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Physiology internationalVol. 108. No 2. (June, 2021)



  • H. Nawaz ,
    M. Aslam ,
    T. Rehman :

    DOI: 10.1556/2060.2021.00018

    Abstract: Hyperbilirubinemia or jaundice has been studied by many researchers because of its diverse causes and potential for toxicity especially in the neonate but to a lesser extent beyond the neonate as well. Several studies have been performed on the normal metabolism and metabolic disorders of bilirubin in last decades of the 20th century. The recent advancement in research and technology facilitated for the researchers to investigate new horizons of the causes and treatment of neonatal hyperbilirubinemia. This review gives a brief introduction to hyperbilirubinemia and jaundice and the recent advancement in the treatment of neonatal hyperbilirubinemia. It reports modifications in the previously used methods and findings of some newly developed ones. At present, ample literature is available discussing the issues regarding hyperbilirubinemia and jaundice, but still more research needs to be done.

    Keywords: bilirubin, neonatal hyperbilirubinemia, neonatal jaundice, phototherapy, treatment methods

Original Papers - Animal and in vitro experiments

  • Y. Yang ,
    M. Zhou ,
    H. Liu :

    DOI: 10.1556/2060.2021.00148

    Abstract: Objective: The present report evaluates the protective effects of luteolin against diabetic retinopathy (DR). Materials and methods: Diabetes was induced in rats by i.p. administration of 60 mg/kg of streptozotocin (STZ), followed by treatment with luteolin for 4 weeks. The effects of luteolin were determined based on the blood glucose and cytokine levels, and parameters of oxidative stress in retinal tissue of DR rats. The diameter of retinal vessels was estimated by fundus photography. A Western blot assay was used to determine the expression of apoptotic proteins and Nod-like receptor 3 (NLRP3) pathway proteins in the retina of DR rats. A molecular docking study was performed to evaluate the interaction between luteolin and NLRP3. Results: The level of blood glucose was reduced in the luteolin-treated group compared with the DR group. Reductions in cytokines and oxidative stress were observed in the retinal tissues of the luteolin-treated group relative to the DR group. Moreover, treatment with luteolin reduced the expression of NLRP1, NOX4, TXNIP, and NLRP3 proteins, and ameliorated the altered expression of apoptotic proteins in the retina of DR rats. Conclusion: In conclusion, luteolin prevents retinal apoptosis in DR rats by regulating the NLRP/NOX4 signalling pathway.

    Keywords: luteolin, diabetic retinopathy, caspase-1, streptozotocin, oxidative stress

  • N. M. Madi ,
    R. E. Abo El Gheit ,
    R. A. Barhoma ,
    A. El Saadany ,
    G. M. Alghazaly ,
    K. Marea ,
    M. H. El-Saka :

    DOI: 10.1556/2060.2021.00176

    Abstract: This study was conducted to explore the beneficial impact of nesfatin-1 on reproductive dysfunction induced by nicotine (NT) in male rats with possible modulation of autophagy and pyroptosis signaling pathways. This research was performed on 40 Wistar male rats. They were distributed into four groups: control, normal+nesfatin-1, NT, and NT+nesfatin-1. At the end of the experimental period, the serum was separated for assay of testosterone, FSH and LH. Also, sperm parameters were determined. Histopathological examination of testicular tissue and immunohistochemical analysis was done for mammalian target of rapamycin, AMP-activated protein kinase, and mitogen-activated protein kinases including phosphorylated extracellular signal regulated kinase and phosphorylated cJun N-terminal kinase. Relative gene expression was determined for testicular nucleotide oligomerization domain (NOD)-like receptors proteins and Caspase-1, and autophagy markers including microtubule-associated protein 1 light chain 3 alpha and Beclin-1. Also, the following testicular parameters were assayed: 3b-hydroxysteroid dehydrogenase, 17bhydroxysteroid dehydrogenase, malondialdehyde, superoxide dismutase activity, catalase, glucose-6 phosphate dehydrogenase, reactive oxygen species, caspase-3 activity, IL-1b, IL-18, mitochondrial transmembrane potential and Complex-I activity. The results revealed that the normal+nesfatin-1 group showed insignificant changes as compared to the control group. Meanwhile, the NT group exhibited prominent reproductive dysfunction in male rats. On the other hand, in the NT+nesfatin-1 group nesfatin- 1 notably attenuated this reproductive dysfunction as evidenced by improvement of hormonal assay, sperm parameters, histopathological picture, immunohistochemical evaluation and real time relative gene expressions. In conclusion: Nesfatin-1 alleviated the impairment of male reproductive functions induced by NT via enhancement of autophagy pathways, suppression of pyroptosis, apoptosis, mitochondrial dysfunction and ROS production. Thus nesfatin-1 may offer a novel protective or therapeutic access for treating male infertility.

    Keywords: nesfatin-1, reproductive dysfunction, nicotine, autophagy, pyroptosis

Human studies

  • Dongyan Zhao ,
    Xizhen Sun ,
    Sidan Long ,
    Shukun Yao :

    DOI: 10.1556/2060.2021.00125

    Abstract: Aim: Long non-coding RNAs (lncRNAs) have been identified to regulate cancers by controlling the process of autophagy and by mediating the post-transcriptional and transcriptional regulation of autophagy-related genes. This study aimed to investigate the potential prognostic role of autophagy-associated lncRNAs in colorectal cancer (CRC) patients. Methods: LncRNA expression profiles and the corresponding clinical information of CRC patients were collected from The Cancer Genome Atlas (TCGA) database. Based on the TCGA dataset, autophagy-related lncRNAs were identified by Pearson correlation test. Univariate Cox regression analysis and the least absolute shrinkage and selection operator analysis (LASSO) Cox regression model were performed to construct the prognostic gene signature. Gene set enrichment analysis (GSEA) was used to further clarify the underlying molecular mechanisms. Results: We obtained 210 autophagyrelated genes from the whole dataset and found 1187 lncRNAs that were correlated with the autophagyrelated genes. Using Univariate and LASSO Cox regression analyses, eight lncRNAs were screened to establish an eight-lncRNA signature, based on which patients were divided into the low-risk and high-risk group. Patients’ overall survival was found to be significantly worse in the high-risk group compared to that in the low-risk group (log-rank p = 2.731E-06). ROC analysis showed that this signature had better prognostic accuracy than TNM stage, as indicated by the area under the curve. Furthermore, GSEA demonstrated that this signature was involved in many cancer-related pathways, including TGF-b, p53, mTOR and WNT signaling pathway. Conclusions: Our study constructed a novel signature from eight autophagy-related lncRNAs to predict the overall survival of CRC, which could assistant clinicians in making individualized treatment.

    Keywords: autophagy, long non-coding RNA, prognostic signature, colorectal cancer, TCGA

  • D. Zhu ,
    R. He ,
    W. Yu ,
    C. Li ,
    H. Cheng ,
    B. Zhu ,
    J. Yan :

    DOI: 10.1556/2060.2021.00137

    Abstract: Background: Hypoxia is a pivotal initiator of tumor angiogenesis and growth through the stabilization of hypoxia-inducible factors (HIFs). This study set out to examine the involvement of HIF-1α and HIF-2α in colon cancer and ascertained whether ORAI3 was involved in the pathway. Materials and methods: Patients and murine models as well as human colorectal adenocarcinoma tumor (CW2) cells were included to examine the levels of ORAI1/3 and HIF-1/2α levels. Calcium imaging was utilized to ascertain the activity of calcium channel. Scratch assay was used to assess the migration capacity of the cells. Results: Tumors from murine colon cancer xenograft models and patients with colon cancer displayed high ORAI1/3 and HIF-1/2α levels. Hypoxia treatment, mimicking the tumor microenvironment in vitro, increased ORAI1/3 and HIF-1/2α expression as well as store-operated Ca²⁺ entry (SOCE). Of note is that HIF-1/2α silencing decreased SOCE, and HIF-1/2a overexpression facilitated SOCE. Furthermore, ORAI3 rather than ORAI1 expression was inhibited by HIF-1/2α silencing while increased by ML228. Luciferase assay also confirmed that ORAI3 was elevated in the presence of ML228, indicating the linkage between HIF-1/2α and ORAI3. Additionally, colony-forming potential and cell migration capacity were decreased in siHIF-1a and siHIF- 2a as well as siORAI3 cells, and the facilitating effect of ML228 on cell migration and colony-forming potential was also decreased in siORAI3 CW-2 cells, which points out the importance of ORAI3 in HIF1/2α pathway. Conclusion: Our findings allow to conclude that both HIF-1a and HIF-2a facilitate ORAI3 expression, hence enhancing colon cancer progression.

    Keywords: store-operated Ca²⁺ entry, ORAI3, colon cancer, HIF1/2α

  • M. Fekete ,
    V. Fazekas-Pongor ,
    P. Balazs ,
    S. Tarantini ,
    G. Szollosi ,
    J. Pako ,
    A. N. Nemeth ,
    J. T. Varga :

    DOI: 10.1556/2060.2021.00170

    Abstract: Background: Pathological alterations in nutritional status may develop in Chronic Obstructive Pulmonary Disease (COPD) patients through production of inflammatory cytokines and inadequate diet. Objective: The aim of our study was to determine the correlation between nutritional status and quality of life of COPD patients. Methods: We evaluated the nutritional status of COPD patients of Hungarian National Koranyi Institute for Pulmonology using the Malnutrition Universal Screening Tool (MUST) and bioelectrical impedance analysis (BIA) between January 1 and June 1, 2019. Lung function, physical fitness, and respiratory muscle strength were included in the assessment. Results: Fifty patients (mean age was 66.3 ± 9.6 years) participated in our study. Mean body mass index (BMI) was 26.2 ± 6.1 kg/m2 and mean fatfree mass index (FFMI) was 16.8 ± 2.4 kg/m2. Overweight patients had better lung function values (FEV1ref %: 46.3 ± 15.2) than normal (FEV1ref%: 45.1 ± 20.9) and underweight patients (FEV1ref%: 43.8 ± 16.0). The Modified Medical Research Council Dyspnea Scale (mMRC) was significantly associated with various parameters; strongest correlation was found with FFMI (r = -0.537, P < 0.001), skeletal muscle mass index (SMMI) (r = -0.530, P < 0.001), and 6-minute walking distance (6MWD) (r = -0.481, P < 0.001). Conclusions: Our results indicate that malnourished COPD patients may have reduced lung function and lower quality of life compared to normal weight patients. Thus, our findings suggest that nutritional therapy be included in the treatment of COPD patients combined with nutritional risk screening and BIA during the follow-up.

    Keywords: chronic obstructive pulmonary disease, bioelectrical impedance analysis, body-mass index, fat-free mass index, nutritional status

  • T. Akdag ,
    A. U. Uca ,
    M. Altas ,
    F. O. Odabas ,
    F. Aktas :

    DOI: 10.1556/2060.2021.00179

    Abstract: Objective: Multiple sclerosis (MS) is a chronic and progressive neurological disease affecting the central nervous system (CNS). Some studies report an association between MS pathogenesis and cytokines. Here, we aimed to determine and evaluate serum kisspeptin-10 level in MS patients and its related clinic parameters. Materials and Methods: A total of 92 participants, 46 patients with relapsing-remitting MS (mean age, 38.92 ± 14.76; 22 men and 24 women) and 46 healthy controls (mean age, 37.04 ± 15.49; 22 men and 24 women) were enrolled in the study. All MS patients were neurologically examined, and magnetic resonance imaging (MRI) was performed. Clinical data (neuropathic pain, expanded disability status scale (EDSS) score, etc.) and the patients’ demographic characteristics were recorded. The serum level of kisspeptin- 10 was analyzed by enzyme-linked immunosorbent assay (ELISA) method. Results: The level of kisspeptin-10 was measured as 2.305 ± 2.781 ng/mL in MS patients and 9.342 ± 9.483 ng/mL in controls. MS patients had significantly lower kisspeptin-10 levels than controls (P = 0.000). Kisspeptin-10 has the highest diagnostic value [Area under curve (AUC) 5 0.881, 95% confidence interval (CI), 0.812–0.950] as cut-off value (2.470), sensitivity (80.40%) and specificity (72.87%) in the MS group. Furthermore, the kisspeptin-10 level was negatively correlated with third ventricle diameter (TVD) (P = 0.048) and vitamin D concentration (P = 0.004). No significant difference was determined between kisspeptin-10 and other clinical parameters. Conclusion: As a potential prognostic biomarker, serum kisspeptin-10 level was significantly lower in patients with MS than in those without. Moreover, we observed negative correlations between vitamin D, TVD size, and kisspeptin-10. We think comprehensive studies are needed to verify and elucidate this issue.

    Keywords: kisspeptin-10, multiple sclerosis, neurological disease, third ventricle, vitamin D

  • V. Fazekas-Pongor ,
    M. Fekete ,
    P. Balazs ,
    D. Árva ,
    M. Pénzes ,
    S. Tarantini ,
    K. Urbán ,
    J. T. Varga :
    Health-related quality of life of COPD patients aged over 40 years261-273en [565.67 kB - PDF]EPA-03963-00020-0080

    DOI: 10.1556/2060.2021.00017

    Abstract: Background: Chronic obstructive pulmonary disease (COPD) is the fourth most frequent disease globally, and its worldwide prevalence is projected to increase in the following decades. Health-related quality of life (HRQOL) of COPD patients depends on multiple factors. Objective: The aim of this study was to identify the most important risk factors affecting HRQOL of COPD patients and to measure how specific clinical parameters can predict HRQOL. Methods: A questionnaire-based cross-sectional study combined with clinical data was conducted among patients diagnosed with COPD (n = 321, 52.6% females, mean age 66.4 ± 9.5) at the National Koranyi Institute for Pulmonology, Budapest in 2019–2020. The inclusion criteria were age ≥40 years and existing COPD. Multivariate linear regression analyses were conducted on three components of the COPD-specific Saint George’s Respiratory Questionnaire (SGRQ-C) and on the physical (PCS) and mental component scales (MCS) of the 36-Item Short Form Health Survey (SF-36). Multiple linear regression analysis was performed to evaluate the effects of patient and disease characteristics on COPD Assessment Test (CAT) scores. Results: We found that frequent exacerbations, multiple comorbidities and tobacco smoking were associated with worse HRQOL. Engaging in more frequent physical activity and better 6-minute walking distance results were associated with better HRQOL. Conclusions: Our results indicate that the complex therapy of COPD should focus not only on improving lung functions and preventing exacerbation, but also on treating comorbidities, encouraging increased physical activity, and supporting smoking cessation to assure better HRQOL for patients.



  • Katsuyuki Tokinoya ,
    Seiko Ono ,
    Kai Aoki ,
    Koki Yanazawa ,
    Yasuhiro Shishikura ,
    Takehito Sugasawa ,
    Kazuhiro Takekoshi :

    DOI: 10.1556/2060.2021.00147

    Abstract: Introduction: Exercise training is beneficial for reducing obesity. In particular, exercise training can lower the catecholamine concentration in circulation. Renalase, whose expression was first confirmed in the kidneys, is a physiologically active substance that decomposes circulating catecholamines; additionally, it has been reported to be present in the skeletal muscles. The aim of this study was to clarify the expression of renalase in the skeletal muscles and kidneys after high-intensity exercise training in obese mice. Material and methods: The mice were divided into four groups: normal diet and sedentary, normal diet and exercise training, highfat diet and sedentary, and high-fat diet and exercise training, and the test was performed for 8 weeks. Results: Body weight and skeletal muscle wet weight were reduced by high-fat diet intake but were rescued by training. Skeletal muscle renalase gene expression was significantly increased by exercise training. However, in the kidneys the gene expression of renalase was significantly increased by high-fat diet intake and exercise training. No significant changes were observed in the gene expression of catecholamine-degrading enzymes, catechol-O-methyltransferase and monoamine oxidase A and B. Conclusion: We demonstrated that exercise training increased the gene expression of renalase in the skeletal muscles and kidneys, thus lowering circulating catecholamine levels. This may lead to amelioration of obesity as catecholamines are lipolytic.

    Keywords: blood pressure, catecholamine, kidney, obesity, skeletal muscle

  • W. Zhou ,
    G. Zeng ,
    C. Lyu ,
    F. Kou ,
    S. Zhang ,
    H. Wei :

    DOI: 10.1556/2060.2021.00150

    Abstract: Aim: Limited investigations on metabolic responses to exercise training in female adolescent volleyball athletes exist. The aim of this study was to obtain serum and urine metabolite markers in female adolescent volleyball athletes within 2-week strength-endurance training using a metabolomics approach coupled with biochemical analysis, which would be potential biomarkers for evaluating the physiological state of athletes. Methods: Twelve female adolescent volleyball athletes were recruited for 2-week strength-endurance training. Differential serum and urine metabolic profiles between the pre- and post-training group were obtained on gas chromatography coupled to mass spectrometry (GC-MS) and data subsequently underwent orthogonal partial least-squares analysis (OPLS). Results: Strength-endurance training exerted a significant influence on the athletes’ serum and urine metabolic profiles. The changed metabolites were primarily involved in energy metabolism, lipid metabolism and amino acids metabolism. Results support the hypothesis that female athletes displayed an increased propensity to oxidize lipids as the major energy source. Exposure to strength-endurance training also led to a significant increase in cortisol, but a decrease in testosterone, indicating disordered hormone adjustment. Exercise-induced oxidative stress occurred, as was evidenced by the decrease in reduced glutathione, and increases in blood malondialdehyde and oxidized glutathione. Since the muscle damage markers creatine kinase and lactate dehydrogenase did not show significant changes, the training might not cause cell membrane damage and the athletes did not cross the adaptive injury level. Conclusion: By measurement of endogenous metabolites, the metabolomics study has the potential to reveal the global physiological changes in response to exercise training.

    Keywords: female adolescent volleyball athletes, strength-endurance training, physiology, metabolomics

  • I. Martinez-Navarro ,
    A. Montoya ,
    M. Mateo-March ,
    C. Blasco-Lafarga :

    DOI: 10.1556/2060.2021.00153

    Abstract: Purpose: The present study aimed to compare the physiological responses of high-intensity race-pace continuous vs. interval workouts commonly used in middle-distance athletics, by means of analyzing postexercise cardiac autonomic regulation and lactate. Methods: Nineteen highly-trained 800-m male runners were asked to run a 600-m race-pace continuous workout and a 2 3 4 3 200-m interval training, counterbalanced and randomized within one week of difference. Blood lactate jointly with linear and nonlinear heart rate dynamics were assessed during the immediate 15-min recovery. Age-category (Under23- Senior vs. Juvenile-Junior) was considered as an inter-subject factor. Results: Peak lactate was higher following the interval training (15.51 ± 0.99 vs 13.83 ± 1.77 mmol L⁻¹; P < 0.05) whereas lactate removal was almost nonexistent 15 min after both workouts (between 0 and 16%). Vagal modulation (ln RMSSD and lnRMSSD to RR ratio) remained significantly depressed at the end of recovery following both workouts, although the alteration was larger following the interval training. Detrended Fluctuation Analysis evidenced a more random HR behavior (DFA₁ closer to 0.5) during the first 9 min of recovery after the interval training, whereas no significant change was observed in heart rate complexity (SampEn). Neither were differences found in post-exercise lactate and HR dynamics as a function of age-category. Conclusions: High-intensity workouts commonly used in middle-distance athletics, both race-pace continuous and intervallic approaches, induce a large depression of vagal modulation in highly trained runners, although interval trainings appear to induce even a greater alteration of both linear and nonlinear HR dynamics and a higher post-exercise peak lactate.

    Keywords: complexity, middle-distance athletics, recovery, supramaximal, running