Frataxin deficiency shifts metabolism to promote reactive microglia via glucose catabolism.

Immunometabolism investigates the intricate relationship between the immune system and cellular metabolism. This study delves into the consequences of mitochondrial frataxin (FXN) depletion, the primary cause of Friedreich's ataxia (FRDA), a debilitating neurodegenerative condition characterized by impaired coordination and muscle control. By using single-cell RNA sequencing, we have identified distinct cellular clusters within the cerebellum of an FRDA mouse model, emphasizing a significant loss in the homeostatic response of microglial cells lacking FXN. Remarkably, these microglia deficient in FXN display heightened reactive responses to inflammatory stimuli. Furthermore, our metabolomic analyses reveal a shift towards glycolysis and itaconate production in these cells. Remarkably, treatment with butyrate counteracts these immunometabolic changes, triggering an antioxidant response via the itaconate-Nrf2-GSH pathways and suppressing the expression of inflammatory genes. Furthermore, we identify Hcar2 (GPR109A) as a mediator involved in restoring the homeostasis of microglia without FXN. Motor function tests conducted on FRDA mice underscore the neuroprotective attributes of butyrate supplementation, enhancing neuromotor performance. In conclusion, our findings elucidate the role of disrupted homeostatic function in cerebellar microglia in the pathogenesis of FRDA. Moreover, they underscore the potential of butyrate to mitigate inflammatory gene expression, correct metabolic imbalances, and improve neuromotor capabilities in FRDA.

CdS-Based Hydrothermal Photocatalysts for Complete Reductive Dehalogenation of a Chlorinated Propionic Acid in Water by Visible Light.

Cadmium sulfide (CdS)-based photocatalysts are prepared following a hydrothermal procedure (with CdCl2 and thiourea as precursors). The HydroThermal material annealed (CdS-HTa) is crystalline with a band gap of 2.31 eV. Photoelectrochemical investigation indicates a very reducing photo-potential of -0.9 V, which is very similar to that of commercial CdS. CdS-HTa, albeit having similar reducing properties, is more active than commercial CdS in the reductive dehalogenation of 2,2-dichloropropionic acid (dalapon) to propionic acid. Spectroscopic, electro-, and photoelectrochemical investigation show that photocatalytic properties of CdS are correlated to its electronic structure. The reductive dehalogenation of dalapon has a double significance: on one hand, it represents a demanding reductive process for a photocatalyst, and on the other hand, it has a peculiar interest in water treatment because dalapon can be considered a representative molecule of persistent organic pollutants and is one of the most important disinfection by products, whose removal from the water is the final obstacle to its complete reuse. HPLC-MS investigation points out that complete disappearance of dalapon passes through 2-monochloropropionic acid and leads to propionic acid as the final product. CdS-HTa requires very mild working conditions (room temperature, atmospheric pressure, natural pH), and it is stable and recyclable without significant loss of activity.

Neuroprotective effects of niclosamide on disease progression via inflammatory pathways modulation in SOD1-G93A and FUS-associated amyotrophic lateral sclerosis models.

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease influenced by genetic, epigenetic, and environmental factors, resulting in dysfunction in cellular and molecular pathways. The limited efficacy of current treatments highlights the need for combination therapies targeting multiple aspects of the disease. Niclosamide, an anthelminthic drug listed as an essential medicine, has been repurposed in clinical trials for different diseases due to its anti-inflammatory and anti-fibrotic properties. Niclosamide can inhibit various molecular pathways (e.g., STAT3, mTOR) that are dysregulated in ALS, suggesting its potential to disrupt these altered mechanisms associated with the pathology. We administered niclosamide intraperitoneally to two transgenic murine models, SOD1-G93A and FUS mice, mimicking key pathological processes of ALS. The treatment was initiated at the onset of symptoms, and we assessed disease progression by neurological scores, rotarod and wire tests, and monitored survival. Furthermore, we investigated cellular and molecular mechanisms affected by niclosamide in the spinal cord and muscle of ALS mice. In both models, the administration of niclosamide resulted in a slowdown of disease progression, an increase in survival rates, and an improvement in tissue pathology. This was characterised by reduced gliosis, motor neuron loss, muscle atrophy, and inflammatory pathways. Based on these results, our findings demonstrate that niclosamide can impact multiple pathways involved in ALS. This multi-targeted approach leads to a slowdown in the progression of the disease, positioning niclosamide as a promising candidate for repurposing in the treatment of ALS.

Ascending aorta dilatation is associated to hard cardiovascular events, follow-up from multicentric ARGO-Perspective project.

Aortic root dilatation has been proposed as hypertension-mediated organ damage (HMOD). Nevertheless, the role of the aortic root dilatation as a possible additional HMOD is still unclear since studies conducted so far are quite heterogeneous regarding the type of population analyzed, the aortic tract considered, and the type of outcomes accounted for. The aim of the present study is to assess whether the presence of aortic dilatation is associated with strong cardiovascular (CV) events (MACE: heart failure, CV death, stroke, acute coronary syndrome, myocardial revascularization) in a population of patients affected by essential hypertension. Four hundred forty-five hypertensive patients from six Italian hospitals were recruited as part of ARGO-SIIA study1. For all centers, follow-up was obtained by re-contacting all patients by telephone and through the hospital's computer system. Aortic dilatation (AAD) was defined through absolute sex-specific thresholds as in previous studies (41 mm for males, 36 mm for females). Median follow-up was 60 months. AAD was found to be associated with the occurrence of MACE (HR = 4.07 [1.81-9.17], p < 0.001). This result was confirmed after correction for main demographic characteristics such as age, sex and BSA (HR = 2.91 [1.18-7.17], p = 0.020). At penalized Cox regression, age, left atrial dilatation, left ventricular hypertrophy and AAD were identified as best predictor of MACEs and AAD resulted a significant predictor of MACEs even after correction for these confounders (HR = 2.43 [1.02-5.78], p = 0.045). The presence of AAD was found to be associated with an increased risk of MACE independently of for major confounders, including established HMODs. AAD ascending aorta dilatation, LAe left atrial enlargement, LVH left ventricular hypertrophy, MACEs major adverse cardiovascular events, SIIA Società Italiana dell'Ipertensione Arteriosa (Italian Society for Arterial Hypertension).

Performance of risk stratification scores and role of comorbidities in older vs younger patients with pulmonary arterial hypertension.

BACKGROUND: Risk scores are important tools for the prognostic stratification of pulmonary arterial hypertension (PAH). Their performance and the additional impact of comorbidities across age groups is unknown. METHODS: Patients with PAH enrolled from 2001 to 2021 were divided in ≥65 years old vs <65 years old patients. Study outcome was 5-year all-cause mortality. French Pulmonary Hypertension Network (FPHN), FPHN noninvasive, Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) and Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL 2.0) risk scores were calculated and patients categorized at low, intermediate and high risk. Number of comorbidities was calculated. RESULTS: Among 383 patients, 152 (40%) were ≥65 years old. They had more comorbidities (number of comorbidities 2, IQR 1-3, vs 1, IQR 0-2 in <65 years patients). Five-year survival was 63% in ≥65 vs 90% in <65 years. Risk scores correctly discriminated the different classes of risk in the overall cohort and in the older and younger groups. REVEAL 2.0 showed the best accuracy in the total cohort (C-index 0.74, standard error-SE- 0.03) and older (C-index 0.69, SE 0.03) patients, whereas COMPERA 2.0 performed better in younger patients (C-index 0.75, SE 0.08). Number of comorbidities was associated with higher 5-year mortality, and consistently increased the accuracy of risk scores, in younger but not in older patients. CONCLUSIONS: Risk scores have similar accuracy in the prognostic stratification of older vs younger PAH patients. REVEAL 2.0 had the best performance in older patients and COMPERA 2.0 had it in younger patients. Comorbidities increased the accuracy of risk scores only in younger patients.

A Novel Hydrothermal CdS with Enhanced Photocatalytic Activity and Photostability for Visible Light Hydrogenation of Azo Bond: Synthesis and Characterization.

A good photocatalyst maximizes the absorption of excitation light while reducing the recombination of photogenerated carriers. Among visible light responsive materials, CdS has good carrier transport capacity; however, its photostability is poor and limits its use. Here, the synthesis of a new hydrothermal CdS is reported, and post-synthesis annealing determines crystal properties and spectroscopic characteristics. The introduction of sulfur vacancies as intra band gap states is the key factor for the enhancement of photocatalytic activity. In fact, by spectroscopic and photo-electrochemical experiments, we demonstrate that sulfur vacancies act as an electron sink, favoring the charge transfer process to methyl orange. In addition, the studied hydrothermal CdS is characterized by very high stability, thus enabling a visible-light active photocatalyst that is overall recyclable, stable and more efficient than the commercial benchmark.

The point on the electronic cigarette more than 10 years after its introduction.

Electronic cigarettes (e-cigarettes) are battery-powered devices containing a liquid based on propylene glycol or vegetable glycerin, compounds which, when vaporized, act as a vehicle for nicotine, flavours, and other chemical components. These devices have been marketed without clear evidence of risks, long-term safety, and efficacy as a means of traditional smoking cessation. Recent clinical studies have shown how the use of the e-cigarette, combined with adequate psychological support, can be effective in reducing traditional smoking but not nicotine addiction. However, meta-analyses of observational studies have not confirmed this efficacy. Several studies have also highlighted an increase in sympathetic tone, vascular stiffness, and endothelial dysfunction, all factors associated with an increased cardiovascular risk. Clinicians, therefore, should carefully monitor the possible risks to public health deriving from the use of e-cigarettes and should discourage non-smokers and adolescents from using such devices. Finally, particular attention should be paid to smokers so that the combined use of electronic and traditional cigarettes can be limited as much as possible.

Neuroinflammation in Friedreich's Ataxia.

Friedreich's ataxia (FRDA) is a rare genetic disorder caused by mutations in the gene frataxin, encoding for a mitochondrial protein involved in iron handling and in the biogenesis of iron-sulphur clusters, and leading to progressive nervous system damage. Although the overt manifestations of FRDA in the nervous system are mainly observed in the neurons, alterations in non-neuronal cells may also contribute to the pathogenesis of the disease, as recently suggested for other neurodegenerative disorders. In FRDA, the involvement of glial cells can be ascribed to direct effects caused by frataxin loss, eliciting different aberrant mechanisms. Iron accumulation, mitochondria dysfunction, and reactive species overproduction, mechanisms identified as etiopathogenic in neurons in FRDA, can similarly affect glial cells, leading them to assume phenotypes that can concur to and exacerbate neuron loss. Recent findings obtained in FRDA patients and cellular and animal models of the disease have suggested that neuroinflammation can accompany and contribute to the neuropathology. In this review article, we discuss evidence about the involvement of neuroinflammatory-related mechanisms in models of FRDA and provide clues for the modulation of glial-related mechanisms as a possible strategy to improve disease features.

Visible Light Reductive Photocatalysis of Azo-Dyes with n-n Junctions Based on Chemically Deposited CdS.

New composite photocatalysts have been obtained by chemical bath deposition of CdS on top of either nanostructured crystalline ZrO2 or TiO2 films previously deposited on conductive glass FTO. Their morphological, photoelectrochemical and photochemical properties have been investigated and compared. Time resolved spectroscopic, techniques show that in FTO/TiO2/CdS films the radiative recombination of charges, separated by visible illumination of CdS, is faster than in FTO/ZrO2/CdS, evidencing that carrier dynamics in the two systems is different. Photoelectrochemical investigation evidence a suppression of electron collection in ZrO2/CdS network, whereas electron injection from CdS to TiO2 is very efficient since trap states of TiO2 act as a reservoir for long lived electrons storage. This ability of FTO/TiO2/CdS films is used in the reductive cleavage of N=N bonds of some azo-dyes by visible light irradiation, with formation and accumulation of reduced aminic intermediates, identified by ESI-MS analysis. Needed protons are provided by sodium formate, a good hole scavenger that leaves no residue upon oxidation. FTO/TiO2/CdS has an approximately 100 meV driving force larger than FTO/ZrO2/CdS under illumination for azo-dye reduction and it is always about 10% more active than the seconds. The films showed very high stability and recyclability, ease of handling and recovering.

Targeting S100A4 with niclosamide attenuates inflammatory and profibrotic pathways in models of amyotrophic lateral sclerosis.

BACKGROUND: An increasing number of studies evidences that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. We previously reported the upregulation in ALS models of a gene called fibroblast-specific protein-1 or S100A4, recognized as a pro-inflammatory and profibrotic factor. Since inflammation and fibrosis are often mutual-sustaining events that contribute to establish a hostile environment for organ functions, the comprehension of the elements responsible for these interconnected pathways is crucial to disclose novel aspects involved in ALS pathology. METHODS: Here, we employed fibroblasts derived from ALS patients harboring the C9orf72 hexanucleotide repeat expansion and ALS patients with no mutations in known ALS-associated genes and we downregulated S100A4 using siRNA or the S100A4 transcriptional inhibitor niclosamide. Mice overexpressing human FUS were adopted to assess the effects of niclosamide in vivo on ALS pathology. RESULTS: We demonstrated that S100A4 underlies impaired autophagy and a profibrotic phenotype, which characterize ALS fibroblasts. Indeed, its inhibition reduces inflammatory, autophagic, and profibrotic pathways in ALS fibroblasts, and interferes with different markers known as pathogenic in the disease, such as mTOR, SQSTM1/p62, STAT3, α-SMA, and NF-κB. Importantly, niclosamide in vivo treatment of ALS-FUS mice reduces the expression of S100A4, α-SMA, and PDGFRß in the spinal cord, as well as gliosis in central and peripheral nervous tissues, together with axonal impairment and displays beneficial effects on muscle atrophy, by promoting muscle regeneration and reducing fibrosis. CONCLUSION: Our findings show that S100A4 has a role in ALS-related mechanisms, and that drugs such as niclosamide which are able to target inflammatory and fibrotic pathways could represent promising pharmacological tools for ALS.

Impact of Perioperative Immunonutrition on Complications in Patients Undergoing Radical Cystectomy: A Retrospective Analysis.

INTRODUCTION: Radical cystectomy (RC) is the gold standard treatment for patients with muscle-invasive or refractory non-muscle invasive bladder cancer. It is estimated that approximately 64% and 13% of RC patients experience any complication and major complications, respectively. Specialized immunonutrition (SIM) aims to reduce the rates of complications after RC. We reported surgical complication rates in RC patients who received (SIM group) versus who did not receive (no-SIM group) perioperative SIM. Moreover, we investigated factors associated with complications after RC. MATERIAL AND METHODS: This is a retrospective cohort study of 52 patients who underwent RC between April 2016 and December 2017. Overall, 26 (50%) patients received perioperative SIM. We recorded age, gender, Charlson Comorbidity Index (CCI), body mass index (BMI), Malnutrition Universal Screening Tool (MUST) score, unintentional weight loss (UWL), SIM drinks consume, surgical approach, urinary diversion, neoadjuvant chemotherapy (NAC), use of total parenteral nutrition (TPN), final pathology, length of stay (LOS), and complications. RESULTS: SIM was associated with higher rates of documented infections (P = .03). Conversely, post-operative ileus was associated with higher rates of overall infections (P = .03). Median LOS was comparable within the 2 groups. Overall, 4 (15.38%) versus 0 (0%) patients in SIM versus no-SIM group were readmitted to hospital (P = .03). Age, CCI, NAC, and TPN were not associated with complication rates. CONCLUSIONS: SIM is not associated with lower rates of post-operative complications in RC candidates. Moreover, higher rates of documented infections were observed in the SIM group. Patients with post-operative ileus experienced more infections. Age, CCI, NAC, and TPN were not predictive of complications.

S100A4 in the Physiology and Pathology of the Central and Peripheral Nervous System.

S100A4 is a member of the large family of S100 proteins, exerting a broad range of intracellular and extracellular functions that vary upon different cellular contexts. While S100A4 has long been implicated mainly in tumorigenesis and metastatization, mounting evidence shows that S100A4 is a key player in promoting pro-inflammatory phenotypes and organ pro-fibrotic pathways in the liver, kidney, lung, heart, tendons, and synovial tissues. Regarding the nervous system, there is still limited information concerning S100A4 presence and function. It was observed that S100A4 exerts physiological roles contributing to neurogenesis, cellular motility and chemotaxis, cell differentiation, and cell-to cell communication. Furthermore, S100A4 is likely to participate to numerous pathological processes of the nervous system by affecting the functions of astrocytes, microglia, infiltrating cells and neurons and thereby modulating inflammation and immune reactions, fibrosis as well as neuronal plasticity and survival. This review summarizes the current state of knowledge concerning the localization, deregulation, and possible functions of S100A4 in the physiology of the central and peripheral nervous system. Furthermore, we highlight S100A4 as a gene involved in the pathogenesis of neurological disorders such as brain tumors, neurodegenerative diseases, and acute injuries.

Metabolic syndrome is related to vascular structural alterations but not to functional ones both in hypertensives and healthy subjects.

BACKGROUND AND AIMS: Metabolic Syndrome (MS) has been related to an impairment in arterial structural and functional properties with heterogeneous results. In this paper we focused on the effects of MS on arterial carotid-femoral PWV and common carotid IMT in two different populations, one of hypertensive patients and one of healthy controls. METHODS AND RESULTS: We enrolled 816 consecutive HT and 536 healthy controls. Vascular structural (IMT) and functional (PWV) properties were evaluated. NCEP-ATP-III criteria were used for diagnosis of MS. MS was diagnosed in 26.9% and 6.9% in hypertensive and control subjects, respectively. PWV was similar in controls with and without MS (7.7 ± 1.9 vs 7.6 ± 1.1 m/s, p = 0.69), while IMT was higher in controls with than those without MS (0.64 ± 0.18 vs 0.57 ± 0.13 mm, p = 0.02). Hypertensives with MS were older (57.9 ± 12.2 vs 52.7 ± 14.1 years, p < 0.001) and showed higher PWV (9.0 ± 2.3 vs 8.4 ± 2.1 m/s, p = 0.001) and IMT (0.72 ± 0.22 vs 0.65 ± 0.17 mm, p < 0.001) than those without MS, however at the age-adjusted analysis only the difference in IMT was confirmed (p = 0.007). Regression models showed that MS was an independent determinant of IMT in both controls (ß = 0.08, p = 0.03) and hypertensives (ß = 0.08, p = 0.01), but not of PWV either in controls (ß = 0.006, p = 0.886 and ß = 0.04, p = 0.19, respectively). CONCLUSIONS: the main finding of our work is that MS is a significant determinant of IMT while this is not the case for PWV. This result have been confirmed both in hypertensive subjects and in healthy controls.

Hyperuricemia prevalence in healthy subjects and its relationship with cardiovascular target organ damage.

BACKGROUND AND AIM: Heterogeneous results have been obtained in the relationship between Uric Acid (UA) and Target Organ Damage (TOD). In the present study we sought to assess the prevalence of hyperuricemia in healthy subjects as well as the role of UA in determining TOD. We evaluated vascular, cardiac and renal TODs in the whole population as well as sub-grouped by gender. METHODS AND RESULTS: As many as 379 blood donors participated at the present analysis. TOD was evaluated as Pulse Wave Velocity (PWV), Left Ventricular Mass Index (LVMI) and carotid Intima-Media Thickness (IMT). Hyperuricemia was defined with the classic cut-off (>7.0 in men and >6.0 mg/dL in women) but also with a most recently defined one (5.6 mg/dL for both sex). Hyperuricemia was present in 6.3% of the whole population (7.3% males, 2.8% females) considering the classic cut-off, while, with the recently identified one, it was present in 28.2% of the whole population (37.3% males, 4.7% females). Despite all the evaluated TODs significantly correlated with UA, linear multivariate regression analysis showed that none of them, except for GFR, displayed UA as a significant covariate. Similar figures were found also when both correlation and linear regression analyses were repeated in the two genders separately. CONCLUSIONS: Hyperuricemia is an important problem also in healthy subjects and its prevalence could further increase if lower cut-off will be used. In this specific population UA is significantly associated with renal impairment while this was not the case for cardiac and vascular damage.

Nutraceuticals in Chronic Coronary Syndromes: Preclinical Data and Translational Experiences.

Non-pharmacological treatments have always been considered important in the management of Chronic Coronary Syndromes. Nutraceuticals ("Nutrition" + "Pharmaceutical") could fall both under the definition of non-pharmacological treatment and pharmacological one or, probably more correctly, in the middle of these two kinds of therapies. However, the word "nutraceuticals" never appears in the latest guidelines on this issue. This is probably determined by the fact that evidences on this topic are scarce and most of the published articles are based on preclinical data while translational experiences are available only for some molecules. In this review we will focus on nutraceutical strategies that act on the ischemic myocardium itself and not only on the cardiovascular risk factors. As demonstrated by the important number of papers published in recent years, this is an evolving topic and evaluated substances principally act on two mechanisms (cardiac energetics and ischemia-reperfusion damage) that will be also reviewed.

Modified-BEP Chemotherapy in Patients With Germ-Cell Tumors Treated at a Comprehensive Cancer Center.

OBJECTIVES: Bleomycin, etoposide, and cisplatin (BEP) is the most common and successful chemotherapy regimen for germ-cell tumor (GCT) patients, accompanied by a bleomycin-induced dose-dependent lung toxicity in certain patients. In an attempt to reduce bleomycin-toxicity, we developed a modified-BEP (mBEP) regimen. MATERIALS AND METHODS: Between August 2008 and February 2018, 182 unselected mainly testicular GCT patients (39 with adjuvant purpose and 143 with curative purpose) received a tri-weekly 5-day hospitalization schedule with bleomycin 15 U intravenous (IV) push on day 1 and 10 U IV continuous infusion over 12 hours on days 1 to 3, cisplatin 20 mg/m IV, and etoposide 100 mg/m IV on days 1 to 5. Pulmonary toxicity was assessed through chest computed tomography scan and clinical monitoring. RESULTS: Median number of mBEP cycles was 3 (range: 1 to 4). In the curative setting, according to the International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic system, 112, 21, and 9 patients had good-risk, intermediate-risk, and poor-risk class, respectively; 66 (46%) patients had complete response (CR), 67 (47%) had partial response (52 of whom became CR afterwards), 6 (4%) had stable disease (that in 3 became CR afterwards), 3 (2%) progressed, and 1 (1%) died of brain stroke. At a median follow-up of 2.67 years (interquartile range: 1.23-5.00 y), 1 and 5-year overall survival and progression-free survival were 99% and 95%, and 90% and 88%, respectively. In the entire patient population, there was grade 3/4 neutropenia in 92 patients (51%), febrile neutropenia in 11 patients (6%), grade 1/2 nausea in 74 patients (41%), and no death due to pulmonary toxicity. CONCLUSION: In GCT patients, our mBEP-schedule would suggest an effective treatment modality without suffering meaningful pulmonary toxicity.

Paclitaxel-releasing mesenchymal stromal cells inhibit in vitro proliferation of human mesothelioma cells.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a rare fatal asbestos-related malignancy originating in the mesothelial cells of the pleura. A platinum-based doublet containing a third-generation antifolate is the front-line standard of care whilst there are no approved second-line treatments for MPM which remains a disease setting to test the efficacy of new therapeutic agents. METHODS: Bone marrow mesenchymal stromal cells (BM-MSCs) were loaded with pemetrexed (PMX) and paclitaxel (PTX) according to a standardized procedure. Drug release by both PMX- and PTX-primed BM-MSCs (BM-MSCs/PMX and BM-MSCs/PTX) was tested on the in vitro proliferation of a panel of tumor cell lines including NCI-H28 mesothelioma. RESULTS: The in vitro anticancer activity of pure PTX was significantly higher than that of PMX against all the cell lines tested (14.7 times higher than that of PMX against NCI-H28). Whereas BM-MSCs did not take up and release PMX in amounts effective on mesothelioma, PTX-loaded BM-MSCs dramatically inhibited mesothelioma proliferation. CONCLUSIONS: PTX-primed mesenchymal stromal cells successfully inhibit the in vitro proliferation of human mesothelioma cells. Further studies and in vivo testing are required to confirm our preliminary in vitro results as a potential new mesothelioma therapy based on cell drug delivery.