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Nathan Goodyear

Gut Endotoxin Leading to a Decline IN Gonadal function (GELDING) - a novel theory for t... - 0 views

www.ncbi.nlm.nih.gov/...PMC4918028

GELDING theory GELDING LPS gut gut health inflammation low T low Testosterone Testosterone hypogonadism obesity

shared by Nathan Goodyear on 30 Jun 16 - No Cached
  • GELDING theory (Gut Endotoxin Leading to a Decline IN Gonadal function)
  • trans-mucosal passage of bacterial lipopolysaccharide (LPS) from the gut lumen into the circulation is a key inflammatory trigger underlying male hypogonadism
  • Obesity and a high fat/high calorie diet are both reported to result in changes to gut bacteria and intestinal wall permeability, leading to the passage of bacterial endotoxin (lipopolysaccharide- LPS) from within the gut lumen into the circulation (metabolic endotoxaemia), where it initiates systemic inflammation.
  • ...1 more annotation...
  • Endotoxin is known to reduce testosterone production by the testis, both by direct inhibition of Leydig cell steroidogenic pathways and indirectly by reducing pituitary LH drive, thereby also leading to a decline in sperm production.
  • Nathan Goodyear on 30 Jun 16
     
    Ever heard of the GELDING theory?  This involves the link between LPS endotoxin from the gut and low Testosterone in obese men.
Nathan Goodyear

Mitochondrial theory of aging matures--roles of mt... [Zhonghua Yi Xue Za Zhi (Taipei).... - 0 views

www.ncbi.nlm.nih.gov/...11499335

mitochondrial theory of aging

shared by Nathan Goodyear on 14 Jan 11 - No Cached
  • Taken together, these observations and our previous findings that mtDNA mutations and oxidative damage are increased in aging human tissues suggest that mitochondrial theory of aging is mature.
  • Nathan Goodyear on 14 Jan 11
     
    Mitochondrial theory of aging matures--roles of mtDNA mutation and oxidative stress in human aging.
Nathan Goodyear

The Free Radical Theory of Aging Matures - 0 views

physrev.physiology.org/...547.full

radical free aging mitochondria disease

shared by Nathan Goodyear on 03 Mar 11 - No Cached
  • The Free Radical Theory of Aging Matures
  • Nathan Goodyear on 03 Mar 11
     
    Great discussion on the free-radical theory of aging and the effects of mitochondria
Nathan Goodyear

Press-pulse: a novel therapeutic strategy for the metabolic management of cancer | Nutr... - 0 views

nutritionandmetabolism.biomedcentral.com/...s12986-017-0178-2

ketogenic diet ketogenic press-pulse hyperbaric oxygen therapy HBOTnutrition diet cancer HBOT IVC IV vitamin C DCA dichloracetic acid cancer therapy cancer treatment alternative cancer treatment

shared by Nathan Goodyear on 09 Jul 17 - No Cached
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  • A “press” disturbance was considered a chronic environmental stress on all organisms in an ecological community
  • “pulse” disturbances were considered acute events that disrupted biological communities to produce high mortality
  • Neoplasia involving dysregulated cell growth is the biological endpoint of the disease
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  • Data from the American Cancer Society show that the rate of increase in cancer deaths/year (3.4%) was two-fold greater than the rate of increase in new cases/year (1.7%) from 2013 to 2017
  • cancer is predicted to overtake heart disease as the leading cause of death in Western societies
  • cancer can also be recognized as a metabolic disease.
  • glucose is first split into two molecules of pyruvate through the Embden–Meyerhof–Parnas glycolytic pathway in the cytosol
  • Aerobic fermentation, on the other hand, involves the production of lactic acid under normoxic conditions
  • persistent lactic acid production in the presence of adequate oxygen is indicative of abnormal respiration
  • Otto Warburg first proposed that all cancers arise from damage to cellular respiration
  • The Crabtree effect is an artifact of the in vitro environment and involves the glucose-induced suppression of respiration with a corresponding elevation of lactic acid production even under hyperoxic (pO2 = 120–160 mmHg) conditions associated with cell culture
  • the Warburg theory of insufficient aerobic respiration remains as the most credible explanation for the origin of tumor cells [2, 37, 51, 52, 53, 54, 55, 56, 57].
  • The main points of Warburg’s theory are; 1) insufficient respiration is the predisposing initiator of tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to produce lactic acid in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible
  • Efraim Racker coined the term “Warburg effect”, which refers to the aerobic glycolysis that occurs in cancer cells
  • Warburg clearly demonstrated that aerobic fermentation (aerobic glycolysis) is an effect, and not the cause, of insufficient respiration
  • all tumor cells that have been examined to date contain abnormalities in the content or composition of cardiolipin
  • The evidence supporting Warburg’s original theory comes from a broad range of cancers and is now overwhelming
  • respiratory insufficiency, arising from any number mitochondrial defects, can contribute to the fermentation metabolism seen in tumor cells.
  • data from the nuclear and mitochondrial transfer experiments suggest that oncogene changes are effects, rather than causes, of tumorigenesis
  • Normal mitochondria can suppress tumorigenesis, whereas abnormal mitochondria can enhance tumorigenesis
  • In addition to glucose, cancer cells also rely heavily on glutamine for growth and survival
  • Glutamine is anapleurotic and can be rapidly metabolized to glutamate and then to α-ketoglutarate for entry into the TCA cycle
  • Glucose and glutamine act synergistically for driving rapid tumor cell growth
  • Glutamine metabolism can produce ATP from the TCA cycle under aerobic conditions
  • Amino acid fermentation can generate energy through TCA cycle substrate level phosphorylation under hypoxic conditions
  • Hif-1α stabilization enhances aerobic fermentation
  • targeting glucose and glutamine will deprive the microenvironment of fermentable fuels
  • Although Warburg’s hypothesis on the origin of cancer has created confusion and controversy [37, 38, 39, 40], his hypothesis has never been disproved
  • Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as “aerobic fermentation” to highlight the abnormal production of lactic acid in the presence of oxygen
  • Emerging evidence indicates that macrophages, or their fusion hybridization with neoplastic stem cells, are the origin of metastatic cancer cells
  • Radiation therapy can enhance fusion hybridization that could increase risk for invasive and metastatic tumor cells
  • Kamphorst et al. in showing that pancreatic ductal adenocarcinoma cells could obtain glutamine under nutrient poor conditions through lysosomal digestion of extracellular proteins
  • It will therefore become necessary to also target lysosomal digestion, under reduced glucose and glutamine conditions, to effectively manage those invasive and metastatic cancers that express cannibalism and phagocytosis.
  • Previous studies in yeast and mammalian cells show that disruption of aerobic respiration can cause mutations (loss of heterozygosity, chromosome instability, and epigenetic modifications etc.) in the nuclear genome
  • The somatic mutations and genomic instability seen in tumor cells thus arise from a protracted reliance on fermentation energy metabolism and a disruption of redox balance through excess oxidative stress.
  • According to the mitochondrial metabolic theory of cancer, the large genomic heterogeneity seen in tumor cells arises as a consequence, rather than as a cause, of mitochondrial dysfunction
  • A therapeutic strategy targeting the metabolic abnormality common to most tumor cells should therefore be more effective in managing cancer than would a strategy targeting genetic mutations that vary widely between tumors of the same histological grade and even within the same tumor
  • Tumor cells are more fit than normal cells to survive in the hypoxic niche of the tumor microenvironment
  • Hypoxic adaptation of tumor cells allows for them to avoid apoptosis due to their metabolic reprograming following a gradual loss of respiratory function
  • The high rates of tumor cell glycolysis and glutaminolysis will also make them resistant to apoptosis, ROS, and chemotherapy drugs
  • Despite having high levels of ROS, glutamate-derived from glutamine contributes to glutathione production that can protect tumor cells from ROS
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      reason to eliminate glutamine in cancer patients and even GSH with cancer patients
  • It is clear that adaptability to environmental stress is greater in normal cells than in tumor cells, as normal cells can transition from the metabolism of glucose to the metabolism of ketone bodies when glucose becomes limiting
  • Mitochondrial respiratory chain defects will prevent tumor cells from using ketone bodies for energy
  • glycolysis-dependent tumor cells are less adaptable to metabolic stress than are the normal cells. This vulnerability can be exploited for targeting tumor cell energy metabolism
  • In contrast to dietary energy reduction, radiation and toxic drugs can damage the microenvironment and transform normal cells into tumor cells while also creating tumor cells that become highly resistant to drugs and radiation
  • Drug-resistant tumor cells arise in large part from the damage to respiration in bystander pre-cancerous cells
  • Because energy generated through substrate level phosphorylation is greater in tumor cells than in normal cells, tumor cells are more dependent than normal cells on the availability of fermentable fuels (glucose and glutamine)
  • Ketone bodies and fats are non-fermentable fuels
  • Although some tumor cells might appear to oxidize ketone bodies by the presence of ketolytic enzymes [181], it is not clear if ketone bodies and fats can provide sufficient energy for cell viability in the absence of glucose and glutamine
  • Apoptosis under energy stress is greater in tumor cells than in normal cells
  • A calorie restricted ketogenic diet or dietary energy reduction creates chronic metabolic stress in the body
  • . This energy stress acts as a press disturbance
  • Drugs that target availability of glucose and glutamine would act as pulse disturbances
  • Hyperbaric oxygen therapy can also be considered another pulse disturbance
  • The KD can more effectively reduce glucose and elevate blood ketone bodies than can CR alone making the KD potentially more therapeutic against tumors than CR
  • Campbell showed that tumor growth in rats is greater under high protein (>20%) than under low protein content (<10%) in the diet
  • Protein amino acids can be metabolized to glucose through the Cori cycle
  • The fats in KDs used clinically also contain more medium chain triglycerides
  • Calorie restriction, fasting, and restricted KDs are anti-angiogenic, anti-inflammatory, and pro-apoptotic and thus can target and eliminate tumor cells through multiple mechanisms
  • Ketogenic diets can also spare muscle protein, enhance immunity, and delay cancer cachexia, which is a major problem in managing metastatic cancer
  • GKI values of 1.0 or below are considered therapeutic
  • The GKI can therefore serve as a biomarker to assess the therapeutic efficacy of various diets in a broad range of cancers.
  • It is important to remember that insulin drives glycolysis through stimulation of the pyruvate dehydrogenase complex
  • The water-soluble ketone bodies (D-β-hydroxybutyrate and acetoacetate) are produced largely in the liver from adipocyte-derived fatty acids and ketogenic dietary fat. Ketone bodies bypass glycolysis and directly enter the mitochondria for metabolism to acetyl-CoA
  • Due to mitochondrial defects, tumor cells cannot exploit the therapeutic benefits of burning ketone bodies as normal cells would
  • Therapeutic ketosis with racemic ketone esters can also make it feasible to safely sustain hypoglycemia for inducing metabolic stress on cancer cells
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      Ketones are much more than energy adaptabilit, but actually are therapeutic.
  • ketone bodies can inhibit histone deacetylases (HDAC) [229]. HDAC inhibitors play a role in targeting the cancer epigenome
  • Therapeutic ketosis reduces circulating inflammatory markers, and ketones directly inhibit the NLRP3 inflammasome, an important pro-inflammatory pathway linked to carcinogenesis and an important target for cancer treatment response
  • Chronic psychological stress is known to promote tumorigenesis through elevations of blood glucose, glucocorticoids, catecholamines, and insulin-like growth factor (IGF-1)
  • In addition to calorie-restricted ketogenic diets, psychological stress management involving exercise, yoga, music etc. also act as press disturbances that can help reduce fatigue, depression, and anxiety in cancer patients and in animal models
  • Ketone supplementation has also been shown to reduce anxiety behavior in animal models
  • This physiological state also enhances the efficacy of chemotherapy and radiation therapy, while reducing the side effects
  • lower dosages of chemotherapeutic drugs can be used when administered together with calorie restriction or restricted ketogenic diets (KD-R)
  • Besides 2-DG, a range of other glycolysis inhibitors might also produce similar therapeutic effects when combined with the KD-R including 3-bromopyruvate, oxaloacetate, and lonidamine
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      oxaloacetate is a glycolytic inhibitor, as is doxycycline, and IVC.
  • A synergistic interaction of the KD diet plus radiation was seen
  • It is important to recognize, however, that the radiotherapy used in glioma patients can damage the respiration of normal cells and increase availability of glutamine in the microenvironment, which can increase risk of tumor recurrence especially when used together with the steroid drug dexamethasone
  • Poff and colleagues demonstrated that hyperbaric oxygen therapy (HBOT) enhanced the ability of the KD to reduce tumor growth and metastasis
  • HBOT also increases oxidative stress and membrane lipid peroxidation of GBM cells in vitro
  • The effects of the KD and HBOT can be enhanced with administration of exogenous ketones, which further suppressed tumor growth and metastasis
  • Besides HBOT, intravenous vitamin C and dichloroacetate (DCA) can also be used with the KD to selectively increase oxidative stress in tumor cells
  • Recent evidence also shows that ketone supplementation may enhance or preserve overall physical and mental health
  • Some tumors use glucose as a prime fuel for growth, whereas other tumors use glutamine as a prime fuel [102, 186, 262, 263, 264]. Glutamine-dependent tumors are generally less detectable than glucose-dependent under FDG-PET imaging, but could be detected under glutamine-based PET imaging
  • GBM and use glutamine as a major fuel
  • Many of the current treatments used for cancer management are based on the view that cancer is a genetic disease
  • Emerging evidence indicates that cancer is a mitochondrial metabolic disease that depends on availability of fermentable fuels for tumor cell growth and survival
  • Glucose and glutamine are the most abundant fermentable fuels present in the circulation and in the tumor microenvironment
  • Low-carbohydrate, high fat-ketogenic diets coupled with glycolysis inhibitors will reduce metabolic flux through the glycolytic and pentose phosphate pathways needed for synthesis of ATP, lipids, glutathione, and nucleotides
  • Nathan Goodyear on 09 Jul 17
     
    Cancer is a mitochondrial disease? So says the well published Dr Seyfried. Glucose and glutamine drive cancer growth.
Nathan Goodyear

Oxidative Stress and the Aging Brain: From Theory to Prevention - Brain Aging - NCBI Bo... - 0 views

www.ncbi.nlm.nih.gov/...NBK3869

stress oxidative aging mitochondria neurodegenerative disease

shared by Nathan Goodyear on 08 Feb 11 - No Cached
  • Nathan Goodyear on 08 Feb 11
     
    Must read on the free radical theory of aging to application of disease prevention as it relates to neurodegenerative disease
Nathan Goodyear

Exercise-Associated Muscle Cramps - 0 views

www.ncbi.nlm.nih.gov/...PMC3445088

EAMC exercise associated muscle cramps athletes muscle cramps

shared by Nathan Goodyear on 27 Jan 15 - No Cached
  • athletes who develop EAMC often ingest similar amounts of fluid during exercise as do their noncramping counterparts
  • Oral fluid ingestion may be ineffective, and intravenous fluid may provide a faster delivery for athletes suffering from acute EAMC
  • It is interesting that stretching the affected muscle almost immediately relieves EAMC
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  • Stretching, the primary treatment for acute EAMC
  • National Athletic Trainers’ Association recommends that athletes prone to muscle cramping add 0.3 to 0.7 g/L of salt to their drinks to stave off muscle cramps
  • Others have recommended adding higher amounts of sodium (about 3.0 to 6.0 g/L) to sports drinks based on the frequency of EAMC
  • intravenous infusion of fluids removes this delay, and it has been used to aid athletes who develop acute EAMC
  • maintaining hydration and adequate electrolyte levels is a good prevention strategy for individuals susceptible to EAMC
  • Fluid volumes of 1.8 L per hour have been well tolerated by tennis athletes who are susceptible to EAMC
  • Monitoring an athlete’s body weight is an easy method of ensuring adequate fluid replacement and individualizes each athlete’s fluid needs
  • the National Athletic Trainers’ Association and the American College of Sports Medicine recommend a volume of fluid that allows for less than a 2% body weight reduction
  • Endurance training may also serve as an effective means of preventing EAMC by expanding plasma volume and the extracellular fluid compartment15 and delaying neuromuscular fatigue
  • Nathan Goodyear on 27 Jan 15
     
    Exercise associated muscle cramps or EAMC is not worked out.  The theories include dehydration, mineral/electrolyte deficiencies, and neuromuscular activity.
Nathan Goodyear

Testosterone replacement therapy and the risk of prostate cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC4814970

Testosterone testosterone therapy saturation theory cancer prostate cancer male hormones

shared by Nathan Goodyear on 01 Oct 16 - No Cached
  • When the level of circulating androgen is below normal, some androgen receptors are inactive, and the secondary downstream effects are decreased. Once androgen receptors within the prostate are saturated, however, increasing testosterone will no longer have an effect
  • the saturation point is thought to occur at low physiologic testosterone levels
  • Only the subset of individuals with pretreatment testosterone level <250 ng dl−1 had PSA level correlating with free and total testosterone level
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  • none of the men stopped testosterone supplementation due to prostate cancer recurrence, and none demonstrated cancer progression
  • PSA level did transiently rise in one patient; however, none exceeded a PSA of 1.5 ng ml−1 to raise concern for biochemical recurrence
  • after 19 months on TRT, 10 hypogonadal patients with a history of undergoing a radical retropubic prostatectomy for prostate cancer had no PSA recurrence and had statistically significant improvements in serum total testosterone and hypogonadal symptoms
  • Similarly, Kaufman and Graydon14 examined case records of seven hypogonadal men who had undergone curative RP with symptoms of hypogonadism and low serum testosterone levels treated with testosterone replacement. No biochemical or clinical evidence of cancer recurrence was noted
  • In a much larger case series, Khera et al.15 reviewed the records of 57 men who received TRT following RP. After an average of 36 months following RP, testosterone replacement was initiated and followed for an average of 13 months. Mean testosterone values rose significantly and once again, there was no increase in PSA values and, therefore, no diagnosed biochemical recurrence
  • Four of the patients in the treatment group were found to have cancer recurrence, compared with eight in the control group
  • All biochemical recurrences were seen in individuals with high-risk disease
  • Nathan Goodyear on 01 Oct 16
     
    Good review of data on Testosterone therapy and prostate cancer risk: the take home is there is no increased risk.  Also, included is a discussion of the prostate saturation theory.
Nathan Goodyear

Testosterone administration to men with testosterone deficiency syndrome after external... - 0 views

www.ncbi.nlm.nih.gov/...18671790

Testosterone low T low Testosterone men male hormones prostate cancer cancer saturation theory prostate

shared by Nathan Goodyear on 10 Oct 16 - No Cached
  • Nathan Goodyear on 10 Oct 16
     
    small study of men post prostate cancer radiotherapy: only 1 of the 5 had a transient rise in PSA, though the level was still below the 1.5 ng/ml threshold.  This fits within the saturation theory concept. F/u in this study was 14.5 months.  Abstract only available here.
Nathan Goodyear

Dysbiosis of Gut Microbiota (DOGMA)--a novel theory for the development of Polycystic O... - 0 views

www.ncbi.nlm.nih.gov/...22543078

PCOS polycystic ovarian syndrome LPS lipopolysaccharides gut DOGMA symbiosis of gut microbiota symbiosis

shared by Nathan Goodyear on 26 May 17 - No Cached
  • Nathan Goodyear on 26 May 17
     
    LPS and PCOS--the DOGMA theory.
Nathan Goodyear

inhibition of estradiol synthesis attenuates renal injury in male streptozotocin-induce... - 0 views

ajprenal.physiology.org/...F634.full.pdf

testosterone hormone hormones kidney kidneys diabetes DM renal system aromatase

shared by Nathan Goodyear on 05 Mar 13 - No Cached
  • Nathan Goodyear on 05 Mar 13
     
    Study finds that inhibition of aromatase activity in diabetic male rats provided renal protection. There has been debate about the effects of testosterone therapy on the renal system. However, I propose that aromatase activity and conversion to estrogen is the negative effects of Testosterone. Other than over dosing men. Though this is a rat study, this study does support the theory.
Nathan Goodyear

Transdermal delivery of bioidentical proge... [J Pharm Pharm Sci. 2010] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...21486536

saliva salivary progesterone 5alpha reductase transdermal progesterone hormone hormones

shared by Nathan Goodyear on 08 Jul 13 - No Cached
  • Nathan Goodyear on 08 Jul 13
     
    Transdermal progesterone levels are quickly transported to saliva.  This quick transport, while serum doesn't equally reflect progesterone, has puzzled many.  Theories have been proposed, yet no answers.   This study looked at whether 5alpha reductase expression in the skin would metabolize the progesterone  and this explain the difference in the two test mediums.  The authors of this study concluded that 5alpha reductase is the not the reason for the difference found in saliva and serum.  the same can be applied to urine as well.
Nathan Goodyear

http://orthomolecular.org/library/jom/1992/pdf/1992-v07n01-p005.pdf - 0 views

orthomolecular.org/...1992-v07n01-p005.pdf

vitamin C CVD Pauling Linus Pauling Lp(a) cardiovascular disease hypertension

shared by Nathan Goodyear on 16 Jan 17 - No Cached
  • Nathan Goodyear on 16 Jan 17
     
    This is the unified paper theory of CVD and vitamin C as published by Pauling and Rath.  Vitamin C deficiency results in a decrease in the integrity and stability of the vascular wall.  Chronic deficiency results in in an increase in and accumulation of Lp(a) which leads to atherosclerotic plaques.
Nathan Goodyear

The origins of age-related proinflammatory state - 0 views

bloodjournal.hematologylibrary.org/...2294.full

inflammation aging cytokines immune system adipocytokines

shared by Nathan Goodyear on 25 Apr 12 - No Cached
  • Nathan Goodyear on 25 Apr 12
     
    aging found to be associated with a rise in inflammatory markers.  This leads to the theory that age-related diseases are in part due to chronic inflammation
Nathan Goodyear

Serum Sex Steroids in Premenopausal Women and Breast Cancer Risk Within the European Pr... - 0 views

jnci.oxfordjournals.org/...755.long

serum hormone hormones Testosterone progesterone estrogen estradiol breast cancer women female

shared by Nathan Goodyear on 21 Mar 14 - No Cached
  • Nathan Goodyear on 21 Mar 14
     
    Study finds that elevated serum Testosterone and androstenedione is associated with an increase risk of breast cancer.  This EPIC study looked at serum hormones in premenopausal women.  This study also found an association with increased breast cancer and low serum progesterone in women.  This was also found in the ORDET study.  This study did not find a link with estrogen.  These are endogenous levels.  Does this translate to exogenous? This theory of elevated androgens and breast cancer was first proposed by Grattarola.
Nathan Goodyear

Testosterone and benign prostatic hyperplasia Jarvis TR, Chughtai B, Kaplan SA, - Asian... - 0 views

www.ajandrology.com/preprintarticle.asp

Testosterone BPH low T low Testosterone prostate cancer men male hormone hormones

shared by Nathan Goodyear on 01 Dec 14 - No Cached
  • The prevalence of hypogonadism (often defined as serum testosterone < 300 ng dl−1 ) ranges from 6% [10] to as high as 38%
  • The process of BPH, however, continues as men age and despite the fact their serum testosterone decreases
  • Liu et al. [12] demonstrated that in a group of older males (mean age 59.8 years) that there was not a significant correlation of serum testosterone levels (total, free or bioavailable) with either prostate volume or International Prostate Symptom Score (IPSS)
  • ...11 more annotations...
  • in eugonadal men, studies have demonstrated that the prostate can increase in volume by approximately 12%
  • There seems to be little doubt that the treatment with testosterone of a young hypogonadal male leads to significant growth of the prostate
  • Behre et al. [22] demonstrated increased prostate volume and prostate-specific antigen (PSA) levels in hypogonadal men
  • Most studies, however, have shown no effect of exogenous androgens on PSA or prostate volume for older hypogonadal males
  • They argue that the prostate is relatively insensitive to changes in androgen concentration at normal levels or in mild hypogonadism because the AR is saturated by androgens and therefore maximal androgen-AR binding is achieved. Conversely, the prostate is very sensitive to changes in androgen levels when testosterone is low
  • saturation model
  • visceral obesity (one of the most significant components of metabolic syndrome) is associated with prostate volume and influences prostate growth during TRT.
  • This hypothesis of inflammation induced LUTS is also argued to be a mechanism for improvement of LUTS with PDE5I
  • The concept, therefore, that treatment with TRT of hypogonadal males with metabolic syndrome might lead to improvement/stabilization of their LUTS, appears to be confirmed in recent work by Francomano et al.
  • There was also an improvement in components of the patient's metabolic syndrome (such as BMI, waist circumference, hemoglobin A1c [HbA1c], insulin sensitivity, and lipid profile) as well as inflammatory markers and C-reactive protein.
  • They concluded that TRT was safe in this group of men, and hypothesize that TRT mitigates the pro-inflammatory factors associated with metabolic syndrome.
  • Nathan Goodyear on 01 Dec 14
     
    Authors review the literature behind Testosterone and BPH.  The authors highlight the 4 proposed theories behind BPH: Testosterone, Estrogen, inflammation, and metabolic.   The conclusion is mixed: pointing out that no high level of evidence exists on either side of the debate of Testosterone and BPH.
Nathan Goodyear

Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxid... - 0 views

www.ncbi.nlm.nih.gov/...PMC3180189

cancer reverse warburg effect warburg effect NF-kapppB HIF-1alpha Cav-1 H2O2

shared by Nathan Goodyear on 12 Nov 14 - No Cached
  • reducing oxidative stress with powerful antioxidants, is an important strategy for cancer prevention, as it would suppress one of the key early initiating steps where DNA damage and tumor-stroma metabolic-coupling begins. This would prevent cancer cells from acting as metabolic “parasites
  • Oxidative stress in cancer-associated fibroblasts triggers autophagy and mitophagy, resulting in compartmentalized cellular catabolism, loss of mitochondrial function, and the onset of aerobic glycolysis, in the tumor stroma. As such, cancer-associated fibroblasts produce high-energy nutrients (such as lactate and ketones) that fuel mitochondrial biogenesis and oxidative metabolism in cancer cells. We have termed this new energy-transfer mechanism the “reverse Warburg effect.
  • Then, oxidative stress, in cancer-associated fibroblasts, triggers the activation of two main transcription factors, NFκB and HIF-1α, leading to the onset of inflammation, autophagy, mitophagy and aerobic glycolysis in the tumor microenvironment
  • ...38 more annotations...
  • oxidative stress and ROS, produced in cancer-associated fibroblasts, has a “bystander effect” on adjacent cancer cells, leading to DNA damage, genomic instability and aneuploidy, which appears to be driving tumor-stroma co-evolution
  • tumor cells produce and secrete hydrogen peroxide, thereby “fertilizing” the tumor microenvironment and driving the “reverse Warburg effect.”
  • This type of stromal metabolism then produces high-energy nutrients (lactate, ketones and glutamine), as well as recycled chemical building blocks (nucleotides, amino acids, fatty acids), to literally “feed” cancer cells
  • loss of stromal caveolin (Cav-1) is sufficient to drive mitochondrial dysfunction with increased glucose uptake in fibroblasts, mimicking the glycolytic phenotype of cancer-associated fibroblasts.
  • oxidative stress initiated in tumor cells is transferred to cancer-associated fibroblasts.
  • Then, cancer-associated fibroblasts show quantitative reductions in mitochondrial activity and compensatory increases in glucose uptake, as well as high ROS production
  • These findings may explain the prognostic value of a loss of stromal Cav-1 as a marker of a “lethal” tumor microenvironment
  • aerobic glycolysis takes place in cancer-associated fibroblasts, rather than in tumor cells, as previously suspected.
  • our results may also explain the “field effect” in cancer biology,5 as hydrogen peroxide secreted by cancer cells, and the propagation of ROS production, from cancer cells to fibroblasts, would create an increasing “mutagenic field” of ROS production, due to the resulting DNA damage
  • Interruption of this process, by addition of catalase (an enzyme that detoxifies hydrogen peroxide) to the tissue culture media, blocks ROS activity in cancer cells and leads to apoptotic cell death in cancer cells
  • In this new paradigm, cancer cells induce oxidative stress in neighboring cancer-associated fibroblasts
  • cancer-associated fibroblasts have the largest increases in glucose uptake
  • cancer cells secrete hydrogen peroxide, which induces ROS production in cancer-associated fibroblasts
  • Then, oxidative stress in cancer-associated fibroblast leads to decreases in functional mitochondrial activity, and a corresponding increase in glucose uptake, to fuel aerobic glycolysis
  • cancer cells show significant increases in mitochondrial activity, and decreases in glucose uptake
  • fibroblasts and cancer cells in co-culture become metabolically coupled, resulting in the development of a “symbiotic” or “parasitic” relationship.
  • cancer-associated fibroblasts undergo aerobic glycolysis (producing lactate), while cancer cells use oxidative mitochondrial metabolism.
  • We have previously shown that oxidative stress in cancer-associated fibroblasts drives a loss of stromal Cav-1, due to its destruction via autophagy/lysosomal degradation
  • a loss of stromal Cav-1 is sufficient to induce further oxidative stress, DNA damage and autophagy, essentially mimicking pseudo-hypoxia and driving mitochondrial dysfunction
  • loss of stromal Cav-1 is a powerful biomarker for identifying breast cancer patients with early tumor recurrence, lymph-node metastasis, drug-resistance and poor clinical outcome
  • this type of metabolism (aerobic glycolysis and autophagy in the tumor stroma) is characteristic of a lethal tumor micro-environment, as it fuels anabolic growth in cancer cells, via the production of high-energy nutrients (such as lactate, ketones and glutamine) and other chemical building blocks
  • the upstream tumor-initiating event appears to be the secretion of hydrogen peroxide
  • one such enzymatically-active protein anti-oxidant that may be of therapeutic use is catalase, as it detoxifies hydrogen peroxide to water
  • numerous studies show that “catalase therapy” in pre-clinical animal models is indeed sufficient to almost completely block tumor recurrence and metastasis
  • by eliminating oxidative stress in cancer cells and the tumor microenvironment,55 we may be able to effectively cut off the tumor's fuel supply, by blocking stromal autophagy and aerobic glycolysis
  • breast cancer patients show systemic evidence of increased oxidative stress and a decreased anti-oxidant defense, which increases with aging and tumor progression.68–70 Chemotherapy and radiation therapy then promote further oxidative stress.69 Unfortunately, “sub-lethal” doses of oxidative stress during cancer therapy may contribute to tumor recurrence and metastasis, via the activation of myofibroblasts.
  • a loss of stromal Cav-1 is associated with the increased expression of gene profiles associated with normal aging, oxidative stress, DNA damage, HIF1/hypoxia, NFκB/inflammation, glycolysis and mitochondrial dysfunction
  • cancer-associated fibroblasts show the largest increases in glucose uptake, while cancer cells show corresponding decreases in glucose uptake, under identical co-culture conditions
  • Thus, increased PET glucose avidity may actually be a surrogate marker for a loss of stromal Cav-1 in human tumors, allowing the rapid detection of a lethal tumor microenvironment.
  • it appears that astrocytes are actually the cell type responsible for the glucose avidity.
  • In the brain, astrocytes are glycolytic and undergo aerobic glycolysis. Thus, astrocytes take up and metabolically process glucose to lactate.7
  • Then, lactate is secreted via a mono-carboxylate transporter, namely MCT4. As a consequence, neurons use lactate as their preferred energy substrate
  • both astrocytes and cancer-associated fibroblasts express MCT4 (which extrudes lactate) and MCT4 is upregulated by oxidative stress in stromal fibroblasts.34
  • In accordance with the idea that cancer-associated fibroblasts take up the bulk of glucose, PET glucose avidity is also now routinely used to measure the extent of fibrosis in a number of human diseases, including interstitial pulmonary fibrosis, postsurgical scars, keloids, arthritis and a variety of collagen-vascular diseases.
  • PET glucose avidity and elevated serum inflammatory markers both correlate with poor prognosis in breast cancers.
  • PET signal over-estimates the actual anatomical size of the tumor, consistent with the idea that PET glucose avidity is really measuring fibrosis and inflammation in the tumor microenvironment.
  • human breast and lung cancer patients can be positively identified by examining their exhaled breath for the presence of hydrogen peroxide.
  • tumor cell production of hydrogen peroxide drives NFκB-activation in adjacent normal cells in culture6 and during metastasis,103 directly implicating the use of antioxidants, NFκB-inhibitors and anti-inflammatory agents, in the treatment of aggressive human cancers.
  • Nathan Goodyear on 12 Nov 14
     
    Good description of the communication between cancer cells and fibroblasts.  This theory is termed the "reverse Warburg effect".
Nathan Goodyear

Testosterone therapy for reduced libido in women - 0 views

www.ncbi.nlm.nih.gov/...PMC3474615

Testosterone libido women

shared by Nathan Goodyear on 28 May 17 - No Cached
  • Nathan Goodyear on 28 May 17
     
    Testosterone and libido in women: the data is limited.  The data that links low T in women to low libido is not present.  That questions the whole low T, libido theory in women.
Nathan Goodyear

Microbial dysbiosis and colon carcinogenesis: could colon cancer be considered a bacter... - 0 views

www.ncbi.nlm.nih.gov/...PMC3625019

dysbiosis colon cancer cancer gut bacteria

shared by Nathan Goodyear on 10 Sep 17 - No Cached
  • Nathan Goodyear on 10 Sep 17
     
    good discussion of the theory and relationship between gut symbiosis and colorectal cancer.
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