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Treating Brain Cancer Using Signaling Pathways

Posted on by sharris7 / 0 Comment

Glioblastoma (GBM), a cancer of the astrocytes which support brain neurons, is the most common brain cancer. This cancer is particularly difficult to treat due to its highly invasive nature, the cellular heterogenicity of the tumors and the vital signaling pathways that the cancer manipulates. For these reasons GBM can be very difficult to treat, leading it to be a cancer with one of the worst survival rates. Novel treatment options are being developed with hopes to improve survival rates by manipulating signaling pathways that are aiding in the development of these cancer cells such as the MAPK, PI3K, and cAMP pathways [3].

Figure 1: The MAPK pathway begins with a ligand binding to an RTK receptor, which allows for the SH2 domain of the adaptor protein to bind and recruit SOS. SOS exchanges GDP for GTP, activating RAS and the kinase cascade. Vemurafenib is a drug used to inhibit RAF in GBM treatment. [3]
The MAPK pathway (Figure 10 is a receptor tyrosine kinase (RTK) pathway that regulates cell proliferation, cell survival, and metastasis. When this pathway is overactive, GBM prognosis is worsened. This pathway can be affected at different points in the process which can elicit different results. The epidermal growth factor (EGFR) gene is commonly upregulated in GBM. EGFR is a growth factor ligand that binds to the RTK receptor and activates the signaling process. Similarly, NF1 (a negative regulator of the pathway) is absent or inactive in some GBM cases which also will allow for greater MAPK signaling [3].

The PI3K pathway (Figure 2) is another RTK pathway that is overactive in GBM. When PI3K activation occurs, it leads to activation of Akt and mTOR, synthesizing proteins which can stimulate cancer cell growth. For this reason, BKM120 is a drug that is used to inhibit PI3K [3].

Figure 2: PI3K activation begins with a ligand binding to an RTK receptor which recruits GTP-activated RAS to begin the signaling process which can result in cellular growth and proliferation. [3]
Figure 3: The cAMP pathway is a GPCR pathway that can aid in cellular regulation of apoptosis, inflammation, differentiation, and proliferation. [3]
A third pathway related to GBM development and treatment is the cAMP pathway. Unlike the previous pathways, cAMP tends to e under-activated in tumors. This pathway uses a G-protein coupled receptor (GPCR) which, when activated, uses adenylyl cyclase to convert ATP into cAMP, a second messenger. This pathway is negatively regulated by phosphodiesterases (PDE). In order to increase the amount of cAMP, which can induce apoptosis of cancer cells, PDE-inhibitor drugs are used [3].

The MAPK, PI3K, and cAMP pathways all converge at CREB (Figure 4), a transcription factor that is positively correlated with patient survival of malignancies. Therapeutic interventions targeting this convergence could be very effective at treating these signaling dysregulations associated with GBM. Utilizing nodes of convergence between pathways as treatment targets may also reduce the toxic load associated with chemotherapies [3].

Figure 4: The MAPK, PI3K and cAMP pathways all converge at the transcription factor CREB. Upregulation of CREB is a potential treatment target that can mitigate the proliferation of cancer cells. [3]
Because of the heterogenous nature and adaptability of cancer cells and GBM cells specifically, utilizing a single drug with a single target that could affect multiple pathways could be extremely helpful in improving the survival rates with these types of cancers.

References:

(1) Glioblastoma: What Every Patient Needs to Know. Glioblastoma Foundation. https://glioblastomafoundation.org/news/glioblastoma-multiforme.
(2) Brittany Ferri. The Anatomy of Astrocytes. VeryWellHealth. https://www.verywellhealth.com/astrocytes-anatomy-4774354.
(3) Fung, N. H.; Grima, C. A.; Widodo, S. S.; Kaye, A. H.; Whitehead, C. A.; Stylli, S. S.; Mantamadiotis, T. Understanding and Exploiting Cell Signalling Convergence Nodes and Pathway Cross-Talk in Malignant Brain Cancer. Cellular Signalling 2019, 57, 2–9. https://doi.org/10.1016/j.cellsig.2019.01.011.
(4) Morrison, D. K. MAP Kinase Pathways. Cold Spring Harb Perspect Biol 2012, 4 (11), a011254. https://doi.org/10.1101/cshperspect.a011254.
(5) Receptor Tyrosine Kinases (Newer Version); 2017. https://www.youtube.com/watch?v=-osiUGKsu7o.
(6) Fruman, D. A.; Chiu, H.; Hopkins, B. D.; Bagrodia, S.; Cantley, L. C.; Abraham, R. T. The PI3K Pathway in Human Disease. Cell 2017, 170 (4), 605–635. https://doi.org/10.1016/j.cell.2017.07.029.
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End of the Semester

Posted on by zariye / 0 Comment

This semester neurochemistry broadened my understanding of neurotransmission and synaptic plasticity by engaging in oral and group discussions. Exploring topics such as dopamine’s role in reward pathways and serotonin’s impact on mood improved my knowledge and ability to communicate complex ideas effectively. Discussing real-world applications of neurochemistry, such as in neurological disorders, emphasized the real-world experiences.Overall, the emphasis on oral communication in this course significantly enhanced my confidence and skills in scientific discourse.The skills, and knowledge gained in this class can relate to future goals in a healthcare career. Understanding neurotransmission, brain function, and mechanisms laid a strong foundation for understanding neurological disorders and psychiatric conditions, which are prevalent in healthcare. Effective oral communication developed through discussions and presentations is crucial for conveying complex medical information to patients and colleagues. Additionally, critical thinking skills learned in neurochemistry are vital for problem-solving in healthcare settings, whether diagnosing conditions or exploring treatment options. Overall, the insights gained from this course directly support my aspirations in healthcare by preparing me to contribute meaningfully to patient care and biomedical research.Learning at a liberal arts institution means studying a various subjects beyond just your major. It’s about developing skills like critical thinking, communication, and problem-solving that are valuable in any career. You learn to see issues from different angles and appreciate diverse perspectives. It’s an education that focuses on developing well-rounded individuals who are adaptable and curious about the world around them.During the Neurochemistry oral class, I improved my listening skills by actively engaging in class discussions and presentations. I learned to better understand complex scientific topics by taking effective notes during lectures. Participating in group discussions also helped me listen attentively, consider different perspectives, and contribute to scientific conversations. These experiences have enhanced my ability to listen effectively and communicate clearly, which are important skills for success in neurochemistry.

Childhood obesity and how healthcare professionals can approach it using different perspectives.  Healthcare providers specializing in pediatrics and nutrition would assess the impact of childhood obesity on children’s health, including associated risks like diabetes and heart disease. Nutrition experts would analyze eating habits and create personalized plans for healthier diets. Exercise specialists would design fun and safe physical activities to improve fitness levels. Public health experts would look at community factors affecting obesity, such as access to healthy food and safe play areas. Psychologists would study behavior patterns and develop strategies to encourage healthier choices. By combining these perspectives, the team can develop effective programs and interventions to prevent and manage childhood obesity, promoting better health outcomes for children and families.

Disease/Health

The Cycle of Obesity

Posted on by sharris7 / 0 Comment

Obesity

Obesity is an extremely dangerous and costly condition affecting 41.9% of US adults and 19.7% of US children and adolescents. This is not just as issue in the US; obesity also affects 650 million adults worldwide [1]. These statistics are alarming, but even more concerning is the fact that these numbers are expected to increase significantly in the coming years. How is it possible that so many people are being affected by this condition? Aside from obvious genetic, epigenetic, and environmental influences, the key stimulus that kickstarts the metabolic changes associated with obesity is overnutrition which leads to altered chemical signaling within the body [2].

Food intake affects and is affected by two sets of neural pathways (Figure 1) within the melanocortin system of the hypothalamus. These two pathways lead to behavioral expressions of energy expenditure and caloric intake with the goal of maintaining nutritional homeostasis. The agouti-related peptide (AGRP) pathway is orexigenic, meaning it induces feeding, and it works antagonistically to the anorexigenic proopiomelanocortin (POMC) pathway which restricts feeding behaviors. Insulin and leptin are hormones that are released following food intake to inhibit AgRP neurons and activate POMC neurons. This sends neural signals to decrease food intake while increasing energy expenditure to limit overnutrition. When insulin and leptin are no longer present in the receptors, feeding behavior will be triggered and energy expenditure should decrease. [2].

Figure 1: Hypothalamic regulation of feeding behavior and energy expenditure homeostasis occurs via two antagonistic pathways. These pathways are regulated by insulin and leptin which are released with food intake. On the left, insulin and leptin inhibit the orexigenic AgRP neurons and excite the anorexigenic POMC neurons. This will send a signal to stop eating. On the right, the neurons are experiencing insulin and leptin resistance. Because insulin and leptin cannot send their signals, AgRP neurons will not be inhibited and POMC neurons will not be excited. There will not be a signal of satiety sent to the hindbrain (NTS) so feeding behaviors will be increased. [2]

Signaling Dysruption

Insulin and leptin signaling dysregulation are one of the first changes that occur in the development of metabolic syndrome and obesity. Just three days of feeding on a high fat diet can significantly reduce hypothalamic insulin sensitivity. This occurs when the insulin receptors are receiving too much input. When there are too many signaling molecules trying to bind to receptors, the receptors become desensitized to the constant stimulation of insulin. When insulin sensitivity is reduced, anorexigenic signals are not able to be properly sent to the brainstem (Figure 1). This not only induces more feeding behavior leading to body weight gain, but also leads to a state of hyperinsulinemia which produces other negative effects [2,3].

High fat diets also affect other signaling pathways in the hypothalamus. Proinflammatory gene expression in the hypothalamus occurs via the IKK complex and NF-kB activation. High fat diets also can impair insulin action by phosphorylating and inhibiting the insulin receptor substrate proteins at serine 307. This is another mechanism that promotes activation of the AgRP neurons (Figure 1) which induces over-eating behaviors [2].

The Cycle

Although there are many different mechanistic explanations for the changes we see in hypothalamic signaling, they all come from the same stimulus and produce similar behavioral and physiological responses. High fat diets are the impetus for each of these metabolic alterations, and each of these alterations produce negative effects of insulin/leptin resistance, increased food consumptions, inflammation, and eventual weight gain. When a high fat diet is consumed regularly, both the acute and long-term effects perpetuate the same behaviors – over fueling and under activity.

Image 1: A representation of the dopamine reward pathway in the brain. Inflammation of hypothalamic neurons can alter this pathway, leading to increases in highly rewarding behaviors. Eating hyper palatable foods activates this pathway leading to rewarding these types of behaviors.

The inflammation associated with obesity specifically affects the brain structures involved in reward and feeding behaviors. Because of this, the reward pathways in the brain seek out more highly-palatable high fat foods, further perpetuating this cycle. Inflammation also affects peripheral tissues and organs within the body leading to negative effects in other body systems.

Conclusion

Through all of the signaling, chemical, metabolic, and behavioral changes that occur with obesity, the most important thing to understand is that they are all connected. Once the cycle of obesity is initiated, it continues to perpetuate itself through all of the mechanisms discussed above. This process is usually initiated by dietary choices and often is not stopped unless deliberate action is taken. The first step in ending the cycle of obesity is bringing awareness to the problem and educating about how and why this is occurring.

References:

(1) Emily Laurence. Obesity Statistics And Facts In 2024. Forbes Health. https://www.forbes.com/health/weight-loss/obesity-statistics/.
(2) Jais, A.; Brüning, J. C. Hypothalamic Inflammation in Obesity and Metabolic Disease. Journal of Clinical Investigation 2017, 127 (1), 24–32. https://doi.org/10.1172/JCI88878.
(3) Hyperinsulinemia. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/24178-hyperinsulinemia.
Disease/Health

Obesity, Metabolic Diseases, and Diet Across The Planet

Posted on by Zimy / 0 Comment

A. Obesity and metabolic diseases

State Obesity Rate Map

Obesity and metabolic diseases such as type 2 diabetes are major public health challenges worldwide, characterized by chronic low-grade inflammation and dysregulated energy homeostasis. The hypothalamus, a key brain region involved in the regulation of appetite, energy expenditure, and glucose metabolism, has recently emerged as a critical site of inflammation in the context of metabolic dysfunction.

B. The Paper

Hypothalamic Inflammation in Obesity and Metabolic Disease explores the role of hypothalamic inflammation in the pathogenesis of obesity and metabolic disorders. The paper focuses on the complex interplay between metabolic dysregulation, immune responses, and neural circuits within the hypothalamus, shedding light on potential therapeutic targets for combating these conditions.

The paper discusses how various factors, including high-fat diet consumption, systemic inflammation, and cellular stress, can trigger inflammatory responses within the hypothalamus. These inflammatory signals disrupt the normal functioning of hypothalamic neurons and glial cells, leading to impaired energy balance and insulin sensitivity.

Furthermore, the paper explores the molecular mechanisms underlying hypothalamic inflammation, highlighting the role of pro-inflammatory cytokines, chemokines, and immune cell infiltration in driving metabolic dysregulation. They also mention the involvement of intracellular signaling pathways, such as the IκB kinase (IKK)/nuclear factor-κB (NF-κB) pathway and the c-Jun N-terminal kinase (JNK) pathway, in mediating the effects of inflammation on hypothalamic function.

Importantly, the paper explains the bidirectional communication between the hypothalamus and peripheral tissues, whereby hypothalamic inflammation can exacerbate systemic metabolic dysfunction, while metabolic signals from peripheral tissues can influence hypothalamic inflammation. This crosstalk between the central nervous system and peripheral organs contributes to the vicious cycle of obesity and metabolic disease.

Furthermore, the paper discusses potential therapeutic strategies for targeting hypothalamic inflammation in the treatment of obesity and metabolic disorders. Strategies aimed at modulating immune responses, restoring neuronal function, or enhancing metabolic flexibility within the hypothalamus hold promise for ameliorating metabolic dysfunction and improving overall health outcomes.

C. Diet across the planet

The AHEI score ranged from 0 to 100 (correction for trans fat shown). Healthy components: fruit, non-starchy vegetables, legumes/nuts, whole grains, PUFAs, and seafood omega-3 fat; unhealthy components: red/processed meat, SSBs, and sodium.

The mean national score was computed as the sum of the stratum-level component scores and aggregated to the national mean using weighted population proportions for 2018 from 0 to 100. The mean national score was computed as the sum of the stratum-level component scores and aggregated to the national mean using weighted population proportions for 2018.

Only ten countries, representing <1% of the world’s population, had AHEI scores ≥50. Among the world’s 25 most populous countries, the mean AHEI score was highest in Vietnam, Iran, Indonesia, and India (54.5 to 48.2) and lowest in Brazil, Mexico, the United States, and Egypt (27.1–33.5).

Reference
Disease/Health

Schizophrenia

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Schizophrenia Symptoms: Mood and Behavior Effects

A. What is Schizophrenia

Schizophrenia is a complex neuropsychiatric disorder characterized by disturbances in cognition, perception, and behavior. While the precise etiology of schizophrenia remains elusive, growing evidence suggests that dysregulation of various signaling pathways may contribute to its development. Schizophrenia can affect anyone, regardless of age, gender, or socioeconomic status.

B. The Paper

An Emerging Role for Wnt and GSK3 Signaling Pathways in Schizophrenia explores the increasingly recognized involvement of the Wnt and GSK3 (glycogen synthase kinase 3) signaling pathways in the pathophysiology of schizophrenia, offering insights into potential mechanisms underlying the disorder.

C. Wnt

The paper begins by providing an overview of the Wnt signaling pathway, which plays critical roles in neurodevelopment, synaptic plasticity, and adult neurogenesis. Singh discusses how aberrant Wnt signaling has been implicated in schizophrenia, with alterations observed in Wnt ligands, receptors, and downstream effectors in postmortem brain studies and animal models of the disorder. Dysfunctional Wnt signaling may disrupt neural circuitry and synaptic connectivity, contributing to the cognitive and behavioral deficits observed in schizophrenia.

D. GSK3 and its relation to Wnt

Furthermore, the paper explores the role of GSK3, a key regulator of the Wnt pathway, in schizophrenia pathogenesis. Dysregulated GSK3 activity has been implicated in various aspects of schizophrenia, including neurodevelopmental abnormalities, neurotransmitter dysregulation, and synaptic dysfunction. GSK3 dysregulation may contribute to the imbalance between excitatory and inhibitory neurotransmission observed in schizophrenia, leading to altered synaptic plasticity and neuronal communication.

Moreover, the paper discusses the potential interactions between the Wnt and GSK3 signaling pathways in schizophrenia. Singh highlights how GSK3 can modulate Wnt signaling by phosphorylating key components of the pathway, thereby influencing downstream transcriptional responses and cellular processes. Dysregulated crosstalk between Wnt and GSK3 signaling may disrupt neurodevelopmental processes and synaptic function, ultimately contributing to the pathophysiology of schizophrenia.

E. Treatment

Schizophrenia Treatment: Medication, Therapy, and More

The paper concludes by underscoring the therapeutic potential of targeting Wnt and GSK3 signaling pathways in schizophrenia. Singh discusses preclinical and clinical studies investigating pharmacological agents that modulate Wnt signaling or inhibit GSK3 activity as potential treatments for schizophrenia. By restoring the balance of Wnt and GSK3 signaling, these interventions may offer novel therapeutic strategies for ameliorating the cognitive and behavioral symptoms of schizophrenia.

In the traditional setting, schizophrenia is treated with antipsychotics with the help of psychotherapy counseling.

Reference:
An Emerging Role for Wnt and GSK3 Signaling Pathways in Schizophrenia
Health

Concussion and Navigating In School

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5 Concussion Facts to Help Protect Your Head

A. The Paper

The New Neurometabolic Cascade of Concussion looks into the evolving understanding of the pathophysiological mechanisms underlying concussions, shedding light on a paradigm shift in how these injuries are conceptualized and managed.

Traditionally, concussions have been viewed as purely functional disturbances, characterized by transient neurological dysfunction without structural damage. However, Giza and Hovda propose a new perspective, suggesting that concussions involve complex neurometabolic cascades that can lead to long-lasting consequences.

B. Steps of concussion

The paper outlines a multi-step cascade of events triggered by concussive impacts, starting with the immediate disruption of ion gradients and neurotransmitter release. This initial phase is followed by a metabolic crisis, characterized by increased energy demands and compromised cerebral blood flow regulation. As a result, neurons experience energy depletion and mitochondrial dysfunction, leading to oxidative stress and cellular damage.

Moreover, the role of neuroinflammation is highlighted in the secondary injury phase of concussions, where activated microglia release inflammatory mediators and exacerbate neuronal damage. This inflammatory response can persist for days to weeks following the initial injury, contributing to ongoing neurological dysfunction and potential long-term consequences.

C. Imaging

The young brain and concussion: imaging as a biomarker for diagnosis and prognosis. - Abstract - Europe PMC

There was a large interest in imaging tools that can be used to diagnose concussions. My part was about fMRI. A Functional Magnetic Resonance Image (fMRI) is an imaging technique used to diagnose concussion and recognize changes in the brain while you are asked to engage in cognitive tasks.

D. Recovery and Being in School

The paper emphasizes the importance of considering individual variability in concussion outcomes, noting that factors such as age, sex, genetic predisposition, and prior injury history can influence the severity and duration of symptoms. It also stresses the need for personalized approaches to concussion management, including targeted interventions aimed at mitigating specific aspects of the neurometabolic cascade.

Furthermore, the paper discusses the implications of their proposed model for concussion diagnosis, treatment, and prevention. They advocate for a comprehensive approach that integrates clinical assessment, neuroimaging, biomarker analysis, and neuropsychological testing to better understand and manage concussive injuries.

I found this website from the University of Michigan particularly helpful for the treatment and recovery information, especially if you are still in school: Concussion Treatment and Recovery

 

Reference:

The New Neurometabolic Cascade of Concussion

Concussion Treatment and Recovery

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Favorite Part; Peer Discussion

Posted on by Hannah / 0 Comment

One aspect of the semester that I would like to highlight is the end of week discussions that the class would have on each paper we read. This discussion really helped me learn how to communicate my ideas effectively, and in an interesting way.

As a chemistry major, I understand how intimidating chemistry and science in general can be. However, I also know and have learned the benefit of understanding how things work. Having knowledge of the natural world around you allows you to make better, more informed decisions. In my mind, chemistry, biology, and neuroscience should not be intimidating topics. Yes, they are notorious for being confusing, but with practice we can be better at explaining them. This is why the discussions are so important because they allow us to explain things to an informal audience. I hope that in my future as a scientist that I will have many science communication opportunities. I have discovered that I adore public speaking when it comes to science communication. I would not have known this if courses like this one and other courses at Concordia had not pushed me to communicate effectively.

In almost every discussion we had for this course, we brought up the idea of how to educate the public on this topic. Although this was just a thought experiment and will not lead to actual implementation, we talked a lot about educating children early on topics such as diet, mental health, physical health, etc. I think it is very important to have scientists who understand science to be the ones to create the educational materials to be presented to these boards of education.

 Additionally, I became better at listening to others. That statement makes it sound like I was not listening to others before, which I believe I was, just not in the most effective nor helpful way. Before, I would have the urge to rapidly jump into a conversation whenever I had something to say. Usually, this was me trying to relate to a person and their thoughts/ideas/emotions, however I realize now I was unknowingly interrupting them. These weekly discussions have taught me that even when someone finishes a sentence, it can be best to wait and let the words hang in the air. This allows for them to add on or clarify their thoughts, or just allows for deeper contemplation of the topic. 

While I was listening more to my peers, I was learning more about them than ever before. Concordia has many goals and policies to promote multiculturalism which I believe are invaluable. However, the most value from having people from different backgrounds and cultures meet is when they actually listen to each other. While we were discussing neurochemical topics like schizophrenia, cancer, and Alzheimer’s disease; I was simultaneously learning about how the school system works in Norway, or the ordinary diet in Nigeria, or how people access mental health care in rural North Dakota. Learning about the background of my peers gave me their own personal context. It allowed me to see the reasons why they think the way they do.

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