Oxidative stress and cardiomyocyte apoptosis play critical roles in doxorubicin (DOX)-induced cardiotoxicity. Previous studies indicated that fibronectin type III domain-containing 5 (FNDC5) and its ...cleaved form, irisin, could preserve mitochondrial function and attenuate oxidative damage as well as cell apoptosis, however, its role in DOX-induced cardiotoxicity remains unknown. Our present study aimed to investigate the role and underlying mechanism of FNDC5 on oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity. Cardiomyocyte-specific FNDC5 overexpression was achieved using an adeno-associated virus system, and then the mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg) to generate DOX-induced cardiotoxicity. Herein, we found that FNDC5 expression was downregulated in DOX-treated murine hearts and cardiomyocytes. Fndc5 deficiency resulted in increased oxidative damage and apoptosis in H9C2 cells under basal conditions, imitating the phenotype of DOX-induced cardiomyopathy in vitro, conversely, FNDC5 overexpression or irisin treatment alleviated DOX-induced oxidative stress and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, we identified that FNDC5/Irisin activated AKT/mTOR signaling and decreased DOX-induced cardiomyocyte apoptosis, and moreover, we provided direct evidence that the anti-oxidant effect of FNDC5/Irisin was mediated by the AKT/GSK3β/FYN/Nrf2 axis in an mTOR-independent manner. And we also demonstrated that heat shock protein 20 was responsible for the activation of AKT caused by FNDC5/Irisin. In line with the data in acute model, we also found that FNDC5/Irisin exerted beneficial effects in chronic model of DOX-induced cardiotoxicity (5 mg/kg, i.p., once a week for three times, the total cumulative dose is 15 mg/kg) in mice. Based on these findings, we supposed that FNDC5/Irisin was a potential therapeutic agent against DOX-induced cardiotoxicity.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Inflammation and myocytes apoptosis play critical roles in the development of doxorubicin (DOX)-induced cardiotoxicity. Our previous study found that C1q/tumour necrosis factor-related protein-3 ...(CTRP3) could inhibit cardiac inflammation and apoptosis of myocytes but its role in DOX-induced heart injury remains largely unknown. Our study aimed to investigate whether CTRP3 protected against DOX-induced heart injury and the underlying mechanism.
We overexpressed CTRP3 in the hearts using an adeno-associated virus system. The mice were subjected to a single intraperitoneal injection of DOX (15mg/kg) to induce short-term model for cardiomyopathy. The morphological examination and biochemical analysis were used to evaluate the effects of CTRP3. H9C2 cells were used to verify the protective role of CTRP3 in vitro.
Myocardial CTRP3 protein levels were reduced in DOX-treated mice. Cardiac specific-overexpression of CTRP3 preserved heart dysfunction, and attenuated cardiac inflammation and cell loss induced by DOX in vivo and in vitro. CTRP3 could activate silent information regulator 1 (Sirt1) in vivo and in vitro. Moreover, specific inhibitor of Sirt1 and the silence of Sirt1 could abolish the protective effects of CTRP3 against DOX-induced inflammation and apoptosis.
CTRP3 protected against DOX-induced heart injury via activation of Sirt1. CTRP3 has therapeutic potential for the treatment of DOX cardiotoxicity.
•CTRP3 attenuated doxorubicin (DOX)-induced cardiac dysfunction, inflammation and cell death.•CTRP3 could activate Sirt1 in vivo and in vitro.•The deficiency of Sirt1 blocked the protective effects of CTRP3 in DOX-induced heart injury.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The D614G mutation in the spike protein of SARS-CoV-2 alters the fitness of the virus, leading to the dominant form observed in the COVID-19 pandemic. However, the molecular basis of the mechanism by ...which this mutation enhances fitness is not clear. Here we demonstrated by cryo-electron microscopy that the D614G mutation resulted in increased propensity of multiple receptor-binding domains (RBDs) in an upward conformation poised for host receptor binding. Multiple substates within the one RBD-up or two RBD-up conformational space were determined. According to negative staining electron microscopy, differential scanning calorimetry, and differential scanning fluorimetry, the most significant impact of the mutation lies in its ability to eliminate the unusual cold-induced unfolding characteristics and to significantly increase the thermal stability under physiological pH. The D614G spike variant also exhibited exceptional long-term stability when stored at 37 °C for up to 2 months. Our findings shed light on how the D614G mutation enhances the infectivity of SARS-CoV-2 through a stabilizing mutation and suggest an approach for better design of spike protein-based conjugates for vaccine development.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This study aimed to establish an effective prognostic nomogram with or without plasma Epstein-Barr virus DNA (EBV DNA) for nondisseminated nasopharyngeal carcinoma (NPC).
The nomogram was based on a ...retrospective study of 4630 patients who underwent radiotherapy with or without chemotherapy at Sun Yat-sen University Cancer Center from 2007 to 2009. The predictive accuracy and discriminative ability of the nomogram were determined by a concordance index (C-index) and calibration curve and were compared with EBV DNA and the current staging system. The results were validated using bootstrap resampling and a prospective cohort study on 1819 patients consecutively enrolled from 2011 to 2012 at the same institution. All statistical tests were two-sided.
Independent factors derived from multivariable analysis of the primary cohort to predict recurrence were age, sex, body mass index (BMI), T stage, N stage, plasma EBV DNA, pretreatment high sensitivity C-reactive protein (hs-CRP), lactate dehydrogenase (LDH), and hemoglobin level (HGB), which were all assembled into the nomogram with (nomogram B) or without EBV DNA (nomogram A). The calibration curve for the probability of recurrence showed that the nomogram-based predictions were in good agreement with actual observations. The C-index of nomogram B for predicting recurrence was 0.728 (P < .001), which was statistically higher than the C-index values for nomogram A (0.690), EBV DNA (0.680), and the current staging system (0.609). The C-index of nomogram B (0.730) and nomogram A (0.681) remained higher for predicting recurrence among patients treated with intensity-modulated radiotherapy (P < .001). The results were confirmed in the validation cohort.
The proposed nomogram with or without plasma EBV DNA resulted in more accurate prognostic prediction for NPC patients.
The Covid-19 shock in European regions McCann, Philip; Ortega-Argilés, Raquel; Yuan, Pei-Yu
Regional studies,
07/2022, Volume:
56, Issue:
7
Journal Article
Peer reviewed
Open access
We examine the regional mortality rates associated with the spread of Covid-19 in Europe. In particular, we analyse the potential contribution of the country's geographical and institutional features ...in shaping the virus's interregional spread and resulting local death rates. Our analysis is based on information from both pandemic waves from March to the end of November 2020. In a multilevel hierarchical regression estimation setting, covering information from over 600 OECD-TL3 areas, over 120 larger OECD-TL2 areas and 15 national-level areas, our findings suggest that local death rates are affected by the geographical and institutional features at the local, regional and national levels.
Full text
Available for:
BFBNIB, IZUM, KILJ, NUK, PILJ, SAZU, UL, UM, UPUK
Aging is an important risk factor for cardiovascular diseases, and aging‐related cardiac dysfunction serves as a major determinant of morbidity and mortality in elderly populations. Our previous ...study has identified fibronectin type III domain‐containing 5 (FNDC5) and its cleaved form, irisin, as the cardioprotectant against doxorubicin‐induced cardiomyopathy. Herein, aging or matched young mice were overexpressed with FNDC5 by adeno‐associated virus serotype 9 (AAV9) vectors, or subcutaneously infused with irisin to uncover the role of FNDC5 in aging‐related cardiac dysfunction. To verify the involvement of nucleotide‐binding oligomerization domain‐like receptor with a pyrin domain 3 (NLRP3) and AMP‐activated protein kinase α (AMPKα), Nlrp3 or Ampkα2 global knockout mice were used. Besides, young mice were injected with AAV9‐FNDC5 and maintained for 12 months to determine the preventive effect of FNDC5. Moreover, neonatal rat cardiomyocytes were stimulated with tumor necrosis factor‐α (TNF‐α) to examine the role of FNDC5 in vitro. We found that FNDC5 was downregulated in aging hearts. Cardiac‐specific overexpression of FNDC5 or irisin infusion significantly suppressed NLRP3 inflammasome and cardiac inflammation, thereby attenuating aging‐related cardiac remodeling and dysfunction. In addition, irisin treatment also inhibited cellular senescence in TNF‐α‐stimulated cardiomyocytes in vitro. Mechanistically, FNDC5 activated AMPKα through blocking the lysosomal degradation of glucagon‐like peptide‐1 receptor. More importantly, FNDC5 gene transfer in early life could delay the onset of cardiac dysfunction during aging process. We prove that FNDC5 improves aging‐related cardiac dysfunction by activating AMPKα, and it might be a promising therapeutic target to support cardiovascular health in elderly populations.
FNDC5 is downregulated in aging hearts, and cardiac‐specific overexpression of FNDC5 or irisin infusion attenuates aging‐related inflammation, cardiac remodeling, and dysfunction. Mechanistically, FNDC5 activates AMPKα through blocking the lysosomal degradation of GLP‐1R.
Full text
Available for:
DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Cancer is a destructive disease that causes high levels of morbidity and mortality. Doxorubicin (DOX) is a highly efficient antineoplastic chemotherapeutic drug, but its use places survivors at risk ...for cardiotoxicity. Many studies have demonstrated that multiple factors are involved in DOX-induced acute cardiotoxicity. Among them, oxidative stress and cell death predominate. In this review, we provide a comprehensive overview of the mechanisms underlying the source and effect of free radicals and dependent cell death pathways induced by DOX. Hence, we attempt to explain the cellular mechanisms of oxidative stress and cell death that elicit acute cardiotoxicity and provide new insights for researchers to discover potential therapeutic strategies to prevent or reverse doxorubicin-induced cardiotoxicity.
Proteasomal activity is compromised in diabetic hearts that contributes to proteotoxic stresses and cardiac dysfunction. Osteocrin (OSTN) acts as a novel exercise-responsive myokine and is implicated ...in various cardiac diseases. Herein, we aim to investigate the role and underlying molecular basis of OSTN in diabetic cardiomyopathy (DCM). Mice received a single intravenous injection of the cardiotrophic adeno-associated virus serotype 9 to overexpress OSTN in the heart and then were exposed to intraperitoneal injections of streptozotocin (STZ, 50 mg/kg) for consecutive 5 days to generate diabetic models. Neonatal rat cardiomyocytes were isolated and stimulated with high glucose to verify the role of OSTN in vitro. OSTN expression was reduced by protein kinase B/forkhead box O1 dephosphorylation in diabetic hearts, while its overexpression significantly attenuated cardiac injury and dysfunction in mice with STZ treatment. Besides, OSTN incubation prevented, whereas OSTN silence aggravated cardiomyocyte apoptosis and injury upon hyperglycemic stimulation in vitro. Mechanistically, OSTN treatment restored protein kinase G (PKG)-dependent proteasomal function, and PKG or proteasome inhibition abrogated the protective effects of OSTN in vivo and in vitro. Furthermore, OSTN replenishment was sufficient to prevent the progression of pre-established DCM and had synergistic cardioprotection with sildenafil. OSTN protects against DCM via restoring PKG-dependent proteasomal activity and it is a promising therapeutic target to treat DCM.
Interleukin 6 (IL-6) was abundant in the tumor microenvironment and played potential roles in tumor progression. In our study, the expression of IL-6 in tumor tissues from 36 gastric cancer (GC) ...patients was significantly higher than in non-tumor tissues. Moreover, the number of CD163
+
CD206
+
M2 macrophages that infiltrated in tumor tissues was significantly greater than those infiltrated in non-tumor tissues. The frequencies of M2 macrophages were positively correlated with the IL-6 expression in GC tumors. We also found that IL-6 could induce normal macrophages to differentiate into M2 macrophages with higher IL-10 and TGF-β expression, and lower IL-12 expression, via activating STAT3 phosphorylation. Accordingly, knocking down STAT3 using small interfering RNA decreased the expression of M2 macrophages-related cytokines (IL-10 and TGF-β). Furthermore, supernatants from IL-6-induced M2 macrophages promote GC cell proliferation and migration. Moreover, IL-6 production and CD163
+
CD206
+
M2 macrophage infiltration in tumors were associated with disease progression and reduced GC patient survival. In conclusion, our data indicate that IL-6 induces M2 macrophage differentiation (IL-10
high
TGF-β
high
IL-12
p35
low
) by activating STAT3 phosphorylation, and the IL-6-induced M2 macrophages exert a pro-tumor function by promoting GC cell proliferation and migration.
Full text
Available for:
EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
PDF
