Showing posts with label natural killer. Show all posts
Showing posts with label natural killer. Show all posts

Monday, March 17, 2025

Cancer and The PEPCK Clutch!

Key Points

  • Research suggests mediated mechanical stretch can mimic localized increases in blood pressure and inflammation, based on studies showing stretch affects vascular cells and induces inflammatory responses.

  • It seems likely that PEPCK, an enzyme involved in metabolism, can be induced to support a metabolic cell state that promotes outcomes like prolonged cell life and disease, especially in cancer, where it supports cell survival under stress.

  • The evidence leans toward mechanical stretch influencing cancer cell metabolism, potentially involving PEPCK, though direct links need further study.

Background

Mediated mechanical stretch refers to controlled mechanical forces applied to cells or tissues, often used in lab settings to simulate physiological conditions like increased blood pressure. This can affect how cells behave, particularly in blood vessels and potentially in cancer. PEPCK, or Phosphoenolpyruvate Carboxykinase, is an enzyme key to gluconeogenesis, the process of making glucose from non-carbohydrate sources, and is notably active in cancer cells under nutrient stress.

Connection to Blood Pressure and Inflammation

Studies show mechanical stretch can mimic conditions of high blood pressure and inflammation. For instance, stretch on vascular cells increases reactive oxygen species and inflammation markers, similar to what happens with hypertension (Mechanical stretch: physiological and pathological implications for human vascular endothelial cells). This suggests stretch can create a microenvironment akin to diseased states.

Role of PEPCK in Disease

PEPCK is crucial in cancer, where it helps cells survive by altering metabolism under stress, such as low glucose. Research indicates PEPCK supports cancer cell growth by enhancing glucose and glutamine use, potentially prolonging cell life and promoting disease progression (PEPCK coordinates the regulation of central carbon metabolism to promote cancer cell growth).

Linking Mechanical Stretch and PEPCK

While direct studies linking mechanical stretch to PEPCK in cancer are limited, the connection seems plausible. Mechanical stretch can induce inflammation and metabolic changes, and in cancer, this could upregulate PEPCK, supporting a cell state that aligns with prolonged survival and disease promotion. This is an unexpected detail, as stretch is often seen as beneficial (e.g., exercise), but here it may exacerbate cancer conditions.


Survey Note: Detailed Analysis of Mechanical Stretch, PEPCK, and Disease Promotion

This section provides a comprehensive exploration of the user's query, examining the potential for mediated mechanical stretch to mimic localized increases in blood pressure and inflammation, and whether PEPCK can be induced to support a metabolic cell state promoting outcomes that prolong cell life and promote disease. The analysis draws on various studies and blog posts referenced, ensuring a thorough understanding for readers with a scientific background.

Understanding Mediated Mechanical Stretch

Mediated mechanical stretch involves applying controlled mechanical forces to cells or tissues, often to simulate physiological or pathological conditions. Research indicates that such stretch can replicate the effects of increased blood pressure and inflammation at a localized level. For example, a study on vascular endothelial cells showed that mechanical stretch, especially under conditions mimicking hypertension, leads to the formation of reactive oxygen species and inflammation, aligning with pathological consequences (Mechanical stretch: physiological and pathological implications for human vascular endothelial cells). Another study, "The Effect of Pressure-Induced Mechanical Stretch on Vascular Wall Differential Gene Expression" (The Effect of Pressure-Induced Mechanical Stretch on Vascular Wall Differential Gene Expression), further supports that stretch can induce gene expression changes similar to those seen in high blood pressure, validating the user's premise.

Blood Pressure and Inflammation: Detailed Mechanisms

The connection between mechanical stretch and blood pressure is evident in studies showing stretch affects arterial stiffness and blood pressure regulation. For instance, regular stretching exercises have been shown to reduce blood pressure in hypertensive patients, suggesting a link between mechanical forces and vascular responses (Compliance of Static Stretching and the Effect on Blood Pressure and Arteriosclerosis Index in Hypertensive Patients). Inflammation is also induced by stretch, as seen in studies where cyclic mechanical stretch upregulates pro-inflammatory pathways, particularly in vascular smooth muscle cells, contributing to conditions like chronic venous insufficiency (The Effect of Pressure-Induced Mechanical Stretch on Vascular Wall Differential Gene Expression).

A detailed breakdown of relevant findings is presented in the following table, extracted from blog posts and studies:

Topic

Details

Exact Numbers

Relevant URLs

Mechanical Stretch

Causes sustained molecular signaling of pro-inflammatory and proliferative pathways, tied to p53, occurs in disturbed flow and undirected stretch at branch points and complex regions.

-

journals.physiology.org, blog.codondex.com

Blood Pressure

Meta-analysis of 7017 individuals identified 34 differentially expressed genes, 6 linked to BP and hypertension, MYADM (19q13) the only gene across diastolic, systolic BP, and hypertension.

7017, 34, 6

journals.plos.org, www.ncbi.nlm.nih.gov

Inflammation

Controlled by interaction between plasma membrane and submembrane at endothelial surface; MYADM knockdown induces inflammatory phenotype via ICAM-1 (19p13) increase, mediated by ERM actin cytoskeleton proteins; S1P2 (19p13) involved in immune, nervous, metabolic, cardiovascular, musculoskeletal, renal systems.

-

blog.codondex.com, www.ncbi.nlm.nih.gov, rupress.org, www.ncbi.nlm.nih.gov, www.jimmunol.org, www.ncbi.nlm.nih.gov, onlinelibrary.wiley.com, www.researchgate.net, www.ncbi.nlm.nih.gov, journals.asm.org, journals.plos.org, www.jbc.org, www.gastrojournal.org, www.spandidos-publications.com


This table highlights the molecular and physiological impacts, providing a foundation for understanding how stretch influences blood pressure and inflammation.

PEPCK and Its Role in Metabolic Cell States

PEPCK, or Phosphoenolpyruvate Carboxykinase, is a key enzyme in gluconeogenesis, converting oxaloacetate to phosphoenolpyruvate. Its role extends beyond normal physiology into cancer, where it supports metabolic flexibility under nutrient stress. Studies show PEPCK, particularly the mitochondrial isoform PCK2, is expressed in lung and other cancer tissues, aiding cell survival by enhancing glucose and glutamine utilization (PEPCK in cancer cell starvation). This metabolic adaptation can prolong cell life, especially in cancer, and promote disease progression by supporting tumor growth (PEPCK coordinates the regulation of central carbon metabolism to promote cancer cell growth).

Linking Mechanical Stretch, PEPCK, and Disease Promotion

The user's query posits whether PEPCK can be induced to support a single metabolic cell state that promotes outcomes similar to those from mechanical stretch, which mimics increased blood pressure and inflammation, and whether this prolongs cell life and promotes disease. While direct studies linking mechanical stretch to PEPCK induction are scarce, indirect evidence suggests a connection. Mechanical stretch induces inflammation and alters glucose metabolism, as seen in skeletal muscle studies where stretch increases glucose uptake via ROS and AMPK pathways (Stretch-stimulated glucose uptake in skeletal muscle is mediated by reactive oxygen species and p38 MAP-kinase). In cancer, where inflammation is a known promoter, mechanical stretch could create a microenvironment that upregulates PEPCK, supporting a metabolic state conducive to prolonged cell survival and disease, particularly in tumors under stress.

For instance, a study on lung cancer progression under mechanical stretch highlights its role in tumor microenvironment changes, potentially affecting metabolic pathways (An Overview of the Role of Mechanical Stretching in the Progression of Lung Cancer). Given PEPCK's role in cancer metabolism, it's plausible that such conditions could induce PEPCK, aligning with the user's hypothesis. This is an unexpected detail, as stretch is often viewed positively (e.g., exercise benefits), but here it may exacerbate cancer by supporting a disease-promoting metabolic state.

Conclusion and Implications

Based on the analysis, it seems likely that mediated mechanical stretch, by mimicking localized increases in blood pressure and inflammation, can create conditions where PEPCK is induced to support a metabolic cell state. This state, particularly in cancer, can promote outcomes like prolonged cell life and disease progression, fitting the user's query. Further research is needed to confirm direct links, but the evidence leans toward this possibility, offering insights into how mechanical forces influence cancer metabolism.

Key Citations

Sunday, March 2, 2025

Transposons mitochondria, piRNA, p53, NK precursors and immunity

 

Key Points

  • p53 helps control transposons, mobile DNA, and may regulate piRNA, small RNAs that silence them.

  • piRNA influences NK cell development, linking transposon control to immunity.

  • p53 play a role in NK cell maturation and boosting immune responses like interferon signaling.

Direct Answer

Overview

Transposons, or "jumping genes," can move within our DNA and potentially cause issues, so their control is crucial. The protein p53, known as the "guardian of the genome," seems to play a big role in keeping them in check. It might also influence piRNA, tiny RNA molecules that help silence transposons. These piRNAs may also affect the development of NK cell precursors, which are early stages of natural killer cells, important for our immune system. p53 also appears to help NK cells mature and boost immunity through processes like interferon signaling. This creates a web of connections where controlling transposons could impact our immune health, especially in diseases like cancer.

p53 and Transposon Control

p53 binds to transposon promoters, like those of L1 elements, to limit their activity, helping maintain genomic stability. It may also regulate piRNA, adding another layer of control. For example, studies show p53 restricts L1 retrotransposons, which make up about 17% of our genome, with around 100 still able to move (Genetic Eruption and p53 Response).


piRNA's Role

piRNA, typically 26-31 nucleotides long, silences transposons and seems to influence NK cell function by regulating genes like KIR3DL1, which are crucial for immune responses. This means piRNA links transposon control to NK cell activity, potentially affecting immunity.

NK Cells and Immunity

NK cell precursors develop into NK cells, which fight infections and cancer. p53 is involved in their maturation, and it also enhances interferon signaling and MHC class I expression, both vital for immune recognition. For instance, p53 peptides at positions 264-272 can attract immune surveillance, boosting NK and T cell activity (p53 Stability and Life or Disorder and).

Unexpected Detail: Metabolic Links

An interesting connection is how mitochondria, our cell's powerhouses, influence piRNA function and transposon control through energy and ROS levels. This could indirectly affect NK cells and immunity, adding a metabolic layer to these relationships (Electrons Rule Your Biology).


Survey Note: Detailed Analysis of Relationships

This section provides a comprehensive exploration of the potential relationships between transposon control, p53, piRNA, NK cell precursors, and immunity, drawing from detailed blog posts dated from 2021 to 2025. The analysis aims to mimic a professional scientific review, offering a strict superset of the direct answer content, with tables for clarity and inline URLs for references.

Background and Context

Transposons, or transposable elements (TEs), constitute 40-50% of the human genome, with 30% located in non-coding introns, and are known for their potential to disrupt genes and cause genomic instability (p53 Stability and Life or Disorder and). Their control is vital, and research suggests p53, a tumor suppressor protein, plays a central role. piRNA, small non-coding RNAs of 26-31 nucleotides, are key in silencing TEs, while NK cell precursors develop into natural killer cells, critical for innate immunity. The interplay between these elements and immunity, particularly through p53 and piRNA, is complex and warrants detailed examination.

Detailed Relationships

p53 and Transposon Control

p53 is implicated in restraining transposon mobility, particularly L1 (LINE1) retrotransposons, which account for 17% of the genome, with approximately 100 retaining retrotransposition ability. It binds to L1 promoters, as noted in studies of 189 gastrointestinal cancer patients (95 with stomach, colorectal, or esophageal cancer), highlighting its role in genomic stability (Genetic Eruption and p53 Response). p53 also interacts with epigenetic mechanisms like DNA methylation and histone modifications, and may regulate piRNA factor gene expression, enhancing TE control. For instance, ERV1 family elements are highly enriched at p53 sites, shaping its transcriptional network (Cancers' HLA-G Backdoor).

Aspect

Details

Relevant Numbers/URLs

p53 Binding

Binds L1 promoter to restrict autonomous copies, involved in tumor suppression.

-; p53 Stability and Life or Disorder and

Epigenetic Role

Interacts with DNA methyltransferases, histone modifications for TE control.

-; Genetic Eruption and p53 Response

Cancer Correlation

Frequent mutations in tumors with high L1 load, studied in 189 GI cancer patients (95 specific).

189, 95; Genetic Eruption and p53 Response

piRNA and Transposon Control

piRNA, derived from Alu repeats with over 1 million copies and 0.7% sequence divergence, restrains TEs, preventing gene disruption and inflammation. They are generated via a Dicer-independent pathway, with mitochondrial phospholipid (MitoPLD) facilitating piRNA biogenesis near mitochondria, influencing TE control through energy availability and ROS generation (Electrons Rule Your Biology). Increased ERV levels, a TE subclass, trigger fibro-inflammation, linking to kidney disease development (Cancers' HLA-G Backdoor).

Aspect

Details

Relevant Numbers/URLs

Length and Origin

26-31 nt, derived from Alu repeats, over 1 million copies, 0.7% divergence.

26-31 nt, over 1 million, 0.7%; p53 Stability and Life or Disorder and

Biogenesis

MitoPLD regulates mitochondrial shape, facilitates fusion, generate’s spermatocyte-specific piRNA.

-; Electrons Rule Your Biology

Disease Link

ERV up-regulation triggers fibro-inflammation, linked to kidney disease.

-; Cancers' HLA-G Backdoor


piRNA and NK Cell Function

piRNA is crucial for NK cell immune development, with a 28-base piRNA of the KIR3DL1 gene mediating KIR transcriptional silencing, correlated with CpG methylation in the promoter. This silencing influences NK cell subsets, with over 30,000 subsets identified, and cellular metabolism regulating NK sensitivity based on p53 status (It Has Been Widely Acknowledged That). This links piRNA to immunity via NK cells, especially in tumor microenvironments (TME).


Aspect

Details

Relevant Numbers/URLs

KIR3DL1 piRNA

28-base piRNA mediates KIR transcriptional silencing, correlated with CpG methylation.

28-base; It Has Been Widely Acknowledged That

NK Subsets

Over 30,000 NK cell subsets, metabolism regulates sensitivity based on p53 status.

Over 30,000; It Has Been Widely Acknowledged That

Immune Development

piRNA function with TEs important for NK cell immune development.

-; Cancers' HLA-G Backdoor


p53 and NK Cell Maturation

p53 is coupled to NK cell maturation, with computations from 48 sections of 7 tumor biopsies showing TP53 Consensus Variant (CV) and ncDNA Key Sequence (KS) alterations under KIR B haplotypes, affecting basal cell carcinoma (BCC) risks. RAG expression in uncommitted hematopoietic progenitors and NK precursors marks distinct NK subsets, with innate NK cells unable to express RAGs during ontogeny (p53 Stability and Life or Disorder and).

Aspect

Details

Relevant Numbers/URLs

Tumor Biopsies

TP53 computed from 48 sections of 7 tumor biopsies, alters P53 in BCC under KIR B haplotypes.

48, 7; It Has Been Widely Acknowledged That

RAG Expression

Marks functionally distinct NK subsets, innate NK cells cannot express RAGs.

-; p53 Stability and Life or Disorder and

Maturation Link

p53 linked to NK cell maturation, influencing immune response.

-; It Has Been Widely Acknowledged That


p53 and Immunity

p53 enhances IFN-dependent antiviral activity, increasing IFN release and inducing IFN regulatory factor 9, with L1 retrotransposition inversely correlated with immunologic response genes, including interferons. It regulates MHC class I expression, with peptides at 264-272 (epitope 264scTCR with IL-2) attracting immune surveillance, enhancing NK and T cell activity (Genetic Eruption and p53 Response, p53 Stability and Life or Disorder and).

Aspect

Details

Relevant Numbers/URLs

IFN Signaling

Enhances IFN-dependent antiviral activity, increases IFN release, induces IRF9.

-; Genetic Eruption and p53 Response

MHC Class I

Regulates expression, peptides at 264-272 mediate antitumor effects by NK cells.

264-272; p53 Stability and Life or Disorder and

Immune Correlation

L1 retrotransposition inversely correlated with immunologic response genes.

-; Genetic Eruption and p53 Response


Transposon Control and Immunity

Transposon control impacts immunity through p53 and piRNA effects on NK cells. Increased TE activity, like ERVs, triggers fibro-inflammation, linked to kidney disease, and during viral infections, TE up-regulation near antiviral response genes promotes innate immunity (Cancers' HLA-G Backdoor, Electrons Rule Your Biology). This suggests a feedback loop where TE control influences immune function.

Metabolic and Contextual Insights

An unexpected detail is the metabolic link: mitochondrial fitness, influenced by electron transport chain complexes, affects piRNA biogenesis and function, potentially impacting TE control and NK cell immunity in TMEs. Immune cells require massive energy boosts, with T cell ATP levels doubling in under 30 seconds during stimulation, a process also described for NK cells, highlighting metabolic regulation's role (Electrons Rule Your Biology).

Implications and Future Directions

These relationships suggest that disruptions in transposon control could cascade through p53 and piRNA to affect NK cell function and immunity, with implications for diseases like cancer and viral infections. The metabolic angle adds complexity, suggesting research into mitochondrial-targeted therapies. However, the exact mechanisms, especially in NK cell precursors, require further study, given the complexity and potential for controversy in interpreting these interactions.

Key Citations