The Citrus Flavanone Naringenin Protects Myocardial Cells against Age-Associated Damage

In recent years, the health-promoting effects of the citrus flavanone naringenin have been examined. The results have provided evidence for the modulation of some key mechanisms involved in cellular damage by this compound. In particular, naringenin has been revealed to have protective properties such as an antioxidant effect in cardiometabolic disorders. Very recently, beneficial effects of naringenin have been demonstrated in old rats. Because aging has been demonstrated to be directly related to the occurrence of cardiac disorders, in the present study, the ability of naringenin to prevent cardiac cell senescence was investigated. For this purpose, a cellular model of senescent myocardial cells was set up and evaluated using colorimetric, fluorimetric, and immunometric techniques. Relevant cellular senescence markers, such as X-gal staining, cell cycle regulator levels, and the percentage of cell cycle-arrested cells, were found to be reduced in the presence of naringenin. In addition, cardiac markers of aging-induced damage, including radical oxidative species levels, mitochondrial metabolic activity, mitochondrial calcium buffer capacity, and estrogenic signaling functions, were also modulated by the compound. These results suggested that naringenin has antiaging effects on myocardial cells

Assessment of Chestnut Gall Toughness: Implications for a Biocontrol Agent

SIMPLE SUMMARY: Torymus sinensis, the biocontrol agent of the gall wasp Dryocosmus kuriphilus, is univoltine, and exhibits a prolonged diapause. Further investigations have been carried out to assess the extent of the diapause and its trend over the years. Moreover, the seasonal variation in the galls’ toughness was measured to assess if the wall of dry galls formed in the previous year was so hard to counteract T. sinensis emergence, thus negatively affecting diapause. The window of vulnerability of the galls was also evaluated in controlled conditions. The results showed that the average number of second year T. sinensis emerging per 100 cells was 0.41 ± 0.05, and dead adults accounted for 4.1 ± 0.23 per 100 cells. Gall toughness resulted in lower values for galls collected in May and June. In general, no difference was detected in the wall toughness of galls formed during the previous year when compared to current-year dry galls. Comparing the number of oviposition events by T. sinensis and the gall toughness, a negative correlation was found. Descriptive information on this gall’s structural traits and the influence on gall wasp management are also discussed. ABSTRACT: (1) Torymus sinensis, the biocontrol agent of the Asian chestnut gall wasp Dryocosmus kuriphilus, is univoltine, but in NW Italy a small percentage of individuals exhibits a prolonged diapause, mainly as late instar larva. (2) In 2020, the diapause was investigated to evaluate its trend over the years. Due to the low survival rate of diapausing T. sinensis adults, the seasonal variation in the galls’ toughness was evaluated, thus assuming that dry galls over time can negatively affect emergence. The window of vulnerability of the gall wasp galls was also evaluated in controlled conditions. (3) The results showed that the average number of second year T. sinensis emerging per 100 cells was 0.41 ± 0.05, and dead adults accounted for 4.1 ± 0.23 per 100 cells. Gall toughness resulted in lower values for galls collected in May and June, and then gradually increased over time. In general, no difference was detected in the wall toughness of galls formed during the previous year when compared to current-year dry galls. Oviposition was recorded on all the tested galls collected in May and June, and no difference in the number of oviposition events was detected. Conversely, no oviposition was observed in July. Comparing the number of oviposition events by T. sinensis and the gall toughness, a negative correlation was found (R(2) = −0.99). (4) The present findings contribute descriptive information on this gall’s structural traits, and the influence on gall wasp management is also discussed

Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients

Natural Killer (NK) cells are a key component of tumor immunosurveillance and thus play an important role in rituximab-dependent killing of lymphoma cells via an antibody-dependent cellular cytotoxicity (ADCC) mechanism. We evaluated the phenotypic and functional assets of peripheral blood NK cell subsets in 32 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients and in 27 healthy controls. We further monitored long-term modifications of patient NK cells for up to 12 months after rituximab-based immunochemotherapy. At diagnosis, patients showed a higher percentage of CD56dim and CD16C NK cells, and a higher frequency of GrzBC cells in CD56dim, CD56bright, and CD16C NK cell subsets than healthy controls. Conversely, DLBCL NK cell killing and interferon g (IFNg) production capability were comparable to those derived from healthy subjects. Notably, NK cells from refractory/relapsed patients exhibited a lower “natural” cytotoxicity. A marked and prolonged therapy-induced reduction of both “natural” and CD16- dependent NK cytotoxic activities was accompanied by the down-modulation of CD16 and NKG2D activating receptors, particularly in the CD56dim subset. However, reduced NK cell killing was not associated with defective lytic granule content or IFNg production capability. This study firstly describes tumor-associated and therapy-induced alterations of the systemic NK cell compartment in DLBCL patients. As these alterations may negatively impact rituximab-based therapy efficacy, our work may provide useful information for improving immunochemotherapeutic strategies

The citrus flavanone naringenin produces cardioprotective effects in hearts from 1 year old rat, through activation of mitoBK channels

Background and Purpose: Incidence of cardiovascular disorders increases with age, because of a dramatic fall of endogenous self-defense mechanisms and increased vulnerability of myocardium. Conversely, the effectiveness of many cardioprotective drugs is blunted in hearts of 1 year old rat. The Citrus flavanone naringenin (NAR) was reported to promote cardioprotective effects against ischemia/reperfusion (I/R) injury, through the activation of mitochondrial large conductance calcium-activated potassium channel (mitoBK). These effects were observed in young adult rats, but no data are available about the possible cardioprotective effects of NAR in aged animals. Experimental Approach: This study aimed at evaluating the potential cardioprotective effects of NAR against I/R damage in 1 year old rats, and the possible involvement of mitoBK. Key Results: Naringenin protected the hearts of 1 year old rats in both ex vivo and in vivo I/R protocols. Noteworthy, these effects were antagonized by paxilline, a selective BK-blocker. The cardioprotective effects of NAR were also observed in senescent H9c2 cardiomyoblasts. In isolated mitochondria from hearts of 1 year old, NAR exhibited the typical profile of a mitoBK opener. Finally, Western Blot analysis confirmed a significant (albeit reduced) presence of BK-forming alpha and beta subunits, both in cardiac tissue of 1 year old rats and in senescent H9c2 cells. Conclusion and Implications: This is the first work reporting cardioprotective effects of NAR in 1 year old rats. Although further studies are needed to better understand the whole pathway involved in the NAR-mediated cardioprotection, these preliminary data represent a promising perspective for a rational nutraceutical use of NAR in aging

Mitochondriotropic and Cardioprotective Effects of Triphenylphosphonium-Conjugated Derivatives of the Diterpenoid Isosteviol

Mitochondria play a crucial role in the cell fate; in particular, reducing the accumulation of calcium in the mitochondrial matrix offers cardioprotection. This affect is achieved by a mild depolarization of the mitochondrial membrane potential, which prevents the assembly and opening of the mitochondrial permeability transition pore. For this reason, mitochondria are an attractive target for pharmacological interventions that prevent ischaemia/reperfusion injury. Isosteviol is a diterpenoid created from the acid hydrolysis of Steviarebaudiana Bertoni (fam. Asteraceae) glycosides that has shown protective effects against ischaemia/reperfusion injury, which are likely mediated through the activation of mitochondrial adenosine tri-phosphate (ATP)-sensitive potassium (mitoKATP) channels. Some triphenylphosphonium (triPP)-conjugated derivatives of isosteviol have been developed, and to evaluate the possible pharmacological benefits that result from these synthetic modifications, in this study, the mitochondriotropic properties of isosteviol and several triPP-conjugates were investigated in rat cardiac mitochondria and in the rat heart cell line H9c2. This study's main findings highlight the ability of isosteviol to depolarize the mitochondrial membrane potential and reduce calcium uptake by the mitochondria, which are typical functions of mitochondrial potassium channel openings. Moreover, triPP-conjugated derivatives showed a similar behavior to isosteviol but at lower concentrations, indicative of their improved uptake into the mitochondrial matrix. Finally, the cardioprotective property of a selected triPP-conjugated derivative was demonstrated in an in vivo model of acute myocardial infarct

Electroconvulsive therapy: eighty years of Croatian and international experience

Elektrokonvulzivna terapija (EKT) i nakon više od 80 godina primjene i dalje predstavlja najučinkovitiju terapiju kod najtežih kliničkih slika psihijatrijskih poremećaja. U Hrvatskoj se EKT primjenjuje od 40-ih godina prošlog stoljeća. Danas se koristi samo u KBC-u Zagreb, najčešće u pacijenata sa shizofrenijom. Brojna istraživanja su utvrdila različite biološke učinke EKT-a koji pridonose antidepresivnom, antimaničnom, antipsihotičnom, antikonvulzivnom i antiparkinsonskom učinku. Konvulzije imaju snažan učinak na perfuziju i metabolizam pojedinih moždanih regija, povećanje propusnosti krvnomoždane barijere te imaju modulatorni učinak na glutamatnu, GABA, serotoninsku, dopaminsku i noradrenergičku neurotransmisiju, hormonalnu sekreciju, promjene u ekspresiji brojnih gena te potiču neuroplastičnost i u konačnici dovode do strukturnih promjena mozga. Neke su od ovih promjena kratkog vijeka, a neke traju mjesecima, poput neuroplastičnosti. Iako se EKT smatra medicinskim postupkom niskog rizika, mnoge teške somatske bolesti zahtijevaju pažljivu procjenu koristi i rizika. Najčešće su neželjene reakcije prolazne teškoće pamćenja i glavobolja. Prije prve aplikacije kandidati prolaze detaljnu dijagnostičku obradu u skladu s međunarodnim standardima. U postupku primjene EKT-a sudjeluje interdisciplinarni tim koji uključuje psihijatra, anesteziologa, anesteziološku sestru/tehničara i psihijatrijsku sestru/tehničara. Primjena opće anestezije omogućuje brz gubitak svijesti, kratkotrajnu mišićnu relaksaciju, smanjenje hiperdinamskog odgovora na električnu stimulaciju te brz oporavak spontane ventilacije i svijesti. Nedavno su predložene Hrvatske nacionalne smjernice o primjeni EKT-a. Zbog učinka u terapijskoj rezistenciji te kod vrlo teških kliničkih slika EKT može ostvariti značajan učinak u pažljivo odabranih bolesnika.Electroconvulsive therapy (ECT), even more than 80 years since its introduction, continues to be the most effective treatment for severe mental disorders. Croatian psychiatrists have used ECT since 1940s. Today it is performed only at the University Hospital Centre Zagreb, predominantly in patients with schizophrenia. Extensive research reported numerous biological effects of ECT, which contribute to its antidepressant, antimanic, antipsychotic, anticonvulsive and antiparkinsonian effects. Convulsions trigger changes in the cerebral blood flow and metabolism, increase the permeability of the blood-brain barrier, modulate glutamatergic, GABAergic, serotonergic, noradrenergic and dopaminergic neurotransmission, affect hormone secretion, gene expression, stimulate neuroplasticity, and eventually induce brain structural changes. Some of these effects are short-lasting and others, such a neuroplasticity, last for at least several months. While ECT is generally considered a low-risk medical treatment, patients with severe somatic comorbidity require careful risk-benefit assessment. The most commonly observed adverse events are transient forgetfulness and headache. Prior to initiation, candidates undergo comprehensive diagnostic evaluation according to international standards. The procedure is performed by an interdisciplinary team, consisting of psychiatrist, anesthesiologist, and psychiatric and anesthesiological nurses. The application of general anesthesia enables rapid loss of consciousness, short-time muscular relaxation, suppression of hyperdynamic response to electrical current and fast recovery of breathing and awareness. Recently, the Croatian expert group has proposed national guidelines for the ECT treatment. Due to its efficacy in both treatment-refractory and very severe symptomatology, ECT might be of a great benefit in carefully selected patients

Anti-Inflammatory Effect of the Natural H2S-Donor Erucin in Vascular Endothelium

Vascular inflammation (VI) represents a pathological condition that progressively affects the integrity and functionality of the vascular wall, thus leading to endothelial dysfunction and the onset of several cardiovascular diseases. Therefore, the research of novel compounds able to prevent VI represents a compelling need. In this study, we tested erucin, the natural isothiocyanate H2S-donor derived from Eruca sativa Mill. (Brassicaceae), in an in vivo mouse model of lipopolysaccharide (LPS)-induced peritonitis, where it significantly reduced the amount of emigrated CD11b positive neutrophils. We then evaluated the anti-inflammatory effects of erucin in LPS-challenged human umbilical vein endothelial cells (HUVECs). The pre-incubation of erucin, before LPS treatment (1, 6, 24 h), significantly preserved cell viability and prevented the increase of reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-alpha) levels. Moreover, erucin downregulated endothelial hyperpermeability and reduced the loss of vascular endothelial (VE)-Cadherin levels. In addition, erucin decreased vascular cell adhesion molecule 1 (VCAM-1), cyclooxygenase-2 (COX-2) and microsomal prostaglandin E-synthase 1 (mPGES-1) expression. Of note, erucin induced eNOS phosphorylation and counteracted LPS-mediated NF-kappa B nuclear translocation, an effect that was partially abolished in the presence of the eNOS inhibitor L-NAME. Therefore, erucin can control endothelial function through biochemical and genomic positive effects against VI

The Citrus Flavonoid Naringenin Protects the Myocardium from Ageing-Dependent Dysfunction: Potential Role of SIRT1

Sirtuin 1 (SIRT1) enzyme plays a pivotal role in the regulation of many physiological functions. In particular, it is implicated in ageing-related diseases, such as cardiac hypertrophy, myocardial infarct, and endothelial dysfunction; moreover, its expression decreases with age. Therefore, an effective strategy to extend the lifespan and improve cardiovascular function is the enhancement of the expression/activity of SIRT1 with exogenous agents. The Citrus flavonoid naringenin (NAR) presents structural similarity with the natural SIRT1 activator resveratrol. In this study, we demonstrate through in vitro assays that NAR significantly activates SIRT1 enzyme and shows antisenescence effects. The binding mode of NAR into SIRT1 was detailed investigated through in silico studies. Moreover, chronic administration (for six months) of NAR (100 mg/kg/day) to 6-month-old mice leads to an enhancement of SIRT1 expression and a marked reduction of reactive oxygen species production in myocardial tissue. Furthermore, at the end of the treatment, the plasma levels of two well-known markers of cardiovascular inflammation, TNF-α and IL6, are significantly reduced in 12-month-old mice treated with NAR, as well as the cardiovascular risk (total cholesterol/HDL ratio) compared to control mice. Finally, the age-associated fibrotic remodeling, which is well detected through a Mallory trichrome staining in the vehicle-treated 12-month-old mice, is significantly reduced by the chronic treatment with NAR. Moreover, an improvement of myocardium functionality is highlighted by the enhancement of citrate synthase activity and stabilization of the mitochondrial membrane potential after NAR treatment. Taken together, these results suggest that a nutraceutical approach with NAR may have positive impacts on many critical hallmarks of myocardial senescence, contributing to improve the cardiac performance in aged subjects

Venous Thromboembolism in Lymphoma: Risk Stratification and Antithrombotic Prophylaxis

Lymphoma is listed among the neoplasias with a high risk of venous thromboembolism (VTE). Risk factors for VTE appear to differ from risk factors in solid tumors. We review the literature of the last 20 years for reports identifying these risk factors in cohorts consisting exclusively of lymphoma patients. We selected 25 publications. The most frequent studies were analyses of retrospective single-center cohorts. We also included two reports of pooled analyses of clinical trials, two meta-analyses, two analyses of patient registries, and three analyses of population-based databases. The VTE risk is the highest upfront during the first two months after lymphoma diagnosis and decreases over time. This upfront risk may be related to tumor burden and the start of chemotherapy as contributing factors. Factors consistently reported as VTE risk factors are aggressive histology, a performance status ECOG 65 2 leading to increased immobility, more extensive disease, and localization to particular sites, such as central nervous system (CNS) and mediastinal mass. Association between laboratory values that are part of risk assessment models in solid tumors and VTE risk in lymphomas are very inconsistent. Recently, VTE risk scores for lymphoma were developed that need further validation, before they can be used for risk stratification and primary prophylaxis. Knowledge of VTE risk factors in lymphomas may help in the evaluation of the individual risk-benefit ratio of prophylaxis and help to design prospective studies on primary prophylaxis in lymphoma

Risk factors for venous thromboembolism in patients with lymphoma requiring hospitalization

Lymphoma is among the malignancies at high risk of venous thromboembolism (VTE)1. The VTE risk is the highest upfront during the first month after lymphoma diagnosis and decreases over time2. This upfront risk may be related to tumor burden and start of chemotherapy as contributing factors