Around 50% of ageing, obese men presenting to the diabetes clinic have lowered testosterone levels relative to reference ranges
based on healthy young men
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Adherence to the Mediterranean diet is associated with the severity of non-al... - 0 views
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mediterranean diet nutrition NAFLD fatty liver insulin resistance liver disease non-alcoholic fatty liver
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R O M Knee Brace - 0 views
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Functional Braces Best for: Sports injuries after surgery functional knee braces knee rehabilitation program knee injuries or knee surgery free movement of the knee joint decrease knee pain improve knee stability
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PF Night Splint Compared to plantar based splints, patients prefer dorsal models because they are less bulky, cooler, lower profile and easier to walk in at night. PF Night Splint includes all of these features and more. Neoprene calf and toe straps along with gel padding on the top of the foot help reduce pressure points and the plastic-free bottom offers safer nighttime ambulation. Even added more room in the forefoot to accommodate wider feet and new flexible shell allows easier nighttime ambulation without compromising the ability to hold the foot at 90° during rest. Finally, a plantar fasciitis splint patients will wear all night! Neoprene calf. Padded foam liner. Fits right or left. Not made with natural rubber latex. PF Night Splint (Derotation) Applications Prevention and correction of foot drop. Night splint for early healing. Ambulatory, can be used as a day splint. Perfect post-operative immobilisation and derotation. Peroneal / Peritibial nerve or muscle damage. Ankle or Plantar flexion contracture and functional alignment. Can be used to protect the diabetic/ injured ankle & foot. PF Night Splint (Derotation) Features Removable de-rotation bar. Moulded foot casing, aesthetically pleasing and durable. Effective Liner, improved comfort. Highly functional Design, customized degree of dorsiflexion. Double strapping mechanism, better grip. Tynor R O M Knee Brace Prefabricated, custom adjusted R.O.M. Knee Brace controls and restrict flexion/extension of the knee joint through a multi-point joint fixation system to allow a range of motion or immobilization to the knee. Universal design allows it to be used on quite a big range of population and for a multiple orthopedic problems associated with knee joint. Immobilization at any angle Controlled motion between any two angles Quick and easy application and removal. Tynor R O M Knee Brace Features R.O.M. Dial 0 to 120 degree flexion. 0 to 60 degree hyper extention Locking at any
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Testosterone and glucose metabolism in men: current concepts and controversies - 0 views
joe.endocrinology-journals.org/...R37.full
Low T Testosterone metabolic syndrome MetS Diabetes men male glucose hormone hormones g
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The absence of high-level evidence in this area is illustrated by the Endocrine Society testosterone therapy in men with androgen deficiency clinical practice guidelines (Bhasin et al. 2010), which are appropriate for, but not specific to men with metabolic disorders. All 32 recommendations made in these guidelines are based on either very low or low quality evidence.
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A key concept relates to making a distinction between replacement and pharmacological testosterone therapy
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Findings similar to type 2 diabetes were reported for men with the metabolic syndrome, which were associated with reductions in total testosterone of −2.2 nmol/l (95% CI −2.41 to 1.94) and in free testosterone
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Cross-sectional studies uniformly show that 30–50% of men with type 2 diabetes have lowered circulating testosterone levels, relative to references based on healthy young men
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In a recent cross-sectional study of 240 middle-aged men (mean age 54 years) with either type 2 diabetes, type 1 diabetes or without diabetes (Ng Tang Fui et al. 2013b), increasing BMI and age were dominant drivers of low total and free testosterone respectively.
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both diabetes and the metabolic syndrome are associated with a modest reduction in testosterone, in magnitude comparable with the effect of 10 years of ageing
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In a cross-sectional study of 490 men with type 2 diabetes, there was a strong independent association of low testosterone with anaemia
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In men, low testosterone is a marker of poor health, and may improve our ability to predict risk
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It remains possible that low testosterone is a consequence of insulin resistance, or simply a biomarker, co-existing because of in-common risk factors.
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In prospective studies, reviewed in detail elsewhere (Grossmann et al. 2010) the inverse association of low testosterone with metabolic syndrome or diabetes is less consistent for free testosterone compared with total testosterone
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In a study from the Framingham cohort, SHBG but not testosterone was prospectively and independently associated with incident metabolic syndrome
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low SHBG (Ding et al. 2009) but not testosterone (Haring et al. 2013) with an increased risk of future diabetes
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In cross-sectional studies of men with (Grossmann et al. 2008) and without (Bonnet et al. 2013) diabetes, SHBG but not testosterone was inversely associated with worse glycaemic control
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SHBG may have biological actions beyond serving as a carrier protein for and regulator of circulating sex steroids
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In men with diabetes, free testosterone, if measured by gold standard equilibrium dialysis (Dhindsa et al. 2004), is reduced
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Low free testosterone remains inversely associated with insulin resistance, independent of SHBG (Grossmann et al. 2008). This suggests that the low testosterone–dysglycaemia association is not solely a consequence of low SHBG.
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Experimental evidence reviewed below suggests that visceral adipose tissue is an important intermediate (rather than a confounder) in the inverse association of testosterone with insulin resistance and metabolic disorders.
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testosterone promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into adipocytes
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testosterone regulates the metabolic functions of mature adipocytes (Xu et al. 1991, Marin et al. 1995) and myocytes (Pitteloud et al. 2005) in ways that reduce insulin resistance.
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Pre-clinical evidence (reviewed in Rao et al. (2013)) suggests that at the cellular level, testosterone may improve glucose metabolism by modulating the expression of the glucose-transported Glut4 and the insulin receptor, as well as by regulating key enzymes involved in glycolysis.
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More recently testosterone has been shown to protect murine pancreatic β cells against glucotoxicity-induced apoptosis
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Interestingly, a reciprocal feedback also appears to exist, given that not only chronic (Cameron et al. 1990, Allan 2013) but also, as shown more recently (Iranmanesh et al. 2012, Caronia et al. 2013), acute hyperglycaemia can lower testosterone levels.
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In men with prostate cancer commencing androgen deprivation therapy, both total as well as, although not in all studies (Smith 2004), visceral fat mass increases (Hamilton et al. 2011) within 3 months
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More prolonged (>12 months) androgen deprivation therapy has been associated with increased risk of diabetes in several large observational registry studies
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Testosterone has also been shown to reduce the concentration of pro-inflammatory cytokines in some, but not all studies, reviewed recently in Kelly & Jones (2013). It is not know whether this effect is independent of testosterone-induced changes in body composition.
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the observations discussed in this section suggest that it is the decrease in testosterone that causes insulin resistance and diabetes. One important caveat remains: the strongest evidence that low testosterone is the cause rather than consequence of insulin resistance comes from men with prostate cancer (Grossmann & Zajac 2011a) or biochemical castration, and from mice lacking the androgen receptor.
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Several large prospective studies have shown that weight gain or development of type 2 diabetes is major drivers of the age-related decline in testosterone levels
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there is increasing evidence that healthy ageing by itself is generally not associated with marked reductions in testosterone
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increased visceral fat is an important component in the association of low testosterone and insulin resistance
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The vast majority of men with metabolic disorders have functional gonadal axis suppression with modest reductions in testosterone levels
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men with Klinefelter syndrome have an increased risk of metabolic disorders. Interestingly, greater body fat mass is already present before puberty
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inhibition of the gonadal axis predominantly takes place in the hypothalamus, especially with more severe obesity
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Metabolic factors, such as leptin, insulin (via deficiency or resistance) and ghrelin are believed to act at the ventromedial and arcuate nuclei of the hypothalamus to inhibit gonadotropin-releasing hormone (GNRH) secretion from GNRH neurons situated in the preoptic area
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hypothesis that obesity-mediated inhibition of kisspeptin signalling contributes to the suppression of the HPT axis, infusion of a bioactive kisspeptin fragment has been recently shown to robustly increase LH pulsatility, LH levels and circulating testosterone in hypotestosteronaemic men with type 2 diabetes
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A smaller study with a similar experimental design found that acute testosterone withdrawal reduced insulin sensitivity independent of body weight, whereas oestradiol withdrawal had no effects
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Obesity and dysglycaemia and associated comorbidities such as obstructive sleep apnoea (Hoyos et al. 2012b) are important contributors to the suppression of the HPT axis
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Modifiable risk factors such as obesity and co-morbidities are more strongly associated with a decline in circulating testosterone levels than age alone
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55% of symptomatic androgen deficiency reverted to a normal testosterone or an asymptomatic state after 8-year follow-up, suggesting that androgen deficiency is not a stable state
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The hypothalamic–pituitary–testicular axis remains responsive to treatment with aromatase inhibitors or selective oestrogen receptor modulators in obese men
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Kisspeptin treatment increases LH secretion, pulse frequency and circulating testosterone levels in hypotestosteronaemic men with type 2 diabetes
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weight loss can lead to genuine reactivation of the gonadal axis by reversal of obesity-associated hypothalamic suppression
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There is pre-clinical and observational evidence that chronic hyperglycaemia can inhibit the HPT axis
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in men who improved their glycaemic control over time, testosterone levels increased. By contrast, in those men in whom glycaemic control worsened, testosterone decreased
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testosterone levels should be measured after successful weight loss to identify men with an insufficient rise in their testosterone levels. Such men may have HPT axis pathology unrelated to their obesity, which will require appropriate evaluation and management.
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JAMA Network | JAMA Pediatrics | Prevalence and Trends in Obesity and Severe Obesity Am... - 0 views
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Salivary 8-OHdG: a useful biomarker for predicting severe ED and hypogonadism. - PubMed... - 0 views
www.ncbi.nlm.nih.gov/...18422497
oxidative stress 8-OHdG 8-hydroxy-2-deoxyguanosine hormones Testosterone phosphodiesterase 5 inhibitors
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Reduced Activation and Increased Inactivation of Thyroid Hormone in Tissues of Critical... - 0 views
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[Serum thyroid hormone levels correlate with cardi... [J Cardiol. 1993] - PubMed result - 0 views
www.ncbi.nlm.nih.gov/...8176632
hypothyroid hypothyroidism T3 T4 rT3 cardiovascular disease CHF tachycardia
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Patients with ventricular tachycardia demonstrated significantly lower serum values of FT3 and FT3/FT4, and significantly higher values of rT3. Serum thyroid hormone levels can provide a quantitative index for evaluating the severity of chronic heart failure and predicting ventricular tachycardia.
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Elsevier: Article Locator - 0 views
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The most striking abnormality detected in 75 sick euthyroid patients was a highly significant reduction in the mean total serum-triiodothyronine (T3) levels, with most patients having total T3 levels in the hypothyroid range. The severity of the illness correlated well with the reduction in total serum-T3 levels.
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Type 1 diabetes associated with acquired generaliz... [J Clin Endocrinol Metab. 2008] -... - 0 views
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Acquired generalized lipodystrophy (AGL) is marked by severe insulin resistance and hypertriglyceridemia. Rarely, AGL and type 1 diabetes (T1D) coexist.
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Long-term recombinant leptin therapy is effective in treating the insulin resistance of patients with the unusual combination of T1D and AGL.
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Stuck at the bench: Potential natural neuroprotective compounds for concussion - 0 views
www.ncbi.nlm.nih.gov/...PMC3205506
concussions concussion natural therapies brain curcumin omega 3 resveratrol green tea EGCG EPA DHA vitamin E vitamin c vitamin D
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Long-chain polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are highly enriched in neuronal synaptosomal plasma membranes and vesicles
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effective supplementation and/or increased ingestion of dietary sources rich in EPA and DHA, such as cold-water fish species and fish oil, may help improve a multitude of neuronal functions, including long-term potentiation and cognition.
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multiple preclinical studies have suggested that DHA and/or EPA supplementation may have potential benefit through a multitude of diverse, but complementary mechanisms
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pre-injury dietary supplementation with fish oil effectively reduces post-traumatic elevations in protein oxidation
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The benefits of pre-traumatic DHA supplementation have not only been independently confirmed,[150] but DHA supplementation has been shown to significantly reduce the number of swollen, disconnected and injured axons when administered following traumatic brain injury.
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DHA has provided neuroprotection in experimental models of both focal and diffuse traumatic brain injury
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potential mechanisms of neuroprotection, in addition to DHA and EPA's well-established anti-oxidant and anti-inflammatory properties
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Despite abundant laboratory evidence supporting its neuroprotective effects in experimental models, the role of dietary DHA and/or EPA supplementation in human neurological diseases remains uncertain
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Several population-based, observational studies have suggested that increased dietary fish and/or omega-3 polyunsaturated fatty acid consumption may reduce risk for ischemic stroke in several populations
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Randomized control trials have also demonstrated significant reductions in ischemic stroke recurrence,[217] relative risk for ischemic stroke,[2] and reduced incidence of both symptomatic vasospasm and mortality following subarachnoid hemorrhage
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curcumin has gained much attention from Western researchers for its potential therapeutic benefits in large part due to its potent anti-oxidant[128,194,236] and anti-inflammatory properties
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Curcumin is highly lipophilic and crosses the blood-brain barrier enabling it to exert a multitude of different established neuroprotective effects
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in the context of TBI, a series of preclinical studies have suggested that pre-traumatic and post-traumatic curcumin supplementation may bolster the brain's resilience to injury and serve as a valuable therapeutic option
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Curcumin may confer significant neuroprotection because of its ability to act on multiple deleterious post-traumatic, molecular cascades
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studies demonstrated that both pre- and post-traumatic curcumin administration resulted in a significant reduction of neuroinflammation via inhibition of the pro-inflammatory molecules interleukin 1β and nuclear factor kappa B (NFκB)
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no human studies have been conducted with respect to the effects of curcumin administration on the treatment of TBI, subarachnoid or intracranial hemorrhage, epilepsy or stroke
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studies have demonstrated that resveratrol treatment reduces brain edema and lesion volume, as well as improves neurobehavioral functional performance following TBI
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green tea consumption or supplementation with its derivatives may bolster cognitive function acutely and may slow cognitive decline
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At least one population based study, though, did demonstrate that increased green tea consumption was associated with a reduced risk for Parkinson's disease independent of total caffeine intake
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a randomized, placebo-controlled trial demonstrated that administration of green tea extract and L-theanine, over 16 weeks of treatment, improved indices of memory and brain theta wave activity on electroencephalography, suggesting greater cognitive alertness
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Other animal studies have also demonstrated that theanine, another important component of green tea extract, exerts a multitude of neuroprotective benefits in experimental models of ischemic stroke,[63,97] Alzheimer's disease,[109] and Parkinson's disease
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Theanine, like EGCG, contains multiple mechanisms of neuroprotective action including protection from excitotoxic injury[97] and inhibition of inflammation
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More recent research has suggested that vitamin D supplementation and the prevention of vitamin D deficiency may serve valuable roles in the treatment of TBI and may represents an important and necessary neuroprotective adjuvant for post-TBI progesterone therapy
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Progesterone is one of the few agents to demonstrate significant reductions in mortality following TBI in human patients in preliminary trials
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in vitro and in vivo studies have suggested that vitamin D supplementation with progesterone administration may significantly enhance neuroprotection
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Vitamin D deficiency may increase inflammatory damage and behavioral impairment following experimental injury and attenuate the protective effects of post-traumatic progesterone treatment.[37]
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emerging evidence has suggested that daily intravenous administration of vitamin E following TBI significantly decreases mortality and improves patient outcomes
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high dose vitamin C administration following injury stabilized or reduced peri-lesional edema and infarction in the majority of patients receiving post-injury treatment
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it has been speculated that combined vitamin C and E therapy may potentiate CNS anti-oxidation and act synergistically with regards to neuroprotection
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one prospective human study has found that combined intake of vitamin C and E displays significant treatment interaction and reduces the risk of stroke
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Pycnogenol has demonstrated the ability to slow or reduce the pathological processes associated with Alzheimer's disease
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Pcynogenol administration, in a clinical study of elderly patients, led to improved cognition and reductions in markers of lipid peroxidase
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One other point of consideration is that in neurodegenerative disease states like Alzheimer's disease and Parkinson's disease, where there are high levels of reactive oxygen species generation, vitamin E can tend to become oxidized itself. For maximal effectiveness and to maintain its anti-oxidant capacity, vitamin E must be given in conjunction with other anti-oxidants like vitamin C or flavonoids
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These various factors might account for the null effects of alpha-tocopherol supplementation in patients with MCI and Alzheimer's disease
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preliminary results obtained in a pediatric population have suggested that post-traumatic oral creatine administration (0.4 g/kg) given within four hours of traumatic brain injury and then daily thereafter, may improve both acute and long-term outcomes
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Acutely, post-traumatic creatine administration seemed to reduce duration of post-traumatic amnesia, length of time spent in the intensive care unit, and duration of intubation
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At three and six months post-injury, subjects in the creatine treatment group demonstrated improvement on indices of self care, communication abilities, locomotion, sociability, personality or behavior and cognitive function when compared to untreated controls
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patients in the creatine-treatment group were less likely to experience headaches, dizziness and fatigue over six months of follow-up
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CNS creatine is derived from both its local biosynthesis from the essential amino acids methionine, glycine and arginine
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Studies of patients with CNS creatine deficiency and/or murine models with genetic ablation of creatine kinase have consistently demonstrated significant neurological impairment in the absence of proper creatine, phosphocreatine, or creatine kinase function; thus highlighting its functional importance
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chronic dosing may partially reverse neurological impairments in human CNS creatine deficiency syndromes
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Several studies have suggested that creatine supplementation may also reduce oxidative DNA damage and brain glutamate levels in Huntington disease patients
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Another study highlighted that creatine supplementation marginally improved indices of mood and reduced the need for increased dopaminergic therapy in patients with Parkinson's disease
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Time-level relationship for lipid peroxidation and the protective effect of alpha-tocop... - 0 views
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Functional Knee Support - 0 views
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Functional Braces Best for: Sports injuries after surgery functional knee braces knee rehabilitation program knee injuries or knee surgery free movement of the knee joint decrease knee pain improve knee stability
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Tynor Functional Knee Support Functional knee Support is an anterior opening device, which offers the advantage of controlled compression around the knee and a rigid lateral support and immobilization. It allows normal flexion and free movement of the knee joint. Anterio Open able Easy application Controlled compression. Perfect lateral splinting. Anatomical design. Tynor Functional Knee Support Features Bi axial heavy duty aluminum hinge Mimics the natural knee joint Ensures full weight bearing. Allows free flexion movement Four way stretchable fabric Controlled and comfortable compression No buckling No vaso constriction Enhanced comfort Open patella design Release patellar pressure Hold the patella in position Can be used for Patellofemoral diseases Wrap design with anterior closing Easy application and removal on swollen or asymmetric knees Easy application and removal for weak or geriatric patients. Allows customized compression Offers flexibility in sizing Ergonomic design Anti tourniquet effect - ensures no constriction to blood flow Better grip of the product to the body. Anatomic construction- Better functionality and Snug fit.
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Cortisol Exerts Bi-Phasic Regulation of Inflammation in Humans - 0 views
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GCs induce increased cellular expression of receptors for several pro-inflammatory cytokines including interleukin (IL)-1 (Spriggs et al. 1990), IL-2 (Wiegers et al. 1995), IL-4 (Paterson et al. 1994), IL-6 (Snyers et al. 1990), and IFN-g (Strickland et al. 1986), as well as GM-CSF
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GCs have also been shown to stimulate effector cell functions including phagocytosis by monocytes (van der Goes et al. 2000), effector cell proliferative responses (Spriggs et al. 1990), macrophage activation (Sorrells and Sapolsky 2010), and a delay of neutrophil apoptosis
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basal (diurnal) concentrations of cortisol do not exert an anti-inflammatory effect on several pro-and anti-inflammatory mediators of the human immune inflammatory response
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withdrawal of cortisol activity in vivo did not lead to increased inflammatory responsiveness of immune effector cells
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maximal suppression of inflammation was achieved by a stress-associated, but still physiologic, cortisol concentration. There was no greater anti-inflammatory effect at higher cortisol concentrations (Yeager et al. 2005) although IL-10 concentrations continued to increase with increasing cortisol concentrations as we and others have shown
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acutely, physiological cortisol concentrations are anti-inflammatory and, as proposed, act to limit over expression of an inflammatory response that could lead to tissue damage
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Acutely, cortisol has anti-inflammatory effects following a systemic inflammatory stimulus (Figure 4). However, a cortisol concentration that acts acutely to suppress systemic inflammation also has a delayed effect of augmenting the inflammatory response to subsequent, delayed stimulu
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1) GCs can exert pro-inflammatory effects on key inflammatory processes and, 2) GC regulation of inflammation can vary from anti- to a pro-inflammatory in a time-dependent manner
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The immediate in vivo effect of both stress-induced and pharmacological GC concentrations is to suppress concurrent inflammation and protect the organism from an excessive or prolonged inflammatory response
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GCs alone, in the absence of an inflammatory stimulus, up-regulate monocyte mRNA and/or receptors for several molecules that participate in pro-inflammatory signaling, as noted above and in the studies presented here.
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In humans, as shown here, if in vivo GC concentrations are elevated concurrent with an inflammatory stimulus, anti-inflammatory effects are observed
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In sharp contrast, with a time delay of 12 or more hours between an increased GC concentration and the onset of an inflammatory stimulus, enhancing effects on inflammation are observed. These effects have been shown to persist in humans for up to 6 days
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GC-induced enhancement of inflammatory responses is maximal at an intermediate concentration, in our studies at a concentration that approximates that observed in vivo following a major systemic inflammatory stimulus
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In addition to enhanced responses to LPS, recently identified pro-inflammatory effects of GCs also show enhanced localization of effector cells at inflammatory sites
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we hypothesize that pre-exposure to stress-associated cortisol concentrations “prime” effector cells of the monocyte/macrophage lineage for an augmented pro-inflammatory response by; a) inducing preparative changes in key regulators of LPS signal transduction, and b) enhancing localization of inflammatory effector cells at potential sites of injury
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Induction of metastasis, cancer stem cell phenotype, and oncogenic metabolism in cancer... - 0 views
www.ncbi.nlm.nih.gov/...PMC5282724
EMT TME metastasis cancer stem cells cancer MMP2 Notch MMP-9 MMP-2 radioresistance Hedgehog CSC MMP9 Snail HIF-1alpha tumor microenvironment epithelial to mesenchymal transition TGF-beta radiation
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Nuclear DNA is the primary target of IR; it causes DNA damage (genotoxic stress) by direct DNA ionization
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EMT, stemness, and oncogenic metabolism are known to be associated with resistance to radiotherapy and chemotherapy
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Hanahan and Weinberg proposed ten hallmarks of cancer that alter cell physiology to enhance malignant growth: 1) sustained proliferation, 2) evasion of growth suppression, 3) cell death resistance, 4) replicative immortality, 5) evasion of immune destruction, 6) tumour-promoting inflammation, 7) activation of invasion and metastasis, 8) induction of angiogenesis, 9) genome instability, and 10) alteration of metabolism
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EMT is a developmental process that plays critical roles in embryogenesis, wound healing, and organ fibrosis
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transforming growth factor-β [TGF-β], epidermal growth factor [EGF]) and their associated signalling proteins (Wnt, Notch, Hedgehog, nuclear-factor kappa B [NF-κB], extracellular signal-regulated kinase [ERK], and phosphatidylinositol 3-kinase [PI3K]/Akt
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activate EMT-inducing transcription factors, including Snail/Slug, ZEB1/δEF1, ZEB2/SIP1, Twist1/2, and E12/E47
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IR has been shown to induce EMT to enhance the motility and invasiveness of several cancer cells, including those of breast, lung, and liver cancer, and glioma cells
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IR may increase metastasis in both the primary tumour site and in normal tissues under some circumstance
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sublethal doses of IR have been shown to enhance the migratory and invasive behaviours of glioma cells
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High levels of ROS trigger cell death by causing irreversible damage to cellular components such as proteins, nucleic acids, and lipids, whereas low levels of ROS have been shown to promote tumour progression—including tumour growth, invasion, and metastasis
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Treatment with the N-acetylcysteine (NAC), a general ROS scavenger, prevents IR-induced EMT, adhesive affinity, and invasion of breast cancer cells
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IR activates the p38 MAPK pathway, which contributes to the induction of Snail expression to promote EMT and invasion
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HIF-1 is a heterodimer composed of an oxygen-sensitive α subunit and a constitutively expressed β subunit.
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Under normoxia, HIF-1α is rapidly degraded, whereas hypoxia induces stabilisation and accumulation of HIF-1α
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levels of HIF-1α mRNA are enhanced by activation of the PI3K/Akt/mammalian target of rapamycin (mTOR)
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IR is known to increase stabilisation and nuclear accumulation of HIF-1α, since hypoxia is a major condition for HIF-1 activation
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IR causes the reoxygenation of hypoxic cancer cells to increase ROS production, which leads to the stabilisation and nuclear accumulation of HIF-1
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IR increases glucose availability under reoxygenated conditions that promote HIF-1α translation by activating the Akt/mTOR pathway
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The stabilised HIF-1α then translocates to the nucleus, dimerizes with HIF-1β, and increases gene expression— including the expression of essential EMT regulators such as Snail—to induce EMT, migration, and invasion
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PAI-1 signalling is also implicated in IR-induced Akt activation that increases Snail levels to induce EMT
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EGFR activation is known to be associated with IR-induced EMT, cell migration, and invasion by activating two downstream pathways: PI3K/Akt and Raf/MEK/ERK
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IR has been shown to induce Akt activation through several signalling pathways (EGFR, C-X-C chemokine receptor type 4 [CXCR4]/C-X-C motif chemokine 12 [CXCL12], plasminogen activator inhibitor 1 [PAI-1]) and upstream regulators (Bmi1, PTEN) that promote EMT and invasion
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CSCs possess a capacity for self-renewal, and they can persistently proliferate to initiate tumours upon serial transplantation, thus enabling them to maintain the whole tumour
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Conventional cancer treatments kill most cancer cells, but CSCs survive due to their resistance to therapy, eventually leading to tumour relapse and metastasis
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identification of CSCs, three types of markers are utilised: cell surface molecules, transcription factors, and signalling pathway molecules
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CSCs express distinct and specific surface markers; commonly used ones are CD24, CD34, CD38, CD44, CD90, CD133, and ALDH
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signalling pathways, including those of TGF-β, Wnt, Hedgehog, Notch, platelet-derived growth factor receptor (PDGFR), and JAK/STAT
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EMT-inducing transcription factors, such as Snail, ZEB1, and Twist1, are known to confer CSC properties
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Signalling pathways involved in EMT, including those of TGF-β, Wnt, and Notch, have been shown to play important roles in inducing the CSC phenotype
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TGF-β1 not only increases EMT markers (Slug, Twist1, β-catenin, N-cadherin), but also upregulates CSC markers (Oct4, Sox2, Nanog, Klf4) in breast and lung cancer cells
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IR has been shown to induce the CSC phenotype in many cancers, including breast, lung, and prostate cancers, as well as melanoma
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Genotoxic stress due to IR or chemotherapy promotes a CSC-like phenotype by increasing ROS production
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In prostate cancer patients, radiotherapy increases the CD44+ cell population that exhibit CSC properties
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IR also induces the re-expression of stem cell regulators, such as Sox2, Oct4, Nanog, and Klf4, to promote stemness in cancer cells
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EMT-inducing transcription factors and signalling pathways, including Snail, STAT3, Notch signalling, the PI3K/Akt pathway, and the MAPK cascade, have been shown to play important roles in IR-induced CSC properties
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STAT3 directly binds to the Snail promoter and increases Snail transcription, which induces the EMT and CSC phenotypes, in cisplatin-selected resistant cells
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Other oncogenic metabolic pathways, including glutamine metabolism, the pentose phosphate pathway (PPP), and synthesis of fatty acids and cholesterol, are also enhanced in many cancers
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cancer cells depend on mitochondrial metabolism and increase mitochondrial production of ROS that cause pseudo-hypoxia
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CAFs have defective mitochondria that lead to the cells exhibiting the Warburg effect; the cells take up glucose, and then secrete lactate to 'feed' adjacent cancer cells
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Epithelial cancer cells express MCT1, while CAFs express MCT4. MCT4-positive, hypoxic CAFs secrete lactate by aerobic glycolysis, and MCT1-expressing epithelial cancer cells then uptake and use that lactate as a substrate for the tricarboxylic acid (TCA) cycle
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MCT4-positive cancer cells depend on glycolysis and then efflux lactate, while MCT1-positive cells uptake lactate and rely on OXPHOS
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metabolic heterogeneity induces a lactate shuttle between hypoxic/glycolytic cells and oxidative/aerobic tumour cells
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bulk tumour cells exhibit a glycolytic phenotype, with increased conversion of glucose to lactate (and enhanced lactate efflux through MCT4), CSC subsets depend on oxidative phosphorylation; most of the glucose entering the cells is converted to pyruvate to fuel the TCA cycle and the electron transport chain (ETC), thereby increasing mitochondrial ROS production
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the major fraction of glucose is directed into the pentose phosphate pathway, to produce redox power through the generation of NADPH and ROS scavengers
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regulatory molecules involved in EMT and CSCs, including Snail, Dlx-2, HIF-1, STAT3, TGF-β, Wnt, and Akt, are implicated in the metabolic reprogramming of cancer cells
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HIF-1 induces the expression of glycolytic enzymes, including the glucose transporter GLUT, hexokinase, lactate dehydrogenase (LDH), and MCT, resulting in the glycolytic switch
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HIF-1 represses the expression of pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), thereby inhibiting mitochondrial activity
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pyruvate kinase M2 (PKM2), LDH, and pyruvate carboxylase (PC), are implicated in the induction of the EMT and CSC phenotypes
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IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
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IR enhances glycolysis by upregulating GAPDH (a glycolysis enzyme), and it increases lactate production by activating LDHA, which converts pyruvate to lactate
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IR also elevates MCT1 expression that exports lactate into the extracellular environment, leading to acidification of the tumour microenvironment
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IR increases intracellular glucose, glucose 6-phosphate, fructose, and products of pyruvate (lactate and alanine), suggesting a role for IR in the upregulation of cytosolic aerobic glycolysis
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lactate stimulates cell migration and enhances secretion of hyaluronan from CAF that promote tumour metastasis
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promote tumour survival, growth, invasion, and metastasis; enhance the stiffness of the ECM; contribute to angiogenesis; and induce inflammation by releasing several growth factors and cytokines (TGF-β, VEGF, hepatocyte growth factor [HGF], PDGF, and stromal cell-derived factor 1 [SDF1]), as well as MMP
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tumours recruit the host tissue’s blood vessel network to perform four mechanisms: angiogenesis (formation of new vessels), vasculogenesis (de novo formation of blood vessels from endothelial precursor cells), co-option, and modification of existing vessels within tissues.
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immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
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immunosuppressive cells such as tumour-associated macrophages (TAM), MDSCs, and regulatory T cells, and the immunosuppressive cytokines, TGF-β and interleukin-10 (IL-10)
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The third phase, tumour escape, is mediated by antigen loss, immunosuppressive cells (TAM, MDSCs, and regulatory T cells), and immunosuppressive cytokines (TGF-β and IL-10).
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IR can elicit various changes in the TME, such as CAF activity-mediated ECM remodelling and fibrosis, cycling hypoxia, and an inflammatory response
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IR activates CAFs to promote the release of growth factors and ECM modulators, including TGF-β and MMP
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TGF-β directly influences tumour cells and CAFs, promotes tumour immune escape, and activates HIF-1 signalling
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MMPs degrade ECM that facilitates angiogenesis, tumour cell invasion, and metastasis
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IR promotes ROS production in cancer cells, which may induce the activation of oncogenes and the inactivation of tumour suppressors, which further promote oncogenic metabolism
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Although IR activates an antitumour immune response, this signalling is frequently suppressed by tumour escape mechanisms
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Glutathione as a Biomarker in Parkinson's Disease: Associations with Aging and Disease ... - 0 views
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Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis - 1 views
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Padayatty and colleagues showed that high-level ascorbic acid plasma concentrations could only be achieved by intravenous administration
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No patient in the low or high dose ascorbic acid treatment arms of this study suffered any identifiable adverse event
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a pharmacologic ascorbic acid treatment strategy in critically ill patients with severe sepsis appears to be safe
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Ascorbic acid depletion in sepsis results from ascorbic acid consumption by the reduction of plasma free iron, ascorbic acid consumption by the scavenging of aqueous free radicals (peroxyl radicals), and by the destruction of the oxidized form of ascorbic acid dehydroascorbic acid
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Sepsis further inhibits intracellular reduction of dehydroascorbic acid, producing acute intracellular ascorbic acid depletion
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Ascorbic acid treated patients in this study exhibited rapid and sustained increases in plasma ascorbic acid levels using an intermittent every six hours administration protocol
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Septic ascorbic acid-deficient neutrophils fail to undergo normal apoptosis. Rather, they undergo necrosis thereby releasing hydrolytic enzymes in tissue beds, thus contributing to organ injury
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Repletion of ascorbic acid in this way allows for normal apoptosis, thus, preventing the release of organ damaging hydrolytic enzymes.
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Study finds IV vitamin C in patients with sepsis is very safe and blunts the effects (endothelial damage, end organ damage...) of sepsis. Of note, the IV vitamin C group reached serum levels of ascorbic acid of 1,592 to 5,722 micromol/L. The IV groups maintained elevated serum C levels for up to 96 hours post infusion.
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Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer ... - 0 views
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daily doses up to 400 mg of HCQ or 250 mg CQ for several years are considered to carry an acceptable risk for CQ-induced retinopathies, with the exception of individuals of short stature
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chronic CQ or HCQ therapy be monitored through regular ophthalmic examinations (3–6 month intervals), full blood counts and blood glucose level checks
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long-term HCQ exposure, skeletal muscle function and tendon reflexes should be monitored for weakness
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both CQ and HCQ, specific caution is advised in patients suffering from impaired hepatic function (especially when associated with cirrhosis), porphyria, renal disease, epilepsy, psoriasis, glucose-6-phosphate dehydrogenase deficiency and known hypersensitivity to 4-aminoquinoline compounds
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CQ can prevent the entrapment of protonated chemotherapeutic drugs by buffering the extracellular tumour environment and intracellular acidic spaces
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the expression levels of TLR9 are higher in hepatocellular carcinoma, oesophageal, lung, breast, gastric and prostate cancer cells as compared with adjacent noncancerous cells, and high expression is often linked with poor prognosis
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TLR9-mediated activation of the NF-κB signalling pathway and the associated enhanced expression of matrix metalloproteinase-2 (MMP-2), MMP-7 and cyclo-oxygenase 2 mRNA
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HCQ can activate caspase-3 and modulate the Bcl-2/Bax ratio inducing apoptosis in CLL, B-cell CLL and glioblastoma cells
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In triple-negative breast cancer, CQ was shown to eliminate cancer stem cells through reduction of the expression of Janus-activated kinase 2 and DNA methyl transferase 1 [106] or through induction of mitochondrial dysfunction, subsequently causing oxidative DNA damage and impaired repair of double-stranded DNA breaks
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Therapies used in combination with CQ or HCQ include chemotherapeutic drugs, tyrosine kinase inhibitors, various monoclonal antibodies, hormone therapies and radiotherapy
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Most studies hypothesise that CQ and HCQ could increase the efficacy of other anti-cancer drugs by blocking pro-survival autophagy.
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daily doses between 400 and 1200 mg for HCQ are safe and well tolerated, but two studies identified 600-mg HCQ daily as the MTD