Antiproliferative Organic Salts Derived from Betulinic Acid: Disclosure of an Ionic Liquid Selective Against Lung and Liver Cancer Cells

In the last few years, we have been witnessing an increasing interest in ionic liquids (ILs) and organic salts, given their potential applications in biological and pharmaceutical sciences. We report the synthesis and in vitro evaluation of novel organic salts combining betulinate, known for its anticancer properties, with antimalarial drugs, primaquine, chloroquine, and mepacrine, and also with the trihexyltetradecylphosphonium ([P6,6,6,14]) cation. The salts were screened for their in vitro activity against tumor lines HepG2 (liver), MG63 (osteosarcoma), T47D (breast), A459 (lung), and RKO (colon), and also on normal human fibroblasts. All betulinates prepared displayed antiproliferative properties, with the trihexyltetradecylphosphonium betulinate standing out for its higher selectivity. This unprecedented disclosure of a betulinic acid (BA)-derived IL with selective antitumor activity constitutes a relevant first step toward development of novel anticancer therapies based on BA-derived IL.info:eu-repo/semantics/publishedVersio

Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies

Objectives: Autoantibodies are thought to play a key role in the pathogenesis of idiopathic inflammatory myopathies (IIM). However, up to 40% of IIM patients, even those with clinical manifestations of anti-synthetase syndrome (ASSD), test seronegative to known myositis-specific autoantibodies. We hypothesized the existence of new potential autoantigens among human cytoplasmic aminoacyl tRNA synthetases (aaRS) in patients with IIM. Methods: Plasma samples from 217 patients with IIM according to 2017 EULAR/ACR criteria, including 50 patients with ASSD, 165 without, and two with unknown ASSD status were identified retrospectively, as well as age and gender-matched sera from 156 population controls, and 219 disease controls. Patients with previously documented ASSD had to test positive for at least one of the five most common anti-aaRS autoantibodies (anti-Jo1, -PL7, -PL12, -EJ, and -OJ) and present with one or more of the following clinical manifestations: interstitial lung disease, myositis, arthritis, Raynaud's phenomenon, fever, or mechanic's hands. Demographics, laboratory, and clinical data of the IIM cohort (ASSD and non-ASSD) were compared. Samples were screened using a multiplex bead array assay for presence of autoantibodies against a panel of 117 recombinant protein variants, representing 33 myositis-related proteins, including all nineteen cytoplasmic aaRS. Prospectively collected clinical data for the IIM cohort were retrieved and compared between groups within the IIM cohort and correlated with the results of the autoantibody screening. Principal component analysis was used to analyze clinical manifestations between ASSD, non-ASSD groups, and individuals with novel anti-aaRS autoantibodies. Results: We identified reactivity towards 16 aaRS in 72 of the 217 IIM patients. Twelve patients displayed reactivity against nine novel aaRS. The novel autoantibody specificities were detected in four previously seronegative patients for myositis-specific autoantibodies and eight with previously detected myositis-specific autoantibodies. IIM individuals with novel anti-aaRS autoantibodies (n = 12) all had signs of myositis, and they had either muscle weakness and/or muscle enzyme elevation, 2/12 had mechanic's hands, 3/12 had interstitial lung disease, and 2/12 had arthritis. The individuals with novel anti-aaRS and a pathological muscle biopsy all presented widespread up-regulation of major histocompatibility complex class I. The reactivities against novel aaRS could be confirmed in ELISA and western blot. Using the multiplex bead array assay, we could confirm previously known reactivities to four of the most common aaRS (Jo1, PL12, PL7, and EJ (n = 45)) and identified patients positive for anti-Zo, -KS, and -HA (n = 10) that were not previously tested. A low frequency of anti-aaRS autoantibodies was also detected in controls. Conclusion: Our results suggest that most, if not all, cytoplasmic aaRS may become autoantigenic. Autoantibodies against new aaRS may be found in plasma of patients previously classified as seronegative with potential high clinical relevance.publishedVersio

Assentment of the influence of liver cirrhosis and minimal hepatic encephalopathy on quality of life

Introduction: Minimal hepatic encephalopathy (MHE) has been associated with changes in the ability to drive, with the onset of the explicit form of hepatic encephalopathy and with a worse prognosis. However, the impact of MHE on quality of life (QoL) remains controversial. With the standardization of the Psychometric Hepatic Encephalopathy Score (PHES) for the diagnosis of MHE in the Portuguese population, this study aimed to determine the effect of this neurocognitive disorder on the patients’ QoL. Methods: The sample consisted of two groups: the control group (CG, n=8) and the liver cirrhosis group (LCG, n=8). Of the eight patients in the LCG, four presented with MHE, diagnosed according to PHES criteria. QoL was assessed using the Medical Outcomes Study, Short Form 36 (SF-36). Results: Compared with the CG, the LCG had significantly lower scores in all domains of the SF-36, except for the physical pain subdomain. When patients with and without HE were compared, no significant differences were found in any of the SF-36 domains. Conclusions: Patients with liver cirrhosis have a worse QoL when compared with healthy controls; EHM does not affect QoL. Further studies with a higher number of patients are required to confirm these findings

Assentment of the influence of liver cirrhosis and minimal hepatic encephalopathy on quality of life

Introduction: Minimal hepatic encephalopathy (MHE) has been associated with changes in the ability to drive, with the onset of the explicit form of hepatic encephalopathy and with a worse prognosis. However, the impact of MHE on quality of life (QoL) remains controversial. With the standardization of the Psychometric Hepatic Encephalopathy Score (PHES) for the diagnosis of MHE in the Portuguese population, this study aimed to determine the effect of this neurocognitive disorder on the patients’ QoL.Methods: The sample consisted of two groups: the control group (CG, n=8) and the liver cirrhosis group (LCG, n=8). Of the eight patients in the LCG, four presented with MHE, diagnosed according to PHES criteria. QoL was assessed using the Medical Outcomes Study, Short Form 36 (SF-36).Results: Compared with the CG, the LCG had significantly lower scores in all domains of the SF-36, except for the physical pain subdomain. When patients with and without HE were compared, no significant differences were found in any of the SF-36 domains.Conclusions: Patients with liver cirrhosis have a worse QoL when compared with healthy controls; EHM does not affect QoL. Further studies with a higher number of patients are required to confirm these findings

Assentment of the influence of liver cirrhosis and minimal hepatic encephalopathy on quality of life

Introduction: Minimal hepatic encephalopathy (MHE) has been associated with changes in the ability to drive, with the onset of the explicit form of hepatic encephalopathy and with a worse prognosis. However, the impact of MHE on quality of life (QoL) remains controversial. With the standardization of the Psychometric Hepatic Encephalopathy Score (PHES) for the diagnosis of MHE in the Portuguese population, this study aimed to determine the effect of this neurocognitive disorder on the patients’ QoL. Methods: The sample consisted of two groups: the control group (CG, n=8) and the liver cirrhosis group (LCG, n=8). Of the eight patients in the LCG, four presented with MHE, diagnosed according to PHES criteria. QoL was assessed using the Medical Outcomes Study, Short Form 36 (SF-36). Results: Compared with the CG, the LCG had significantly lower scores in all domains of the SF-36, except for the physical pain subdomain. When patients with and without HE were compared, no significant differences were found in any of the SF-36 domains. Conclusions: Patients with liver cirrhosis have a worse QoL when compared with healthy controls; EHM does not affect QoL. Further studies with a higher number of patients are required to confirm these findings

Calcitriol Prevents Cardiovascular Repercussions in Puromycin Aminonucleoside-Induced Nephrotic Syndrome

Puromycin aminonucleoside-induced nephrotic syndrome (PAN-NS) is characterized by cardiac remodeling and increased local inflammatory activity. Patients with NS and animal models of NS have vitamin D3 deficiency. The aim of the present study was to evaluate the influence of calcitriol on cardiac remodeling and local inflammatory state in PAN-NS rat model. Male Sprague-Dawley rats were injected with PAN or vehicle on day 0. PAN and control rats were divided into two subgroups for the administration of calcitriol (PAN-D and Ct-D groups) or the vehicle (PAN-V and Ct-V groups) during 21 days. On day 21, the renal function, metabolic balance, calcitriol and FGF-23 plasma levels, prohypertrophy and proinflammatory markers (ET-1, TGF-β1, TNF-α, and IL-1β), and calcium signaling molecules (PLB and SERCA-2a) were evaluated. Twenty-one days after injection, PAN-V group presented cardiac hypertrophy and a modulation of proinflammatory markers local expression. Calcitriol treatment of PAN rats prevented cardiac hypertrophy and was associated with marked reduction in the cardiac expression levels of proinflammatory markers. Our results suggest that vitamin D3 deficiency in PAN-NS may contribute to cardiac remodeling and to the increase in local inflammatory activity. Calcitriol treatment prevents both cardiac repercussions and local inflammatory processes in PAN-NS