scholarly journals Drug Combinations targeting multiple cellular mechanisms enable axonal regeneration from crushed optic nerve into the brain

2017 ◽  
Author(s):  
Mustafa M. Siddiq ◽  
Yana Zorina ◽  
Arjun Yadaw ◽  
Jens Hansen ◽  
Vera Rabinovich ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Drug Treatment ◽  
Cell Body ◽  
Drug Combination ◽  
Axonal Regeneration ◽  
Computational Models ◽  
Drug Combinations ◽  
Systems Pharmacology ◽  
Injury Site ◽  
The Brain

Injured central nervous system (CNS) axons do not regenerate, due to lack of intrinsic capacity of the neurons and the inhibitory environment at the injury site. Currently, there are no drugs or drug combinations to promote axonal regeneration in the injured spinal cord or optic nerve. We used a systems pharmacology approach to develop a four-drug combination with the potential to increase neuronal capacity by regulating multiple subcellular processes at the cell body to trigger long neurites in inhibitory environments. Dynamical computational models of neurite outgrowth showed that the transcriptional effects of drugs applied at the cell body when combined with drugs that work locally near the site of the injured axons could produce extensive synergistic growth. We used the optic nerve crush in rats to test the drug combinations. We intravitreally injected two drugs, HU-210 (cannabinoid receptor-1 agonist) and IL-6 (interleukin 6 receptor agonist) to stimulate retinal ganglion cells (RGCs) whose axons had been crushed, and applied two drugs in gel foam, taxol to stabilize microtubules and activated protein C (APC) to potentially clear the injury site debris field. Morphology experiments using the injured optic nerve show that the four-drug combination promotes robust axonal regeneration from the RGC to the chiasm. Electrophysiologically the four-drug treatment restored pattern electroretinograms (pERG), and about 25% of the animals had detectable visual evoked potentials (VEP) in the brain. We conclude that systems pharmacology-based drug treatment can promote functional axonal regeneration after nerve injury.

scholarly journals Essentiality and Transcriptome-Enriched Pathway Scores Predict Drug-Combination Synergy

Biology ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 278
Author(s):  
Jin Li ◽  
Yang Huo ◽  
Xue Wu ◽  
Enze Liu ◽  
Zhi Zeng ◽  
...  
Keyword(s):  
Cell Lines ◽  
Drug Combination ◽  
Computational Models ◽  
Target Genes ◽  
Statistical Significance ◽  
Drug Combinations ◽  
Cancer Therapies ◽  
Gene Expressions ◽  
Association Analyses ◽  
Kegg Pathways

In the prediction of the synergy of drug combinations, systems pharmacology models expand the scope of experiment screening and overcome the limitations of current computational models posed by their lack of mechanical interpretation and integration of gene essentiality. We therefore investigated the synergy of drug combinations for cancer therapies utilizing records in NCI ALMANAC, and we employed logistic regression to test the statistical significance of gene and pathway features in that interaction. We trained our predictive models using 43 NCI-60 cell lines, 165 KEGG pathways, and 114 drug pairs. Scores of drug-combination synergies showed a stronger correlation with pathway than gene features in overall trend analysis and a significant association with both genes and pathways in genome-wide association analyses. However, we observed little overlap of significant gene expressions and essentialities and no significant evidence that associated target and non-target genes and their pathways. We were able to validate four drug-combination pathways between two drug combinations, Nelarabine-Exemestane and Docetaxel-Vermurafenib, and two signaling pathways, PI3K-AKT and AMPK, in 16 cell lines. In conclusion, pathways significantly outperformed genes in predicting drug-combination synergy, and because they have very different mechanisms, gene expression and essentiality should be considered in combination rather than individually to improve this prediction.

scholarly journals Predicting Tumor Cell Response to Synergistic Drug Combinations Using a Novel Simplified Deep Learning Model

2020 ◽  
Author(s):  
Heming Zhang ◽  
Jiarui Feng ◽  
Amanda Zeng ◽  
Philip Payne ◽  
Fuhai Li
Keyword(s):  
Deep Learning ◽  
Signaling Pathways ◽  
Drug Combination ◽  
Computational Models ◽  
Learning Model ◽  
Drug Combinations ◽  
Small Set ◽  
Novel Drug ◽  
Deep Learning Model ◽  
Synergistic Drug Combinations

AbstractDrug combinations targeting multiple targets/pathways are believed to be able to reduce drug resistance. Computational models are essential for novel drug combination discovery. In this study, we proposed a new simplified deep learning model, DeepSignalingSynergy, for drug combination prediction. Compared with existing models that use a large number of chemical-structure and genomics features in densely connected layers, we built the model on a small set of cancer signaling pathways, which can mimic the integration of multi-omics data and drug target/mechanism in a more biological meaningful and explainable manner. The evaluation results of the model using the NCI ALMANAC drug combination screening data indicated the feasibility of drug combination prediction using a small set of signaling pathways. Interestingly, the model analysis suggested the importance of heterogeneity of the 46 signaling pathways, which indicates that some new signaling pathways should be targeted to discover novel synergistic drug combinations.

Discovering Synergistic Drug Combination from a Computational Perspective

2018 ◽  
Vol 18 (12) ◽  
pp. 965-974 ◽  
Author(s):  
Pingjian Ding ◽  
Jiawei Luo ◽  
Cheng Liang ◽  
Qiu Xiao ◽  
Buwen Cao ◽  
...  
Keyword(s):  
Computational Methods ◽  
Drug Combination ◽  
Computational Models ◽  
Rapid Development ◽  
Drug Combinations ◽  
Effective Drug ◽  
In Vitro Method ◽  
Feature Based ◽  
Synergistic Drug Combinations

Synergistic drug combinations play an important role in the treatment of complex diseases. The identification of effective drug combination is vital to further reduce the side effects and improve therapeutic efficiency. In previous years, in vitro method has been the main route to discover synergistic drug combinations. However, many limitations of time and resource consumption lie within the in vitro method. Therefore, with the rapid development of computational models and the explosive growth of large and phenotypic data, computational methods for discovering synergistic drug combinations are an efficient and promising tool and contribute to precision medicine. It is the key of computational methods how to construct the computational model. Different computational strategies generate different performance. In this review, the recent advancements in computational methods for predicting effective drug combination are concluded from multiple aspects. First, various datasets utilized to discover synergistic drug combinations are summarized. Second, we discussed feature-based approaches and partitioned these methods into two classes including feature-based methods in terms of similarity measure, and feature-based methods in terms of machine learning. Third, we discussed network-based approaches for uncovering synergistic drug combinations. Finally, we analyzed and prospected computational methods for predicting effective drug combinations.

scholarly journals Drug Combination in Cancer Treatment—From Cocktails to Conjugated Combinations

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 669
Author(s):  
Yosi Gilad ◽  
Gary Gellerman ◽  
David M. Lonard ◽  
Bert W. O’Malley
Keyword(s):  
Drug Treatment ◽  
Cancer Treatment ◽  
Drug Combination ◽  
Drug Combinations ◽  
Cytotoxic Agents ◽  
Small Molecule Drug ◽  
Drug Conjugates ◽  
Future Improvement ◽  
Combinational Treatment ◽  
Selective Delivery

It is well recognized today that anticancer drugs often are most effective when used in combination. However, the establishment of chemotherapy as key modality in clinical oncology began with sporadic discoveries of chemicals that showed antiproliferative properties and which as a first attempt were used as single agents. In this review we describe the development of chemotherapy from its origins as a single drug treatment with cytotoxic agents to polydrug therapy that includes targeted drugs. We discuss the limitations of the first chemotherapeutic drugs as a motivation for the establishment of combined drug treatment as standard practice in spite of concerns about frequent severe, dose limiting toxicities. Next, we introduce the development of targeted treatment as a concept for advancement within the broader field of small-molecule drug combination therapy in cancer and its accelerating progress that was boosted by recent scientific and technological progresses. Finally, we describe an alternative strategy of drug combinations using drug-conjugates for selective delivery of cytotoxic drugs to tumor cells that potentiates future improvement of drug combinations in cancer treatment. Overall, in this review we outline the development of chemotherapy from a pharmacological perspective, from its early stages to modern concepts of using targeted therapies for combinational treatment.

Effect of combined citicoline and glutamate antibodies on acute, generalized convusions induced by pentylenetetrazole in mice

2018 ◽  
pp. 24-29
Author(s):  
М.Н. Карпова ◽  
Л.В. Кузнецова ◽  
Н.Ю. Клишина ◽  
Л.А. Ветрилэ
Keyword(s):  
Drug Combination ◽  
Subcutaneous Injection ◽  
Seizure Activity ◽  
Experimental Conditions ◽  
Slow Progression ◽  
Experiment Control ◽  
Effective Doses ◽  
Experimental Justification ◽  
Series Of Experiments ◽  
The Brain

Цель исследования. На 2 моделях острых генерализованных судорог (ОГС), вызванных конвульсантом пентилентетразолом (ПТЗ), изучить эффективность сочетанного применения ноотропа цитиколина - препарата с противосудорожным действием, нейрорегенеративной, нейропротекторной активностью и антител (АТ) к глутамату, обладающих противосудорожной активностью. Методика. Эксперименты выполнены на мышах-самцах линии C57Bl/6 (n = 87) массой 22-28 г. Эффективность сочетанного применения цитиколина и АТ к глутамату изучали на двух моделях ОГС. Выполнено 2 серии экспериментов. В 1-й серии ОГС вызывали внутривенным введением 1% раствора ПТЗ со скоростью 0,01 мл/с. Для изучения эффективности сочетанного применения препаратов определяли минимальное противосудорожное действие цитиколина (Цераксон, «Nicomed Ferrer Internaсional, S.A.») и АТ к глутамату при их внутрибрюшинном введении. С этой целью цитиколин вводили в дозах 500 и 300 мг/кг за 1 ч до введения ПТЗ, АТ к глутамату - в дозах 5 и 2,5 мг/кг за 1 ч 30 мин до введения ПТЗ. АТ к глутамату получали путем гипериммунизации кроликов соответствующим конъюгированным антигеном. Во 2-й серии ОГС вызывали подкожным введением ПТЗ в дозе 85 мг/кг. Для изучения эффективности сочетанного действия изучаемых препаратов последние вводили в минимально действующих дозах, установленных в 1-й серии экспериментов. Контролем во всех сериях опытов служили животные, которым вводили в аналогичных условиях и в том же объеме физиологический раствор. Результаты. Показано, что сочетанное применение цитиколина и АТ к глутамату в минимально действующих дозах (300 и 2,5 мг/кг соответственно) при моделировании ОГС не вызывало повышения судорожной активности мозга и усиления противосудорожных свойств препаратов. Заключение. Cочетанное применение цитиколина и АТ к глутамату в минимально действующих дозах не вызывало повышения судорожной активности мозга, что свидетельствует о безопасности совместного применения препаратов. Проведенное исследование может служить также экспериментальным обоснованием возможности использования сочетанного применения данных препаратов при судорогах с целью замедления прогрессирования нейродегенеративных процессов и благоприятного влияния на когнитивные функции. Aim. To study the effectivity of a combination of citicoline, a nootropic substance with neuroregenerative, neuroprotective, and anticonvulsant actions, and glutamate antibodies (АB) with an anticonvulsant action in two models of acute generalized convulsions (AGC) caused by the convulsant pentylenetetrazole (PTZ). Methods. Experiments were conducted on C57Bl/6 mice (n = 87) weighing 22-28 g. Effects of combined citicoline and glutamate АB were studied on two models of AGС. In the first series of experiments, AGС was induced by intravenous infusion of a 1% PTZ solution at 0.01 ml/sec. In the second series, AGС was induced by a subcutaneous injection of PTZ 85 mg/kg. To evaluate efficacy of the drug combination minimum intraperitoneal anticonvulsant doses of citicoline (Tserakson, Nicomed Ferrer Internacional, S.A.) and glutamate АB were determined. To this purpose, citicoline was administered at 500 and 300 mg/kg 1 h prior to PTZ, and glutamate АB was administered at 5 and 2.5 mg/kg 90 min prior to PTZ. Glutamate АB was obtained by hyperimmunization of rabbits with a respective conjugated antigen. In the second series of experiments, AGС was induced by a subcutaneous injection of PTZ 85 mg/kg. To evaluate the effect of the drug combination, the drugs were administered at the minimum effective doses determined in the first series of experiment. Control animals were injected with the same volume of saline in the same experimental conditions. Results. The combination of citicoline and glutamate AB used at minimum effective doses of 300 and 2.5 mg/kg, respectively, did not increase the seizure activity in the brain and enhanced anticonvulsant properties of the drugs in two models of AGС. Conclusion. The combination of citicoline and glutamate AT at minimum effective doses did not increase the convulsive activity in the brain, which supported safety of the drug combination. Besides, this study can serve as an experimental justification for using the drug combination in convulsions to favorably influence cognitive functions and slow progression of neurodegenerative processes.

scholarly journals Endocrine Dysfunction in Children with Zika-Related Microcephaly Who Were Born during the 2015 Epidemic in the State of Pernambuco, Brazil

Viruses ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 1
Author(s):  
Andréia Veras Gonçalves ◽  
Demócrito de B. Miranda-Filho ◽  
Líbia Cristina Rocha Vilela ◽  
Regina Coeli Ferreira Ramos ◽  
Thalia V. B. de Araújo ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Viral Infections ◽  
Case Series ◽  
Optic Nerve Hypoplasia ◽  
Endocrine Dysfunction ◽  
Careful Monitoring ◽  
Early Puberty ◽  
Growth Impairment ◽  
Appropriate Treatment ◽  
The Brain

Congenital viral infections and the occurrence of septo-optic dysplasia, which is a combination of optic nerve hypoplasia, abnormal formation of structures along the midline of the brain, and pituitary hypofunction, support the biological plausibility of endocrine dysfunction in Zika-related microcephaly. In this case series we ascertained the presence and describe endocrine dysfunction in 30 children with severe Zika-related microcephaly from the MERG Pediatric Cohort, referred for endocrinological evaluation between February and August 2019. Of the 30 children, 97% had severe microcephaly. The average age at the endocrinological consultation was 41 months and 53% were female. The most frequently observed endocrine dysfunctions comprised short stature, hypothyroidism, obesity and variants early puberty. These dysfunctions occurred alone 57% or in combination 43%. We found optic nerve hypoplasia (6/21) and corpus callosum hypoplasia (20/21). Seizure crises were reported in 86% of the children. The most common—and clinically important—endocrine dysfunctions were pubertal dysfunctions, thyroid disease, growth impairment, and obesity. These dysfunctions require careful monitoring and signal the need for endocrinological evaluation in children with Zika-related microcephaly, in order to make early diagnoses and implement appropriate treatment when necessary.

scholarly journals Power Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models

Antioxidants ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 229
Author(s):  
JunHyuk Woo ◽  
Hyesun Cho ◽  
YunHee Seol ◽  
Soon Ho Kim ◽  
Chanhyeok Park ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Dysfunction ◽  
Computational Models ◽  
Neuronal Damage ◽  
Living Organism ◽  
The Body ◽  
Mitochondrial Functions ◽  
A Cell ◽  
The Brain ◽  
And Oxidative Stress

The brain needs more energy than other organs in the body. Mitochondria are the generator of vital power in the living organism. Not only do mitochondria sense signals from the outside of a cell, but they also orchestrate the cascade of subcellular events by supplying adenosine-5′-triphosphate (ATP), the biochemical energy. It is known that impaired mitochondrial function and oxidative stress contribute or lead to neuronal damage and degeneration of the brain. This mini-review focuses on addressing how mitochondrial dysfunction and oxidative stress are associated with the pathogenesis of neurodegenerative disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease. In addition, we discuss state-of-the-art computational models of mitochondrial functions in relation to oxidative stress and neurodegeneration. Together, a better understanding of brain disease-specific mitochondrial dysfunction and oxidative stress can pave the way to developing antioxidant therapeutic strategies to ameliorate neuronal activity and prevent neurodegeneration.

scholarly journals Systems Pharmacology of Adverse Event Mitigation by Drug Combinations

2013 ◽  
Vol 5 (206) ◽  
pp. 206ra140-206ra140 ◽  
Author(s):  
S. Zhao ◽  
T. Nishimura ◽  
Y. Chen ◽  
E. U. Azeloglu ◽  
O. Gottesman ◽  
...  
Keyword(s):  
Adverse Event ◽  
Drug Combinations ◽  
Systems Pharmacology

scholarly journals Biomolecular Network-Based Synergistic Drug Combination Discovery

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Xiangyi Li ◽  
Guangrong Qin ◽  
Qingmin Yang ◽  
Lanming Chen ◽  
Lu Xie
Keyword(s):  
Drug Combination ◽  
Complex Disease ◽  
Recent Decade ◽  
Drug Combinations ◽  
Network Medicine ◽  
Disease Therapy ◽  
Biomolecular Network ◽  
Disease Related Genes ◽  
Disease Specific ◽  
Synergistic Drug Combinations

Drug combination is a powerful and promising approach for complex disease therapy such as cancer and cardiovascular disease. However, the number of synergistic drug combinations approved by the Food and Drug Administration is very small. To bridge the gap between urgent need and low yield, researchers have constructed various models to identify synergistic drug combinations. Among these models, biomolecular network-based model is outstanding because of its ability to reflect and illustrate the relationships among drugs, disease-related genes, therapeutic targets, and disease-specific signaling pathways as a system. In this review, we analyzed and classified models for synergistic drug combination prediction in recent decade according to their respective algorithms. Besides, we collected useful resources including databases and analysis tools for synergistic drug combination prediction. It should provide a quick resource for computational biologists who work with network medicine or synergistic drug combination designing.

scholarly journals Blocking LINGO-1 in vivo reduces degeneration and enhances regeneration of the optic nerve

2016 ◽  
Vol 2 ◽  
pp. 205521731664170 ◽  
Author(s):  
Melissa M Gresle ◽  
Yaou Liu ◽  
Trevor J Kilpatrick ◽  
Dennis Kemper ◽  
Qi-Zhu Wu ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Axonal Regeneration ◽  
Antibody Therapy ◽  
Experimental Models ◽  
Therapeutic Effects ◽  
Axonal Loss ◽  
Nerve Crush ◽  
Acute Optic Neuritis ◽  
Injury Models

Background Two ongoing phase II clinical trials (RENEW and SYNERGY) have been developed to test the efficacy of anti-LINGO-1 antibodies in acute optic neuritis and relapsing forms of multiple sclerosis, respectively. Across a range of experimental models, LINGO-1 has been found to inhibit neuron and oligodendrocyte survival, axon regeneration, and (re)myelination. The therapeutic effects of anti-LINGO-1 antibodies on optic nerve axonal loss and regeneration have not yet been investigated. Objective In this series of studies we investigate if LINGO-1 antibodies can prevent acute inflammatory axonal loss, and promote axonal regeneration after injury in rodent optic nerves. Methods The effects of anti-LINGO-1 antibody on optic nerve axonal damage were assessed using rodent myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (EAE), and its effects on axonal regeneration were assessed in optic nerve crush injury models. Results In the optic nerve, anti-LINGO-1 antibody therapy was associated with improved optic nerve parallel diffusivity measures on MRI in mice with EAE and reduced axonal loss in rat EAE. Both anti-LINGO-1 antibody therapy and the genetic deletion of LINGO-1 reduced nerve crush-induced axonal degeneration and enhanced axonal regeneration. Conclusion These data demonstrate that LINGO-1 blockade is associated with axonal protection and regeneration in the injured optic nerve.

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