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Nathan Goodyear

Role of sphingolipids in oestrogen signalling in breast cancer cells: an update - 0 views

joe.endocrinology-journals.org/...R25.full

Sphingolipids estrogen breast cancer

shared by Nathan Goodyear on 04 Feb 14 - No Cached
  • Nathan Goodyear on 04 Feb 14
     
    to be read.  
Nathan Goodyear

JCI - Inflammatory links between obesity and metabolic disease - 0 views

www.jci.org/57132

obesity overweight weight-loss inflammation metabolic disease

shared by Nathan Goodyear on 04 Jan 12 - No Cached
  • metainflammation
  • The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time
  • It is clear that inflammation participates in the link between obesity and disease
  • ...25 more annotations...
  • Multiple inflammatory inputs contribute to metabolic dysfunction, including increases in circulating cytokines (10), decreases in protective factors (e.g., adiponectin; ref. 11), and communication between inflammatory and metabolic cells
  • adipose tissue macrophage (ATM)
  • Physiologic enhancement of the M2 pathways (e.g., eosinophil recruitment in parasitic infection) also appears to be capable of reducing metainflammation and improving insulin sensitivity (27).
  • increasing adiposity results in a shift in the inflammatory profile of ATMs as a whole from an M2 state to one in which classical M1 proinflammatory signals predominate (21–23).
  • The M2 activation state is intrinsically linked to the activity of PPARδ and PPARγ
  • well-known regulators of lipid metabolism and mitochondrial activity
  • Independent of obesity, hypothalamic inflammation can impair insulin release from β cells, impair peripheral insulin action, and potentiate hypertension (63–65).
  • inflammation in pancreatic islets can reduce insulin secretion and trigger β cell apoptosis leading to decreased islet mass, critical events in the progression to diabetes (33, 34)
  • Since an estimated excess of 20–30 million macrophages accumulate with each kilogram of excess fat in humans, one could argue that increased adipose tissue mass is de facto a state of increased inflammatory mass
  • JNK, TLR4, ER stress)
  • NAFLD is associated with an increase in M1/Th1 cytokines and quantitative increases in immune cells
  • Upon stimulation by LPS and IFN-γ, macrophages assume a classical proinflammatory activation state (M1) that generates bactericidal or Th1 responses typically associated with obesity
  • DIO, metabolites such as diacylglycerols and ceramides accumulate in the hypothalamus and induce leptin and insulin resistance in the CNS (58, 59)
  • saturated FAs, which activate neuronal JNK and NF-κB signaling pathways with direct effects on leptin and insulin signaling (60)
  • Lipid infusion and a high-fat diet (HFD) activate hypothalamic inflammatory signaling pathways, resulting in increased food intake and nutrient storage (57)
  • Maternal obesity is associated with endotoxemia and ATM accumulation that may affect the developing fetus (73)
  • Placental inflammation is a characteristic of maternal obesity
  • a risk factor for obesity in offspring, and involves inflammatory macrophage infiltration that can alter the maternal-fetal circulation (74
  • Of these PRRs, TLR4 has received the most attention, as this receptor can be activated by free FAs to generate proinflammatory signals and activate NF-κB
  • Nod-like receptor (NLR) family of PRRs
  • ceramides and sphingolipids
  • The adipokine adiponectin has long been recognized to have positive benefits on multiple cell types to promote insulin sensitivity and deactivate proinflammatory pathways.
  • adiponectin stimulates ceramidase activity and modulates the balance between ceramides and sphingosine-1-phosphate
  • Inhibition of ceramide production blocks the ability of saturated FAs to induce insulin resistance (101)
  • NF-κB, obesity also activates JNK in insulin-responsive tissues
  • Nathan Goodyear on 04 Jan 12
     
    must read to see our current knowledge on the link between inflammation and obesity.
Nathan Goodyear

The current state and future perspectives of cannabinoids in cancer biology - 0 views

www.ncbi.nlm.nih.gov/...PMC5852356

Cancer CBD THC cannabinoids

shared by Nathan Goodyear on 19 Sep 18 - No Cached
hoangkimchi liked it
  • The activation of each of them leads to an inhibition of adenylyl cyclase via G proteins (Gi/o), which in turn activates many metabolic pathways such as mitogen‐activated protein kinase pathway (MAPK), phosphoinositide 3‐kinase pathway (PI3K), cyclooxygenase‐2 pathway (COX‐2), accumulation of ceramide, modulation of protein kinase B (Akt), and ion channels
  • phytocannabinoids, endocannabinoids, and synthetic cannabinoids
  • Action of THC in human organism relies on mimicking endogenous agonists of CB receptors—endocannabinoids
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  • The upregulated expression of CB receptors and the elevated levels of endocannabinoids have been observed in a variety of cancer cells (skin, prostate, and colon cancer, hepatocellular carcinoma, endometrial sarcoma, glioblastoma multiforme, meningioma and pituitary adenoma, Hodgkin lymphoma, chemically induced hepatocarcinoma, mantel cell lymphoma)
  • concentration of endocannabinoids, expression level of their receptors, and the enzymes involved in their metabolism frequently are associated with an aggressiveness of cancer
  • CB2 receptor contributes to human epidermal growth factor receptor (HER2) pro‐oncogenic signaling and an overexpression of CB2 increases susceptibility for leukemia development after leukemia viral infection
  • endocannabinoid‐degrading enzymes are upregulated in cancer cell lines and in human tumors
  • Many cannabinoids, ranging from phytocannabinoids (THC, CBD), endocannabinoids (2‐arachidonoylglycerol, anandamide), to synthetic cannabinoids (JWH‐133, WIN‐55,212‐2), have shown ability to inhibit proliferation, metastasis, and angiogenesis in a variety of models of cancer
  • Despite some inconsistent data, the main effect of cannabinoids in a tumor is the inhibition of cancer cells’ proliferation and induction of cancer cell death by apoptosis
  • CB1 and CB2 receptor agonists stimulate apoptotic cell death in glioma cells by induction of de novo synthesis of ceramide, sphingolipid with proapoptotic activity
  • process of autophagy is upstream of apoptosis in mechanism of cell death induced by cannabinoids
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