scholarly journals Antibody and Protein Profiles in Glaucoma: Screening of Biomarkers and Identification of Signaling Pathways

Biology ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1296
Author(s):  
Nadine Auler ◽  
Henrik Tonner ◽  
Norbert Pfeiffer ◽  
Franz H. Grus
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Recent Literature ◽  
Expression Profiles ◽  
Molecular Signaling ◽  
Therapeutic Approaches ◽  
Main Risk Factor ◽  
New Therapeutic Approaches ◽  
Elevated Intraocular Pressure ◽  
The Impact

Glaucoma represents a group of chronic neurodegenerative diseases, constituting the second leading cause of blindness worldwide. To date, chronically elevated intraocular pressure has been identified as the main risk factor and the only treatable symptom. However, there is increasing evidence in the recent literature that IOP-independent molecular mechanisms also play an important role in the progression of the disease. In recent years, it has become increasingly clear that glaucoma has an autoimmune component. The main focus nowadays is elucidating glaucoma pathogenesis, finding early diagnostic options and new therapeutic approaches. This review article summarizes the impact of different antibodies and proteins associated with glaucoma that can be detected for example by microarray and mass spectrometric analyzes, which (i) provide information about expression profiles and associated molecular signaling pathways, (ii) can possibly be used as a diagnostic tool in future and, (iii) can identify possible targets for therapeutic approaches.

scholarly journals Neuroinflammatory Nexus of Pediatric Epilepsy

2018 ◽  
Vol 07 (02) ◽  
pp. 032-039
Author(s):  
Shruti Bagla ◽  
Alan Dombkowski
Keyword(s):  
Inflammatory Mediators ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Recent Literature ◽  
Refractory Epilepsy ◽  
Genetic Mutation ◽  
Pediatric Epilepsy ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches

AbstractA rapidly growing body of evidence supports the premise that neuroinflammation plays an important role in initiating and sustaining seizures in a range of pediatric epilepsies. Clinical and experimental evidence indicates that neuroinflammation is both an outcome and a contributor to seizures. In this manner, seizures that arise from an initial insult (e.g., infection, trauma, and genetic mutation) contribute to an inflammatory response that subsequently promotes recurrent seizures. This cyclic relationship between seizures and neuroinflammation has been described as a “vicious cycle.” Studies of human tissue resected for surgical treatment of refractory epilepsy have reported activated inflammatory and immune signaling pathways, while animal models have been used to demonstrate that key inflammatory mediators lead to increased seizure susceptibility. Further characterization of the molecular mechanisms involved in this cycle may ultimately enable the development of new therapeutic approaches for the treatment of epilepsy. In this brief review, we focus on key inflammatory mediators that have become prominent in recent literature of epilepsy, including newly characterized microRNAs and their potential role in neuroinflammatory signaling.

Autophagy in health and disease. 3. Involvement of autophagy in muscle atrophy

2010 ◽  
Vol 298 (6) ◽  
pp. C1291-C1297 ◽  
Author(s):  
Marco Sandri
Keyword(s):  
Signaling Pathways ◽  
Muscle Mass ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Muscle Loss ◽  
Muscle Proteins ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Health And Disease

Loss of muscle mass aggravates a variety of diseases, and understanding the molecular mechanisms that control muscle wasting is critical for developing new therapeutic approaches. Weakness is caused by loss of muscle proteins, and recent studies have underlined a major role for the autophagy-lysosome system in regulating muscle mass. Some key components of the autophagy machinery are transcriptionally upregulated during muscle wasting, and their induction precedes muscle loss. However, it is unclear whether autophagy is detrimental, causing atrophy, or beneficial, promoting survival during catabolic conditions. This review discusses recent findings on signaling pathways regulating autophagy.

scholarly journals SLC6A8-mediated intracellular creatine accumulation enhances hypoxic breast cancer cell survival via ameliorating oxidative stress

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Qiao Li ◽  
Manran Liu ◽  
Yan Sun ◽  
Ting Jin ◽  
Pengpeng Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Histological Grade ◽  
Metabolic Adaptation ◽  
Mitochondrial Activity ◽  
Cell Viability Assay ◽  
Ki 67 ◽  
The Impact

Abstract Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, with poor prognosis and limited treatment options. Hypoxia is a key hallmark of TNBC. Metabolic adaptation promotes progression of TNBC cells that are located within the hypoxic tumor regions. However, it is not well understood regarding the precise molecular mechanisms underlying the regulation of metabolic adaptions by hypoxia. Methods RNA sequencing was performed to analyze the gene expression profiles in MDA-MB-231 cell line (20% O2 and 1% O2). Expressions of Slc6a8, which encodes the creatine transporter protein, were detected in breast cancer cells and tissues by quantitative real-time PCR. Immunohistochemistry was performed to detect SLC6A8 protein abundances in tumor tissues. Clinicopathologic correlation and overall survival were evaluated by chi-square test and Kaplan-Meier analysis, respectively. Cell viability assay and flow cytometry analysis with Annexin V/PI double staining were performed to investigate the impact of SLC6A8-mediated uptake of creatine on viability of hypoxic TNBC cells. TNBC orthotopic mouse model was used to evaluate the effects of creatine in vivo. Results SLC6A8 was aberrantly upregulated in TNBC cells in hypoxia. SLC6A8 was drastically overexpressed in TNBC tissues and its level was tightly associated with advanced TNM stage, higher histological grade and worse overall survival of TNBC patients. We found that SLC6A8 was transcriptionally upregulated by p65/NF-κB and mediated accumulation of intracellular creatine in hypoxia. SLC6A8-mediated accumulation of creatine promoted survival and suppressed apoptosis via maintaining redox homeostasis in hypoxic TNBC cells. Furthermore, creatine was required to facilitate tumor growth in xenograft mouse models. Mechanistically, intracellular creatine bolstered cell antioxidant defense by reducing mitochondrial activity and oxygen consumption rates to reduce accumulation of intracellular reactive oxygen species, ultimately activating AKT-ERK signaling, the activation of which protected the viability of hypoxic TNBC cells via mediating the upregulation of Ki-67 and Bcl-2, and the downregulation of Bax and cleaved Caspase-3. Conclusions Our study indicates that SLC6A8-mediated creatine accumulation plays an important role in promoting TNBC progression, and may provide a potential therapeutic strategy option for treatment of SLC6A8 high expressed TNBC.

scholarly journals Transcriptomic Modification in the Cerebral Cortex following Noninvasive Brain Stimulation: RNA-Sequencing Approach

2016 ◽  
Vol 2016 ◽  
pp. 1-15 ◽  
Author(s):  
Ben Holmes ◽  
Seung Ho Jung ◽  
Jing Lu ◽  
Jessica A. Wagner ◽  
Liudmilla Rubbi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cerebral Cortex ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Current Intensity ◽  
Beneficial Effects ◽  
Group A ◽  
The Impact

Transcranial direct current stimulation (tDCS) has been shown to modulate neuroplasticity. Beneficial effects are observed in patients with psychiatric disorders and enhancement of brain performance in healthy individuals has been observed following tDCS. However, few studies have attempted to elucidate the underlying molecular mechanisms of tDCS in the brain. This study was conducted to assess the impact of tDCS on gene expression within the rat cerebral cortex. Anodal tDCS was applied at 3 different intensities followed by RNA-sequencing and analysis. In each current intensity, approximately 1,000 genes demonstrated statistically significant differences compared to the sham group. A variety of functional pathways, biological processes, and molecular categories were found to be modified by tDCS. The impact of tDCS on gene expression was dependent on current intensity. Results show that inflammatory pathways, antidepressant-related pathways (GTP signaling, calcium ion binding, and transmembrane/signal peptide pathways), and receptor signaling pathways (serotonergic, adrenergic, GABAergic, dopaminergic, and glutamate) were most affected. Of the gene expression profiles induced by tDCS, some changes were observed across multiple current intensities while other changes were unique to a single stimulation intensity. This study demonstrates that tDCS can modify the expression profile of various genes in the cerebral cortex and that these tDCS-induced alterations are dependent on the current intensity applied.

scholarly journals The Influence of Inflammation on Anemia in CKD Patients

2020 ◽  
Vol 21 (3) ◽  
pp. 725 ◽  
Author(s):  
Anna Gluba-Brzózka ◽  
Beata Franczyk ◽  
Robert Olszewski ◽  
Jacek Rysz
Keyword(s):  
Treatment Strategies ◽  
Progression Rate ◽  
Therapeutic Approaches ◽  
Pharmacological Interventions ◽  
Anemia Of Chronic Disease ◽  
New Therapeutic Approaches ◽  
Persistent Inflammation ◽  
Inflammatory State ◽  
The Impact

Anemia is frequently observed in the course of chronic kidney disease (CKD) and it is associated with diminishing the quality of a patient’s life. It also enhances morbidity and mortality and hastens the CKD progression rate. Patients with CKD frequently suffer from a chronic inflammatory state which is related to a vast range of underlying factors. The results of studies have demonstrated that persistent inflammation may contribute to the variability in Hb levels and hyporesponsiveness to erythropoietin stimulating agents (ESA), which are frequently observed in CKD patients. The understanding of the impact of inflammatory cytokines on erythropoietin production and hepcidin synthesis will enable one to unravel the net of interactions of multiple factors involved in the pathogenesis of the anemia of chronic disease. It seems that anti-cytokine and anti-oxidative treatment strategies may be the future of pharmacological interventions aiming at the treatment of inflammation-associated hyporesponsiveness to ESA. The discovery of new therapeutic approaches towards the treatment of anemia in CKD patients has become highly awaited. The treatment of anemia with erythropoietin (EPO) was associated with great benefits for some patients but not all.

scholarly journals Emerging role of circadian clock disruption in alcohol-induced liver disease

2018 ◽  
Vol 315 (3) ◽  
pp. G364-G373 ◽  
Author(s):  
Shannon M. Bailey
Keyword(s):  
Liver Disease ◽  
Circadian Clock ◽  
Therapeutic Approaches ◽  
Excessive Alcohol Consumption ◽  
Peripheral Tissues ◽  
New Therapeutic Approaches ◽  
Timing System ◽  
Excessive Alcohol ◽  
The Impact

The detrimental health effects of excessive alcohol consumption are well documented. Alcohol-induced liver disease (ALD) is the leading cause of death from chronic alcohol use. As with many diseases, the etiology of ALD is influenced by how the liver responds to other secondary insults. The molecular circadian clock is an intrinsic cellular timing system that helps organisms adapt and synchronize metabolism to changes in their environment. The clock also influences how tissues respond to toxic, environmental, and metabolic stressors, like alcohol. Consistent with the essential role for clocks in maintaining health, genetic and environmental disruption of the circadian clock contributes to disease. While a large amount of rich literature is available showing that alcohol disrupts circadian-driven behaviors and that circadian clock disruption increases alcohol drinking and preference, very little is known about the role circadian clocks play in alcohol-induced tissue injuries. In this review, recent studies examining the effect alcohol has on the circadian clock in peripheral tissues (liver and intestine) and the impact circadian clock disruption has on development of ALD are presented. This review also highlights some of the rhythmic metabolic processes in the liver that are disrupted by alcohol and potential mechanisms through which alcohol disrupts the liver clock. Improved understanding of the mechanistic links between the circadian clock and alcohol will hopefully lead to the development of new therapeutic approaches for treating ALD and other alcohol-related organ pathologies.

Transgenic Mouse Modeling of Therapeutic Responses in Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2747-2747
Author(s):  
Brian G. Van Ness ◽  
Christine Ramos ◽  
Mary Gosse
Keyword(s):  
Transgenic Mouse ◽  
Plasma Cell ◽  
Genetic Background ◽  
Tumor Heterogeneity ◽  
Chromosomal Abnormalities ◽  
Expression Profiles ◽  
Major Influence ◽  
Therapeutic Approaches ◽  
Mouse Population ◽  
The Impact

Abstract While myeloma is still considered a fatal disease, new therapeutic approaches, including combination of drugs that target different intracellular pathways, have shown marked improvements in response and survival. Yet there are wide variations in responses seen in the patient population. One major source is the variation in chromosomal abnormalities and the genes deregulated among the plasma cell (PC) tumors. Another may be in inherited variations (SNPs) that can have a major influence on drug distribution, transport and metabolism. Our laboratory has developed a transgenic mouse model targeting overexpression of c-myc and bcl-xL in late B cells, that results in early expansion of non-malignant PCs, followed by development of clonal plasma cell malignancies in 100% of the mice. We have reported on cell surface, chromosomal abnormalities, and gene expression profiles of the mouse plasma cell tumors, that demonstrate a very similar profile and heterogeneity to human myelomas. The mouse PC tumors can be adoptively transferred to syngenic recipient mice, as well as grown in culture. The advantage of this model is that the impact of tumor heterogeneity can be assessed in a common germline genetic background in the mice; and an intact immune system is maintained, unlike many common xenograft models. We find that disease progression is variable among tumors and have extended this observed heterogeneity of progression to analysis of drug sensitivity; for example, identifying tumors that are highly sensitive to dexamethasone, and others extremely resistant, and others that show protection in the presence of IL-6. Although bcl-xL expression is important in the initiation of the transgenic malignancy, it was not clear if Bcl-xL was required to maintain the transformed phenotype. To test this, we blocked Bcl-xL with the inhibitor BH3I-2′(Calbiochem). We find that inhibition of Bcl-xL is effective in killing the PC tumors in vitro, and dose is directly related to levels of bcl-xL expression. We also examined various dose combinations of dexamethasone and BH3I-2′ and found an antagonistic relationship of the two drugs. We are in the process of expanding the tumor mouse population to target other therapeutic approaches in the transgenic mouse that models tumor heterogeneity in a common genetic background.

The Parallel Signaling Pathways Of Phosphatidylserine (PS) Exposure Downstream Of Platelet FcγRIIa

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3514-3514 ◽  
Author(s):  
Pierrette Andre ◽  
Steven E. McKenzie ◽  
Wolfgang Bergmeier
Keyword(s):  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Annexin V ◽  
Therapeutic Benefit ◽  
Human Platelets ◽  
Molecular Signaling ◽  
P2y12 Inhibitor ◽  
Immune Mediated ◽  
Static Conditions

Abstract Platelet FcγRIIa is an important component of heparin-induced thrombocytopenia and other immune-mediated thrombocytopenia and thrombosis syndromes. Platelet FcγRIIa, an ITAM receptor, signals not only to cause aggregation and secretion, but also to PS exposure in the platelet procoagulant response when platelets are co-stimulated via the GCPR PARs. The molecular mechanisms downstream of FcγRIIa that lead to PS exposure are incompletely understood. Recently, we (WB; Ahmad et al., JTH 2011; 9:2077) demonstrated that downstream of PAR and GPVI/FcRγ, another ITAM receptor, there are CalDAG-GEF I (CDGI)-dependent and CDGI-independent, ADP/P2Y12-dependent parallel signaling pathways to PS exposure. In this study, we investigated the molecular signaling requirements for PS exposure downstream of FcγRIIa + PAR dual stimulation. We studied the exposure of PS in FcγRIIa transgenic (tg) mouse platelets following dual stimulation through FcγRIIa via anti-mouse CD9 and through PAR4 via PAR4 activating peptide (PAR4AP; AYPGKF). Washed platelets from FcγRIIa-tg mice and FcγRIIa-tg/CDG1-/- mice were stimulated with varying concentrations of anti-mouse CD9 and PAR4-AP (200uM) under static conditions and immediately measured for PS exposure by labeled Annexin-V in flow cytometry. We observed that at 0.5ug/ml of anti-mouse CD9 that the PS exposure of the FcγRIIa-tg/CDG1-/- platelets is approximately 70% of the FcγRIIa-tg platelets. However, when the platelets are pre-incubated with P2Y12 inhibitor MesAMP at 100uM, the PS exposure of the FcγRIIa-tg platelets is decreased by approximately 50% (n=3). For the FcγRIIa-tg/CDG1-/- platelets in the presence of MesAMP, PS exposure is completely abolished (n=3). This indicates that CDG1 contributes part of the signal that leads to PS exposure, while ADP/P2Y12 contributes the other CDGI-independent part of PS exposure downstream of FcγRIIa and GPCR dual stimulation. At a lower concentration of anti-mouse CD9 (0.25ug/ml; near threshold), the level of PS exposure of the FcγRIIa-tg/CDG1-/- platelets is approximately 80% of the FcgRIIa-tg platelets. In addition, at 0.25 ug/ml of anti-CD9, FcγRIIa-tg/CDG1-/- platelets pre-incubated with the P2Y12 inhibitor revealed no stimulated PS exposure. This observation indicates that ADP/P2Y12 plays a more significant role in PS exposure as the concentration of FcγRIIa stimulant nears threshold. Eradication of procoagulant PS exposure may require targeting of both the CDGI-dependent and CDGI-independent pathways for optimum therapeutic benefit in HIT and other immune-mediated thrombocytopenia and thrombosis disorders. CDGI inhibitors useful in human platelets will allow translation of these findings. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Pathogenesis of Ischemic Stroke: Role of Epigenetic Mechanisms

Genes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 89 ◽  
Author(s):  
Rosita Stanzione ◽  
Maria Cotugno ◽  
Franca Bianchi ◽  
Simona Marchitti ◽  
Maurizio Forte ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Epigenetic Modifications ◽  
Review Article ◽  
Epigenetic Changes ◽  
Therapeutic Approaches ◽  
Nutritional Factors ◽  
New Therapeutic Approaches ◽  
Different Types ◽  
The Impact

Epigenetics is the branch of molecular biology that studies modifications able to change gene expression without altering the DNA sequence. Epigenetic modulations include DNA methylation, histone modifications, and noncoding RNAs. These gene modifications are heritable and modifiable and can be triggered by lifestyle and nutritional factors. In recent years, epigenetic changes have been associated with the pathogenesis of several diseases such as diabetes, obesity, renal pathology, and different types of cancer. They have also been related with the pathogenesis of cardiovascular diseases including ischemic stroke. Importantly, since epigenetic modifications are reversible processes they could assist with the development of new therapeutic approaches for the treatment of human diseases. In the present review article, we aim to collect the most recent evidence concerning the impact of epigenetic modifications on the pathogenesis of ischemic stroke in both animal models and humans.

scholarly journals Pressure Point Thresholds and ME/CFS Comorbidity as Indicators of Patient’s Response to Manual Physiotherapy in Fibromyalgia

2020 ◽  
Vol 17 (21) ◽  
pp. 8044
Author(s):  
Francisco Javier Falaguera-Vera ◽  
María Garcia-Escudero ◽  
Javier Bonastre-Férez ◽  
Mario Zacarés ◽  
Elisa Oltra
Keyword(s):  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Blood Collection ◽  
Pharmacological Treatments ◽  
Baseline Sensitivity ◽  
Pressure Point ◽  
Chronic Drug Use ◽  
Pre Treatment ◽  
The Impact

Current pharmacological treatments of Fibromyalgia (FM) are merely symptom palliative, as clinical trials have so far failed to provide overall benefits without associated harms. Polypharmacy often leads to patient’s health deterioration and chronic drug use to an eventual lack of patient’s response. Emerging evidence supports that physiotherapy treatments based on mechanical triggers improve FM symptoms and therefore could be used for therapeutic purposes by themselves or in combination with current pharmacological treatments, as part of integrative medicine programs. However, a paucity of studies rigorously and systematically evaluating this possibility exists. This study uses scores from validated standardized questionnaires, algometer pressure point threshold (PPT) readings and responses from a custom self-developed questionnaire to determine the impact of a pressure-controlled custom manual protocol on FM hyperalgesia/allodynia, fatigue and patient’s quality of life. The results show that patient’s baseline sensitivity to pain inversely correlates with treatment response in FM. Moreover, post-stratification analysis unexpectedly reveals that patients presenting comorbid ME/CFS do not seem to respond to the applied therapy as those presenting FM only. Therefore, pre-treatment PPTs and ME/CFS comorbidity may serve as indicators to predict patient’s response to physiotherapy programs based on mechanical triggers. Further exploration of these findings is granted. In addition, the study of gene expression profiles in the blood collection generated by this study should help unveil the molecular mechanisms behind patient’s differential response to manual therapy.

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