#Metabolic pathway

[pharmaguidelines]

Amino Acid Metabolism: The Crossroads of Cellular Nutrient Use

Amino Acid Metabolism: The Crossroads of Cellular Nutrient Use In the intricate symphony of cellular processes, amino acids stand as versatile players, serving as the building blocks of proteins, precursors for various molecules, and even energy sources. Their metabolic fate is determined by the body’s needs and energetic demands, making amino acid metabolism a crucial pathway that ensures the…

[whats-in-a-sentence]

A comparison of metabolic pathways that are either stimulated (by SAGs) or repressed (by SDGs) during sequential leaf senescence in Arabidopsis is shown in Figure 22.17.

"Plant Physiology and Development" int'l 6e - Taiz, L., Zeiger, E., Møller, I.M., Murphy, A.

[tenth-sentence]

The major metabolic pathway in the starchy endosperm is, as the name implies, starch biosynthesis: the precursor molecule, ADP-glucose, is synthesized in the cytosol and then imported into the amyloplast, where it is enzymatically polymerized into amylose and amylopectin.

"Plant Physiology and Development" int'l 6e - Taiz, L., Zeiger, E., Møller, I.M., Murphy, A.

[prussianmemes]

when i'm at the schizophrenic incoherent rambling competition and an embryologist shows up

[freddyfreeman]

Finally discovered a combination of supplements to help me get 4h of sleep: .05 Estradiol, 100mg micronized progesterone (sometimes additional progesterone cream), DIM, 400mg magnesium citrate, 50mg allithiamine, a B Complex. That’s it.

[hidden-but]

For work, I’m reading the article where Moderna shows how different ionizable lipids they synthetised work when tested on mice and non-human primates, to optimise them to serve as safe and effective carriers for mRNA vaccines (”We sought lipids that enabled high levels of protein expression, demonstrated rapid tissue clearance, and resulted in a toxicity profile that would support chronic therapeutic indications”).

This is your regular reminder that all the We Can Replace ALL Animal Testing With Simulations, AI and Testing On Human Volunteers are, and will be for the next decades at the very least, naively hopeful sci-fi at best, maliciously misleading misinformation at worst.

[onion-existence]

Really got into designing magazine covers for a bit. So I made one for Raven. See if you can spot all the dumb molecular biology jokes I’ve put in here

[opaleyedprince]

just typed rate limiting step as rat limiting step. ratatouille real

[mehmetyildizmelbourne-blog]

MTHFR Gene Mutation: Why It Matters & How to Get Tested

Discover the Role of the MTHFR Gene, the Impact of Its Mutations on Your Health, & How You Can Get Tested to Understand Your Genetic Risk Factors You may not have heard of MTHFR, but this enzyme plays a vital role in our body’s ability to process folate (vitamin B9) and maintain your DNA. Related to another critical B vitamin, I recently wrote a story about the global B12 epidemic.  Analyzing…

[blueoaknx]

Mitochondria Combat Chronic Inflammation

Introduction

Chronic inflammation is a pathophysiological condition linked to numerous diseases, including obesity, diabetes, cardiovascular diseases, and neurodegenerative disorders. Mitochondria, the cellular powerhouses, are pivotal not only for ATP production but also for regulating cellular metabolism, redox balance, and apoptosis. Recent studies reveal that mitochondria play a crucial role in modulating inflammatory responses, and their dysfunction is often implicated in chronic inflammatory states. This article explores the intricate mechanisms by which mitochondria influence chronic inflammation and their potential as therapeutic targets.

Mitochondrial Structure and Function

Mitochondria possess a double-membrane structure that includes:

Outer Membrane: Contains porins that allow the passage of small molecules.

Inner Membrane: Rich in cardiolipin and contains the electron transport chain (ETC) complexes crucial for oxidative phosphorylation.

Matrix: Contains enzymes for the tricarboxylic acid (TCA) cycle, mitochondrial DNA (mtDNA), and ribosomes.

These structural features enable mitochondria to perform several essential functions, including ATP synthesis, calcium buffering, and reactive oxygen species (ROS) regulation.

Mitochondrial Dysfunction and Chronic Inflammation

Mitochondrial dysfunction is characterized by reduced ATP production, increased ROS generation, and impaired metabolic signaling. Key contributors to mitochondrial dysfunction include:

Oxidative Stress: Excessive ROS can damage mitochondrial components, leading to a vicious cycle of increased inflammation.

Aging: Aging is associated with mitochondrial dysfunction, contributing to the onset of chronic inflammatory diseases.

Environmental Toxins: Exposure to pollutants and toxins can induce mitochondrial damage.

Mitochondrial dysfunction is implicated in the activation of pro-inflammatory pathways, including:

NLRP3 Inflammasome Activation: Mitochondrial ROS and mtDNA release can activate the NLRP3 inflammasome, leading to the maturation and secretion of pro-inflammatory cytokines such as IL-1β and IL-18.

NF-κB Pathway: Mitochondrial stress can activate the NF-κB signaling pathway, promoting the expression of pro-inflammatory genes.

Mechanisms by Which Mitochondria Combat Chronic Inflammation

Energy Homeostasis and Immune Cell Function

Mitochondria are essential for the bioenergetic demands of immune cells, particularly during inflammatory responses. Immune cells like macrophages and T-cells switch from oxidative phosphorylation to glycolysis during activation, a process known as the Warburg effect. Mitochondria facilitate this metabolic flexibility by:

Providing substrates for glycolysis and subsequent oxidative phosphorylation.

Regulating ATP levels to support energy-intensive processes, such as cytokine production and phagocytosis.

Regulation of ROS and Redox Signaling

Mitochondria generate ROS as byproducts of the ETC. While excessive ROS can induce oxidative stress, physiological levels of ROS act as signaling molecules that modulate immune responses:

ROS can activate redox-sensitive transcription factors such as Nrf2, promoting the expression of antioxidant genes that mitigate oxidative stress.

Controlled ROS production aids in the differentiation of T-helper cells and enhances the immune response.

Apoptosis and Clearance of Damaged Cells

Mitochondria are central to the intrinsic apoptotic pathway, releasing cytochrome c and other pro-apoptotic factors that initiate caspase cascades. Effective apoptosis is crucial for:

Removing damaged or dysfunctional cells that could perpetuate inflammation.

Promoting an anti-inflammatory environment through the clearance of dead cells and debris, thereby preventing secondary necrosis and the associated inflammatory response.

Mitophagy: Mitochondrial Quality Control

Mitophagy is the selective autophagic degradation of damaged mitochondria, crucial for maintaining mitochondrial quality. Key mechanisms involved in mitophagy include:

PINK1/Parkin Pathway: PINK1 accumulates on damaged mitochondria, recruiting Parkin, which ubiquitinates mitochondrial proteins, signaling for degradation by the autophagy machinery.

Enhanced mitophagy reduces the release of pro-inflammatory factors and maintains cellular homeostasis.

Mitochondrial Biogenesis and Adaptation

Mitochondrial biogenesis is regulated by PGC-1α and other transcription factors. Increasing mitochondrial biogenesis can enhance cellular energy capacity and improve metabolic flexibility, which is particularly beneficial in inflammation. Strategies to promote mitochondrial biogenesis include:

Exercise: Physical activity enhances PGC-1α expression and mitochondrial function.

Nutritional Interventions: Certain bioactive compounds, like resveratrol and curcumin, have been shown to stimulate mitochondrial biogenesis.

Therapeutic Implications

Given their critical role in modulating inflammation, mitochondria represent promising therapeutic targets. Potential strategies include:

Nutraceuticals: Compounds like Coenzyme Q10 and α-lipoic acid may enhance mitochondrial function and reduce oxidative stress.

Exercise Interventions: Regular physical activity can improve mitochondrial health and reduce chronic inflammation.

Mitochondrial-targeted Therapies: Developing drugs that specifically target mitochondrial pathways could provide new treatment avenues for inflammatory diseases.

Conclusion

Mitochondria are integral to the regulation of chronic inflammation through their roles in energy metabolism, ROS management, apoptosis, mitophagy, and biogenesis. Understanding the complex interplay between mitochondrial function and inflammatory processes is essential for developing effective therapeutic strategies. By targeting mitochondrial health, we can potentially mitigate chronic inflammation and its associated diseases, paving the way for innovative approaches to improve public health outcomes. Continued research into mitochondrial biology will undoubtedly reveal further insights into their role in inflammation and disease.

[pharmaguidelines]

Gluconeogenesis: The Backbone of Cellular Metabolism

In the intricate symphony of cellular processes, glucose stands as the maestro, providing energy for a diverse array of cellular operations. However, when blood glucose levels plummet, a backup plan kicks in, ensuring that energy demands are met. This remarkable process is known as gluconeogenesis. A Journey from Non-Carbohydrates to Glucose Gluconeogenesis revolves around the conversion of…

[xtruss]

Stanford Reverses Cognitive Decline in Alzheimer’s With Brain Metabolism Drug

Neuroscientists at Stanford have Linked Alzheimer’s Disease to the Disruption of Brain Metabolism via the Kynurenine Pathway, which is Affected by Amyloid Plaque and Tau Proteins.

— By Stanford University | August 22, 2024

Stanford Researchers Have Found That Blocking the Kynurenine Pathway in the Brain Can Reverse the Metabolic Disruptions Caused By Alzheimer’s Disease, Improving Cognitive Functions in Mice. Credit: SciTechDaily.com

Alzheimer’s Disease and Brain Energy Metabolism

Their research has demonstrated that drugs blocking this pathway can restore cognitive function in Alzheimer’s mice by improving brain metabolism. This discovery not only bridges the gap between neuroscience and oncology but also provides a fast track to repurposing existing drugs for Alzheimer’s treatment.

Neuroscientists believe one of the key mechanisms by which Alzheimer’s disease impairs brain function is through the disruption of glucose metabolism, which is essential for energizing a healthy brain. Essentially, a decrease in metabolism deprives the brain of vital energy, thereby hindering cognitive functions and memory.

Against that backdrop, a team of neuroscientists at the Knight Initiative for Brain Resilience at Stanford’s Wu Tsai Neurosciences Institute have zeroed in on a critical regulator of brain metabolism known as the kynurenine pathway. They hypothesize that the kynurenine pathway is overactivated as a result of amyloid plaque and tau proteins that accumulate in the brains of patients with Alzheimer’s disease.

Restoring Cognitive Function in Lab Mice

Now, with support from research and training grants from the Knight Initiative, they have shown that by blocking the kynurenine pathway in lab mice with Alzheimer’s Disease, they can improve, or even restore, cognitive function by reinstating healthy brain metabolism.

“We were surprised that these metabolic improvements were so effective at not just preserving healthy synapses, but in actually rescuing behavior. The mice performed better in cognitive and memory tests when we gave them drugs that block the kynurenine pathway,” said senior author, Katrin Andreasson, a neurologist at the Stanford School of Medicine and member of the Wu Tsai Neurosciences Institute.

The study, which included collaborations with researchers at the Salk Institute for Biological Studies, Penn State University, and others, was published on August 22, 2024, in the journal Science.

Hungry Neurons

In the brain, kynurenine regulates production of the energy molecule lactate, which nourishes the brain’s neurons and helps maintain healthy synapses. Andreasson and her fellow researchers specifically looked at the enzyme indoleamine-2,3-dioxygenase 1 — or IDO1, for short — which generates kynurenine. Their hypothesis was that increases in IDO1 and kynurenine triggered by accumulation of amyloid and tau proteins would disrupt healthy brain metabolism and lead to cognitive decline.

“The kynurenine pathway is over activated in astrocytes, a critical cell type that metabolically supports neurons. When this happens, astrocytes cannot produce enough lactate as an energy source for neurons, and this disrupts healthy brain metabolism and harms synapses” Andreasson said. Blocking production of kynurenine by blocking IDO1 restores the ability of astrocytes to nourish neurons with lactate.

Potential Fast-Tracking of IDO1 Inhibitors

Best of all for Andreasson, and for Alzheimer’s patients, IDO1 is well known in oncology and there are already drugs in clinical trials to suppress IDO1 activity and production of kynurenine. That meant Andreasson could circumvent the time-intensive work of identifying new drugs and to begin testing in lab mice almost immediately.

In those tests, in which mice with Alzheimer’s Disease must navigate an obstacle course before and after drug intervention, Andreasson and team found that the drugs improved hippocampal glucose metabolism, corrected deficient astrocytic performance, and improved the mice’s spatial memory.

Promising Results Across Different Pathologies

“We also can’t overlook the fact that we saw this improvement in brain plasticity in mice with both amyloid and tau mice models. These are completely different pathologies, and the drugs appear to work for both,” Andreasson noted. “That was really exciting to us.”

Better yet, this intersection between neuroscience, oncology, and pharmacology could help speed drugs to market if proved effective in ongoing human clinical trials for cancer.

“We’re hopeful that IDO1 inhibitors developed for cancer could be repurposed for treatment of AD,” Andreasson stressed.

A Glimpse into the Future of Alzheimer’s Treatment

The next step is to test IDO1 inhibitors in human Alzheimer’s patients to see if they show similar improvements in cognition and memory. Prior clinical tests in cancer patients tested the effectiveness of IDO1 inhibitors on cancer but did not anticipate or measure improvements in cognition and memory. Andreasson is hoping to investigate IDO1 inhibitors in human trials for Alzheimer’s disease in the near future.

Reference: “Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies” 22 August 2024, Science. DOI: 10.1126/science.abm6131

Stanford Wu Tsai Neurosciences Institute / Knight Initiative for Brain Resilience Authors:

Paras S. Minhas (co-lead), Amira Latif-Hernandez (co-lead), Aarooran S. Durairaj, Qian Wang, Siddhita D. Mhatre, Takeshi Uenaka, Joshua Crapser, Travis Conley, Hannah Ennerfelt, Yoo Jin Jung, Yeonglong Albert Ay, Matthew Matrongolo, Edward N. Wilson, Tao Yang, Marius Wernig, Frank M. Longo, and Katrin I. Andreasson (corresponding).

Other Contributing Institutions

The Salk Institute for Biological Studies (including co-lead author Jeffrey R. Jones), Keio University, Princeton University, Penn State University, UC San Francisco, and the Banner Sun Research Institute.

Wu Tsai Neurosciences Institute / Knight Initiative for Brain Resilience Support:

The research was supported by an Innovation Award and a Brain Resilience Scholar Award from the Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute. The study made use of Wu Tsai Neurosciences Institute Community Laboratories: the Stanford Behavioral and Functional Neuroscience Laboratory and the Stanford Neuroscience Microscopy Service, as well as the Stanford Mass Spectroscopy Core.

— Competing Interests: Andreasson is a Co-Founder, Board Member, and Consultant for Willow Neuroscience, Inc. Longo is a Founder of, Board Member of, and Consultant for and has Financial Interest in PharmatrophiX, a Company Focused on Small-Molecule Development for Treatment of Neurodegenerative Disorders.

[er-cryptid]

NAD-Linked Glycerol Dehydrogenase

-- part of oxidoreductase family

-- catalyst is NAD+

-- oxidizes glycerol

-- forms glycerone

[rro-bots]

AAAGGGH i should have majored in microbio but i will utilize my biochem degree to work in microbio EVENTUALLY