vitro, inhibiting tumour cell proliferation. In contrast, PSK shows a synergistic effect with IL-2 that increases PBL proliferation.Conclusion These results indicate that PSK has cytotoxic activity in vitro on tumour cell lines. This new cytotoxic activity of PSK on tumour cells is independent of its previously described immunomodulatory activity on NK cells.AGL was supported by FIS Postdoctoral Research Contract CP03/00111. Studies were partially supported by a grant from Kureha Chemical Industry (Japan)

External validation of a deep learning electrocardiogram algorithm to detect ventricular dysfunction

Objective - To validate a novel artificial-intelligence electrocardiogram algorithm (AI-ECG) to detect left ventricular systolic dysfunction (LVSD) in an external population. Background - LVSD, even when asymptomatic, confers increased morbidity and mortality. We recently derived AI-ECG to detect LVSD using ECGs based on a large sample of patients treated at the Mayo Clinic. Methods - We performed an external validation study with subjects from the Know Your Heart Study, a cross-sectional study of adults aged 35–69 years residing in two cities in Russia, who had undergone both ECG and transthoracic echocardiography. LVSD was defined as left ventricular ejection fraction ≤ 35%. We assessed the performance of the AI-ECG to identify LVSD in this distinct patient population. Results - Among 4277 subjects in this external population-based validation study, 0.6% had LVSD (compared to 7.8% of the original clinical derivation study). The overall performance of the AI-ECG to detect LVSD was robust with an area under the receiver operating curve of 0.82. When using the LVSD probability cut-off of 0.256 from the original derivation study, the sensitivity, specificity, and accuracy in this population were 26.9%, 97.4%, 97.0%, respectively. Other probability cut-offs were analysed for different sensitivity values. Conclusions - The AI-ECG detected LVSD with robust test performance in a population that was very different from that used to develop the algorithm. Population-specific cut-offs may be necessary for clinical implementation. Differences in population characteristics, ECG and echocardiographic data quality may affect test performance

Animal welfare attitudes: Effects of gender and diet in university samples from 22 countries

Animal Welfare Attitudes (AWA) are defined as human attitudes towards the welfare of animals in different dimensions and settings. Demographic factors, such as age and gender are associated with AWA. The aim of this study was to assess gender differences among university students in a large convenience sample from twenty-two nations in AWA. A total of 7914 people participated in the study (5155 women, 2711 men, 48 diverse). Participants completed a questionnaire that collected demographic data, typical diet and responses to the Composite Respect for Animals Scale Short version (CRAS-S). In addition, we used a measure of gender empowerment from the Human Development Report. The largest variance in AWA was explained by diet, followed by country and gender. In terms of diet, 6385 participants reported to be omnivores, 296 as pescatarian, 637 ate a vegetarian diet and 434 were vegans (n = 162 without answer). Diet was related with CRAS-S scores; people with a vegan diet scored higher in AWA than omnivores. Women scored significantly higher on AWA than men. Furthermore, gender differences in AWA increased as gender inequality decreased

Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis

CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7∆ex2 mouse model of CLN7 disease, that failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria. In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons. Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks. Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis and targeting PFKFB3 could alleviate this and other lysosomal storage diseases

Comparison of next-generation sequencing (NGS) and next-generation flow (NGF) for minimal residual disease (MRD) assessment in multiple myeloma

Detecting persistent minimal residual disease (MRD) allows the identification of patients with an increased risk of relapse and death. In this study, we have evaluated MRD 3 months after transplantation in 106 myeloma patients using a commercial next-generation sequencing (NGS) strategy (LymphoTrack®), and compared the results with next-generation flow (NGF, EuroFlow). The use of different marrow pulls and the need of concentrating samples for NGS biased the applicability for MRD evaluation and favored NGF. Despite that, correlation between NGS and NGF was high (R = 0.905). The 3-year progression-free survival (PFS) rates by NGS and NGF were longer for undetectable vs. positive patients (NGS: 88.7% vs. 56.6%; NGF: 91.4% vs. 50%; p < 0.001 for both comparisons), which resulted in a 3-year overall survival (OS) advantage (NGS: 96.2% vs. 77.3%; NGF: 96.6% vs. 74.9%, p < 0.01 for both comparisons). In the Cox regression model, NGS and NGF negativity had similar results but favoring the latter in PFS (HR: 0.20, 95% CI: 0.09-0.45, p < 0.001) and OS (HR: 0.21, 95% CI: 0.06-0.75, p = 0.02). All these results reinforce the role of MRD detection by different strategies in patient prognosis and highlight the use of MRD as an endpoint for multiple myeloma treatment

Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis

CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7∆ex2 mouse model of CLN7 disease, that failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria. In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis. Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons. Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks. Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis and targeting PFKFB3 could alleviate this and other lysosomal storage diseases.This work was funded by the European Regional Development Fund, European Union’s Horizon 2020 Research and Innovation Programme (BATCure grant No. 666918 to J.P.B., S.E.M., D.L.M., S.S., and T.R.M.; PANA grant No. 686009 to A.A.), Agencia Estatal de Investigación (PID2019-105699RB-I00/AEI/10.13039/501100011033 and RED2018‐102576‐T to J.P.B.; SAF2017-90794-REDT to A.A.), Instituto de Salud Carlos III (CB16/10/00282 to J.P.B.; PI18/00285; RD16/0019/0018 to A.A.), Junta de Castilla y León (CS/151P20 and Escalera de Excelencia CLU-2017-03 to J.P.B. and A.A.), Ayudas Equipos Investigación Biomedicina 2017 Fundación BBVA (to J.P.B.), and Fundación Ramón Areces (to J.P.B. and A.A.). SM benefits from MRC funding to the MRC Laboratory for Molecular Cell Biology University Unit at UCL (award code MC_U12266B) towards lab and office space. Part of this work was funded by Gero Discovery L.L.C. M.G.M. is an ISCIII-Sara Borrel contract recipient (CD18/00203)

Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) has been implicated in important metabolic processes. A mouse lacking PGC-1β (PGC1βKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1βKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1β ablation was partially compensated by up-regulation of PGC-1α in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1βKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1β was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1βKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1βKO mice have impaired mitochondrial function. Lack of PGC-1β also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1β plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress