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processdocument

EU ,USA and Canadian driving license(whatsapp +19042995971) - 0 views

https://www.processdocumentdmv.com Buy UK driver license online EU ,USA and Canadian driving license Need A Real Driving License! buy uk driving licence online buy eu driving licence WANT TO LIVE I...

WANT TO LIVE IN EUROPE? "BUY" A RESIDENCY PERMIT

started by processdocument on 21 Dec 19 no follow-up yet
spineneuro

Firas Ali From Oman Finds Relief after Cervical Laminoplasty Surgery in India by Riche... - 0 views

www.apsense.com/...noplasty-surgery-in-india.html

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shared by spineneuro on 20 Aug 21 - No Cached
  • spineneuro on 20 Aug 21
     
    When Firas's back started to ache, the 51-year-old resident of Oman thought it was just a normal part of the aging process for someone as active as he was.
indiacardiacsurg

Dr. Rajiv Parakh Medanta Improving Surgical Strategies: PAD and Critical Limb Ischemia ... - 0 views

www.101pressrelease.com/pad-and-critical-limb-ischemia

Dr Rajiv Parakh Dr Rajiv Parakh Medanta Best vascular surgeon in Gurgaon Top Endovascular Surgeon in Gurgaon medanta hospital

shared by indiacardiacsurg on 07 Jan 22 - No Cached
  • indiacardiacsurg on 07 Jan 22
     
    Almost 2 million people dwelling with limb loss in India. Amongst the ones residing with limb loss, the primary causes are vascular ailment (54%) - inclusive of diabetes and peripheral arterial disorder. nearly 185,000 amputations arise in India each year. Write to Doctor - dr.rajivparakh@indiacardiacsurgerysite.com Call for Appointment- +91-9370586696
Nathan Goodyear

JAMA Network | Archives of Surgery | Death Rates and Causes of Death After Bariatric Su... - 0 views

archsurg.jamanetwork.com/article.aspx

Bariatric surgery overweight obese weight-loss death rates

shared by Nathan Goodyear on 02 Nov 12 - No Cached
  • Nathan Goodyear on 02 Nov 12
     
    Study reveals that death rate increased per year post-Bariatric surgery.  Up to 6.4% at 5 years.  This study did not follow up on additional procedures/surgeries.  The re-operation rate is 50%.
Nathan Goodyear

Vitamin D is associated with testosterone and hypogonadism in Chinese men: Results from... - 0 views

www.ncbi.nlm.nih.gov/...PMC4504177

vitamin d male hormones low T low Testosterone Testosterone

shared by Nathan Goodyear on 09 Jan 17 - No Cached
  • lower 25(OH)D level was significantly associated with lower total T, E2, SHBG, LH and FSH levels after adjusting for age, residence area, economic status and current smoker
  • association between 25(OH)D status and hypogonadism in Chinese men and confirms that this relationship is present in a large population
  • VDR knockout mutant mice showed gonadal insufficiencies
  • ...6 more annotations...
  • High LH and FSH levels in the male mice indicated hypergonadotropic hypogonadism
  • Another mouse study reported a tendency towards low testosterone/LH ratio and Leydig cell hyperplasia in VDR null mice
  • The serum testosterone levels could increase to normal values in vitamin D-deficient rats replete with vitamin D
  • VDR knockout mice had decreased sperm count, reduced sperm motility, and histological abnormality of the testis
  • vitamin D supplementation increases testosterone levels in non-diabetic subjects
  • The data from the European Male Ageing Study [9] indicated that 25(OH)D is positively associated with total T
  • Nathan Goodyear on 09 Jan 17
     
    Study of 713 Chinese men finds a correlation between low vitamin D and low total Testosterone.
Meredith Blige

Effective Solution to Snoring Problem - 1 views

I have been snoring for almost a year now and my wife is constantly complaining about it. Since I cannot point out the exact reason that causes this problem, I went to our resident doctor for consu...

sleep apnea symptoms

started by Meredith Blige on 15 Dec 11 no follow-up yet
Ciara Usher

Effective Solution to Snoring Problem - 1 views

I have been snoring for almost a year now and my wife is constantly complaining about it. Since I cannot point out the exact reason that causes this problem, I went to our resident doctor for consu...

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started by Ciara Usher on 17 Nov 11 no follow-up yet
Nathan Goodyear

Inflammatory cause of metabolic syndrome via brain stress and NF-κB - 0 views

www.ncbi.nlm.nih.gov/...PMC3314172

metabolic syndrome TLR cytokines hypothalamus brain neurology metabolic syndrome NF-kappaB DIO diet induced obesity over nutrition nutrition inflammation

shared by Nathan Goodyear on 09 Jul 13 - No Cached
  • Mechanistic studies further showed that such metabolic inflammation is related to the induction of various intracellular stresses such as mitochondrial oxidative stress, endoplasmic reticulum (ER) stress, and autophagy defect under prolonged nutritional excess
  • intracellular stress-inflammation process for metabolic syndrome has been established in the central nervous system (CNS) and particularly in the hypothalamus
  • the CNS and the comprised hypothalamus are known to govern various metabolic activities of the body including appetite control, energy expenditure, carbohydrate and lipid metabolism, and blood pressure homeostasis
  • ...56 more annotations...
  • Reactive oxygen species (ROS) refer to a class of radical or non-radical oxygen-containing molecules that have high oxidative reactivity with lipids, proteins, and nucleic acids
  • a large measure of intracellular ROS comes from the leakage of mitochondrial electron transport chain (ETC)
  • Another major source of intracellular ROS is the intentional generation of superoxides by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
  • there are other ROS-producing enzymes such as cyclooxygenases, lipoxygenases, xanthine oxidase, and cytochrome p450 enzymes, which are involved with specific metabolic processes
  • To counteract the toxic effects of molecular oxidation by ROS, cells are equipped with a battery of antioxidant enzymes such as superoxide dismutases, catalase, peroxiredoxins, sulfiredoxin, and aldehyde dehydrogenases
  • intracellular oxidative stress has been indicated to contribute to metabolic syndrome and related diseases, including T2D [72; 73], CVDs [74-76], neurodegenerative diseases [69; 77-80], and cancers
  • intracellular oxidative stress is highly associated with the development of neurodegenerative diseases [69] and brain aging
  • dietary obesity was found to induce NADPH oxidase-associated oxidative stress in rat brain
  • mitochondrial dysfunction in hypothalamic proopiomelanocortin (POMC) neurons causes central glucose sensing impairment
  • Endoplasmic reticulum (ER) is the cellular organelle responsible for protein synthesis, maturation, and trafficking to secretory pathways
  • unfolded protein response (UPR) machinery
  • ER stress has been associated to obesity, insulin resistance, T2D, CVDs, cancers, and neurodegenerative diseases
  • brain ER stress underlies neurodegenerative diseases
  • under environmental stress such as nutrient deprivation or hypoxia, autophagy is strongly induced to breakdown macromolecules into reusable amino acids and fatty acids for survival
  • intact autophagy function is required for the hypothalamus to properly control metabolic and energy homeostasis, while hypothalamic autophagy defect leads to the development of metabolic syndrome such as obesity and insulin resistance
  • prolonged oxidative stress or ER stress has been shown to impair autophagy function in disease milieu of cancer or aging
  • TLRs are an important class of membrane-bound pattern recognition receptors in classical innate immune defense
  • Most hypothalamic cell types including neurons and glia cells express TLRs
  • overnutrition constitutes an environmental stimulus that can activate TLR pathways to mediate the development of metabolic syndrome related disorders such as obesity, insulin resistance, T2D, and atherosclerotic CVDs
  • Isoforms TLR1, 2, 4, and 6 may be particularly pertinent to pathogenic signaling induced by lipid overnutrition
  • hypothalamic TLR4 and downstream inflammatory signaling are activated in response to central lipid excess via direct intra-brain lipid administration or HFD-feeding
  • overnutrition-induced metabolic derangements such as central leptin resistance, systemic insulin resistance, and weight gain
  • these evidences based on brain TLR signaling further support the notion that CNS is the primary site for overnutrition to cause the development of metabolic syndrome.
  • circulating cytokines can limitedly travel to the hypothalamus through the leaky blood-brain barrier around the mediobasal hypothalamus to activate hypothalamic cytokine receptors
  • significant evidences have been recently documented demonstrating the role of cytokine receptor pathways in the development of metabolic syndrome components
  • entral administration of TNF-α at low doses faithfully replicated the effects of central metabolic inflammation in enhancing eating, decreasing energy expenditure [158;159], and causing obesity-related hypertension
  • Resistin, an adipocyte-derived proinflammatory cytokine, has been found to promote hepatic insulin resistance through its central actions
  • both TLR pathways and cytokine receptor pathways are involved in central inflammatory mechanism of metabolic syndrome and related diseases.
  • In quiescent state, NF-κB resides in the cytoplasm in an inactive form due to inhibitory binding by IκBα protein
  • IKKβ activation via receptor-mediated pathway, leading to IκBα phosphorylation and degradation and subsequent release of NF-κB activity
  • Research in the past decade has found that activation of IKKβ/NF-κB proinflammatory pathway in metabolic tissues is a prominent feature of various metabolic disorders related to overnutrition
  • it happens in metabolic tissues, it is mainly associated with overnutrition-induced metabolic derangements, and most importantly, it is relatively low-grade and chronic
  • this paradigm of IKKβ/NF-κB-mediated metabolic inflammation has been identified in the CNS – particularly the comprised hypothalamus, which primarily accounts for to the development of overnutrition-induced metabolic syndrome and related disorders such as obesity, insulin resistance, T2D, and obesity-related hypertension
  • evidences have pointed to intracellular oxidative stress and mitochondrial dysfunction as upstream events that mediate hypothalamic NF-κB activation in a receptor-independent manner under overnutrition
  • In the context of metabolic syndrome, oxidative stress-related NF-κB activation in metabolic tissues or vascular systems has been implicated in a broad range of metabolic syndrome-related diseases, such as diabetes, atherosclerosis, cardiac infarct, stroke, cancer, and aging
  • intracellular oxidative stress seems to be a likely pathogenic link that bridges overnutrition with NF-κB activation leading to central metabolic dysregulation
  • overnutrition is an environmental inducer for intracellular oxidative stress regardless of tissues involved
  • excessive nutrients, when transported into cells, directly increase mitochondrial oxidative workload, which causes increased production of ROS by mitochondrial ETC
  • oxidative stress has been shown to activate NF-κB pathway in neurons or glial cells in several types of metabolic syndrome-related neural diseases, such as stroke [185], neurodegenerative diseases [186-188], and brain aging
  • central nutrient excess (e.g., glucose or lipids) has been shown to activate NF-κB in the hypothalamus [34-37] to account for overnutrition-induced central metabolic dysregulations
  • overnutrition can present the cell with a metabolic overload that exceeds the physiological adaptive range of UPR, resulting in the development of ER stress and systemic metabolic disorders
  • chronic ER stress in peripheral metabolic tissues such as adipocytes, liver, muscle, and pancreatic cells is a salient feature of overnutrition-related diseases
  • recent literature supports a model that brain ER stress and NF-κB activation reciprocally promote each other in the development of central metabolic dysregulations
  • when intracellular stresses remain unresolved, prolonged autophagy upregulation progresses into autophagy defect
  • autophagy defect can induce NF-κB-mediated inflammation in association with the development of cancer or inflammatory diseases (e.g., Crohn's disease)
  • The connection between autophagy defect and proinflammatory activation of NF-κB pathway can also be inferred in metabolic syndrome, since both autophagy defect [126-133;200] and NF-κB activation [20-33] are implicated in the development of overnutrition-related metabolic diseases
  • Both TLR pathway and cytokine receptor pathways are closely related to IKKβ/NF-κB signaling in the central pathogenesis of metabolic syndrome
  • Overnutrition, especially in the form of HFD feeding, was shown to activate TLR4 signaling and downstream IKKβ/NF-κB pathway
  • TLR4 activation leads to MyD88-dependent NF-κB activation in early phase and MyD88-indepdnent MAPK/JNK pathway in late phase
  • these studies point to NF-κB as an immediate signaling effector for TLR4 activation in central inflammatory response
  • TLR4 activation has been shown to induce intracellular ER stress to indirectly cause metabolic inflammation in the hypothalamus
  • central TLR4-NF-κB pathway may represent one of the early receptor-mediated events in overnutrition-induced central inflammation.
  • cytokines and their receptors are both upstream activating components and downstream transcriptional targets of NF-κB activation
  • central administration of TNF-α at low dose can mimic the effect of obesity-related inflammatory milieu to activate IKKβ/NF-κB proinflammatory pathways, furthering the development of overeating, energy expenditure decrease, and weight gain
  • the physiological effects of IKKβ/NF-κB activation seem to be cell type-dependent, i.e., IKKβ/NF-κB activation in hypothalamic agouti-related protein (AGRP) neurons primarily leads to the development of energy imbalance and obesity [34]; while in hypothalamic POMC neurons, it primarily results in the development of hypertension and glucose intolerance
  • the hypothalamus, is the central regulator of energy and body weight balance [
  • Nathan Goodyear on 09 Jul 13
     
    Great article chronicles the biochemistry of "over nutrition" and inflammation through NF-kappaB activation and its impact on the brain.
Nathan Goodyear

Bacteria in the Intestine, Helpful Residents or Enemies from Within? - 0 views

iai.asm.org/...3360.full

bacteria intestine gut flora gut microbiome gut microbiota

shared by Nathan Goodyear on 24 Aug 15 - No Cached
  • Nathan Goodyear on 24 Aug 15
     
    To be read
Nathan Goodyear

Testosterone level in men with type 2 diabetes mellitus and related metabolic... - 0 views

www.ncbi.nlm.nih.gov/...PMC4364844

low T low Testosterone Diabetes Testosterone men male hormones metabolic syndrome

shared by Nathan Goodyear on 30 Mar 15 - No Cached
  • defined by consistent symptoms and signs of androgen deficiency, and an unequivocally low serum testosterone level
  • the threshold serum testosterone level below which adverse clinical outcomes occur in the general population is not known
  • most population-based studies use the serum testosterone level corresponding to the lower limit, quoted from 8.7 to 12.7 nmol/L, of the normal range for young Caucasian men as the threshold
    • Nathan Goodyear
      Nathan Goodyear on 31 Mar 15
       
      this equals 251 to 366 in serum Total Testosterone
  • ...57 more annotations...
  • Researchers tried to examine whether serum total or free testosterone would be a better/more reliable choice when studying the effect of testosterone. The results were mixed. Some reported significant associations of both serum total and free testosterone level with clinical parameters25, whereas others reported that only serum free testosterone26 or only serum total testosterone6 showed significant associations.
  • −0.124 nmol/L/year in serum total testosterone
    • Nathan Goodyear
      Nathan Goodyear on 31 Mar 15
       
      this equates to a 4 ng/dl decline annually in total Testosterone.
  • In experimental studies, androgen receptor knockout mice developed significant insulin resistance rapidly
  • In mouse models, testosterone promoted differentiation of pluripotent stem cells to the myogenic lineage
  • testosterone decreased insulin resistance by enhancing catecholamine induced lipolysis in vitro, and reducing lipoprotein lipase activity and triglyceride uptake in human abdominal tissue in vivo
  • by promoting lipolysis and myogenesis, testosterone might lead to improved insulin resistance
  • testosterone regulated skeletal muscle genes involved in glucose metabolism that led to decreased systemic insulin resistance
  • In the liver, hepatic androgen receptor signaling inhibited development of insulin resistance in mice
  • independent and inverse association of testosterone with hepatic steatosis shown in a cross-sectional study carried out in humans
  • In short, androgen improves insulin resistance by changing body composition and reducing body fat.
  • Although a low serum testosterone level could contribute to the development of obesity and type 2 diabetes through changes in body composition, obesity might also alter the metabolism of testosterone
  • In obese men, the peripheral conversion from testosterone to estrogen could attenuate the amplitude of luteinizing hormone pulses and centrally inhibit testosterone production
  • leptin, an adipokine, has been shown to be inversely correlated with serum testosterone level in men
  • Leydig cells expressed leptin receptors and leptin has been shown to inhibit testosterone secretion, suggesting a role of obesity and leptin in the pathogenesis of low testosterone
    • Nathan Goodyear
      Nathan Goodyear on 31 Mar 15
       
      So what is "unequivocal"?
  • Baltimore Longitudinal Study of Aging (BLSA) cohort made up of 3,565 middle-class, mostly Caucasian men from the USA, the incidence of low serum total testosterone increased from approximately 20% of men aged over 60 years, 30% over 70 years, to 50% over 80 years-of-age
  • 30–44% sex hormone binding globulin (SHBG)-bound testosterone and 54–68% albumin-bound testosterone
  • As the binding of testosterone to albumin is non-specific and therefore not tight, the sum of free and albumin-bound testosterone is named bioavailable testosterone, which reflects the hormone available at the cellular level
  • Serum total testosterone is composed of 0.5–3.0% of free testosterone unbound to plasma proteins
  • alterations in SHBG concentration might affect total serum testosterone level without altering free or bioavailable testosterone
  • listed in Table​T
  • A significant, independent and longitudinal effect of age on testosterone has been observed with an average change of −0.124 nmol/L/year in serum total testosterone28. The same trend has been shown in Europe and Australia
  • Asian men residing in HK and Japan, but not those living in the USA, had 20% higher serum total testosterone than in Caucasians living in the USA, as shown in a large multinational observational prospective cohort of the Osteoporotic Fractures in Men Study
  • subjects with chronic diseases consistently had a 10–15% lower level compared with age-matched healthy subjects
  • In Caucasians, the mean serum total testosterone level for men in large epidemiological studies has been reported to range from 15.1 to 16.6 nmol/L
  • Asians, higher values, ranging from 18.1 to 19.1 nmol/L, were seen in Korea and Japan
  • Chinese middle-aged men reported a similar mean serum testosterone level of 17.1 nmol/L in 179 men who had a family history of type 2 diabetes and 17.8 nmol/L in 128 men who had no family history of type 2 diabetes
  • The reduction of total testosterone was 0.4% per year in both groups
  • HK involving a cohort of 1,489 community-dwelling men with a mean age of 72 years, a mean serum total testosterone of 19.0 nmol/L was reported
  • pro-inflammatory factors, such as tumor necrosis factor-α in the testes, could locally inhibit testosterone biosynthesis in Leydig cells47, and testosterone treatment in men was shown to reduce the level of tumor necrosis factor-α
  • In Asians, a genetic deletion polymorphism of uridine diphosphate-glucuronosyltransferase UGT2B17 was associated with reduced androgen glucuronidation. This resulted in higher level of active androgen in Asians as compared to Caucasians, as Caucasians' androgen would be glucuronidated into inactive forms faster.
  • Compared with Caucasians, the frequency of this deletion polymorphism of UGT2B17 was 22-fold higher in Asian subjects
  • Other researchers have suggested that environmental, but not genetic, factors influenced serum total testosterone
  • The basal and ligand-induced activity of the AR is inversely associated with the length of the CAG repeat chain
  • In the European Male Aging Study, increased estrogen/androgen ratio in association with longer AR CAG repeat was observed
  • a smaller number of AR CAG repeat had been shown to be associated with benign prostate hypertrophy and faster prostate growth during testosterone treatment
  • In India, men with CAG ≤19 had increased risk of prostate cancer
  • the odds of having a short CAG repeat (≤17) were substantially higher in patients with lymph node-positive prostate cancer than in those with lymph node-negative disease or in the general population
  • assessing the polymorphism at the AR level could be a potential tool towards individualized assessment and treatment of hypogonadism.
  • In elderly men, there was reduced testicular response to gonadotropins with suppressed and altered pulsatility of the hypothalamic pulse generator
  • a significant, independent and longitudinal effect of age on serum total testosterone level had been observed
  • A significant graded inverse association between serum testosterone level and insulin levels independent of age has also been reported in Caucasian men
  • Low testosterone is commonly associated with a high prevalence of MES
  • most studies showed that changes in serum testosterone level led to changes in body composition, insulin resistance and the presence of MES, the reverse might also be possible
  • MES predicted a 2.6-fold increased risk of development of low serum testosterone level independent of age, smoking and other potential confounders
  • Other prospective studies have shown that development of MES accelerated the age-related decline in serum testosterone level
  • In men with type 2 diabetes, changes in serum testosterone level over time correlated inversely with changes in insulin resistance
  • weight loss by either diet control or bariatric surgery led to a substantial increase in total testosterone, especially in morbidly obese men, and the rise in serum testosterone level was proportional to the amount of weight lost
  • To date, published clinical trials are small, of short duration and often used pharmacological, not physiological, doses of testosterone
  • In the population-based Osteoporotic Fractures in Men Study cohort from Sweden, men in the highest quartile of serum testosterone level had the lowest risk of cardiovascular events compared with men in the other three quartiles (hazard ratio [HR] 0.70
  • low serum total testosterone was associated with a significant fourfold higher risk of cardiovascular events when comparing men from the lowest testosterone tertile with those in the highest tertile
  • Shores et al. were the first to report that low serum testosterone level, including both serum total and free testosterone, was associated with increased mortality
  • low serum total testosterone predicted increased risk of cardiovascular mortality with a HR of 1.38
  • low serum total testosterone increased all-cause (HR 1.35, 95% CI 1.13–1.62, P < 0.001) and cardiovascular mortality (HR 1.25
  • European Association for the Study of Diabetes 2013 suggested there was an inverse relationship between serum testosterone level and acute myocardial infarction
  • Diabetic men in the highest quartile of serum total testosterone had a significantly reduced risk of acute MI when compared with those in the lower quartiles
  • serum total testosterone level in the middle two quartiles at baseline predicted reduced incidence of death compared with having the highest and lowest levels
  • Nathan Goodyear on 30 Mar 15
     
    Nice review of Testosterone levels and some of the evidence linking Diabetes with low T.  However, the conclusion by the authors regarding what is causing the low T in men with Diabetes is baffling.  The literature does not point to one cause, it is clearly multifactorial--obesity, inflammation, high aromatase activity...I would suggest the authors continue their readings in the manner.
wheelchairindia9

Transport Chairs - 0 views

www.wheelchairindia.com/...TRAVEL-WHEELCHAIR

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shared by wheelchairindia9 on 21 May 15 - No Cached
  • wheelchairindia9 on 21 May 15
     
    Lightweight wheelchairs provide convenience and comfort to the user and caregiver alike and are often built using materials like aluminum and titanium alloy, while foldable wheelchairs allow for easy storage and transport. Merge the two styles, and got a great mobility aid that isn't a pain to lug around. Utilizing small wheels and lighter materials, transport wheelchairs can tip the scale at as little as 19 lbs, ideal for those looking for a highly portable option. Transport chairs also tend to be more affordable and offer the benefit of increased mobility without breaking the bank. This type of lightweight wheelchair is often referred to as a "transfer chair" and is typically used for shorter trips. Since it's geared towards storability and portability, it features four smaller wheels and dispenses with the larger, rear-mounted wheels that characterize standard wheelchairs. Its construction ensures that it's always foldable and portable, but does so at the expense of self-propulsion. Instead, a transport chair is built so that a caregiver can easily push the user. Transport wheelchairs or companion chairs are companion wheelchairs where the purpose is for a companion to push the user. Most transporters have swing-away leg rests, fixed armrests, and side panels. Instead of the usual 'large back - small front' wheels typical of most wheelchairs, light travel chairs have four small wheels providing much easier maneuverability of the chair. Karma Travel Wheelchair KM TV 20.2: Karma Travel Wheelchair KM TV 20.2 - 606 T-6 aircraft-grade aluminum-alloy frame provides incredible strength. Easy-to-fold in three seconds. Karma Travel Wheelchair KM TV 20.2 Features: Type: Travel Wheelchair. T-6 aircraft-grade aluminum. Secure brake improve safety. Padded flip back armrest. PU front caster & rear wheel. Karma Travel Wheelchair KM TV 20.2 Measurements: Weight: 8.9kg. Seat width: 39.5cm. Tyre: PU front casters and rear wheels. Capacity: 100
Nathan Goodyear

How is the Immune System Suppressed by Cancer - 1 views

www.cancertutor.com/ancer-suppresses-immune-system

iNOS cancer immune system

shared by Nathan Goodyear on 23 May 18 - No Cached
  • nitric oxide (NO) released by tumor cells
  • Excellent work by Prof de Groot of Essen, indicated by adding exogenous xanthine oxidase ( XO) in hepatoma cells, hydrogen peroxide was produced to destroy the hepatoma cells
  • NO from eNOS in cancer cells can travel through membranes and over long distances in the body
  • ...43 more annotations...
  • NO also is co linked to VEGF which in turn increases the antiapoptotic gene bcl-2
  • The other important influence of NO is in its inhibition of the proapoptoic caspases cascade. This in turn protects the cells from intracellular preprogrammed death.
  • nitric oxide in immune suppression in relation to oxygen radicals is its inhibitory effect on the binding of leukocytes (PMN) at the endothelial surface
  • Inhibition of inducible Nitric Oxide Synthase (iNOS)
  • NO from the tumor cells actually suppresses the iNOS, and in addition it reduces oxygen radicals to stop the formation of peroxynitrite in these cells. But NO is not the only inhibitor of iNOS in cancer.
  • Spermine and spermidine, from the rate limiting enzyme for DNA synthases, ODC, also inhibit iNOS
  • tolerance in the immune system that decreases the immune response to antigens on the tumors
  • Freund’s adjuvant
  • increase in kinases in these cells which phosphorylate serine, and tyrosine
  • responsible for activation of many growth factors and enzymes
  • phosphorylated amino acids suppress iNOS activity
  • Hexokinase II
  • Prostaglandin E2, released from tumor cells is also an inhibitor of iNOS, as well as suppressing the immune system
  • Th-1 subset of T-cells. These cells are responsible for anti-viral and anti-cancer activities, via their cytokine production including Interleukin-2, (IL-2), and Interleukin-12 which stimulates T-killer cell replication and further activation and release of tumor fighting cytokines.
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      Th1 cells stimulate NK and other tumor fighting macrophages via IL-2 and IL-12; In contrast, Th2, which is stimulated in allergies and parasitic infections, produce IL-4 and IL-10.  IL-4 and IL-10 inhibit TH-1 activation and the histamine released from mast cell degranulation upregulates T suppressor cells to further immune suppression.
  • Th-2 subset of lymphocytes, on the other hand are activated in allergies and parasitic infections to release Interleukin-4 and Interleukin-10
  • These have respectively inhibitory effects on iNOS and lymphocyte Th-1 activation
  • Mast cells contain histamine which when released increases the T suppressor cells, to lower the immune system and also acts directly on many tumor Histamine receptors to stimulate tumor growth
  • Tumor cells release IL-10, and this is thought to be one of the important areas of Th-1 suppression in cancer patients
  • IL-10 is also increased in cancer causing viral diseases such as HIV, HBV, HCV, and EBV
  • IL-10 is also a central regulator of cyclooxygenase-2 expression and prostaglandin production in tumor cells stimulating their angiogenesis and NO production
  • nitric oxide in tumor cells even prevents the activation of caspases responsible for apoptosis
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      NO produced by cancer cells inhibits proapoptotic pathways such as the caspases.
  • early stages of carcinogenesis, which we call tumor promotion, one needs a strong immune system, and fewer oxygen radicals to prevent mutations but still enough to destroy the tumor cells should they develop
  • later stages of cancer development, the oxygen radicals are decreased around the tumors and in the tumor cells themselves, and the entire cancer fighting Th-1 cell replication and movement are suppressed. The results are a decrease in direct toxicity and apoptosis, which is prevented by NO, a suppression of the macrophage and leukocyte toxicity and finally, a suppression of the T-cell induced tumor toxicity
  • cGMP is increased by NO
  • NO in cancer is its ability to increase platelet-tumor cell aggregates, which enhances metastases
  • the greater the malignancies and the greater the metastatic potential of these tumors
  • The greater the NO production in many types of tumors,
  • gynecological
  • elevated lactic acid which neutralizes the toxicity and activity of Lymphocyte immune response and mobility
  • The lactic acid is also feeding fungi around tumors and that leads to elevated histamine which increases T-suppressor cells.  Histamine alone stimulates many tumor cells.
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      The warburg effect in cancer cells results in the increase in local lactic acid production which suppresses lymphocyte activity and toxicity as well as stimulates histamine production with further stimulates tumor cell growth.
  • T-regulatory cells (formerly,T suppressor cells) down regulate the activity of Natural killer cells
  • last but not least, the Lactic acid from tumor cells and acidic diets shifts the lymphocyte activity to reduce its efficacy against cancer cells and pathogens in addition to altering the bacteria of the intestinal tract.
  • intestinal tract bacteria in cancer cells release sterols that suppress the immune system and down regulate anticancer activity from lymphocytes.
  • In addition to the lactic acid, adenosine is also released from tumors. Through IL-10, adenosine and other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state
  • Adenosine up regulates the PD1 receptor in T-1 Lymphocytes and inhibits their activity
  • Adenosine is a purine nucleoside found within the interstitial fluid of solid tumors at concentrations that are able to inhibit cell-mediated immune responses to tumor cells
  • Adenosine appears to up-regulate the PD1 receptor in T-1 Lymphocytes and inhibits the immune system further
  • Mast cells with their release of histamine lower the immune system and also stimulate tumor growth and activate the metalloproteinases involved in angiogenesis and metastases
  • COX 2 inhibitors or all trans-retinoic acid
  • Cimetidine, an antihistamine has been actually shown to increase in apoptosis in MDSC via a separate mechanism than the antihistamine effect
    • Nathan Goodyear
      Nathan Goodyear on 23 May 18
       
      cimetidine is an H2 blocker
  • interleukin-8 (IL-8), a chemokine related to invasion and angiogenesis
  • In vitro analyses revealed a striking induction of IL-8 expression in CAFs and LFs by tumor necrosis factor-alpha (TNF-alpha)
  • these data raise the possibility that the majority of CAFs in CLM originate from resident LFs. TNF-alpha-induced up-regulation of IL-8 via nuclear factor-kappaB in CAFs is an inflammatory pathway, potentially permissive for cancer invasion that may represent a novel therapeutic target
  • Nathan Goodyear on 23 May 18
     
    Great review of the immunosuppression in cancer driven by the likes of NO.
Nathan Goodyear

Frontiers | Microbiome-Derived Lipopolysaccharide Enriched in the Perinuclear Region of... - 0 views

journal.frontiersin.org/...full

LPS lipopolysaccharides Alzheimer's disease brain inflammation

shared by Nathan Goodyear on 23 Sep 17 - No Cached
  • lipopolysaccharides (LPS), either alone or in combination, have indicated that when compared, bacterial LPSs exhibit the strongest induction of pro-inflammatory signaling in human neuronal–glial cells in primary coculture of any single inducer, and different LPS extracts from different gastrointestinal (GI)-tract resident Gram-negative bacteria appeared to have different pro-inflammatory potential
  • powerful inducer of the NF-κB
  • In both neocortex and hippocampus, LPS has been detected to range from a ~7- to ~21-fold increase abundance in AD brain
  • ...15 more annotations...
  • Major Gram-negative bacilli of the human GI-tract, such as the abundant B. fragilis and Escherichia coli (E. coli), are capable of discharging a remarkably complex assortment of pro-inflammatory neurotoxins
  • (i) bacterial amyloids (10, 21); (ii) endotoxins and exotoxins (5, 12); (iii) LPS (12, 18); and (iv) small non-coding RNAs (sncRNAs)
  • integral components of the outer leaflet of the outer membrane of Gram-negative bacteria, LPS
  • LPS, the major molecular component of the outer membrane of Gram-negative bacteria normally serves as a physical barrier providing the bacteria protection from its surroundings
  • LPS is also recognized by the immune system as a marker for the detection of bacterial pathogen invasion and responsible for the development of inflammatory response is perhaps the most potent stimulator and trigger of inflammation known
  • AD-affected brains have remarkably large loads of bacterial-derived toxins compared to controls. The transfer of noxious, pro-inflammatory molecules from the GI-tract microbiome to the CNS may be increasingly important during the course of aging when both the GI-tract and blood–brain barriers become significantly more permeable
  • first evidence of a perinuclear association of LPS with AD brain cell nuclei
  • LPS-mediated stimulation of chronic inflammation, beta-amyloid accumulation, and episodic memory decline in murine models of AD (39, 40) and a biophysical association of LPS with amyloid deposits and blood vessels in human AD patients
  • Strong adherence of LPS to the nuclear periphery has recently been shown to inhibit nuclear maturation and function that may impair or block export of mRNA signals from brain cell nuclei, a highly active organelle with extremely high rates of transcription, mRNA processing, and export into the cytoplasm
  • LPS may be further injurious to the nuclear membrane just as LPS contributes to cerebrovascular endothelial cell membrane injury
  • high intake of dietary fiber is a strong inhibitor of B. fragilis abundance and proliferation in the intact human GI-tract and as such is a potent inhibitor of the neurotoxic B. fragilis-derived amyloids, LPS, enterotoxins, and sncRNAs.
  • GI-tract microbiome-derived LPS may be an important initiator and/or significant contributor to inflammatory degeneration in the AD CNS
  • LPS has been recently localized to the same anatomical regions involved in AD-type neuropathology
  • a known pro-inflammatory transcription factor complex that triggers the expression of pathogenic pathways involved in neurodegenerative inflammation
  • pro-inflammatory amyloids, endo- and exotoxins, LPSs, and sncRNAs but also serve as potent sources of membrane-disrupting agents
  • Nathan Goodyear on 23 Sep 17
     
    LPS links gut to inflammation in Alzheimer's disease
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