1,568 results on '"Brooks, B. R."'
Search Results
2. Allosteric competition and inhibition in AMPA receptors.
- Author
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Hale WD, Montaño Romero A, Gonzalez CU, Jayaraman V, Lau AY, Huganir RL, and Twomey EC
- Abstract
Excitatory neurotransmission is principally mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype ionotropic glutamate receptors (AMPARs). Negative allosteric modulators are therapeutic candidates that inhibit AMPAR activation and can compete with positive modulators to control AMPAR function through unresolved mechanisms. Here we show that allosteric inhibition pushes AMPARs into a distinct state that prevents both activation and positive allosteric modulation. We used cryo-electron microscopy to capture AMPARs bound to glutamate, while a negative allosteric modulator, GYKI-52466, and positive allosteric modulator, cyclothiazide, compete for control of the AMPARs. GYKI-52466 binds in the ion channel collar and inhibits AMPARs by decoupling the ligand-binding domains from the ion channel. The rearrangement of the ligand-binding domains ruptures the cyclothiazide site, preventing positive modulation. Our data provide a framework for understanding allostery of AMPARs and for rational design of therapeutics targeting AMPARs in neurological diseases., (© 2024. The Author(s).)
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- 2024
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3. A potential allosteric inhibitor of SARS-CoV-2 main protease (Mpro) identified through metastable state analysis.
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Fatima, Asma, Geethakumari, Anupriya M., Ahmed, Wesam S., and Biswas, Kabir H.
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- 2024
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4. The role of ALDH2 rs671 polymorphism and C-reactive protein in the phenotypes of male ALS patients.
- Author
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Lifang Huang, Mao Liu, Jiahui Tang, Zhenxiang Gong, Zehui Li, Yuan Yang, and Min Zhang
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C-reactive protein ,AMYOTROPHIC lateral sclerosis ,ALDEHYDE dehydrogenase ,BLOOD cell count ,DISEASE risk factors - Abstract
Background: The aldehyde dehydrogenase 2 (ALDH2) rs671 (A) allele has been implicated in neurodegeneration, potentially through oxidative and inflammatory pathways. The study aims to investigate the effects of the ALDH2 rs671 (A) allele and high sensitivity C-reactive protein (hs-CRP) on the clinical phenotypes of amyotrophic lateral sclerosis (ALS) in male and female patients. Methods: Clinical data and ALDH2 rs671 genotype of 143 ALS patients, including 85 males and 58 females, were collected from January 2018 to December 2022. All patients underwent assessment using the Chinese version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Complete blood count and metabolic profiles were measured. Clinical and laboratory parameters were compared between carriers and non-carriers of the rs671 (A) allele in males and females, respectively. The significant parameters and rs671 (A) Allele were included in multivariate linear regression models to identify potential contributors to motor and cognitive impairment. Mediation analysis was employed to evaluate any mediation effects. Results: Male patients carrying rs671 (A) allele exhibited higher levels of hs-CRP than non-carriers (1.70 mg/L vs. 0.50 mg/L, p = 0.006). The rs671 (A) allele was identified as an independent risk factor for faster disease progression only in male patients (b = 0.274, 95% CI = 0.048-0.499, p = 0.018). The effect of the rs671 (A) allele on the executive function in male patients was fully mediated by hs-CRP (Indirect effect = -1.790, 95% CI = -4.555--0.225). No effects of the rs671 (A) allele or hs-CRP were observed in female ALS patients. The effects of the ALDH2 rs671 (A) allele and the mediating role of hs-CRP in male patients remained significant in the sensitivity analyses. Conclusion: The ALDH2 rs671 (A) allele contributed to faster disease progression and hs-CRP mediated cognitive impairment in male ALS patients. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Pathological Spontaneous Activity in Different Thoracic Paraspinal Muscles in Amyotrophic Lateral Sclerosis.
- Author
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Ren, Yuting, Chen, Na, Zhang, Kang, Chen, Bin, Niu, Songtao, Wang, Xingao, Jian, Fan, Zhang, Zaiqiang, Pan, Hua, and Sala, Gessica
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AMYOTROPHIC lateral sclerosis ,VITAL capacity (Respiration) ,LINEAR statistical models ,STATISTICAL correlation - Abstract
Objective: The aim of our study was to compare the clinical value of pathological spontaneous activity (PSA) in different thoracic paraspinal muscles (TPMs) in amyotrophic lateral sclerosis (ALS). Methods: A total of 116 ALS patients were retrospectively analyzed over 31 ± 8 months concerning the occurrence of PSA in T9–T11 TPM. The occurrence of PSA was correlated with pulmonary function and clinical disability. Results: The positive sharp wave (PSW) potentials were more frequently observed than fibrillation (fib) in T9–T11 segments. The PSA positive frequency of bulbar‐onset ALS (B‐ALS) is less than upper limb‐onset ALS (U‐ALS) and lower limb‐onset ALS (L‐ALS) at the levels of T10 and T11 TPM (p = 0.050, p = 0.001). The fibs/PSWs in TPM indicated high sensitivity and negative predictive value for forced vital capacity (FVC) < 80%. Linear correlation analysis indicated that PSA of TPM was associated with pulmonary ventilation function (PVF). Associations also exist between clinical parameters and PVF as well as the disease severity. Conclusions: The occurrence of T9‐TPM fibs/PSWs was correlated with clinical disability and is extremely helpful in implying an involvement of PVF. The T9‐TPM typically provided a good practical indicator for comprehensive disease evaluation, which was irrelevant to the site of onset. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Phenoxyacetic acid enhances nodulation symbiosis during the rapid growth stage of soybean.
- Author
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Weijun Li, Xinfang Zhu, Mengyue Zhang, Xifeng Yan, Junchen Leng, Yuhong Zhou, Like Liu, Dajian Zhang, Xianzheng Yuan, Dawei Xue, Huiyu Tian, and Zhaojun Ding
- Subjects
PLANT exudates ,PHENOXYACETIC acid ,ROOT-tubercles ,BLUEGRASSES (Plants) ,LEGUMES - Abstract
Root exudates are known signaling agents that influence legume root nodulation, but the molecular mechanisms for nonflavonoid molecules remain largely unexplored. The number of soybean root nodules during the initial growth phase shows substantial discrepancies at distinct developmental junctures. Using a combination of metabolomics analyses on root exudates and nodulation experiments, we identify a pivotal role for certain root exudates during the rapid growth phase in promoting nodulation. Phenoxyacetic acid (POA) was found to activate the expression of GmGA2ox10 and thereby facilitate rhizobial infection and the formation of infection threads. Furthermore, POA exerts regulatory control on the miR172c-NNC1 module to foster nodule primordia development and consequently increase nodule numbers. These findings collectively highlight the important role of POA in enhancing nodulation during the accelerated growth phase of soybeans. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Computational insights into rational design and virtual screening of pyrazolopyrimidine derivatives targeting Janus kinase 3 (JAK3).
- Author
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Faris, Abdelmoujoud, Cacciatore, Ivana, Alnajjar, Radwan, Aouidate, Adnane, Mughram, Mohammed H. AL, Elhallaoui, Menana, Darwish, Khaled Mohamed, Abdel-Maksoud, Mohammed, and Castro, Alejandro
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VIRTUAL design ,RHEUMATOID arthritis ,AMES test ,AUTOIMMUNE diseases ,MOLECULAR dynamics - Abstract
The Janus kinase 3 (JAK3) family, particularly JAK3, is pivotal in initiating autoimmune diseases such as rheumatoid arthritis. Recent advancements have focused on developing antirheumatic drugs targeting JAK3, leading to the discovery of novel pyrazolopyrimidine-based compounds as potential inhibitors. This research employed covalent docking, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis, molecular dynamics modeling, and MM/GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy techniques to screen 41 in silico-designed pyrazolopyrimidine derivatives. Initially, 3D structures of the JAK3 enzyme were generated using SWISS-MODEL, followed by virtual screening and covalent docking via AutoDock4 (AD4). The selection process involved the AMES test, binding affinity assessment, and ADMET analysis, narrowing down the candidates to 27 compounds that passed the toxicity test. Further covalent docking identified compounds 21 and 41 as the most promising due to their high affinity and favourable ADMET profiles. Subsequent development led to the creation of nine potent molecules, with derivatives 43 and 46 showing exceptional affinity upon evaluation through molecular dynamics simulation and MM/GBSA calculations over 300 nanoseconds, comparable to tofacitinib, an approved RA drug. However, compounds L21 and L46 demonstrated stable performance, suggesting their effectiveness in treating rheumatoid arthritis and other autoimmune conditions associated with JAK3 inhibition. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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8. Environment-dependent chlorophyll-chlorophyll charge transfer states in Lhca4 pigment-protein complex.
- Author
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Rankelytė, Gabrielė, Gelzinis, Andrius, Robert, Bruno, Valkunas, Leonas, and Chmeliov, Jevgenij
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CHARGE transfer ,PHOTOSYSTEMS ,QUANTUM chemistry ,ATOMIC charges ,ELECTROSTATIC interaction ,ELECTRON donors - Abstract
Photosystem I (PSI) light-harvesting antenna complexes LHCI contain spectral forms that absorb and emit photons of lower energy than that of its primary electron donor, P700. The most red-shifted fluorescence is associated with the Lhca4 complex. It has been suggested that this red emission is related to the inter-chlorophyll charge transfer (CT) states. In this work we present a systematic quantum-chemical study of the CT states in Lhca4, accounting for the influence of the protein environment by estimating the electrostatic interactions. We show that significant energy shifts result from these interactions and propose that the emission of the Lhca4 complex is related not only to the previously proposed a603+-a608-state, but also to the a602+-a603-state. We also investigate how different protonation patterns of protein amino acids affect the energetics of the CT states. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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9. Discovery of an 8-oxoguanine regulator PCBP1 inhibitor by virtual screening and its synergistic effects with ROS-modulating agents in pancreatic cancer.
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Kexiong Qiao, Chengjie Xu, Chaolei Zhang, Qianqian Wang, Jun Jiang, Zongrong Chen, Liangjing Zhou, Shengnan Jia, and Liping Cao
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- 2024
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10. Physical exercise in amyotrophic lateral sclerosis: a potential co-adjuvant therapeutic option to counteract disease progression.
- Author
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Fenili, Gianmarco, Scaricamazza, Silvia, Ferri, Alberto, Valle, Cristiana, and Paronetto, Maria Paola
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AMYOTROPHIC lateral sclerosis ,EXERCISE physiology ,DISEASE progression ,SURVIVAL rate ,MUSCLE weakness - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the selective degeneration of upper and lower motor neurons, leading to progressive muscle weakness and atrophy. The mean survival time is two to five years. Although the hunt for drugs has greatly advanced over the past decade, no cure is available for ALS yet. The role of intense physical activity in the etiology of ALS has been debated for several decades without reaching a clear conclusion. The benefits of organized physical activity on fitness and mental health have been widely described. Indeed, by acting on specific mechanisms, physical activity can influence the physiology of several chronic conditions. It was shown to improve skeletal muscle metabolism and regeneration, neurogenesis, mitochondrial biogenesis, and antioxidant defense. Interestingly, all these pathways are involved in ALS pathology. This review will provide a broad overview of the effect of different exercise protocols on the onset and progression of ALS, both in humans and in animal models. Furthermore, we will discuss challenges and opportunities to exploit physiological responses of imposed exercise training for therapeutic purposes. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Edaravone for the Treatment of Motor Neurone Disease: A Critical Review of Approved and Alternative Formulations against a Proposed Quality Target Product Profile.
- Author
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O'Neill, Riuna, Yoo, Okhee, Burcham, Philip, and Lim, Lee Yong
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AMYOTROPHIC lateral sclerosis ,DRUG absorption ,EDARAVONE ,GASTROINTESTINAL system ,CYCLODEXTRINS - Abstract
Edaravone is one of two main drugs for treating motor neurone disease (MND). This review proposes a specific quality target product profile (QTPP) for edaravone following an appraisal of the issues accounting for the poor clinical uptake of the approved IV and oral liquid edaravone formulations. This is followed by a review of the alternative oral formulations of edaravone described in the published patent and journal literature against the QTPP. A total of 14 texts published by six research groups on 18 novel oral formulations of edaravone for the treatment of MND have been reviewed. The alternative oral formulations included liquid and solid formulations developed with cyclodextrins, lipids, surfactants, co-surfactants, alkalising agents, tablet excipients, and co-solvents. Most were intended to deliver edaravone for drug absorption in the lower gastrointestinal tract (GIT); however, there were also four formulations targeting the oral mucosal absorption of edaravone to avoid first-pass metabolism. All the novel formulations improved the aqueous solubility, stability, and oral bioavailability (BA) of edaravone compared to an aqueous suspension of edaravone. A common limitation of the published formulations is the lack of MND-patient-centred data. Except for TW001, no other formulations have been trialled in MND patients. To meet the QTPP of an oral edaravone formulation for MND patients, it is recommended that a tablet of appropriate size and with acceptable taste and stability be designed for the effective sublingual or buccal absorption of edaravone. This tablet should be designed with input from the MND community. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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12. Growth Factors and Their Application in the Therapy of Hereditary Neurodegenerative Diseases.
- Author
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Issa, Shaza, Fayoud, Haidar, Shaimardanova, Alisa, Sufianov, Albert, Sufianova, Galina, Solovyeva, Valeriya, and Rizvanov, Albert
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HUNTINGTON disease ,ALZHEIMER'S disease ,PARKINSON'S disease ,GROWTH factors ,GENETIC disorders - Abstract
Hereditary neurodegenerative diseases (hNDDs) such as Alzheimer's, Parkinson's, Huntington's disease, and others are primarily characterized by their progressive nature, severely compromising both the cognitive and motor abilities of patients. The underlying genetic component in hNDDs contributes to disease risk, creating a complex genetic landscape. Considering the fact that growth factors play crucial roles in regulating cellular processes, such as proliferation, differentiation, and survival, they could have therapeutic potential for hNDDs, provided appropriate dosing and safe delivery approaches are ensured. This article presents a detailed overview of growth factors, and explores their therapeutic potential in treating hNDDs, emphasizing their roles in neuronal survival, growth, and synaptic plasticity. However, challenges such as proper dosing, delivery methods, and patient variability can hinder their clinical application. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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13. miRNA profiling as a complementary diagnostic tool for amyotrophic lateral sclerosis.
- Author
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Cheng J, Ho WK, Wu BT, Liu HP, and Lin WY
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- Humans, Gene Expression Profiling, Machine Learning, Amyotrophic Lateral Sclerosis diagnosis, MicroRNAs analysis, MicroRNAs genetics
- Abstract
Amyotrophic lateral sclerosis (ALS), the most prevalent motor neuron disease characterized by its complex genetic structure, lacks a single diagnostic test capable of providing a conclusive diagnosis. In order to demonstrate the potential for genetic diagnosis and shed light on the pathogenic role of miRNAs in ALS, we developed an ALS diagnostic rule by training the model using 80% of a miRNA profiling dataset consisting of 253 ALS samples and 103 control samples. Subsequently, we validated the diagnostic rule using the remaining 20% of unseen samples. The diagnostic rule we developed includes miR-205-5p, miR-206, miR-376a-5p, miR-412-5p, miR-3927-3p, miR-4701-3p, miR-6763-5p, and miR-6801-3p. Remarkably, the rule achieved an 82% true positive rate and a 73% true negative rate when predicting the unseen samples. Furthermore, the identified miRNAs target 21 genes in the PI3K-Akt pathway and 27 genes in the ALS pathway, including notable genes such as BCL2, NEFH, and OPTN. We propose that miRNA profiling may serve as a complementary diagnostic tool to supplement the clinical presentation and aid in the early recognition of ALS., (© 2023. Springer Nature Limited.)
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- 2023
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14. Interaction of DNA with Bifunctional Aldehydes.
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Brooks, B. R. and Klamerth, O. L.
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DNA , *ALDEHYDES , *ORGANIC compounds , *SUGARS , *ENZYMES , *RADIATION chemistry - Abstract
The bifunctional aldehydes glyoxal and malondialdehyde, known to be toxic products of the radiolysis of sugar and other food constituents, interact with DNA in vitro and in vivo as demonstrated by thermal denaturation profiles, chromatographic behavior, and incomplete degradation of the reaction product by deoxyribonuclease. After irradiation of DNA in diluted radioactive glucose solution followed by incubation at slightly acid pH, the radioactivity is found in the core of the enzymic digest only. Attempts to locate the binding site proved that the radiolytic compound is associated preferentially with the guanine and cytidine moiety of the DNA core. [ABSTRACT FROM AUTHOR]
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- 1968
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15. Genetic link between KIF1A mutations and amyotrophic lateral sclerosis: evidence from whole-exome sequencing.
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Wei Zheng, Ji He, Lu Chen, Weiyi Yu, Nan Zhang, Xiaoxuan Liu, and Dongsheng Fan
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GENETICS of amyotrophic lateral sclerosis ,PERIPHERAL neuropathy ,RESEARCH funding ,CELL physiology ,FAMILIES ,DNA ,DESCRIPTIVE statistics ,GENE expression ,CYTOPLASM ,NERVOUS system ,GENETIC disorders ,GENETIC mutation ,KINESIN ,FAMILIAL spastic paraplegia ,DATA analysis software ,GENETICS ,SEQUENCE analysis ,MOLECULAR motor proteins ,COGNITION - Abstract
Objectives: Genetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS. Methods: The analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis. Results: In our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations. Conclusion: Our investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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16. Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS.
- Author
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Jin-Hong Min, Sarlus, Heela, and Harris, Robert A.
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COPPER poisoning ,COPPER ,HOMEOSTASIS ,INCURABLE diseases ,PROTEINS ,COPPER proteins ,RESPIRATION - Abstract
The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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17. Olfactory–trigeminal integration in the primary olfactory cortex.
- Author
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Karunanayaka, Prasanna R., Lu, Jiaming, Elyan, Rommy, Yang, Qing X., and Sathian, K.
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OLFACTORY cortex ,SNOEZELEN ,SMELL ,FUNCTIONAL magnetic resonance imaging ,NEURAL circuitry ,LARGE-scale brain networks - Abstract
Humans naturally integrate signals from the olfactory and intranasal trigeminal systems. A tight interplay has been demonstrated between these two systems, and yet the neural circuitry mediating olfactory–trigeminal (OT) integration remains poorly understood. Using functional magnetic resonance imaging (fMRI), combined with psychophysics, this study investigated the neural mechanisms underlying OT integration. Fifteen participants with normal olfactory function performed a localization task with air‐puff stimuli, phenylethyl alcohol (PEA; rose odor), or a combination thereof while being scanned. The ability to localize PEA to either nostril was at chance. Yet, its presence significantly improved the localization accuracy of weak, but not strong, air‐puffs, when both stimuli were delivered concurrently to the same nostril, but not when different nostrils received the two stimuli. This enhancement in localization accuracy, exemplifying the principles of spatial coincidence and inverse effectiveness in multisensory integration, was associated with multisensory integrative activity in the primary olfactory (POC), orbitofrontal (OFC), superior temporal (STC), inferior parietal (IPC) and cingulate cortices, and in the cerebellum. Multisensory enhancement in most of these regions correlated with behavioral multisensory enhancement, as did increases in connectivity between some of these regions. We interpret these findings as indicating that the POC is part of a distributed brain network mediating integration between the olfactory and trigeminal systems. Practitioner Points: Psychophysical and neuroimaging study of olfactory–trigeminal (OT) integration.Behavior, cortical activity, and network connectivity show OT integration.OT integration obeys principles of inverse effectiveness and spatial coincidence.Behavioral and neural measures of OT integration are correlated. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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18. Assessing pH-Dependent Conformational Changes in the Fusion Peptide Proximal Region of the SARS-CoV-2 Spike Glycoprotein.
- Author
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Stepanenko, Darya, Wang, Yuzhang, and Simmerling, Carlos
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MEMBRANE fusion ,BANKING industry ,CORONAVIRUSES ,PEPTIDES ,MOLECULAR dynamics - Abstract
One of the entry mechanisms of the SARS-CoV-2 coronavirus into host cells involves endosomal acidification. It has been proposed that under acidic conditions, the fusion peptide proximal region (FPPR) of the SARS-CoV-2 spike glycoprotein acts as a pH-dependent switch, modulating immune response accessibility by influencing the positioning of the receptor binding domain (RBD). This would provide indirect coupling of RBD opening to the environmental pH. Here, we explored this possible pH-dependent conformational equilibrium of the FPPR within the SARS-CoV-2 spike glycoprotein. We analyzed hundreds of experimentally determined spike structures from the Protein Data Bank and carried out pH-replica exchange molecular dynamics to explore the extent to which the FPPR conformation depends on pH and the positioning of the RBD. A meta-analysis of experimental structures identified alternate conformations of the FPPR among structures in which this flexible regions was resolved. However, the results did not support a correlation between the FPPR conformation and either RBD position or the reported pH of the cryo-EM experiment. We calculated pKa values for titratable side chains in the FPPR region using PDB structures, but these pKa values showed large differences between alternate PDB structures that otherwise adopt the same FPPR conformation type. This hampers the comparison of pKa values in different FPPR conformations to rationalize a pH-dependent conformational change. We supplemented these PDB-based analyses with all-atom simulations and used constant-pH replica exchange molecular dynamics to estimate pKa values in the context of flexibility and explicit water. The resulting titration curves show good reproducibility between simulations, but they also suggest that the titration curves of the different FPPR conformations are the same within the error bars. In summary, we were unable to find evidence supporting the previously published hypothesis of an FPPR pH-dependent equilibrium: neither from existing experimental data nor from constant-pH MD simulations. The study underscores the complexity of the spike system and opens avenues for further exploration into the interplay between pH and SARS-CoV-2 viral entry mechanisms. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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19. The role of statins in amyotrophic lateral sclerosis: protective or not?
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Al-kuraishy, Hayder M., Jabir, Majid S., Sulaiman, Ghassan M., Mohammed, Hamdoon A., Al-Gareeb, Ali I., Albuhadily, Ali K., Jawad, Sabrean F., Swelum, Ayman A., and Abomughaid, Mosleh M.
- Subjects
AMYOTROPHIC lateral sclerosis ,MOTOR neuron diseases ,ALZHEIMER'S disease ,STATINS (Cardiovascular agents) ,DYSLIPIDEMIA ,PARKINSON'S disease - Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons characterized by muscle weakness, muscle twitching, and muscle wasting. ALS is regarded as the third-most frequent neurodegenerative disease, subsequent to Alzheimer's disease (AD) and Parkinson's disease (PD). The World Health Organization (WHO) in 2007 declared that prolonged use of statins may induce development of ALS-like syndrome and may increase ALS risk. Subsequently, different studies have implicated statins in the pathogenesis of ALS. In contrast, results from preclinical and clinical studies highlighted the protective role of statins against ALS neuropathology. Recently, meta-analyses and systematic reviews illustrated no association between long-term use of statins and ALS risk. These findings highlighted controversial points regarding the effects of statins on ALS pathogenesis and risk. The neuroprotective effects of statins against the development and progression of ALS may be mediated by regulating dyslipidemia and inflammatory changes. However, the mechanism for induction of ALS neuropathology by statins may be related to the dysregulation of liver X receptor signaling (LXR) signaling in the motor neurons and reduction of cholesterol, which has a neuroprotective effect against ALS neuropathology. Nevertheless, the exact role of statins on the pathogenesis of ALS was not fully elucidated. Therefore, this narrative review aims to discuss the role of statins in ALS neuropathology. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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20. Automatic detection of ALS from single-trial MEG signals during speech tasks: a pilot study.
- Author
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Dash, Debadatta, Teplansky, Kristin, Ferrari, Paul, Babajani-Feremi, Abbas, Calley, Clifford S., Heitzman, Daragh, Austin, Sara G., and Jun Wang
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SPEECH ,AMYOTROPHIC lateral sclerosis ,DELAYED diagnosis ,PILOT projects ,MOTOR neurons ,CLASSIFICATION ,SIALON ,REVERBERATION time - Abstract
Amyotrophic lateral sclerosis (ALS) is an idiopathic, fatal, and fast-progressive neurodegenerative disease characterized by the degeneration of motor neurons. ALS patients often experience an initial misdiagnosis or a diagnostic delay due to the current unavailability of an efficient biomarker. Since impaired speech is typical in ALS, we hypothesized that functional differences between healthy and ALS participants during speech tasks can be explained by cortical pattern changes, thereby leading to the identification of a neural biomarker for ALS. In this pilot study, we collected magnetoencephalography (MEG) recordings from three early-diagnosed patients with ALS and three healthy controls during imagined (covert) and overt speech tasks. First, we computed sensor correlations, which showed greater correlations for speakers with ALS than healthy controls. Second, we compared the power of the MEG signals in canonical bands between the two groups, which showed greater dissimilarity in the beta band for ALS participants. Third, we assessed differences in functional connectivity, which showed greater beta band connectivity for ALS than healthy controls. Finally, we performed single-trial classification, which resulted in highest performance with beta band features (~98%). These findings were consistent across trials, phrases, and participants for both imagined and overt speech tasks. Our preliminary results indicate that speech-evoked beta oscillations could be a potential neural biomarker for diagnosing ALS. To our knowledge, this is the first demonstration of the detection of ALS from singletrial neural signals. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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21. Self-assembling dendrimer nanosystems for specific fluorine magnetic resonance imaging and effective theranostic treatment of tumors.
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Zhenbin Lyu, Ralahy, Brigino, Perles-Barbacaru, Teodora-Adriana, Ling Ding, Yifan Jiang, Baoping Lian, Roussel, Tom, Xi Liu, Galanakou, Christina, Laurini, Erik, Tintaru, Aura, Giorgio, Suzanne, Pricl, Sabrina, Xiaoxuan Liu, Bernard, Monique, Iovanna, Juan, Viola, Angèle, and Ling Ping
- Subjects
MAGNETIC resonance imaging ,FLUORINE ,TUMOR treatment ,FIRE detectors ,PANCREATIC cancer ,SUPRAMOLECULAR chemistry - Abstract
Fluorine magnetic resonance imaging (
19 F-MRI) is particularly promising for biomedical applications owing to the absence of fluorine in most biological systems. However, its use has been limited by the lack of safe and water-soluble imaging agents with high fluorine contents and suitable relaxation properties. We report innovative19 F-MRI agents based on supramolecular dendrimers self-assembled by an amphiphilic dendrimer composed of a hydrophobic alkyl chain and a hydrophilic dendron. Specifically, this amphiphilic dendrimer bears multiple negatively charged terminals with high fluorine content, which effectively prevented intra- and intermolecular aggregation of fluorinated entities via electrostatic repulsion. This permitted high fluorine nuclei mobility alongside good water solubility with favorable relaxation properties for use in19 F-MRI. Importantly, the self-assembling19 F-MRI agent was able to encapsulate the near-infrared fluorescence (NIRF) agent DiR and the anticancer drug paclitaxel for multimodal19 F-MRI and NIRF imaging of and theranostics for pancreatic cancer, a deadly disease for which there remains no adequate early detection method or efficacious treatment. The19 F-MRI and multimodal19 F-MRI and NIRF imaging studies on human pancreatic cancer xenografts in mice confirmed the capability of both imaging modalities to specifically image the tumors and demonstrated the efficacy of the theranostic agent in cancer treatment, largely outperforming the clinical anticancer drug paclitaxel. Consequently, these dendrimer nanosystems constitute promising19 F-MRI agents for effective cancer management. This study offers a broad avenue to the construction of19 F-MRI agents and theranostics, exploiting self-assembling supramolecular dendrimer chemistry. [ABSTRACT FROM AUTHOR]- Published
- 2024
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22. Targeting Leishmania infantum Mannosyl-oligosaccharide glucosidase with natural products: potential pH-dependent inhibition explored through computer-aided drug design.
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Daniel Goyzueta-Mamani, Luis, Luz Barazorda-Ccahuana, Haruna, Antonio Candia-Puma, Mayron, Sobreira Galdino, Alexsandro, Andrez Machado-de-Avila, Ricardo, Cordeiro Giunchetti, Rodolfo, Medina-Franco, José L., Florin-Christensen, Mónica, Ferraz Coelho, Eduardo Antonio, and Angel Chávez-Fumagalli, Miguel
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COMPUTER-assisted drug design ,NATURAL products ,LEISHMANIA infantum ,VISCERAL leishmaniasis ,PUBLIC health - Abstract
Visceral Leishmaniasis (VL) is a serious public health issue, documented in more than ninety countries, where an estimated 500,000 new cases emerge each year. Regardless of novel methodologies, advancements, and experimental interventions, therapeutic limitations, and drug resistance are still challenging. For this reason, based on previous research, we screened natural products (NP) from Nuclei of Bioassays, Ecophysiology, and Biosynthesis of Natural Products Database (NuBBEDB), Mexican Compound Database of Natural Products (BIOFACQUIM), and Peruvian Natural Products Database (PeruNPDB) databases, in addition to structural analogs of Miglitol and Acarbose, which have been suggested as treatments for VL and have shown encouraging action against parasite's N-glycan biosynthesis. Using computer-aided drug design (CADD) approaches, the potential inhibitory effect of these NP candidates was evaluated by inhibiting the Mannosyloligosaccharide Glucosidase Protein (MOGS) from Leishmania infantum, an enzyme essential for the protein glycosylation process, at various pH to mimic the parasite's changing environment. Also, computational analysis was used to evaluate the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profile, while molecular dynamic simulations were used to gather information on the interactions between these ligands and the protein target. Our findings indicated that Ocotillone and Subsessiline have potential antileishmanial effects at pH 5 and 7, respectively, due to their high binding affinity to MOGS and interactions in the active center. Furthermore, these compounds were non-toxic and had the potential to be administered orally. This research indicates the promising anti-leishmanial activity of Ocotillone and Subsessiline, suggesting further validation through in vitro and in vivo experiments. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Protein aggregation and therapeutic strategies in SOD1- and TDP-43-linked ALS.
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Tsekrekou, Maria, Giannakou, Maria, Papanikolopoulou, Katerina, and Skretas, Georgios
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- 2024
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24. Structure and inhibition of the human lysosomal transporter Sialin.
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Schmiege, Philip, Donnelly, Linda, Elghobashi-Meinhardt, Nadia, Chia-Hsueh Lee, and Xiaochun Li
- Abstract
Sialin, a member of the solute carrier 17 (SLC17) transporter family, is unique in its ability to transport not only sialic acid using a pH-driven mechanism, but also transport mono and diacidic neurotransmitters, such as glutamate and N-acetylaspartylglutamate (NAAG), into synaptic vesicles via a membrane potential-driven mechanism. While most transporters utilize one of these mechanisms, the structural basis of how Sialin transports substrates using both remains unclear. Here, we present the cryogenic electron-microscopy structures of human Sialin: apo cytosol-open, apo lumen-open, NAAG-bound, and inhibitor-bound. Our structures show that a positively charged cytosolopen vestibule accommodates either NAAG or the Sialin inhibitor Fmoc-LeuOH, while its luminal cavity potentially binds sialic acid. Moreover, functional analyses along with molecular dynamics simulations identify key residues in binding sialic acid and NAAG. Thus, our findings uncover the essential conformational states in NAAG and sialic acid transport, demonstrating a working model of SLC17 transporters. [ABSTRACT FROM AUTHOR]
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- 2024
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25. Experimental and computational study on anti-gastric cancer activity and mechanism of evodiamine derivatives.
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Jingli Liu, Yingying Xue, Kaidi Bai, Fei Yan, Xu Long, Hui Guo, Hao Yan, Guozheng Huang, Jing Zhou, and Yuping Tang
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FRONTIER orbitals ,MOLECULAR dynamics ,STRUCTURE-activity relationships ,DNA topoisomerase I ,CANCER cell proliferation ,DENSITY functional theory - Abstract
Introduction: Human topoisomerase 1 (TOP1) is an important target of various anticancer compounds. The design and discovery of inhibitors targeting TOP1 are of great significance for the development of anticancer drugs. Evodiamine and thieno [2,3-d] pyridine hybrids show potential antitumor activity. Herein, the antigastric cancer activities of these hybrids were investigated. Methods: The inhibitory effects of different concentrations of ten evodiamine derivatives on the gastric cancer cell line SGC-7901 were assessed using a methyl thiazolyl tetrazolium assay. Compounds EVO-1 and EVO-6 strongly inhibited gastric cancer cell proliferation, with inhibition rates of 81.17% ± 5.08% and 80.92% ± 2.75%, respectively. To discover the relationship between the structure and activity of these two derivatives, density functional theory was used to investigate their optimized geometries, natural population charges, frontier molecular orbitals, and molecular electrostatic potentials. To clarify their antigastric cancer mechanisms, molecular docking, molecular dynamics simulations, and binding free energy calculations were performed against TOP1. Results: The results demonstrated that these compounds could intercalate into the cleaved DNA-binding site to form a TOP1-DNA-ligand ternary complex, and the ligand remained secure at the cleaved DNA-binding site to form a stable ternary complex. As the binding free energy of compound EVO-1 with TOP1 (-38.33 kcal·mol-1) was lower than that of compound EVO-6 (-33.25 kcal·mol-1), compound EVO-1 could be a more potent anti-gastric cancer agent than compound EVO-6. Discussion: Thus, compound EVO-1 could be a promising anti-gastric cancer drug candidate. This study may facilitate the design and development of novel TOP1 inhibitors. [ABSTRACT FROM AUTHOR]
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- 2024
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26. Potential JAK2 Inhibitors from Selected Natural Compounds: A Promising Approach for Complementary Therapy in Cancer Patients.
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Vaziri-Amjad, Samaneh, Rahgosha, Reza, and Taherkhani, Amir
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PHYTOTHERAPY ,THERAPEUTIC use of antineoplastic agents ,COMPUTER simulation ,LIGANDS (Chemistry) ,FLAVONOIDS ,QUINONE ,CELL proliferation ,APOPTOSIS ,CANCER patients ,PHYTOCHEMICALS ,PLANT extracts ,CARBOCYCLIC acids ,JANUS kinases ,ALTERNATIVE medicine ,MOLECULAR structure ,RESEARCH methodology ,NEUROTRANSMITTER uptake inhibitors ,TUMORS ,DATA analysis software - Abstract
Background. Janus-activated kinase 2 (JAK2) plays a pivotal role in numerous essential biological processes, including proliferation, apoptosis, and metastasis in human cells. Prior studies have indicated that inhibiting JAK2 could be a promising strategy to mitigate cell proliferation and induce apoptosis in tumor cells. Objectives. This study aimed to estimate the binding affinity of 79 herbal compounds, comprising 46 flavonoids, 21 anthraquinones, and 12 cinnamic acids, to the ATP-binding cleft of JAK2 to identify potential herbal inhibitors of JAK2. Methods. The binding affinities between ligands and JAK2 were calculated utilizing AutoDock 4.0 software in conjunction with the Cygwin environment. Cross-validation was conducted using the Schrödinger tool. Molecular dynamics simulations were employed to evaluate the stability of docked poses for the most significant JAK2 inhibitors. Furthermore, the Discovery Studio Visualizer tool was utilized to elucidate interactions between the top-ranked JAK2 inhibitors and residues within the JAK2 ATP-binding site. Results. Twelve flavonoids, two anthraquinones, and three cinnamic acids demonstrated substantial binding affinities to the protein kinase domain of the receptor, with a criterion of Δ G binding < −10 kcal/mol. Among the studied flavonoids, anthraquinones, and cinnamic acid derivatives, orientin, chlorogenic acid, and pulmatin emerged as the most potent JAK2 inhibitors, exhibiting Δ G binding scores of −14.49, −11.87, and −10.76 kcal/mol, respectively. Furthermore, the docked poses of orientin, pulmatin, and chlorogenic acid remained stable throughout 60 ns computer simulations. The average root mean square deviation values calculated for JAK2 when complexed with orientin, chlorogenic acid, and pulmatin were 2.04 Å, 2.06 Å, and 1.95 Å, respectively. Conclusion. This study underscores the robust inhibitory potential of orientin, pulmatin, and chlorogenic acid against JAK2. The findings hold promise for the development of novel and effective drugs for cancer treatment. [ABSTRACT FROM AUTHOR]
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- 2024
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27. Knockdown of tgfb1a partially improves ALS phenotype in a transient zebrafish model.
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Gonzalez, David, Cuenca, Xiomara, and Allende, Miguel L.
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MOTOR neuron diseases ,TRANSFORMING growth factors ,AMYOTROPHIC lateral sclerosis ,BRACHYDANIO ,MOTOR neurons ,SPINAL cord - Abstract
Amyotrophic lateral sclerosis (ALS) corresponds to a neurodegenerative disorder marked by the progressive degeneration of both upper and lower motor neurons located in the brain, brainstem, and spinal cord. ALS can be broadly categorized into two main types: sporadic ALS (sALS), which constitutes approximately 90% of all cases, and familial ALS (fALS), which represents the remaining 10% of cases. Transforming growth factor type-β (TGF-β) is a cytokine involved in various cellular processes and pathological contexts, including inflammation and fibrosis. Elevated levels of TGF-β have been observed in the plasma and cerebrospinal fluid (CSF) of both ALS patients and mouse models. In this perspective, we explore the impact of the TGF-β signaling pathway using a transient zebrafish model for ALS. Our findings reveal that the knockdown of tgfb1a lead to a partial prevention of motor axon abnormalities and locomotor deficits in a transient ALS zebrafish model at 48 h post-fertilization (hpf). In this context, we delve into the proposed distinct roles of TGF-β in the progression of ALS. Indeed, some evidence suggests a dual role for TGF-β in ALS progression. Initially, it seems to exert a neuroprotective effect in the early stages, but paradoxically, it may contribute to disease progression in later stages. Consequently, we suggest that the TGF-β signaling pathway emerges as an attractive therapeutic target for treating ALS. Nevertheless, further research is crucial to comprehensively understand the nuanced role of TGF-β in the pathological context. [ABSTRACT FROM AUTHOR]
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- 2024
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28. Exploring Cinnamic Acids as Potent Antimetastatic Agents for Cancer Therapy: Molecular Docking and Dynamic Simulation against MMP2.
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Shojaei, Setareh, Zandieh, Mohammad-Reza, Jamshidi, Shokoofeh, Taherkhani, Amir, and Azadian, Zahra
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COMPUTER-assisted molecular modeling ,IN vitro studies ,CROSS-sectional method ,COMPUTER simulation ,PHENOMENOLOGICAL biology ,CARDIOVASCULAR diseases ,ROSMARINIC acid ,BIOCHEMISTRY ,CARBOXYLIC acids ,IN vivo studies ,DESCRIPTIVE statistics ,EXPERIMENTAL design ,PLANT extracts ,CARBOCYCLIC acids ,PHYSICAL & theoretical chemistry ,PROTEOLYTIC enzymes ,MOLECULAR structure ,MEDICINAL plants ,RESEARCH methodology ,AMINO acids ,GLYCOSIDES ,TUMORS ,DENTAL caries ,DRUGS ,COMPARATIVE studies ,CHROMATOGRAPHIC analysis ,CHEMICAL inhibitors - Abstract
Objective. Matrix metalloproteinase-2 (MMP2) overexpression has been considered as a hallmark of tumor aggressiveness. The significant roles of MMP2 in other human disorders, such as cardiovascular diseases and dental caries, have also been demonstrated. Herein, we used in silico approaches to evaluate the binding affinity of selected cinnamic acids to the MMP2 catalytic domain. The obtained findings were subsequently juxtaposed with those attributed to oleandrin, utilized as a reference pharmaceutical agent. Methods. This research employed the AutoDock software to assess the affinity of 19 herbal compounds derived from cinnamic acid to the catalytic cleft of MMP2. The ligands attaining the most negative scores, as determined by the Gibbs free binding energy assessments, were accorded the highest rankings. The interactions between the MMP2 and cinnamic acids ranked highest were elucidated using the Discovery Studio Visualizer tool. Molecular dynamics simulations were performed to investigate the structural stability of MMP2 backbone atoms when forming complexes with both the top-ranked inhibitor from this study and a standard drug. Results. Eight cinnamic acids were indicated with Δ G binding values less than −10 kcal/mol. Cynarin emerged as the most potent inhibitor of the enzyme, with the Δ G binding score and inhibition constant value of −15.19 kcal/mol and 7.29 pM, respectively. The MMP2 backbone atoms achieve stability around the 20 ns mark, displaying a root mean square deviation of approximately 3.2 Å when influenced by the top-ranked cinnamic acid, the standard drug, or in their free form. Conclusion. The inhibition of MMP2 by cinnamic acids, particularly cynarin, holds promise as a valuable therapeutic strategy for various human disorders, encompassing cancer, cardiovascular conditions, and dental caries. [ABSTRACT FROM AUTHOR]
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- 2024
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29. Coping as a resource to allow for psychosocial adjustment in fatal disease: results from patients with amyotrophic lateral sclerosis.
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Finsel, Julia, Rosenbohm, Angela, Peter, Raphael S., Bäzner, Hansjörg, Börtlein, Axel, Dempewolf, Silke, Schabet, Martin, Hecht, Martin, Kohler, Andreas, Opherk, Christian, Nägele, Andrea, Sommer, Norbert, Lindner, Alfred, Rothenbacher, Dietrich, Ludolph, Albert C., Nagel, Gabriele, and Lulé, Dorothée E.
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AMYOTROPHIC lateral sclerosis ,PSYCHOLOGICAL adaptation ,FAILURE (Psychology) ,FEAR of failure ,PATIENTS' attitudes - Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a fatal disorder, which imposes a severe emotional burden on patients. Appropriate copingmechanisms may alleviate this burden and facilitate wellbeing, with social support known to be a successful coping strategy. This observational study aimed to determine the interplay of general coping traits of hope for success and fear of failure, coping behavior of social activity, and patients' wellbeing. Methods: In this cross-sectional study, patients with ALS from a clinical-epidemiological registry in Southwestern Germany were interviewed regarding coping traits (achievement-motivated behavior: hope for success and fear of failure), coping behavior of social activity, and psychosocial adjustment, determined using measures of depressiveness, anxiety [both measured by Hospital Anxiety and Depression Scale (HADS)], and quality of life [Anamnestic Comparative Self-Assessment (ACSA)]. Demographics, clinical [ALS Functional Rating Scale revised version (ALSFRS-R)], and survival data were recorded. Results: A total of 868 patients [60.70% male patients, mean age: 64.70 (±10.83) years, mean ALSFRS-R: 37.36 ± 7.07] were interviewed. Anxiety in patients was found to be associated with a high fear of failure. In contrast, a generally positive attitude in patients exemplified in high hopes for success was associated with better wellbeing. Finally, coping behavior of social activity explained up to 65% of the variance of depressiveness among the patients with ALS. Conclusion: In this study, we present evidence that the wellbeing of patients with ALS is not an immediate fatalistic consequence of physical degradation but rather determined by coping traits and behavior, which may be trained to substantially increase the wellbeing of patients with ALS. [ABSTRACT FROM AUTHOR]
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- 2024
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30. Evaluation of Intraperitoneal [ 18 F]-FDOPA Administration for Micro-PET Imaging in Mice and Assessment of the Effect of Subchronic Ketamine Dosing on Dopamine Synthesis Capacity.
- Author
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Halff, Els F., Natesan, Sridhar, Bonsall, David R., Veronese, Mattia, Garcia-Hidalgo, Anna, Kokkinou, Michelle, Tang, Sac-Pham, Riggall, Laura J., Gunn, Roger N., Irvine, Elaine E., Withers, Dominic J., Wells, Lisa A., Howes, Oliver D., and Vasdev, Neil
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KETAMINE ,DOPAMINE ,DOPAMINERGIC neurons ,POSITRON emission tomography ,INTRACLASS correlation ,METHYL aspartate receptors ,JUGULAR vein ,RADIOACTIVE tracers - Abstract
Positron emission tomography (PET) using the radiotracer [
18 F]-FDOPA provides a tool for studying brain dopamine synthesis capacity in animals and humans. We have previously standardised a micro-PET methodology in mice by intravenously administering [18 F]-FDOPA via jugular vein cannulation and assessment of striatal dopamine synthesis capacity, indexed as the influx rate constant K i Mod of [18 F]-FDOPA, using an extended graphical Patlak analysis with the cerebellum as a reference region. This enables a direct comparison between preclinical and clinical output values. However, chronic intravenous catheters are technically difficult to maintain for longitudinal studies. Hence, in this study, intraperitoneal administration of [18 F]-FDOPA was evaluated as a less-invasive alternative that facilitates longitudinal imaging. Our experiments comprised the following assessments: (i) comparison of [18 F]-FDOPA uptake between intravenous and intraperitoneal radiotracer administration and optimisation of the time window used for extended Patlak analysis, (ii) comparison of K i Mod in a within-subject design of both administration routes, (iii) test-retest evaluation of K i Mod in a within-subject design of intraperitoneal radiotracer administration, and (iv) validation of K i Mod estimates by comparing the two administration routes in a mouse model of hyperdopaminergia induced by subchronic ketamine. Our results demonstrate that intraperitoneal [18 F]-FDOPA administration resulted in good brain uptake, with no significant effect of administration route on K i Mod estimates (intraperitoneal: 0.024 ± 0.0047 min − 1 , intravenous: 0.022 ± 0.0041 min − 1 , p = 0.42) and similar coefficient of variation (intraperitoneal: 19.6%; intravenous: 18.4%). The technique had a moderate test-retest validity (intraclass correlation coefficient ICC = 0.52 , N = 6) and thus supports longitudinal studies. Following subchronic ketamine administration, elevated K i Mod as compared to control condition was measured with a large effect size for both methods (intraperitoneal: Cohen's d = 1.3 ; intravenous: Cohen's d = 0.9), providing further evidence that ketamine has lasting effects on the dopamine system, which could contribute to its therapeutic actions and/or abuse liability. [ABSTRACT FROM AUTHOR]- Published
- 2024
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31. Evaluation of Adenanthera pavonina-derived compounds against diabetes mellitus: insight into the phytochemical analysis and in silico assays.
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Rahman, Md. Sojiur, Hosen, Md. Eram, Faruqe, Md. Omar, Khalekuzzaman, Md., Islam, Md. Asadul, Acharjee, Uzzal Kumar, Bin Jardan, Yousef A., Nafidi, Hiba-Allah, Mekonnen, Amare Bitew, Bourhia, Mohammed, and Zaman, Rashed
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- 2024
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32. Pore-forming peptide C14R exhibits potent antifungal activity against clinical isolates of Candida albicans and Candida auris.
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Vélez, Norida, Argel, Andreys, Kissmann, Ann-Kathrin, Alpízar-Pedraza, Daniel, Escandón, Patricia, Rosenau, Frank, Ständker, Ludger, and Firacative, Carolina
- Subjects
PEPTIDES ,CANDIDA albicans ,ANTIMICROBIAL peptides ,ANTIFUNGAL agents ,INVASIVE candidiasis ,MYCOSES - Abstract
Introduction: Invasive candidiasis is a global public health problem as it poses a significant threat in hospital-settings. The aim of this study was to evaluate C14R, an analog derived from peptide BP100, as a potential antimicrobial peptide against the prevalent opportunistic yeast Candida albicans and the emergent multidrug-resistant yeast Candida auris. Methods: Antifungal susceptibility testing of C14R against 99 C. albicans and 105 C. auris clinical isolates from Colombia, was determined by broth microdilution. Fluconazole was used as a control antifungal. The synergy between C14R and fluconazole was assessed in resistant isolates. Assays against fungal biofilm and growth curves were also carried out. Morphological alterations of yeast cell surface were evaluated by scanning electron microscopy. A permeability assay verified the pore-forming ability of C14R. Results: C. albicans and C. auris isolates had a geometric mean MIC against C14R of 4.42 µg/ml and 5.34 µg/ml, respectively. Notably, none of the isolates of any species exhibited growth at the highest evaluated peptide concentration (200 µg/ml). Synergistic effects were observed when combining the peptide and fluconazole. C14R affects biofilm and growth of C. albicans and C. auris. Cell membrane disruptions were observed in both species after treatment with the peptide. It was confirmed that C14R form pores in C. albicans' membrane. Discussion: C14R has a potent antifungal activity against a large set of clinical isolates of both C. albicans and C. auris, showing its capacity to disrupt Candida membranes. This antifungal activity remains consistent across isolates regardless of their clinical source. Furthermore, the absence of correlation between MICs to C14R and resistance to fluconazole indicates the peptide's potential effectiveness against fluconazole-resistant strains. Our results suggest the potential of C14R, a pore-forming peptide, as a treatment option for fungal infections, such as invasive candidiasis, including fluconazole and amphotericin B -resistant strains. [ABSTRACT FROM AUTHOR]
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- 2024
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33. Timing and impact of percutaneous endoscopic gastrostomy insertion in patients with amyotrophic lateral sclerosis: a comprehensive analysis.
- Author
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Son, Bugyeong, Lee, Jisu, Ryu, Soorack, Park, Yongsoon, and Kim, Seung Hyun
- Subjects
PERCUTANEOUS endoscopic gastrostomy ,DEGLUTITION ,AMYOTROPHIC lateral sclerosis ,KOREANS ,GASTROSTOMY ,ENTERAL feeding - Abstract
Dysphagia is common in amyotrophic lateral sclerosis (ALS) patients, often requiring percutaneous endoscopic gastrostomy (PEG) for enteral nutrition. We retrospectively analyzed data from 188 Korean patients with ALS who underwent PEG tube insertion at five-time points: symptom onset (t
1 ), diagnosis (t2 ), recommended time for gastrostomy (t3 ), PEG insertion (t4 ), and one-year post-insertion (t5 ). The recommended time point for gastrostomy (T-rec for gastrostomy) was defined as the earlier time point between a weight loss of more than 10% and advanced dysphagia indicated by the ALSFRS-R swallowing subscore of 2 or less. The T-rec for gastrostomy was reached at 22 months after symptom onset, followed by PEG insertion at 30 months, resulting in an 8-month delay. During the delay, the ALSFRS-R declined most rapidly at 1.7 points/month, compared to 0.8 points/month from symptom onset to diagnosis, 0.7 points/month from diagnosis to T-rec for gastrostomy, and 0.6 points/month after the PEG insertion. It is crucial to discuss PEG insertion before significant weight loss or severe dysphagia occurs and minimize the delay between the recommended time for gastrostomy and the actual PEG insertion. A stratified and individualized multidisciplinary team approach with careful symptom monitoring and proactive management plans, including early PEG insertion, should be prioritized to improve patient outcomes. [ABSTRACT FROM AUTHOR]- Published
- 2024
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34. Anti-leishmanial activity of Eleutherine plicata Herb. and predictions of isoeleutherin and its analogues.
- Author
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Oliveira de Albuquerque, Kelly Cristina, Silva da Veiga, Andreza do Socorro, Tobias Silveira, Fernando, Batista Campos, Marliane, Lima da Costa, Ana Paula, Martins Brito, Ananda Karolyne, de Souza Melo, Paulo Ricardo, Percario, Sandro, de Molfetta, Fábio Alberto, Fâni Dolabela, Maria, Etxebeste-Mitxeltorena, Mikel, and Yadav, Susmita
- Subjects
TRYPANOTHIONE ,MEDICINAL plants ,LEISHMANIASIS ,CELL permeability ,DRUG toxicity - Abstract
Introduction: Leishmaniasis is caused by protozoa of the genus Leishmania, classified as tegumentary and visceral. The disease treatment is still a serious problem, due to the toxic effects of available drugs, the costly treatment and reports of parasitic resistance, making the search for therapeutic alternatives urgent. This study assessed the in vitro anti-leishmanial potential of the extract, fractions, and isoeleutherin from Eleutherine plicata, as well as the in silico interactions of isoeleutherin and its analogs with Trypanothione Reductase (TR), in addition to predicting pharmacokinetic parameters. Methods: From the ethanolic extract of E. plicata (EEEp) the dichloromethane fraction (FDEp) was obtained, and isoeleutherin isolated. All samples were tested against promastigotes, and parasite viability was evaluated. Isoeleutherin analogues were selected based on similarity in databases (ZINK and eMolecules) to verify the impact on structural change. Results and Discussion: The extract and its fractions were not active against the promastigote form (IC
50 > 200 μg/mL), while isoeleutherin was active (IC50 = 25 μg/mL). All analogues have high intestinal absorption (HIA), cell permeability was moderate in Caco2 and low to moderate in MDCK. Structural changes interfered with plasma protein binding and blood-brain barrier permeability. Regarding metabolism, all molecules appear to be CYP3A4 metabolized and inhibited 2-3 CYPs. Molecular docking and molecular dynamics assessed the interactions between the most stable configurations of isoeleutherin, analogue compound 17, and quinacrine (control drug). Molecular dynamics simulations demonstrated stability and favorable interactions with TR. In summary, fractionation contributed to antileishmanial activity and isoleutherin seems to be promising. Structural alterations did not contribute to improve pharmacokinetic aspects and analogue 17 proved to be more promising than isoeleutherin, presenting better stabilization in TR. [ABSTRACT FROM AUTHOR]- Published
- 2024
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35. Unveiling the affinity--stability relationship in anti-measles virus antibodies: a computational approach for hotspots prediction.
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Paul, Rimpa, Keisuke Kasahara, Jiei Sasaki, Fernández Pérez, Jorge, Ryo Matsunaga, Takao Hashiguchi, Daisuke Kuroda, and Kouhei Tsumoto
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- 2024
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36. Amyotrophic Lateral Sclerosis and Pain: A Narrative Review from Pain Assessment to Therapy.
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Pota, Vincenzo, Sansone, Pasquale, De Sarno, Sara, Aurilio, Caterina, Coppolino, Francesco, Barbarisi, Manlio, Barbato, Francesco, Fiore, Marco, Cosenza, Gianluigi, Passavanti, Maria Beatrice, and Pace, Maria Caterina
- Subjects
AMYOTROPHIC lateral sclerosis ,PAIN measurement ,SPASTICITY ,PAIN management ,MUSCLE weakness ,PATIENT satisfaction - Abstract
Amyotrophic lateral sclerosis (ALS) is the most frequent neurodegenerative disease of the motor system that affects upper and lower motor neurons, leading to progressive muscle weakness, spasticity, atrophy, and respiratory failure, with a life expectancy of 2–5 years after symptom onset. In addition to motor symptoms, patients with ALS have a multitude of nonmotor symptoms; in fact, it is currently considered a multisystem disease. The purpose of our narrative review is to evaluate the different types of pain, the correlation between pain and the disease's stages, the pain assessment tools in ALS patients, and the available therapies focusing above all on the benefits of cannabis use. Pain is an underestimated and undertreated symptom that, in the last few years, has received more attention from research because it has a strong impact on the quality of life of these patients. The prevalence of pain is between 15% and 85% of ALS patients, and the studies on the type and intensity of pain are controversial. The absence of pain assessment tools validated in the ALS population and the dissimilar study designs influence the knowledge of ALS pain and consequently the pharmacological therapy. Several studies suggest that ALS is associated with changes in the endocannabinoid system, and the use of cannabis could slow the disease progression due to its neuroprotective action and act on pain, spasticity, cramps, sialorrhea, and depression. Our research has shown high patients' satisfaction with the use of cannabis for the treatment of spasticity and related pain. However, especially due to the ethical problems and the lack of interest of pharmaceutical companies, further studies are needed to ensure the most appropriate care for ALS patients. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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37. O-Antigen decorations in Salmonella enterica play a key role in eliciting functional immune responses against heterologous serovars in animal models.
- Author
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Gasperini, Gianmarco, Massai, Luisa, De Simone, Daniele, Raso, Maria Michelina, Palmieri, Elena, Alfini, Renzo, Rossi, Omar, Ravenscroft, Neil, Kuttel, Michelle M., and Micoli, Francesca
- Subjects
SALMONELLA enterica ,SALMONELLA enterica serovar Typhi ,IMMUNE response ,TYPHOID fever ,ANIMAL models in research ,SALMONELLA diseases ,POLYSACCHARIDES - Abstract
Introduction: Different serovars of Salmonella enterica cause systemic diseases in humans including enteric fever, caused by S. Typhi and S. Paratyphi A, and invasive nontyphoidal salmonellosis (iNTS), caused mainly by S. Typhimurium and S. Enteritidis. No vaccines are yet available against paratyphoid fever and iNTS but different strategies, based on the immunodominant O-Antigen component of the lipopolysaccharide, are currently being tested. The O-Antigens of S. enterica serovars share structural features including the backbone comprising mannose, rhamnose and galactose as well as further modifications such as O-acetylation and glucosylation. The importance of these O-Antigen decorations for the induced immunogenicity and cross-reactivity has been poorly characterized. Methods: These immunological aspects were investigated in this study using Generalized Modules for Membrane Antigens (GMMA) as delivery systems for the different O-Antigen variants. This platform allowed the rapid generation and in vivo testing of defined and controlled polysaccharide structures through genetic manipulation of the O-Antigen biosynthetic genes. Results: Results from mice and rabbit immunization experiments highlighted the important role played by secondary O-Antigen decorations in the induced immunogenicity. Moreover, molecular modeling of O-Antigen conformations corroborated the likelihood of cross-protection between S. enterica serovars. Discussion: Such results, if confirmed in humans, could have a great impact on the design of a simplified vaccine composition able to maximize functional immune responses against clinically relevant Salmonella enterica serovars. [ABSTRACT FROM AUTHOR]
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- 2024
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38. TUBA4A downregulation as observed in ALS post-mortem motor cortex causes ALS-related abnormalities in zebrafish.
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Van Schoor, Evelien, Strubbe, Dufie, Braems, Elke, Weishaupt, Jochen, Ludolph, Albert C., Van Damme, Philip, Rudolf, Dietmar, Thal, Bercier, Valérie, and Van Den Bosch, Ludo
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AMYOTROPHIC lateral sclerosis ,MOTOR neuron diseases ,MOTOR cortex ,BRACHYDANIO ,POSTMORTEM changes ,SYNAPTIC vesicles ,STARTLE reaction ,POST-translational modification - Abstract
Disease-associated variants of TUBA4A (alpha-tubulin 4A) have recently been identified in familial ALS. Interestingly, a downregulation of TUBA4A protein expression was observed in familial as well as sporadic ALS brain tissue. To investigate whether a decreased TUBA4A expression could be a driving factor in ALS pathogenesis, we assessed whether TUBA4A knockdown in zebrafish could recapitulate an ALS-like phenotype. For this, we injected an antisense oligonucleotide morpholino in zebrafish embryos targeting the zebrafish TUBA4A orthologue. An antibody against synaptic vesicle 2 was used to visualize motor axons in the spinal cord, allowing the analysis of embryonic ventral root projections. Motor behavior was assessed using the touch-evoked escape response. In post-mortem ALS motor cortex, we observed reduced TUBA4A levels. The knockdown of the zebrafish TUBA4A orthologue induced a motor axonopathy and a significantly disturbed motor behavior. Both phenotypes were dose-dependent and could be rescued by the addition of human wild-type TUBA4A mRNA. Thus, TUBA4A downregulation as observed in ALS post-mortem motor cortex could be modeled in zebrafish and induced a motor axonopathy and motor behavior defects reflecting a motor neuron disease phenotype, as previously described in embryonic zebrafish models of ALS. The rescue with human wild-type TUBA4A mRNA suggests functional conservation and strengthens the causal relation between TUBA4A protein levels and phenotype severity. Furthermore, the loss of TUBA4A induces significant changes in post-translational modifications of tubulin, such as acetylation, detyrosination and polyglutamylation. Our data unveil an important role for TUBA4A in ALS pathogenesis, and extend the relevance of TUBA4A to the majority of ALS patients, in addition to cases bearing TUBA4A mutations. [ABSTRACT FROM AUTHOR]
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- 2024
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39. Multistaged In Silico Discovery of the Best SARS-CoV-2 Main Protease Inhibitors amongst 3009 Clinical and FDA-Approved Compounds.
- Author
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Eissa, Ibrahim H., Saleh, Abdulrahman M., Al-Rashood, Sara T., El-Attar, Abdul-Aziz M. M., and Metwaly, Ahmed M.
- Subjects
PROTEASE inhibitors ,SARS-CoV-2 ,DNA fingerprinting ,MOLECULAR docking ,PHARMACOPHORE ,PRILOCAINE - Abstract
As a follow-up to our teamwork's former work against SARS-CoV-2, eight compounds (ramelteon (68), prilocaine (224), nefiracetam (339), cyclandelate (911), mepivacaine (2325), ropivacaine (2351), tasimelteon (2384), and levobupivacaine (2840)) were revealed as the best potentially active SARS-CoV-2 inhibitors targeting the main protease (PDB ID: 5R84), M
pro . The compounds were named in the midst of 3009 FDA and clinically approved compounds employing a multistaged in silico method. A molecular fingerprints study with GWS, the cocrystallized ligand of the Mpro , indicated the resemblance of 150 candidates. Consequently, a structure similarity experiment disclosed the best twenty-nine analogous. Then, molecular docking studies were done against the Mpro active site and showed the binding of the best compounds. Next, a 3D-pharmacophore study confirmed the obtained results for the eight compounds by exhibiting relative fit values of more than 90% (except for 68, 74%, and 2384, 83%). Levobupivacaine (2840) showed the most accurate docking and pharmacophore scores and was picked for further MD simulations experiments (RMSD, RMSF, Rg , SASA, and H-H bonding) over 100 ns. The MD simulations results revealed the accurate binding as well as the optimum dynamics of the Mpro -levobupivacaine complex. Finally, MM-PBSA studies were conducted and indicated the favorable bonding of the Mpro -levobupivacaine complex with a free energy value of −235 kJ/mol. The fulfilled outcomes hold out hope of beating COVID-19 through more in vitro and in vivo research for the named compounds. [ABSTRACT FROM AUTHOR]- Published
- 2024
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40. Design and In Silico and In Vitro Evaluations of a Novel Nicotinamide Derivative as a VEGFR-2 Inhibitor.
- Author
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Eissa, Ibrahim H., Bkrah, Muhammad Abd ElGayed, Yousef, Reda G., Elkady, Hazem, Elkaeed, Eslam B., Alsfouk, Bshra A., Ibrahim, Ibrahim M., Metwaly, Ahmed M., and Husein, Dalal Z.
- Subjects
NICOTINAMIDE ,PROTEIN-ligand interactions ,DENSITY functional theory ,MOLECULAR dynamics ,BINDING energy ,CYTOTOXINS - Abstract
A new nicotinamide derivative, (E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazone)ethyl)phenyl)nicotinamide, was designed as a VEGFR-2 inhibitor. Utilizing the density functional theory (DFT) calculations, the three-dimensional structure of the designed compound was determined, shedding light on its stability and reactivity. Molecular docking revealed its capability to inhibit VEGFR-2, which was further supported by molecular dynamics (MD) simulations confirming its binding to the target protein. In addition, molecular mechanics-generalized born surface area (MM-GBSA), protein-ligand interactions profiler (PLIP), and essential dynamics studies provided further validation of the compound's precise binding with optimal energy. Then, the "compound 10" was synthesized and subjected to in vitro assays. Compound 10 inhibited VEGFR-2 with an IC
50 value of 105.4 ± 0.896 nM, comparing sorafenib's IC50 value of 61.65 ± 0.934 nM. Besides, it exhibited cytotoxicity against HepG2 and MCF-7 cancer cell lines, with IC50 values of 35.78 ± 0.863 μM and 57.62 μM ± 0.871, comparing sorafenib's IC50 values of 5.95 ± 0.917 μM and 8.45 ± 0.912 μM. Furthermore, compound 10 demonstrated a lower level of toxicity towards Vero cell lines, with an IC50 value of 127.3 μM. Likewise, compound 10 induced apoptosis in HepG2 cell lines through a flow cytometric analysis in addition to an increase in the levels of caspase-3 and caspase-9. Moreover, compound 10 hindered the migration and healing abilities of HepG2 cells. In conclusion, our study positions compound 10 as a promising candidate for further chemical modifications and biological evaluations. [ABSTRACT FROM AUTHOR]- Published
- 2024
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- View/download PDF
41. SEROTONIN AND AMYOTROPHIC LATERAL SCLEROSIS (ALS).
- Author
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Kekenadze, Mariam, kvirkvelia, Nana, Beridze, Maia, and Vashadze, Shorena
- Published
- 2024
42. Mechanistics of pH-Dependent Sulfmyoglobin Formation: Spin Control and His64 Proton Relay.
- Author
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Rodriguez-Mackenzie, Angel D., Santos-Velazquez, Lysmarie, Arbelo-Lopez, Héctor D., Wymore, Troy, and Lopez-Garriga, Juan
- Subjects
MYOGLOBIN ,HEMOPROTEINS ,CHARGE transfer ,DOUBLE bonds ,HEME ,HYDROGEN bonding - Abstract
The chemistry of hydrogen sulfide (H
2 S) has been directed towards physiologically relevant hemeproteins, including myoglobin, hemoglobin, and other similar proteins. Despite substantial efforts, there remains a need to elucidate the mechanism and identify the species involved in the reaction between oxy-hemeproteins and H2 S. Here, we summarize both our experimental data and computational modeling results revealing the mechanisms by which sulfmyoglobin (sulfMb) and sulfhemoglobin (sulfHb) are formed. Our experimental data at pH 7.4 reveal differences in intensity between sulfMb and sulfHb chromophores in the 620 nm charge transfer region. This behavior could be attributed to the incomplete reaction of tetrameric oxy-Hb with H2 S, where not all heme groups form sulfheme. The data also show that, for the reaction of oxy-myoglobin (oxy-Mb) and H2 S, the 622 nm charge transfer band increases in intensity from a pH of 6.6 to 5.0. This increase is attributed to the presence of the heme pocket distal His64εδ , which is positively charged, resulting in an elevated yield of sulfMb formation compared to the mono-protonated tautomer, His64ε. Computational hybrid QM/MM methods support the conclusion, indicating that oxy-Mb His64εδ (pH 5.0) reacts with H2 S in the triplet state, favored by −31.0 kcal/mol over the singlet His64ε (pH 6.6) species. The phenomenon is facilitated by a hydrogen bonding network within the heme pocket, between His64εδ , heme Fe(II)O2 , and H2 S. The results establish an energetically favored quantitative mechanism to produce sulfMb (−69.1 kcal/mol) from the reactions of oxy-Mb and H2 S. Curiously, the mechanism between met-aquo Mb, H2 O2 , and H2 S shows similar reaction pathways and leads to sulfheme formation (−135.3 kcal/mol). The energetic barrier towards intermediate Cpd-0 is the limiting step in sulfheme formation for both systems. Both mechanisms show that the thiyl radical, HS• , is the species attacking the β-β double bond of heme pyrrole B, leading to the sulfheme structure. [ABSTRACT FROM AUTHOR]- Published
- 2024
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43. Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency.
- Author
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Prew MS, Camara CM, Botzanowski T, Moroco JA, Bloch NB, Levy HR, Seo HS, Dhe-Paganon S, Bird GH, Herce HD, Gygi MA, Escudero S, Wales TE, Engen JR, and Walensky LD
- Subjects
- Acyl-CoA Dehydrogenase, Long-Chain genetics, Acyl-CoA Dehydrogenase, Long-Chain metabolism, Congenital Bone Marrow Failure Syndromes genetics, Humans, Muscular Diseases, Lipid Metabolism, Inborn Errors genetics, Lipid Metabolism, Inborn Errors metabolism, Mitochondrial Diseases genetics
- Abstract
Very long-chain acyl-CoA dehydrogenase (VLCAD) is an inner mitochondrial membrane enzyme that catalyzes the first and rate-limiting step of long-chain fatty acid oxidation. Point mutations in human VLCAD can produce an inborn error of metabolism called VLCAD deficiency that can lead to severe pathophysiologic consequences, including cardiomyopathy, hypoglycemia, and rhabdomyolysis. Discrete mutations in a structurally-uncharacterized C-terminal domain region of VLCAD cause enzymatic deficiency by an incompletely defined mechanism. Here, we conducted a structure-function study, incorporating X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, computational modeling, and biochemical analyses, to characterize a specific membrane interaction defect of full-length, human VLCAD bearing the clinically-observed mutations, A450P or L462P. By disrupting a predicted α-helical hairpin, these mutations either partially or completely impair direct interaction with the membrane itself. Thus, our data support a structural basis for VLCAD deficiency in patients with discrete mutations in an α-helical membrane-binding motif, resulting in pathologic enzyme mislocalization., (© 2022. The Author(s).)
- Published
- 2022
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44. Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets.
- Author
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Watts, Michelle E., Giadone, Richard M., Ordureau, Alban, Holton, Kristina M., Harper, J. Wade, and Rubin, Lee L.
- Abstract
Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron (MN) disease with severely limited treatment options. Identification of effective treatments has been limited in part by the lack of predictive animal models for complex human disorders. Here, we utilized pharmacologic ER stressors to exacerbate underlying sensitivities conferred by ALS patient genetics in induced pluripotent stem cell (iPSC)-derived motor neurons (MNs). In doing so, we found that thapsigargin and tunicamycin exposure recapitulated ALS-associated degeneration, and that we could rescue this degeneration via MAP4K4 inhibition (MAP4K4i). We subsequently identified mechanisms underlying MAP4K4imediated protection by performing phosphoproteomics on iPSC-derived MNs treated with ER stressors MAP4K4i. Through these analyses, we found JNK, PKC, and BRAF to be differentially modulated in MAP4K4i-protected MNs, and that inhibitors to these proteins could also rescue MN toxicity. Collectively, this study highlights the value of utilizing ER stressors in ALS patient MNs to identify novel druggable targets. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
45. pH-dependent interactions of coacervate-forming histidine-rich peptide with model lipid membranes.
- Author
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Gudlur, Sushanth, Ferreira, Filipe Viana, Shu Ming Ting, Javier, Domene, Carmen, Maricar, Syed, Le Brun, Anton P., Yepuri, Nageshwar, Moir, Michael, Russell, Robert, Darwish, Tamim, Miserez, Ali, and Cárdenas, Marité
- Abstract
Peptide-based liquid droplets (coacervates) produced by spontaneous liquid-liquid phase separation (LLPS), have emerged as a promising class of drug delivery systems due to their high entrapping efficiency and the simplicity of their formulation. However, the detailed mechanisms governing their interaction with cell membranes and cellular uptake remain poorly understood. In this study, we investigated the interactions of peptide coacervates composed of HBpep--peptide derived from the histidine-rich beak proteins (HBPs) of the Humboldt squid--with model cellular membranes in the form of supported lipid bilayers (SLBs). We employed quartz crystal microbalance with dissipation monitoring (QCM-D), neutron reflectometry (NR) and atomistic molecular dynamics (MD) simulations to reveal the nature of these interactions in the absence of fluorescent labels or tags. HBpep forms small oligomers at pH 6 whereas it forms µm-sized coacervates at physiological pH. Our findings reveal that both HBpep oligomers and HBpep-coacervates adsorb onto SLBs at pH 6 and 7.4, respectively. At pH 6, when the peptide carries a net positive charge, HBpep oligomers insert into the SLB, facilitated by the peptide's interactions with the charged lipids and cholesterol. Importantly, however, HBpep coacervate adsorption at physiological pH, when it is largely uncharged, is fully reversible, suggesting no significant lipid bilayer rearrangement. HBpep coacervates, previously identified as efficient drug delivery vehicles, do not interact with the lipid membrane in the same manner as traditional cationic drug delivery systems or cell-penetrating peptides. Based on our findings, HBpep coacervates at physiological pH cannot cross the cell membrane by a simple passive mechanism and are thus likely to adopt a non-canonical cell entry pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
46. Reduction of inflammation and mitochondrial degeneration in mutant SOD1 mice through inhibition of voltage-gated potassium channel Kv1.3.
- Author
-
Ratano, Patrizia, Cocozza, Germana, Pinchera, Cecilia, Busdraghi, Ludovica Maria, Cantando, Iva, Martinello, Katiuscia, Scioli, Mariarosaria, Rosito, Maria, Bezzi, Paola, Fucile, Sergio, Wulff, Heike, Limatola, Cristina, and D'Alessandro, Giuseppina
- Subjects
AMYOTROPHIC lateral sclerosis ,POTASSIUM channels ,MOTOR neurons ,MITOCHONDRIA ,SPINAL cord ,MOTOR cortex ,MICE - Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no effective therapy, causing progressive loss of motor neurons in the spinal cord, brainstem, and motor cortex. Regardless of its genetic or sporadic origin, there is currently no cure for ALS or therapy that can reverse or control its progression. In the present study, taking advantage of a human superoxide dismutase-1 mutant (hSOD1-G93A) mouse that recapitulates key pathological features of human ALS, we investigated the possible role of voltagegated potassium channel Kv1.3 in disease progression. We found that chronic administration of the brain-penetrant Kv1.3 inhibitor, PAP-1 (40 mg/Kg), in early symptomatic mice (i) improves motor deficits and prolongs survival of diseased mice (ii) reduces astrocyte reactivity, microglial Kv1.3 expression, and serum proinflammatory soluble factors (iii) improves structural mitochondrial deficits in motor neuron mitochondria (iv) restores mitochondrial respiratory dysfunction. Taken together, these findings underscore the potential significance of Kv1.3 activity as a contributing factor to the metabolic disturbances observed in ALS. Consequently, targeting Kv1.3 presents a promising avenue for modulating disease progression, shedding new light on potential therapeutic strategies for ALS. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
47. Inhibition of Pancreatic Lipase by Flavonoid Derivatives: In Vitro and In Silico Investigations.
- Author
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Tran, The-Huan, Mai, Thanh-Tan, Ho, Thi-Thu-Trang, Le, Thi-Ngoc-Dung, Cao, Thi-Cam-Nhung, Thai, Khac-Minh, and Tran, Thai-Son
- Subjects
LIPASES ,FLAVONOIDS ,BINDING sites ,ANTIOBESITY agents ,PANCREATIC enzymes ,FUNCTIONAL groups - Abstract
Obesity, characterized by excessive adipose tissue accumulation, has emerged as a crucial determinant for a wide range of chronic medical conditions. The identification of effective interventions for obesity is of utmost importance. Widely researched antiobesity agents focus on pancreatic lipase, a significant therapeutic target. This study presented the evaluation of ten flavonoid compounds in terms of their inhibitory activities against pancreatic lipase, utilizing both in vitro and in silico approaches. The results indicated that all tested compounds demonstrated modest and weaker inhibitory activities compared to the reference compound, orlistat. Among the compounds investigated, F01 exhibited the highest potency, with an IC
50 value of 17.68 ± 1.43 µM. The enzymatic inhibition kinetic analysis revealed that F01 operated through a competitive inhibition mechanism with a determined K i of 7.16 μM. This value suggested a moderate binding affinity for the pancreatic lipase enzyme. Furthermore, the associated V max value was quantified at 0.03272 ΔA·min−1 . In silico studies revealed that F01 displayed a binding mode similar to that of orlistat, despite lacking an active functional group capable of forming a covalent bond with Ser152 of the catalytic triad. However, F01 formed a hydrogen bond with this crucial amino acid. Furthermore, F01 interacted with other significant residues at the enzyme's active site, particularly those within the lid domain. Based on these findings, F01 demonstrates substantial potential as a candidate for further investigations. [ABSTRACT FROM AUTHOR]- Published
- 2024
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- View/download PDF
48. Design of protein-binding peptides with controlled binding affinity: the case of SARS-CoV-2 receptor binding domain and angiotensin-converting enzyme 2 derived peptides.
- Author
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Parisi, Giacomo, Piacentini, Roberta, Incocciati, Alessio, Bonamore, Alessandra, Macone, Alberto, Rupert, Jakob, Zacco, Elsa, Miotto, Mattia, Milanetti, Edoardo, Tartaglia, Gian Gaetano, Ruocco, Giancarlo, Boffi, Alberto, and Di Rienzo, Lorenzo
- Published
- 2024
- Full Text
- View/download PDF
49. Cystatin C is associated with poor survival in amyotrophic lateral sclerosis patients.
- Author
-
Qirui Jiang, Yuan Guo, Tianmi Yang, Shirong Li, Yanbing Hou, Junyu Lin, Yi Xiao, Ruwei Ou, Qianqian Wei, and Huifang Shang
- Subjects
AMYOTROPHIC lateral sclerosis ,CYSTATIN C ,FRONTAL lobe ,LOGISTIC regression analysis ,AGE of onset - Abstract
Background: Cystatin C (CysC) levels in amyotrophic lateral sclerosis (ALS) have been found changes, however, the associations between serum CysC levels and the progression and survival of ALS remain largely unknown. Methods: A total of 1,086 ALS patients and 1,026 sex-age matched healthy controls (HCs) were enrolled in this study. Serum CysC, other renal function, and metabolic parameters were measured. Correlation analysis and binary logistic regression were used to explore the factors related to serum CysC. Kaplan-Meier curve and Cox regression model were used for survival analysis. Results: CysC levels were significantly higher in ALS patients compared to HCs (0.94 vs. 0.85 mg/L, p < 0.001). Compared with ALS patients with lower CysC levels, those with higher CysC levels had an older age of onset, significantly lower ALSFRS-R scores (40.1 vs. 41.3, p < 0.001), a faster disease progression rate (0.75 vs. 0.67, p = 0.011), and lower frontal lobe function scores (15.8 vs. 16.1, p = 0.020). In the correlation analysis, CysC levels were significantly negatively correlated with ALSFRS-R scores (r = -0.16, p < 0.001). Additionally, ALS patients with higher CysC levels had significantly shorter survival time (40.0 vs. 51.8, p < 0.001) compared to patients with lower CysC levels. Higher CysC levels were associated with a higher risk of death in Cox analysis (HR: 1.204, 95% CI: 1.012-1.433). However, when treatment was included in the model, the result was no longer significant. Conclusion: CysC levels in ALS patients were higher compared to HCs. Higher CysC levels were associated with greater disease severity, faster progression rate and shorter survival, needing early intervention. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
50. Protein-lipid interactions and protein anchoring modulate the modes of association of the globular domain of the Prion protein and Doppel protein to model membrane patches.
- Author
-
Soto, Patricia, Thalhuber, Davis T., Luceri, Frank, Janos, Jamie, Borgman, Mason R., Greenwood, Noah M., Acosta, Sofia, and Stoffel, Hunter
- Published
- 2024
- Full Text
- View/download PDF
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