scholarly journals A Multiscale, Systems-Level, Neuropharmacological Model of Cortico-Basal Ganglia System for Arm Reaching Under Normal, Parkinsonian, and Levodopa Medication Conditions

2022 ◽  
Vol 15 ◽  
Author(s):  
Sandeep Sathyanandan Nair ◽  
Vignayanandam Ravindernath Muddapu ◽  
V. Srinivasa Chakravarthy
Keyword(s):  
Basal Ganglia ◽  
Molecular Mechanisms ◽  
Cell Loss ◽  
Patient Characteristics ◽  
Drug Dosage ◽  
Substantia Nigra Pars Compacta ◽  
Reaching Task ◽  
Arm Reaching ◽  
Cardinal Symptoms ◽  
The Impact

In order to understand the link between substantia nigra pars compacta (SNc) cell loss and Parkinson's disease (PD) symptoms, we developed a multiscale computational model that can replicate the symptoms at the behavioural level by incorporating the key cellular and molecular mechanisms underlying PD pathology. There is a modelling tradition that links dopamine to reward and uses reinforcement learning (RL) concepts to model the basal ganglia. In our model, we replace the abstract representations of reward with the realistic variable of extracellular DA released by a network of SNc cells and incorporate it in the RL-based behavioural model, which simulates the arm reaching task. Our results successfully replicated the impact of SNc cell loss and levodopa (L-DOPA) medication on reaching performance. It also shows the side effects of medication, such as wearing off and peak dosage dyskinesias. The model demonstrates how differential dopaminergic axonal degeneration in basal ganglia results in various cardinal symptoms of PD. It was able to predict the optimum L-DOPA medication dosage for varying degrees of cell loss. The proposed model has a potential clinical application where drug dosage can be optimised as per patient characteristics.

scholarly journals A Multiscale, Systems-level, Neuropharmacological Model of Cortico-Basal Ganglia System for Arm Reaching under Normal, Parkinsonian and Levodopa Medication Conditions

2021 ◽  
Author(s):  
Sandeep Sathyanandan Nair ◽  
Vignayanandam Ravindernath Muddapu ◽  
V. Srinivasa Chakravarthy
Keyword(s):  
Basal Ganglia ◽  
Success Rate ◽  
Cell Loss ◽  
Drug Dosage ◽  
Biophysical Model ◽  
Substantia Nigra Pars Compacta ◽  
Reaching Task ◽  
Arm Reaching ◽  
Proposed Model ◽  
Cardinal Symptoms

ABSTRACTThe root cause of Parkinson’s disease (PD) is the death of dopaminergic neurons in Substantia Nigra pars compacta (SNc). The exact cause of this cell death is still not known. Loss of SNc cells manifest as the cardinal symptoms of PD, including tremor, rigidity, bradykinesia, and postural imbalance. To investigate the PD condition in detail and understand the link between loss of cells in SNc and PD symptoms, it is important to have an integrated multiscale computational model that can replicate the symptoms at the behavioural level by evoking the key cellular and molecular underlying mechanisms that contribute to the pathology. In line with this objective, we present a multiscale integrated model of cortico-basal ganglia motor circuitry for arm reaching task, incorporating a detailed biophysical model of SNc dopaminergic neuron. Earlier researchers have shown that fluctuations in dopamine (DA) signals are analogous to reward/punishment signals, thereby prompting application of concepts from reinforcement learning (RL) to modelling the basal ganglia system. In our model, we replace the abstract representations of reward with the realistic variable of extracellular DA released by a network of SNc cells and incorporate it with the RL-based behavioural model, which simulates the arm reaching task. Our results showed that as SNc cell loss increases, the percentage success rate to reach the target decreases, and average time to reach the target increases. With levodopa (L-DOPA) medication, both the success rate and the average time to reach the target improved significantly. The proposed model also exhibits how differential dopaminergic axonal degeneration in basal ganglia results in various cardinal symptoms of PD as manifest in reaching movements. From the model results, we were able to show the side effects of L-DOPA mediation, such as wearing off and peak dosage dyskinesias. Moreover, from the results, we were able to predict the optimum dosage for varying degrees of cell loss and L-DOPA medication. The proposed model has a potential clinical application where drug dosage can be optimized as per patient characteristics. We conclude that our model presents a realistic and efficient way of simulating the PD pathology conditions and the effect of levodopa medication, thereby giving a reliable indicator towards the optimization of the drug dosage.

scholarly journals Saponins as Modulators of the Blood Coagulation System and Perspectives Regarding Their Use in the Prevention of Venous Thromboembolic Incidents

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5171
Author(s):  
Beata Olas ◽  
Karina Urbańska ◽  
Magdalena Bryś
Keyword(s):  
Molecular Mechanisms ◽  
Anticoagulant Activity ◽  
Patient Characteristics ◽  
Coagulation System ◽  
Marine Animals ◽  
Sugar Chain ◽  
Heterogenous Group ◽  
Venous Thromboembolic ◽  
Dicotyledonous Plants ◽  
The Impact

Saponins comprise a heterogenous group of chemical compounds containing a triterpene or steroid aglycone group and at least one sugar chain. They exist as secondary metabolites, occurring frequently in dicotyledonous plants and lower marine animals. Plant saponin extracts or single saponins have indicated antiplatelet and anticoagulant activity. Venous thromboembolism (VTE), including deep venous thrombosis and pulmonary embolism, is a multifactorial disease influenced by various patient characteristics such as age, immobility, previous thromboembolism and inherited thrombophilia. This mini-review (1) evaluates the current literature on saponins as modulators of the coagulation system, (2) discusses the impact of chemical structure on the modulation of the coagulation system, which may further provide a basis for drug or supplement design, (3) examines perspectives of their use in the prevention of VTE. It also describes the molecular mechanisms of action of the saponins involved in the prevention of VTE.

scholarly journals Dopamine neurons encode errors in predicting movement trigger occurrence

2015 ◽  
Vol 113 (4) ◽  
pp. 1110-1123 ◽  
Author(s):  
Benjamin Pasquereau ◽  
Robert S. Turner
Keyword(s):  
Hazard Rate ◽  
Dynamic Environment ◽  
Reaction Times ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Prediction Errors ◽  
Reaching Task ◽  
Foreperiod Duration ◽  
Arm Reaching ◽  
Other Information

The capacity to anticipate the timing of events in a dynamic environment allows us to optimize the processes necessary for perceiving, attending to, and responding to them. Such anticipation requires neuronal mechanisms that track the passage of time and use this representation, combined with prior experience, to estimate the likelihood that an event will occur (i.e., the event's “hazard rate”). Although hazard-like ramps in activity have been observed in several cortical areas in preparation for movement, it remains unclear how such time-dependent probabilities are estimated to optimize response performance. We studied the spiking activity of dopamine neurons in the substantia nigra pars compacta of monkeys during an arm-reaching task for which the foreperiod preceding the “go” signal varied randomly along a uniform distribution. After extended training, the monkeys' reaction times correlated inversely with foreperiod duration, reflecting a progressive anticipation of the go signal according to its hazard rate. Many dopamine neurons modulated their firing rates as predicted by a succession of hazard-related prediction errors. First, as time passed during the foreperiod, slowly decreasing anticipatory activity tracked the elapsed time as if encoding negative prediction errors. Then, when the go signal appeared, a phasic response encoded the temporal unpredictability of the event, consistent with a positive prediction error. Neither the anticipatory nor the phasic signals were affected by the anticipated magnitudes of future reward or effort, or by parameters of the subsequent movement. These results are consistent with the notion that dopamine neurons encode hazard-related prediction errors independently of other information.

The Impact of Ultraviolet Radiation on Barrier Function in Human Skin: Molecular Mechanisms and Topical Therapeutics

2019 ◽  
Vol 25 (40) ◽  
pp. 5503-5511 ◽  
Author(s):  
Abdulaziz Alhasaniah ◽  
Michael J. Sherratt ◽  
Catherine A. O'Neill
Keyword(s):  
Ultraviolet Radiation ◽  
Barrier Function ◽  
Molecular Mechanisms ◽  
Transepidermal Water Loss ◽  
Protective Effects ◽  
Barrier Dysfunction ◽  
Epidermal Barrier ◽  
Positive Effects ◽  
Terrestrial Mammals ◽  
The Impact

A competent epidermal barrier is crucial for terrestrial mammals. This barrier must keep in water and prevent entry of noxious stimuli. Most importantly, the epidermis must also be a barrier to ultraviolet radiation (UVR) from the sunlight. Currently, the effects of ultraviolet radiation on epidermal barrier function are poorly understood. However, studies in mice and more limited work in humans suggest that the epidermal barrier becomes more permeable, as measured by increased transepidermal water loss, in response UVR, at doses sufficiently high to induce erythema. The mechanisms may include disturbance in the organisation of lipids in the stratum corneum (the outermost layer of the epidermis) and reduction in tight junction function in the granular layer (the first living layer of the skin). By contrast, suberythemal doses of UVR appear to have positive effects on epidermal barrier function. Topical sunscreens have direct and indirect protective effects on the barrier through their ability to block UV and also due to their moisturising or occlusive effects, which trap water in the skin, respectively. Some topical agents such as specific botanical extracts have been shown to prevent the loss of water associated with high doses of UVR. In this review, we discuss the current literature and suggest that the biology of UVR-induced barrier dysfunction, and the use of topical products to protect the barrier, are areas worthy of further investigation.

The Role of Vascular Aging in Atherosclerotic Plaque Development and Vulnerability

2019 ◽  
Vol 25 (29) ◽  
pp. 3098-3111 ◽  
Author(s):  
Luca Liberale ◽  
Giovanni G. Camici
Keyword(s):  
Atherosclerotic Plaque ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Plaque Burden ◽  
Vascular Aging ◽  
Age Related ◽  
Plaque Development ◽  
Increased Risk ◽  
The Impact ◽  
Over Time

Background: The ongoing demographical shift is leading to an unprecedented aging of the population. As a consequence, the prevalence of age-related diseases, such as atherosclerosis and its thrombotic complications is set to increase in the near future. Endothelial dysfunction and vascular stiffening characterize arterial aging and set the stage for the development of cardiovascular diseases. Atherosclerotic plaques evolve over time, the extent to which these changes might affect their stability and predispose to sudden complications remains to be determined. Recent advances in imaging technology will allow for longitudinal prospective studies following the progression of plaque burden aimed at better characterizing changes over time associated with plaque stability or rupture. Oxidative stress and inflammation, firmly established driving forces of age-related CV dysfunction, also play an important role in atherosclerotic plaque destabilization and rupture. Several genes involved in lifespan determination are known regulator of redox cellular balance and pre-clinical evidence underlines their pathophysiological roles in age-related cardiovascular dysfunction and atherosclerosis. Objective: The aim of this narrative review is to examine the impact of aging on arterial function and atherosclerotic plaque development. Furthermore, we report how molecular mechanisms of vascular aging might regulate age-related plaque modifications and how this may help to identify novel therapeutic targets to attenuate the increased risk of CV disease in elderly people.

VDAC1 Mediated Anticancer Activity of Gallic Acid in Human Lung Adenocarcinoma A549 Cells

2018 ◽  
Vol 18 (2) ◽  
pp. 255-262 ◽  
Author(s):  
Aikebaier Maimaiti ◽  
Amier Aili ◽  
Hureshitanmu Kuerban ◽  
Xuejun Li
Keyword(s):  
Western Blot ◽  
Cell Viability ◽  
Gallic Acid ◽  
Molecular Mechanisms ◽  
A549 Cells ◽  
Dependent Manner ◽  
Lung Carcinoma Cells ◽  
Induced Apoptosis ◽  
The Impact

Aims: Gallic acid (GA) is generally distributed in a variety of plants and foods, and possesses cell growth-inhibiting activities in cancer cell lines. In the present study, the impact of GA on cell viability, apoptosis induction and possible molecular mechanisms in cultured A549 lung carcinoma cells was investigated. Methods: In vitro experiments showed that treating A549 cells with various concentrations of GA inhibited cell viability and induced apoptosis in a dose-dependent manner. In order to understand the mechanism by which GA inhibits cell viability, comparative proteomic analysis was applied. The changed proteins were identified by Western blot and siRNA methods. Results: Two-dimensional electrophoresis revealed changes that occurred to the cells when treated with or without GA. Four up-regulated protein spots were clearly identified as malate dehydrogenase (MDH), voltagedependent, anion-selective channel protein 1(VDAC1), calreticulin (CRT) and brain acid soluble protein 1(BASP1). VDAC1 in A549 cells was reconfirmed by western blot. Transfection with VDAC1 siRNA significantly increased cell viability after the treatment of GA. Further investigation showed that GA down regulated PI3K/Akt signaling pathways. These data strongly suggest that up-regulation of VDAC1 by GA may play an important role in GA-induced, inhibitory effects on A549 cell viability.

scholarly journals SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms

2020 ◽  
Vol 21 (15) ◽  
pp. 5475 ◽  
Author(s):  
Manuela Pennisi ◽  
Giuseppe Lanza ◽  
Luca Falzone ◽  
Francesco Fisicaro ◽  
Raffaele Ferri ◽  
...  
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Neurological Complications ◽  
Neurological Manifestations ◽  
Wide Range ◽  
Inflammatory State ◽  
Acute Polyneuropathy ◽  
The Central Nervous System ◽  
The Impact

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called “cytokine storm”), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

scholarly journals The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Kanzaki ◽  
Tetsuhiro Chiba ◽  
Junjie Ao ◽  
Keisuke Koroki ◽  
Kengo Kanayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Progression Free Survival ◽  
Erk Signaling ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antitumor Effects ◽  
The Impact

AbstractFGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.

scholarly journals Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

2021 ◽  
Vol 22 (8) ◽  
pp. 3955
Author(s):  
László Bálint ◽  
Zoltán Jakus
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mechanical Forces ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Development ◽  
And Function ◽  
The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

scholarly journals Aerobic Exercise Induces Alternative Splicing of Neurexins in Frontal Cortex

2021 ◽  
Vol 6 (2) ◽  
pp. 48
Author(s):  
Elisa Innocenzi ◽  
Ida Cariati ◽  
Emanuela De Domenico ◽  
Erika Tiberi ◽  
Giovanna D’Arcangelo ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Aerobic Exercise ◽  
Frontal Cortex ◽  
Molecular Mechanisms ◽  
Splice Variants ◽  
Brain Regions ◽  
Synaptic Function ◽  
Molecular Changes ◽  
Beneficial Effects ◽  
The Impact

Aerobic exercise (AE) is known to produce beneficial effects on brain health by improving plasticity, connectivity, and cognitive functions, but the underlying molecular mechanisms are still limited. Neurexins (Nrxns) are a family of presynaptic cell adhesion molecules that are important in synapsis formation and maturation. In vertebrates, three-neurexin genes (NRXN1, NRXN2, and NRXN3) have been identified, each encoding for α and β neurexins, from two independent promoters. Moreover, each Nrxns gene (1–3) has several alternative exons and produces many splice variants that bind to a large variety of postsynaptic ligands, playing a role in trans-synaptic specification, strength, and plasticity. In this study, we investigated the impact of a continuous progressive (CP) AE program on alternative splicing (AS) of Nrxns on two brain regions: frontal cortex (FC) and hippocampus. We showed that exercise promoted Nrxns1–3 AS at splice site 4 (SS4) both in α and β isoforms, inducing a switch from exon-excluded isoforms (SS4−) to exon-included isoforms (SS4+) in FC but not in hippocampus. Additionally, we showed that the same AE program enhanced the expression level of other genes correlated with synaptic function and plasticity only in FC. Altogether, our findings demonstrated the positive effect of CP AE on FC in inducing molecular changes underlying synaptic plasticity and suggested that FC is possibly a more sensitive structure than hippocampus to show molecular changes.

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