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As Parkinson’s disease (PD) progresses, treatment needs to be adapted to maintain symptom control. Once patients develop advanced PD, an optimised regimen of oral and transdermal medications may no longer provide adequate relief of OFF periods and motor complications can emerge. At this point, patients may wish to consider a device-aided therapy (DAT) that provides continuous dopaminergic stimulation to help overcome these issues. Levodopa–entacapone–carbidopa intestinal gel (LECIG) infusion is a recently developed DAT option. The aim of this article is twofold: (1) to give an overview of the pharmacokinetics of LECIG infusion and clinical experience to date of its use in patients with advanced PD, including real-world data and patient-reported outcomes from a cohort of patients treated in Sweden, the first country where it was introduced, and (2) based on that information to provide practical guidance for healthcare teams starting patients on LECIG infusion, whether they are transitioning from oral medications or from other DATs, including recommendations for stepwise dosing calculation and titration. In terms of clinical efficacy, LECIG infusion has been shown to have a similar effect on motor function to standard levodopa–carbidopa intestinal gel (LCIG) infusion but, due to the presence of entacapone in LECIG, the bioavailability of levodopa is increased such that lower overall levodopa doses can be given to achieve therapeutically effective plasma concentrations. From a practical standpoint, LECIG infusion is delivered using a smaller cartridge and pump system than LCIG infusion. In addition, for patients previously treated with LCIG infusion who have an existing percutaneous endoscopic transgastric jejunostomy (PEG-J) system, this is compatible with the LECIG infusion system. As it is a relatively new product, the long-term efficacy and safety of LECIG infusion remain to be established; however, real-world data will continue to be collected and analysed to provide this information and help inform future clinical decisions.

N[sup.6]-methyladenosine (m[sup.6]A) has recently emerged as a post-transcriptional modulator governing cell-specific gene expression in innate immune cells, particularly in monocytes. Disruptions in m[sup.6]A homeostasis, manifested as the altered expression of m[sup.6]A-related proteins and m[sup.6]A levels, have been implicated in autoimmune disorders. Perturbations in m[sup.6]A dynamics within total Peripheral blood mononuclear cells (PBMCs) have shown strong correlations with disease severity in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It remains unclear in which specific cell type(s) m[sup.6]A homeostasis is disturbed, and also whether other rheumatic diseases such as juvenile idiopathic arthritis (JIA) show similar features. Here, we assess the involvement of m[sup.6]A and m[sup.6]A-regulatory proteins in JIA monocytes. Notably, the diminished expression of m[sup.6]A-eraser proteins FTO and ALKBH5 was observed in JIA monocytes extracted from the inflamed joint. This resulted in increased m[sup.6]A-methylated transcripts in monocytes from these patients. Correspondingly, we observed that culturing monocytes in the presence of synovial fluid from JIA inflamed joints reduced the expression of both FTO and ALKBH5. The knock-out of FTO in human monocytes of healthy controls increased monocyte activation, indicating the relevance of FTO and m[sup.6]A in the context of JIA. These findings underscore the potential of ALKBH5 and FTO expression as a biomarker in JIA and identify the m[sup.6]A machinery as a potential therapeutic target for the treatment of JIA and possibly other autoimmune diseases in the future.

Sepsis refers to the systemic inflammatory response syndrome caused by infection. It is a major clinical problem and cause of death for patients in intensive care units worldwide. The Fat mass and obesity-related protein (FTO) is the primary N 6 -methyladenosine demethylase. However, the role of FTO in the pathogenesis of inflammatory diseases remains unclear. We herein show that nanoparticle-mediated Fto -siRNA delivery or FTO inhibitor entacapone administration dramatically inhibited macrophage activation, reduced the tissue damage and improved survival in a mouse model of LPS-induced endotoxic shock. Importantly, ablation of FTO could inhibit NLRP3 inflammasome through FoxO1/NF-κB signaling in macrophages. In conclusion, FTO is involved in inflammatory response of LPS-induced septic shock and inhibition of FTO is promising for the treatment of septic shock.

N6-methyladenosine (m 6 A) is dynamically regulated by methyltransferases (termed “writers”) and demethylases (referred to as “erasers”), facilitating a reversible modulation. Changes in m 6 A levels significantly influence cellular functions, such as RNA export from the nucleus, mRNA metabolism, protein synthesis, and RNA splicing. They are intricately associated with a spectrum of pathologies. Moreover, dysregulation of m 6 A modulation has emerged as a promising therapeutic target across many diseases. m 6 A plays a pivotal role in controlling vital downstream molecules and critical biological pathways, contributing to the pathogenesis and evolution of numerous conditions. This review provides an overview of m 6 A demethylases, explicitly detailing the structural and functional characteristics of FTO and ALKBH5. Additionally, we explore their distinct involvement in various diseases, examine factors regulating their expression, and discuss the progress in inhibitor development.

A class of piperazine hybridized coumarin indolylcyanoenones was exploited as new structural antibacterial frameworks to combat intractable bacterial resistance. Bioactive assessment discovered that 4-chlorobenzyl derivative 11f showed a prominent inhibition on Pseudomonas aeruginosa ATCC 27853 with a low MIC of 1 μg/mL, which was four-fold more effective than norfloxacin. Importantly, the highly active 11f with inconspicuous hemolysis towards human red blood cells displayed quite low proneness to trigger bacterial resistance. Preliminary explorations on its antibacterial behavior disclosed that 11f possessed the ability to destroy bacterial cell membrane, leading to increased permeability of inner and outer membranes, the depolarization and fracture of membrane, and the effusion of intracellular components. Furthermore, bacterial oxidative stress and metabolic turbulence aroused by 11f also accelerated bacterial apoptosis. In particular, 11f could not only effectively inset into DNA, but also bind with DNA gyrase through forming supramolecular complex, thereby affecting the biological function of DNA. The above findings of new piperazine hybridized coumarin indolylcyanoenones provided an inspired possibility for the treatment of resistant bacterial infections.

Introduction: The management of sedation during percutaneous endoscopic gastrojejunostomy (PEG-J) placement in patients with advanced Parkinson’s disease (PD) is challenging due to the complex interactions between PD treatment, anesthetic agents, and the disease’s motor and non-motor symptoms. This study evaluates the effectiveness and safety of a target-controlled infusion (TCI) propofol protocol in the context of PEG-J placement in advanced PD patients. Materials and Methods: This prospective study included 169 patients diagnosed with advanced Parkinson’s disease (Hoehn and Yahr stages 4 and 5) who underwent PEG-J placement at Târgu Mureș County Emergency Clinical Hospital, Romania. Sedation was induced and maintained using TCI propofol, with additional benzodiazepines and short-acting opioids, while muscle relaxants were not used. Procedural success rates and adverse outcomes were assessed for 30 days post-procedure. Results: The sedation protocol demonstrated a high procedural success rate. No deaths were reported within 30 days post-procedure. Conclusion: This study highlights the feasibility and clinical applicability of a TCI propofol protocol for PEG-J placement in patients with advanced PD (stages 4 and 5). While no deaths were recorded within the 30-day follow-up, the sample size is insufficient to draw definitive conclusions regarding long-term safety.

Parkinson disease (PD) is associated with cognitive impairment. We aimed to determine the effects of intranasal insulin (INI) on cognition and motor performance in PD. This was a proof of concept, randomized, double-blinded, placebo-controlled trial evaluating the effects of 40 international units (IU) of insulin or saline once daily for four weeks on cognitive and functional performance. Of 16 subjects enrolled, eight in the INI group and six in the placebo group completed verbal fluency (FAS), Unified Parkinson Disease Scale (UPDRS), and modified Hoehn and Yahr scale (HY, PD severity) at baseline and post-treatment and were included in the analyses. After treatment, the INI group had a better total FAS score (p = 0.02) (41 ± 8.2 vs. 30.8 ± 7.1, mean ±SD, p = 0.02) compared to the placebo group. The INI group also had improved HY (p = 0.04) and UPDRS-Motor (Part III) (p = 0.02) scores when compared to baseline. One INI treated patient with multiple system atrophy (MSA) remained stable and did not show disease progression. The placebo group had no change. INI administration was well tolerated and there were no hypoglycemic episodes or serious study related adverse events or medications interactions. INI is safe in PD and MSA patients and may provide clinically relevant functional improvement. Larger studies are warranted to determine the INI effect in treatment of cognitive and motor impairment in Parkinson disease. Trial Registration: ClinicalTrial.gov NCT02064166.

Background Entacapone has been widely used in the treatment of moderate to advanced Parkinson’s disease (PD), and its efficacy for motor symptoms has been well-known from several clinical trials and long-term clinical use. The efficacy of Levodopa/Carbidopa/Entacapone (LCE) on neuropsychological functions in moderate to advanced PD has not been validated yet, and little is known about the effect of LCE on peripheral inflammatory cytokines. Objectives The aim of this study was to investigate the efficacy of LCE on neuropsychological functions in moderate to advanced PD and to explore its relationship with the changes in peripheral inflammatory cytokine levels. Methods All patients were randomly assigned to the experimental group receiving treatment of LCE or the control group receiving treatment of Levodopa/Carbidopa (LC). All patients were clinically evaluated using the Unified Parkinson’s Disease Rating Scale part III (UPDRS III), the total score of the Parkinson’s Disease Questionnaire-39 (PDQ-39), the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Hamilton Anxiety Scale (HAMA), and the Hamilton Depression Scale (HAMD), and serum homocysteine (HCY) as well as serum inflammatory cytokines were measured at baseline and after 8 weeks. Results The moderate to advanced PD patients treated with LCE had more significant improvement in MMSE scores ( P  = 0.004) and MoCA scores ( P  = 0.001), as well as a greater decline in IL-6 levels ( P  = 0.002) than those treated with LC. There were no significant differences in the changes of the UPDRS III, PDQ39, HAMA, and HAMD scores between the two treatment groups. Linear correlation analysis revealed that there was a significant negative correlation between the improvement of MoCA scores (ΔMoCA) and the reduction of IL-6 levels (ΔIL-6) (correlation coefficient: -0.252; P  = 0.024). Conclusions The ability of LCE to improve cognitive function and to downregulate the peripheral inflammatory cytokine IL-6 levels in moderate to advanced PD is superior to the traditional dopamine preparation—LC. LCE may improve cognitive function by suppressing the levels of inflammatory cytokines like IL-6. Trial registration The full name of the registry: Dongyang People’s Hospital, Affiliated to Wenzhou Medical University. The trial registration number (TRN): ChiCTR2400091631. The date of registration: October 31, 2024 (Retrospectively registered).