Search Results (30)

Background/aim: A growing body of evidence suggests a link between dyslipidemias and neurodegenerative diseases, highlighting the crucial role of lipid metabolism in the health of the central nervous system. The aim of our work was to provide an update on this topic, with a focus on clinical practice from an endocrinological point of view. Endocrinologists, being experts in the management of dyslipidemias, can play a key role in the prevention and treatment of neurodegenerative conditions, through precocious and effective lipid profile optimization. Methods: The literature was scanned to identify clinical trials and correlation studies on the association between dyslipidemia, statin therapy, and the following neurodegenerative diseases: Alzheimer’s disease (AD), Parkisons’s disease (PD), Multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS). Results: Impaired lipid homeostasis, such as that frequently observed in patients affected by obesity and diabetes, is related to neurodegenerative diseases, such as AD, PD, and other cognitive deficits related to aging. AD and related dementias are now a real priority health problem. In the United States, there are approximately 7 million subjects aged 65 and older living with AD and related dementias, and this number is projected to grow to 12 million in the coming decades. Lipid-lowering therapy with statins is an effective strategy in reducing serum low-density lipoprotein cholesterol to normal range concentrations and, therefore, cardiovascular disease risk; moreover, statins have been reported to have a positive effect on neurodegenerative diseases. Conclusions: Several pieces of research have found inconsistent information following our review. There was no association between statin use and ALS incidence. More positive evidence has emerged regarding statin use and AD/PD. However, further large-scale prospective randomized control trials are required to properly understand this issue. Full article

Many clinico-pathological studies point to the presence of multiple comorbidities/co-pathologies in the course of Parkinson disease (PD). Lewy body pathology, the morphological hallmark of PD, rarely exists in isolation, but is usually associated with other concomitant pathologies, in particular Alzheimer disease-related changes (ADNC), cerebrovascular pathologies (macro- and microinfarcts, cerebral small vessel disease, cerebral amyloid angiopathy), TDP-43 pathology as well as multiple pathological combinations. These include cardiovascular disorders, metabolic syndrome, diabetes mellitus, autoimmune and rheumatic diseases, myasthenia gravis, Sjögren’s syndrome, restless leg syndrome or other rare disorders, like Fabry disease. A combination of PD and multiple sclerosis (MS) may be due to the immune function of LRRK2 and its interrelation with α-synuclein. COVID-19 and HIV posed considerable impacts on patients with PD. Epidemiological evidence points to a decreased risk for the majority of neoplasms, except melanoma and other skin cancers, while some tumors (breast, brain) are increased. On the other hand, a lower frequency of malignancies preceding early PD markers may argue for their protective effect on PD risk. Possible pathogenetic factors for the association between PD and cancer are discussed. The tremendous heterogeneity of concomitant pathologies and comorbidities observed across the PD spectrum is most likely caused by the complex interplay between genetic, pathogenic and other risk factors, and further research should provide increasing insight into their relationship with idiopathic PD (and other parkinsonian disorders) in order to find better diagnostic tools and probable disease-modifying therapies. Full article

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths globally. Current treatment options including chemotherapy and targeted therapies face challenges such as resistance and toxicity. Cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5) has emerged as a promising target for CRC therapy due to its role in regulating cellular processes like proliferation and apoptosis. This study focuses on the in silico design of a novel PDE5 inhibitor MS01 derived from the lead compound exisulind which has shown apoptotic effects but failed due to hepatotoxicity. Using Schrödinger’s Induced Fit Docking (IFD) and molecular dynamic simulations, MS01 was designed to enhance binding affinity and reduce toxicity. The docking studies showed that MS01 exhibits stronger interactions with key PDE5 residues, particularly Gln817 and Phe820. ADMET predictions indicate favorable pharmacokinetic profiles, with reduced risk of drug–drug interactions and improved bioavailability. Toxicity assessments revealed that MS01 and its analogs have moderate toxicity, with MS20 and MS21 demonstrating lower hepatotoxicity compared to exisulind. These findings suggest that MS01 has the potential to be a more effective and safer PDE5 inhibitor for CRC treatment pending further experimental validation. Full article

Tacrolimus (TAC) has emerged as a potential therapy for Alzheimer’s disease (AD), with the challenge of balancing its therapeutic benefits against its immunosuppressive effects. This study explores the efficacy of a sub-immunosuppressive TAC dosing regimen to ameliorate AD-related pathologies. TAC was administered daily for 14 days, with drug concentrations measured via liquid chromatography tandem mass spectrometry (LC-MS/MS) in whole blood and hippocampal tissue from C57BL6J mice, while immunofluorescence analyses and Western blotting (performed on hippocampal extracts) were conducted in 10–12 month old 3xTg-AD mice to evaluate levels of tau and amyloid-beta (Aβ) proteins. The results from LC-MS/MS revealed that lower TAC doses resulted in sub-immunosuppressive blood levels, while still penetrating the hippocampi. Immunofluorescence showed reductions in tau and Aβ proteins in 3xTg-AD mice. Additionally, Western blot analyses revealed reductions in tau and Aβ, along with increases in synaptic and autophagy-related proteins. These findings highlight the potential of sub-immunosuppressive TAC doses in effectively targeting AD pathology while minimizing the risk of chronic systemic immunosuppression. Further research and clinical trials are warranted to establish the optimal TAC dosing regimen for AD treatment. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), which are a consequence of the progressive loss of neuronal function and structure, cause significant cognitive impairment. The incidence of these diseases in the world’s population is constantly increasing as a result of an aging population. Although genetic and environmental factors are most often mentioned as the pathogenetic factors of these diseases, increasing evidence points to the important role of proper nutrition in the prevention and support of the treatment of these disorders. A healthy, balanced diet can mitigate the risks associated with the risk factors mentioned above and slow the progression of the disease by reducing oxidative stress and inflammation. Vitamins B, D, E, C, K, and A have been shown to support cognitive functions and protect the nervous system. This review demonstrates the importance of vitamins in preventing and supporting the therapy of neurodegenerative diseases. Information regarding the health-promoting properties of these vitamins must be effectively communicated to consumers seeking to protect their health, particularly in the context of neurodegenerative diseases. Consequently, this review also examines the authorized health claims under EU food law related to these vitamins, assessing their role in promoting awareness of the vitamins’ potential benefits for neuroprotection and the management of neurodegenerative diseases. Full article

Background/Objectives: Multiple sclerosis (MS) is a chronic autoimmune disease marked by inflammatory demyelination in the central nervous system, leading to debilitating spasticity. Managing spasticity in MS remains a challenge, and intrathecal baclofen (ITB) therapy has emerged as a potential targeted treatment. This systematic review investigated the efficacy of ITB pumps in managing MS-related spasticity and explored their immunomodulatory effects. Methods: This review adhered to PRISMA guidelines and was submitted for registration retrospectively with the Open Science Foundation. A comprehensive literature search was conducted in PubMed, Embase, Scopus, and Web of Science from January 2013 to August 2024. Studies were included if they examined adult MS patients receiving ITB for spasticity, reporting outcomes related to spasticity and quality of life. Risk of bias was assessed using the Joanna Briggs Institute Critical Appraisal Tools, and findings were synthesized narratively. Results: Eight studies (n = 723 participants) met inclusion criteria. ITB was associated with significant reductions in spasticity severity and improvements in quality of life, with reduced reliance on oral antispasticity medications. Immunologically, ITB has demonstrated potential in modulating inflammatory pathways, downregulating pro-inflammatory cytokines, and shifting immune responses toward an anti-inflammatory profile. Common complications included catheter-related issues and infections, with low overall complication rates. Sensitivity analyses indicated robustness in outcomes across higher-quality studies. Conclusions: ITB pumps are effective in controlling spasticity and offer additional immunological benefits for MS patients. Further research should explore ITB’s long-term immunomodulatory effects and its potential in combined therapeutic strategies. The review was not financially supported, and no conflicts of interest were declared by the authors. Full article

Background: Serum C-reactive protein (CRP) levels vary depending on radiological and bacteriological findings at the time of tuberculosis (TB) diagnosis. However, the utility of this biomarker in monitoring response to anti-TB treatment and identifying patients at risk of treatment failure is not well established. Objectives: This study evaluated the impact of patients’ baseline characteristics and anti-TB drug plasma exposure on the early reduction in serum CRP levels and its relationship with treatment response. Methods: We enrolled 42 patients with drug-susceptible pulmonary TB, who received a standard six-month regimen. The plasma concentrations of four anti-TB drugs were analysed using LC-MS/MS. Clinically relevant data, including serum CRP levels before and 10–12 days after treatment initiation (CRP_10–12d), were obtained from electronic medical records and patient questionnaires. Results: In 10–12 days, the median serum CRP level decreased from 21.9 to 6.4 mg/L. Lower body mass index, positive sputum-smear microscopy results, and lung cavitations at diagnosis were related to higher biomarker levels at both time points; smoking had a more pronounced effect on serum CRP_10–12d levels. Variability in anti-TB drug plasma exposure did not significantly affect the reduction in serum CRP levels. The serum CRP_10–12d levels, or fold change from the baseline, did not predict the time to sputum culture conversion. Conclusions: Disease severity and patient characteristics may influence the pattern of early CRP reduction, while anti-TB drug plasma exposure had no significant effect at this stage. These early changes in serum CRP levels were not a predictor of response to anti-TB therapy. Full article

Background: Adjuvant chemotherapy, particularly cisplatin, is recommended for non-small cell lung carcinoma (NSCLC) patients at high risk of recurrence. EF-hand domain-containing protein D2 (EFHD2) has been recently shown to increase cisplatin resistance and is significantly associated with recurrence in early-stage NSCLC patients. Natural products, commonly used as phytonutrients, are also recognized for their potential as pharmaceutical anticancer agents. Result: In this study, a range of Chinese herbs known for their antitumor or chemotherapy-enhancing properties were evaluated for their ability to inhibit EFHD2 expression in NSCLC cells. Among the herbs tested, Stephania tetrandra (S. tetrandra) exhibited the highest efficacy in inhibiting EFHD2 and sensitizing cells to cisplatin. Through LC-MS identification and functional assays, coclaurine was identified as a key molecule in S. tetrandra responsible for EFHD2 inhibition. Coclaurine not only downregulated EFHD2-related NOX4-ABCC1 signaling and enhanced cisplatin sensitivity, but also suppressed the stemness and metastatic properties of NSCLC cells. Mechanistically, coclaurine disrupted the interaction between the transcription factor FOXG1 and the EFHD2 promoter, leading to a reduction in EFHD2 transcription. Silencing FOXG1 further inhibited EFHD2 expression and sensitized NSCLC cells to cisplatin. Conclusions: S. tetrandra and its active compound coclaurine may serve as effective adjuvant therapies to improve cisplatin efficacy in the treatment of NSCLC. Full article

Background: Recent studies underscore the intricate relationship between cognitive and motor impairments in Multiple Sclerosis (MS), often exacerbated by CNS damage compromising neural connections. These cognitive–motor deficits contribute to reduced efficiency in daily activities and heightened risks of falls and accidents. The combination of challenging cognitive–motor training in a more ecological setting could improve cognitive functions in people with MS (PwMS). Objective: This study aims to compare the impact of dynamic cognitive–motor training versus computer-based cognitive training on overall cognitive efficiency in PwMS. Methods: Thirty-eight PwMS were recruited through the neurorehabilitation services of an Institute of research and health. Twenty-four participants were randomly assigned to the Cognitive-Motor group (CMg) and Cognitive Therapy group (CTg). Participants underwent three training sessions per week for four weeks, each lasting 50 min. The primary outcome was a comprehensive cognitive assessment using the Cognitive Impairment Index (CII), and the secondary outcomes were the Multiple Sclerosis Quality of Life Questionnaire MSQOL-54 and the Stroop Color Word Interference Test (SCWT). Results: Significant differences in the CII scores across T0, T1, and T2, as indicated by Friedman’s test (χ2(2) = 14.558, p = .001), were found in the CMg. A significant difference in the change in health subscale of the MSQOL-54 was observed when comparing the groups across T0, T1, and T2 (χ2(2) = 6.059, p = .048). There were also statistically significant differences for the emotional well-being (χ2(2) = 7.581, p = .023) and health distress (χ2(2) = 11.902, p = .003) subscales. Post hoc analysis showed a statistically significant improvement in health-related quality of life (HRQOL) for the former at T1 vs. T0 (Z = −2.502, p = .012 and for the latter at T2 vs. T0 (Z = −2.670, p = .008), respectively. Conclusions: Our results support the combination of cognitive–motor training to enhance cognitive functional outcomes and quality of life compared to computer-based cognitive training in PwMS. Full article

Fingolimod is an immunomodulatory sphingosine-1-phosphate (S1P) analogue approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The identification of biomarkers of clinical responses to fingolimod is a major necessity in MS to identify optimal responders and avoid the risk of disease progression in non-responders. With this aim, we used RNA sequencing to study the transcriptomic changes induced by fingolimod in peripheral blood mononuclear cells of MS-treated patients and their association with clinical response. Samples were obtained from 10 RRMS patients (five responders and five non-responders) at baseline and at 12 months of fingolimod therapy. Fingolimod exerted a vast impact at the transcriptional level, identifying 7155 differentially expressed genes (DEGs) compared to baseline that affected the regulation of numerous signaling pathways. These DEGs were predominantly immune related, including genes associated with S1P metabolism, cytokines, lymphocyte trafficking, master transcription factors of lymphocyte functions and the NF-kB pathway. Responder and non-responder patients exhibited a differential transcriptomic regulation during treatment, with responders presenting a higher number of DEGs (6405) compared to non-responders (2653). The S1P, NF-kB and TCR signaling pathways were differentially modulated in responder and non-responder patients. These transcriptomic differences offer the potential of being exploited as biomarkers of a clinical response to fingolimod. Full article

Patients with multiple sclerosis (MS) often take multiple drugs at the same time to modify the course of disease, alleviate neurological symptoms and manage co-existing conditions. A major consequence for a patient taking different medications is a higher risk of treatment failure and side effects. This is because a drug may alter the pharmacokinetic and/or pharmacodynamic properties of another drug, which is referred to as drug-drug interaction (DDI). We aimed to predict interactions of drugs that are used by patients with MS based on a deep neural network (DNN) using structural information as input. We further aimed to identify potential drug-food interactions (DFIs), which can affect drug efficacy and patient safety as well. We used DeepDDI, a multi-label classification model of specific DDI types, to predict changes in pharmacological effects and/or the risk of adverse drug events when two or more drugs are taken together. The original model with ~34 million trainable parameters was updated using >1 million DDIs recorded in the DrugBank database. Structure data of food components were obtained from the FooDB database. The medication plans of patients with MS (n = 627) were then searched for pairwise interactions between drug and food compounds. The updated DeepDDI model achieved accuracies of 92.2% and 92.1% on the validation and testing sets, respectively. The patients with MS used 312 different small molecule drugs as prescription or over-the-counter medications. In the medication plans, we identified 3748 DDIs in DrugBank and 13,365 DDIs using DeepDDI. At least one DDI was found for most patients (n = 509 or 81.2% based on the DNN model). The predictions revealed that many patients would be at increased risk of bleeding and bradycardic complications due to a potential DDI if they were to start a disease-modifying therapy with cladribine (n = 242 or 38.6%) and fingolimod (n = 279 or 44.5%), respectively. We also obtained numerous potential interactions for Bruton’s tyrosine kinase inhibitors that are in clinical development for MS, such as evobrutinib (n = 434 DDIs). Food sources most often related to DFIs were corn (n = 5456 DFIs) and cow’s milk (n = 4243 DFIs). We demonstrate that deep learning techniques can exploit chemical structure similarity to accurately predict DDIs and DFIs in patients with MS. Our study specifies drug pairs that potentially interact, suggests mechanisms causing adverse drug effects, informs about whether interacting drugs can be replaced with alternative drugs to avoid critical DDIs and provides dietary recommendations for MS patients who are taking certain drugs. Full article

Background: The purpose of this study was to evaluate the intensity and frequency of low back pain (LBP) in people with multiple sclerosis (PwMS) and patients’ knowledge of physiotherapeutic methods for combating LBP. Methods: This study included all MS patients attending consecutive follow-up visits for treatment related to MS between March and May 2023. Only current pain sensations in the lumbar spine were taken into account. The inclusion criteria were age 18–60 years, a definite diagnosis of MS according to the 2017 McDonald criteria, treatment with disease-modifying drugs (DMTs), and consent to participate in the study. This study was carried out using an original survey questionnaire and a Visual Analogue Scale. PwMS were divided into three age groups: 18–30 years, 31–50 years, and over 50 years. Results: Ninety PwMS (68 women and 22 men) were included in the study. The mean duration of the disease was 9.5 ± 4.9 years, and the mean EDSS was 3.5 ± 1.6. Most patients had a relapsing-remitting form of the disease. Overall, 68.9% of PwMS felt low back pain (n = 62). The relationship tested was statistically significant (p < 0.001), and the strength of the relationship was high (r_c = 0.695). The average level of low back pain among PwMS was 4.7 out of 10 on the VAS. The prevalence of LBP was higher in female patients (p < 0.001), patients with a secondary progressive form of MS (p < 0.001), and patients with a longer duration of disease (p < 0.05). The most widely used methods for treating LBP were kinesitherapy and manual therapy. Conclusions: LBP is common in patients with multiple sclerosis. Female sex, a secondary progressive form of MS, and a longer duration of disease increase the risk of LBP. It is important to implement properly planned physiotherapy activities and educate patients on how to combat LBP. Full article

Gestational diabetes mellitus (GDM) is a condition characterized by glucose intolerance, with hyperglycemia of varying severity with onset during pregnancy. An uncontrolled GDM can lead to an increased risk of morbidity in the fetus and newborn, and an increased risk of obesity or developing type 2 diabetes, hypertension or neurocognitive developmental impairment in adulthood. In this study, we used nuclear magnetic resonance (NMR) spectroscopy and gas chromatography–mass spectrometry (GS-MS) to analyze the urinary metabolomic profile of newborns of diabetic mothers (NDMs) with the aim of identifying biomarkers useful for the monitoring of NDMs and for early diagnosis of predisposition to develop related chronic diseases. A total of 26 newborns were recruited: 21 children of diabetic mothers, comprising 13 in diet therapy (NDM-diet) and 8 in insulin therapy (NDM-insulin), and 5 control children of non-diabetic mothers (CTR). Urine samples were collected at five time points: at birth (T1), on the third day of life (T2), one week (T3), one month (T4) and six months postpartum (T5). At T1, variations were observed in the levels of seven potential biomarkers (acetate, lactate, glycylproline/proline, isocitrate, N,N-dimethylglycine, N-acetylglucosamine and N-carbamoyl-aspartate) in NMD-insulin infants compared to NDM-diet and CTR infants. In particular, the altered metabolites were found to be involved in several metabolic pathways such as citrate metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, amino sugar and nucleotide sugar metabolism, and pyruvate metabolism. In contrast, these changes were not visible at subsequent sampling times. The impact of early nutrition (maternal and formula milk) on the metabolomic profile was considered as a potential contributing factor to this finding. Full article

Background. Cladribine belongs to the group of disease-modifying therapies (DMTs) used to treat multiple sclerosis (MS). According to the highlights of a meeting held by the Pharmacovigilance Risk Assessment Committee (PRAC) on 14 January 2022, cladribine may be associated with the occurrence of liver injury, and thus liver function monitoring is recommended. Objectives and methods. Using data from the European spontaneous reporting database (EudraVigilance-EV), we aimed to describe the main characteristics of Individual Case Safety Reports (ICSRs) reporting cases of hepatobiliary disorders related to cladribine. The reporting odds ratio (ROR) was calculated to provide the probability of reporting hepatobiliary ICSRs among DMTs used to treat MS. Results. Overall, 118 ICSRs described the occurrence of cladribine-induced hepatobiliary ADRs. The majority of the ICSRs reported ADRs that were classified as serious (93%), and the outcome was mostly reported as “unknown” (50.8%). The most reported hepatobiliary disorders were drug-induced liver injury, abnormal hepatic function, ALT increases, liver disorders, hepatic failure, jaundice, lymphocyte count decreases, hepatotoxicity and hypertransaminasemia. The majority of cladribine-induced hepatic ADRs occurred in female patients belonging to the age group of 18–65 years. Conclusion. Considering the seriousness of cladribine-induced hepatic ADRs, a close monitoring of patients receiving this drug is highly recommended. In this context, further pharmacovigilance studies evaluating the hepatic safety profile of cladribine are strongly needed. Full article

Increasingly prevalent acute and chronic human brain diseases are scourges for the elderly. Besides the lack of therapies, these ailments share a neuroinflammation that is triggered/sustained by different innate immunity-related protein oligomers called inflammasomes. Relevant neuroinflammation players such as microglia/monocytes typically exhibit a strong NLRP3 inflammasome activation. Hence the idea that NLRP3 suppression might solve neurodegenerative ailments. Here we review the recent Literature about this topic. First, we update conditions and mechanisms, including RNAs, extracellular vesicles/exosomes, endogenous compounds, and ethnic/pharmacological agents/extracts regulating NLRP3 function. Second, we pinpoint NLRP3-activating mechanisms and known NLRP3 inhibition effects in acute (ischemia, stroke, hemorrhage), chronic (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, MS, ALS), and virus-induced (Zika, SARS-CoV-2, and others) human brain diseases. The available data show that (i) disease-specific divergent mechanisms activate the (mainly animal) brains NLRP3; (ii) no evidence proves that NLRP3 inhibition modifies human brain diseases (yet ad hoc trials are ongoing); and (iii) no findings exclude that concurrently activated other-than-NLRP3 inflammasomes might functionally replace the inhibited NLRP3. Finally, we highlight that among the causes of the persistent lack of therapies are the species difference problem in disease models and a preference for symptomatic over etiologic therapeutic approaches. Therefore, we posit that human neural cell-based disease models could drive etiological, pathogenetic, and therapeutic advances, including NLRP3’s and other inflammasomes’ regulation, while minimizing failure risks in candidate drug trials. Full article