MicroRNAs (miRNAs), a major family of small RNAs, are ∼23 nt-long single strands of RNA that bind to mRNA transcripts to inhibit their translation
A recent study by Zhang et al. reported that plant-derived miRNAs can be found in human serum.
The group demonstrates that the plant miRNA miR168 may be taken up through dietary intake to inhibit the expression of its target low-density lipoprotein receptor 1 in the liver21, providing the first evidence that miRNA in food may influence gene expression in mammalian organs.
A more recent finding by the same group shows that a plant miRNA from honeysuckle is able to inhibit Influenza A replication22, indicating that plant miRNAs may be useful for treating human diseases.
We found that plant miR159 could be detected in human sera and its levels were inversely correlated with BC incidence and progression.
We further identified TCF7 as a mammalian target for miR159 and showed the anti-proliferative function of miR159 in BC cells using in vitro and in vivo models, demonstrating for the first time that a plant miRNA is able to influence BC cell growth.
certain dietary miRNAs from plants and other species may serve as highly affordable and powerful means of treatment with minimal inconvenience to patients.
miR159 which (using a synthetic mimic) targets TCF7 to inhibit the proliferation of cells whose growth is dependent on TCF7 such as the BC cells MDA-MB-231
our study using a BC model clearly indicates the anti-tumor effect of orally administered synthetic miR159 in its naturally existing form with the plant-specific 2'-O-methylation, suggesting the feasibility of using synthetic forms of plant miRNAs as dietary supplements in the treatment of human cancers, including those outside of the GI track
Oxidative stress/inflammation via HIF-1alpha increase D3 which increases rT3 to increase proliferation in cancer; in contrast, there is a decrease in D1 and D2 to decrease T3 and T4. The question is the systemic versus the TME.
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
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
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
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 TableT
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
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.
Gut bacteria in the cecum and large intestine produce SCFAs mainly from nondigestible carbohydrates that pass the small intestine unaffected
plant cell-wall polysaccharides, oligosaccharides, and resistant starches
inulin shifted the relative production of SCFAs from acetate to propionate and butyrate
age of approximately 3–4 years, when it becomes mature
SCFAs affect lipid, glucose, and cholesterol metabolism
colonocytes, the first host cells that take up SCFAs and which depend largely on butyrate for their energy supply
the microbiota educate the immune system and increase the tolerance to microbial immunodeterminants
the microbiota act as a metabolic organ that can break down otherwise indigestible food components, degrade potentially toxic food compounds like oxalate, and synthesize certain vitamins and amino acids
a large part of the SCFAs is used as a source of energy
The general idea is that colonocytes prefer butyrate to acetate and propionate, and oxidize it to ketone bodies and CO2
Exogenous acetate formed by colonic bacterial fermentation enters the blood compartment and is mixed with endogenous acetate released by tissues and organs (103, 104). Up to 70% of the acetate is taken up by the liver (105), where it is not only used as an energy source, but is also used as a substrate for the synthesis of cholesterol and long-chain fatty acids and as a cosubstrate for glutamine and glutamate synthesis
SCFAs regulate the balance between fatty acid synthesis, fatty acid oxidation, and lipolysis in the body.
Fatty acid oxidation is activated by SCFAs, while de novo synthesis and lipolysis are inhibited
obese animals in this study showed a 50% reduction in relative abundance of the Bacteroidetes (i.e., acetate and propionate producers), whereas the Firmicutes (i.e., butyrate producers) were proportionally increased compared with the lean counterparts.
increase in total fecal SCFA concentrations in obese humans.
In humans the distinct relation between the Firmicutes:Bacteroidetes ratio and obesity is less clear.
During the enterohepatic circulation (EC), bile salts are synthesized in the liver, concentrated in the gallbladder, and
function in the lumen of the small intestine to absorb dietary lipids and limit microbial growth at the site of nutrient uptake
Bile acid 7α/β-dehydroxylating bacteria are organisms capable of converting primary bile acids made by the host to harmful
secondary bile acids, deoxycholic acid, and lithocholic acid
These bacteria normally comprise a small proportion of the gut microbiota (∼103–104/g wet weight) and consist of species within the genus Clostridium
C. scindens and a small number of species belonging to the genus Clostridium are responsible for significant alterations in the human bile acid pool composition through bile acid 7α/β dehydroxylation
bile acids play an important role in maintaining intestinal barrier function as antimicrobial agents in the
small bowel (37, 38) and inducers of antimicrobial peptides
Perturbations in the biliary bile acid pool composition can be indicative of hepatogastrointestinal diseases such as fat
malabsorption (40), gallstones (3), gastrointestinal cancers (41), and possibly type II diabetes
Gut microbiota appears to be source of androgen production that originates from the gut. Who would have thought that the Gut as an androgen producing endocrine gland.
The relationship of low testosterone to MetS often is considered to be bidirectional; however, the relationships probably are not direct
Many of the components of the MetS are recognized risk factors for the development of cardiovascular disease (CVD)
Multiple cross-sectional studies have found low TT and low sex hormone binding globulin (SHBG) levels in Caucasian and African-American men with the MetS, irrespective of age
Low TT and SHBG levels also are prevalent in Chinese [7],[8] and Korean [9] men with the MetS
Normally 40%-50% of TT is bound to SHBG, so reducing SHBG levels will decrease TT.
Hyperinsulinism suppresses SHBG synthesis and secretion by the liver
significant increase in SHBG levels occurred after acutely lowering insulin levels in obese men
Estradiol levels are increased in men with the MetS, and they are positively correlated with the number of abnormal components of the MetS.
Although it is known that estrogen will increase SHBG levels, apparently the hyperinsulinism associated with obesity has a greater effect on SHBG levels
Estradiol also can inhibit luteinizing hormone (LH) secretion
Inflammatory cytokines are thought to have a direct effect on the pituitary to reduce LH secretion [15] and also a direct effect on Leydig cell secretion of testosterone
Low TT Levels have been shown to predict development of the MetS in men with normal BMI
Men in the lowest quartiles of serum TT, calculated free testosterone (cFT) and SHBG at baseline had the highest odds ratios for developing the MetS or DM during the 11 years follow-up
More recently, investigators conducting population-based studies have reported that only SHBG is associated with future development of the MetS
Additional evidence that low TT increases the risk of MetS comes from androgen deprivation treatment of prostate cancer
Low TT and low bioavailable testosterone (bT) were each significantly associated with elevated 20 years risk of CVD mortality in an older population in which cause-specific mortality was age, adiposity, and lifestyle-adjusted.
combination of low bT and ATP III-defined MetS is associated with increased cardiovascular mortality in men aged 40 years and above
in elderly men, testosterone may weakly protect against CVD. Alternatively, low TT may indicate poor general health
Muraleedharan and Jones [27] concluded that there is convincing evidence that low T is a biomarker for disease severity and mortality.
The evidence that TRT improves insulin sensitivity and glucose control is conflicted
It is widely recognized that testosterone treatment can reduce fat mass and increase lean body mass; however, until recently most reports have not been associated with much weight loss
Changes in body composition and weight loss are considered potential mechanisms by which testosterone treatment improves insulin sensitivity and glucose control in patients with diabetes. Effects on inflammatory cytokines [38] and changes in oxidative metabolism [39] also have been reported to improve glucose metabolism.
Testosterone replacement therapy has been reported to improve some or all of the components of the MetS.
use of PET in clinical research, clinical trials, and drug discovery
use of PET/CT in assessing response to therapy
In some cases, such as Hodgkins lymphoma, quantitative PET/CT imaging may not actually be needed, as success can be defined by the complete absence of tracer uptake in the PET image following a course of standardized therapy
The utilization of PET/CT to assess response to therapy is increasing in the US related, in part, to the creation and subsequent favorable results of the National Oncologic PET Registry (NOPR)
Changes in size as a result of therapy may take many months to develop and any opportunity to make early decisions about therapy success or failure is often unduly delayed or lost altogether
measures of changes in metabolic activity via FDG PET/CT can provide an alternate approach to assess response to therapy -- often very early in the course of treatment
Current recommendations are that tumor SUVs should be reported
The true tracer uptake in a patient is composed of two components: the first being the amount of tracer uptake (e.g. FDG) associated with the disease status (the signal of interest), which can be modified by the biophysiological status of the patient. One of the more important patient parameters is the blood glucose level, which has been shown to inversely-linearly affect SUVs
A prospective study by Crippa et al.30 in eight patients showed that as blood glucose levels were increased from 92.4 ±10.2 to 158 ± 13.8 mg/100 ml by glucose loading, the average SUV of 20 liver metastases decreased from 9.4 ± 5.7 to 4.3 ± 8.3
chemotherapy can result in impaired renal function, significantly reducing the clearance of plasma FDG through the kidney and thus increasing tumor SUV relative to an initial PET scan
The second component of the true tracer uptake is biological variability
The biological variability has been estimated in several test-retest studies7,32–35 at approximately 10% for scans repeated within a few days