BNP and NT-proBNP associated with HF and worsening HF. Also, in the same setting, elevated BNP and NT-proBNP is found to be associated with increased cardiovascular events and mortality.
HSP70 did not
activate NK cells directly. Instead, HSP70 induced the expression
of an NKG2D ligand MICA on DCs, which then activated NK cells in
an NKG2D-dependent manner.
DCs are the most powerful professional
antigen presenting cells (APCs) that are instrumental in processing
antigens and orchestrating antigen-specific adaptive immunity and
tolerance
NK cells and DCs can functionally interact with each other both in
vitro and in vivo
autologous HSP70 could stimulate significant IFN-γ production
The magnitude
of the IFN-γ response was different from patient to patient and correlated
with the number of functional NK cells
In addition, 10 out of 14 patients had significantly
increased IFN-γ producing cells in the peripheral blood after HSP70 vaccinations,
which is again in line with increased NK cell activity as reported
in our original study in these patients
Hyperthermia differs fundamentally from fever in that it elevates the core body temperature without changing the physiological set point
hyperthermia is induced by increasing the heat load and/or inactivating heat dissipation
mor cells [2]. Although significant cell killing could be achieved by heating cells or tissues to temperatures > 42°C for 1 or more hours, the application, measurement and consistency of this temperature range within the setting of cancer clinical trials
mild temperature hyperthermia (ie, within the fever-range, 39–41°C)
they are key regulators of cellular protein activity, turnover and trafficking
Hsps ensure appropriate post-translational protein folding, and are able to refold denatured proteins, or mark irreversibly damaged proteins for destruction
the ability of fever-range hyperthermia to induce reactive immunity against tumor antigens through DCs and NK-cells is likely mediated by Hsps
thermotolerance
Hsps support the malignant phenotype of cancer cells by not only affecting the cells’ survival, but also participating in angiogenesis, invasion, metastasis and immortalization mechanisms
Hsps released from stressed or dying cells activate dendritic cells (DCs), transforming them into mature APCs
In theory, fever-range hyperthermia may take advantage of tumor cell Hsps by inducing their release from tumor cells and augmenting DC priming against tumor antigens
In several models of hyperthermia, heat-treated tumors exhibited improved DC priming and generation of systemic immunity to tumor cell
hyperthermia alone can enhance antigen display by tumor cells, thus rendering them even more susceptible to programmed immune clearance
Fever-range hyperthermia may also induce Hsps
Hsps may exert an adjuvant effect by bolstering MHC class II and co-stimulatory molecule expression by DCs
thermal ablation of liver tumors in particular has demonstrated an ability to potentiate immune responses [57, 58] and elicit robust T-cell infiltrates at ablation sites
specific Hsp, Hsp70, directly inhibits apoptosis pathways in cancer cells, as demonstrated in human pancreatic, prostate and gastric cancer cells
Cross-priming is the ability of extracellular Hsps complexed to tumor peptides to be internalized and presented in the context of MHC class I molecules on APCs, thus allowing potent priming of CTLs against tumor antigens
It has been reported that Hsps are generated from necrotic tumor cell lysates, but not from tumor cells undergoing apoptosis
tumor cells exposed to hyperthermia in the heat shock range (42°C for 4h) prior to lysing, DC activation and cross-priming were significantly enhanced with the application of heat
Due to the ability of Hsps to activate DCs directly by chaperoning tumor antigens upon their release [28], it is possible that both local and regional immune stimulation can be achieved with hyperthermia.
support the use of hyperthermia as an inducer of Hsps to serve as ‘danger signals’, activating antitumor immune responses
whole-body hyperthermia not only augments immune responses, but also stimulates the migration of skin-derived DCs to draining lymph nodes
Hyperthermia increased NK cell activation, proliferation, and infiltration, which equals increased cytotoxicity.
exposure to fever-range hyperthermia resulted in improved endogenous NK-cell cytotoxicity to several cancer types
improved activation and function of DCs and NK cells following hyperthermia
Hyperthermia increases the expression ICAM-1 a key adhesion molecule,
The combined effects of hyperthermia on lymphoid tissue endothelium and lymphocytes can promote immune surveillance and increase the probability of naive lymphocytes leaving the circulation and encountering their cognate antigen displayed by DCs in lymphoid organs.
In independent clinical studies, whole-body hyperthermia resulted in a transient decrease in circulating lymphocytes in patients with advanced cancer [12, 94, 99, 100], a finding which mirrored observations in animal models in which lymphocyte entry into lymph noeds was increased following hyperthermia treatment [93]. Enhanced recruitment of lymphocytes to lymphoid tissues may be exploited in the treatment of malignancies.
The initial tumor antigen presentation and initiation of clonal expansion of CTLs transpires in the lymph nodes and cannot take place outside this specialized compartment
the ability of DCs present in the lymph nodes to stimulate an anti-tumor immune response is critical
hyperthermia has been shown to improve immune surveillance by T-cell
The gut microbial composition is altered during pregnancy
probiotic supplements may contribute to the maintenance of bacterial diversity and glucose homeostasis in individuals with metabolic disturbances
Assessment of four randomized controlled trials in this review involving 288 pregnant women with GDM found that a 6–8 week probiotic intervention did not improve FBG or LDL-cholesterol levels
probiotic supplementation in women with GDM was associated with significant reductions in insulin resistance
One proposed method is by the production of short chain fatty acids (SCFAs), generated as a by-product of bacterial fermentation of dietary fibers. SCFAs act as an energy source for intestinal cells and have been found to regulate the production of hormones effecting energy intake and expenditure such as leptin and grehlin
Another hypothesized mechanism of SCFA action includes reducing gastrointestinal permeability by upregulating transcription of tight junction proteins, enhancing production of Glucagon-like peptide-2 (GLP-2) which promotes crypt cell proliferation, and reducing inflammation in colonic epithelial cells by increasing PPAR-gamma activation
Maintenance of the integrity of the gut barrier minimizes the concentration of lipopolysaccharide (LPS) in circulation
LPS is a structural component of gram negative bacterial cell walls, which induces an immune-cell response upon absorption into the human bloodstream, stimulating proinflammatory cytokine production and the onset of insulin resistance and hyperglycemia
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The levels of LH in the ibuprofen group had increased by 23% after 14 d of administration
This increase was even more pronounced at 44 d, at 33%
We found an 18% decrease (P = 0.056) in the ibuprofen group compared with the placebo group after 14 d (Fig. 1A) and a 23% decrease (P = 0.02) after 44 d (Fig. 1C). Taken together, these in vivo data suggest that ibuprofen induced a state of compensated hypogonadism during the trial,
which occurred as early as 14 d and was maintained until the end of the trial at 44 d
We first investigated testosterone production after 24 and 48 h of ibuprofen
exposure to assess its effects on Leydig cell steroidogenesis. Inhibition of testosterone levels was significant and dose-dependent
(β = −0.405, P = 0.01 at 24 h and β = −0.664, P < 0.0001 at 48 h) (Fig. 2A) and was augmented over time
The AMH data show that the hypogonadism affected not only Leydig cells but also Sertoli cells and also occurred as early
as 14 d of administration
Sertoli cell activity showed that AMH levels decreased significantly with ibuprofen
administration, by 9% (P = 0.02) after 14 d (Fig. 1B) and by 7% (P = 0.05) after 44 d compared with the placebo group
Examination of the effect of ibuprofen exposure on both the ∆4 and ∆5 steroid pathways (Fig. 2B) showed that it generally inhibited all steroids from pregnenolone down to testosterone and 17β-estradiol; the production
of each steroid measured decreased at doses of 10−5–10−4 M. Under control conditions, production of androstenediol and dehydroepiandrosterone (DHEA) was below the limit of detection
except in one experiment with DHEA
Measuring the mRNA expression of genes involved in steroidogenesis in vitro showed that ibuprofen had a profound inhibitory
effect on the expression of these genes (Fig. 3 B–D), consistent with that seen above in our ex vivo organ model. Taken together, these data examining effects on the endocrine
cells confirm that ibuprofen-induced changes in the transcriptional machinery were the likely reason for the inhibition of
steroidogenesis.
Suppression of gene expression concerned the initial conversion of cholesterol to the final testosterone synthesis. Hence,
expression of genes involved in cholesterol transport to the Leydig cell mitochondria was impaired
A previous study reported
androsterone levels decreased by 63% among men receiving 400 mg of ibuprofen every 6 h for 4 wk
We next examined the gene expression involved in testicular steroidogenesis ex vivo and found that levels of expression of
every gene that we studied except CYP19A1 decreased after exposure for 48 h compared with controls
the changes in gene expression indicate that the transcriptional machinery behind the endocrine action
of Leydig cells was most likely impaired by ibuprofen exposure.
Together, these data show that ibuprofen also directly impairs Sertoli cell function ex vivo by inhibiting transcription
ibuprofen use in men led to (i) elevation of LH; (ii) a decreased testosterone/LH ratio and, to a lesser degree, a decreased inhibin B/FSH ratio; and (iii) a reduction in the levels of the Sertoli cell hormone AMH
The decrease in the free testosterone/LH ratio resulted primarily
from the increased LH levels, revealing that testicular responsiveness to gonadotropins likely declined during the ibuprofen
exposure. Our data from the ex vivo experiments support this notion, indicating that the observed elevation in LH resulted
from ibuprofen’s direct antiandrogenic action
AMH levels were consistently suppressed by ibuprofen both in vivo and ex vivo, indicating that this hormone is uncoupled from
gonadotropins in adult men. The ibuprofen suppression of AMH further demonstrated that the analgesic targeted not only the
Leydig cells but also the Sertoli cells, a feature encountered not only in the human adult testis but also in the fetal testis
a chemical compound, through its effects on the signaling
compounds, can result in changes in the testis at gene level, resulting in perturbations at higher physiological levels in
the adult human
The analgesics acetaminophen/paracetamol and ibuprofen have previously been shown to inhibit the postexercise
response in muscles by repressing transcription
Previous ex vivo studies on adult testis have indeed pointed to an antiandrogenicity, only on Leydig cells, of phthalates
(41), aspirin, indomethacin (42), and bisphenol A (BPA) and its analogs
ibuprofen’s effects were not restricted to Leydig and Sertoli cells, as data showed that the expression of genes
in peritubular cells was also affected
short-term
exposure
In the clinical setting, compromised Leydig cell function resulting in increased insensitivity to LH is defined as compensated
hypogonadism (4), an entity associated with all-cause mortality
compensated hypogonadic men present with an increased likelihood of reproductive, cognitive, and physical symptoms
an inverse relationship was recently reported between endurance exercise training and male sexual libido
AMH concentrations are lower in seminal plasma from patients with azoospermia than
from men with normal sperm levels
inhibin B is a key clinical marker of reproductive health (32). The function of AMH, also secreted by Sertoli cells, and its regulation through FSH remain unclear in men
the striking dual effect of ibuprofen observed here on both Leydig and Sertoli cells makes this NSAID the chemical
compound, of all the chemical classes considered, with the broadest endocrine-disturbing properties identified so far in men.
after administration of 600 mg of ibuprofen to healthy
volunteers
PNC-27 selectively kills colon cancer stem cells by binding to membrane H/MDM-2. This was an in vivo study. As with other studies, the result was tumor cell necrosis and associated high LDH release.
PNC-27 binds to HDM-2 which is highly expressed on ovarian cancer cancer cell lines. The result is transmembrane pore formation and apoptosis independent cell necrosis.
Awesome review article on TA-1 and its broad immunomodulatory effects, i.e. increase IL-1, IFN-gamma, increase dendritic cell activity, inhibition of tumor growth…
TA-1 induces apoptosis through PTEN mediated PI3k/Akt/mTOR pathway inhibition. Sorry, only abstract available here. Significant in that TA-1 works beyond just immune stimulation.
Not an article, but a drug review of the medication Zadaxin, which is a commercial synthetic form of TA-1; Thymosin alpha 1 improved immunological parameters increased tumor response rates, and improved survival and quality of life