The Interaction of Botanicals and AMPK Signaling in the Inhibition of Castrate-Resistant Prostate Cancer

Reprogramming of metabolic pathways and abnormal acetylation of DNA are two common features of cancer, including prostate cancer (PCa)

Allometric scaling of dietary linoleic acid on changes in tissue arachidonic acid using human equivalent diets in mice

<p>Abstract</p> <p>Background</p> <p>It is hypothesized that dietary linoleic acid (LA) promotes chronic and acute diseases in humans by enriching tissues with arachidonic acid (AA), its downstream metabolite, and dietary studies with rodents have been useful for validation. However, levels of LA in research diets of rodents, as published in the literature, are notoriously erratic making interspecies comparisons unreliable. Therefore, the ability to extrapolate the biological effects of dietary LA from experimental rodents to humans necessitates an allometric scaling model that is rooted within a human equivalent context.</p> <p>Methods</p> <p>To determine the physiological response of dietary LA on tissue AA, a mathematical model for extrapolating nutrients based on energy was used, as opposed to differences in body weight. C57BL/6J mice were divided into 9 groups fed a background diet equivalent to that of the US diet (% energy) with supplemental doses of LA or AA. Changes in the phospholipid fatty acid compositions were monitored in plasma and erythrocytes and compared to data from humans supplemented with equivalent doses of LA or AA.</p> <p>Results</p> <p>Increasing dietary LA had little effect on tissue AA, while supplementing diets with AA significantly increased tissue AA levels, importantly recapitulating results from human trials.</p> <p>Conclusions</p> <p>Thus, interspecies comparisons for dietary LA between rodents and humans can be achieved when rodents are provided human equivalent doses based on differences in metabolic activity as defined by energy consumption.</p

Increasing dietary linoleic acid does not increase tissue arachidonic acid content in adults consuming Western-type diets: a systematic review

<p>Abstract</p> <p>Background</p> <p>Linoleic acid, with a DRI of 12-17 g/d, is the most highly consumed polyunsaturated fatty acid in the Western diet and is found in virtually all commonly consumed foods. The concern with dietary linoleic acid, being the metabolic precursor of arachidonic acid, is its consumption may enrich tissues with arachidonic acid and contribute to chronic and overproduction of bioactive eicosanoids. However, no systematic review of human trials regarding linoleic acid consumption and subsequent changes in tissue levels of arachidonic acid has been undertaken.</p> <p>Objective</p> <p>In this study, we reviewed the human literature that reported changes in dietary linoleic acid and its subsequent impact on changing tissue arachidonic acid in erythrocytes and plasma/serum phospholipids.</p> <p>Design</p> <p>We identified, reviewed, and evaluated all peer-reviewed published literature presenting data outlining changes in dietary linoleic acid in adult human clinical trials that reported changes in phospholipid fatty acid composition (specifically arachidonic acid) in plasma/serum and erythrocytes within the parameters of our inclusion/exclusion criteria.</p> <p>Results</p> <p>Decreasing dietary linoleic acid by up to 90% was not significantly correlated with changes in arachidonic acid levels in the phospholipid pool of plasma/serum (<it>p = 0.39</it>). Similarly, when dietary linoleic acid levels were increased up to six fold, no significant correlations with arachidonic acid levels were observed (<it>p = 0.72)</it>. However, there was a positive relationship between dietary gamma-linolenic acid and dietary arachidonic acid on changes in arachidonic levels in plasma/serum phospholipids.</p> <p>Conclusions</p> <p>Our results do not support the concept that modifying current intakes of dietary linoleic acid has an effect on changing levels of arachidonic acid in plasma/serum or erythrocytes in adults consuming Western-type diets.</p

Is [F-18]-fluorodeoxy-D-glucose positron emission tomography of value in the management of patients with craniofacial bone sarcomas undergoing neo-adjuvant treatment?

We evaluated the role of 18FDG PET/CT used to assess response to preoperative chemotherapy in patients with primary craniofacial bone sarcomas

Concurrent regulation of LKB1 and CaMKK2 in the activation of AMPK in castrate-resistant prostate cancer by a well-defined polyherbal mixture with anticancer properties

Abstract Background Zyflamend, a blend of herbal extracts, effectively inhibits tumor growth using preclinical models of castrate-resistant prostate cancer mediated in part by 5′-adenosine monophosphate-activated protein kinase (AMPK), a master energy sensor of the cell. Clinically, treatment with Zyflamend and/or metformin (activators of AMPK) had benefits in castrate-resistant prostate cancer patients who no longer responded to treatment. Two predominant upstream kinases are known to activate AMPK: liver kinase B1 (LKB1), a tumor suppressor, and calcium-calmodulin kinase kinase-2 (CaMKK2), a tumor promotor over-expressed in many cancers. The objective was to interrogate how Zyflamend activates AMPK by determining the roles of LKB1 and CaMKK2. Methods AMPK activation was determined in CWR22Rv1 cells treated with a variety of inhibitors of LKB1 and CaMKK2 in the presence and absence of Zyflamend, and in LKB1-null HeLa cells that constitutively express CaMKK2, following transfection with wild type LKB1 or catalytically-dead mutants. Upstream regulation by Zyflamend of LKB1 and CaMKK2 was investigated targeting protein kinase C-zeta (PKCζ) and death-associated protein kinase (DAPK), respectively. Results Zyflamend’s activation of AMPK appears to be LKB1 dependent, while simultaneously inhibiting CaMKK2 activity. Zyflamend failed to rescue the activation of AMPK in the presence of pharmacological and molecular inhibitors of LKB1, an effect not observed in the presence of inhibitors of CaMKK2. Using LKB1-null and catalytically-dead LKB1-transfected HeLa cells that constitutively express CaMKK2, ionomycin (activator of CaMKK2) increased phosphorylation of AMPK, but Zyflamend only had an effect in cells transfected with wild type LKB1. Zyflamend appears to inhibit CaMKK2 by DAPK-mediated phosphorylation of CaMKK2 at Ser511, an effect prevented by a DAPK inhibitor. Alternatively, Zyflamend mediates LKB1 activation via increased phosphorylation of PKCζ, where it induced translocation of PKCζ and LKB1 to their respective active compartments in HeLa cells following treatment. Altering the catalytic activity of LKB1 did not alter this translocation. Discussion Zyflamend’s activation of AMPK is mediated by LKB1, possibly via PKCζ, but independent of CaMKK2 by a mechanism that appears to involve DAPK. Conclusions Therefore, this is the first evidence that natural products simultaneously and antithetically regulate upstream kinases, known to be involved in cancer, via the activation of AMPK.https://deepblue.lib.umich.edu/bitstream/2027.42/144515/1/12906_2018_Article_2255.pd

Zyflamend, a polyherbal mixture, down regulates class I and class II histone deacetylases and increases p21 levels in castrate-resistant prostate cancer cells

Background Zyflamend, a mixture containing extracts of ten herbs, has shown promise in a variety of preclinical cancer models, including prostate cancer. The current experiments were designed to investigate the effects of Zyflamend on the expression of class I and II histone deacetylases, a family of enzymes known to be over expressed in a variety of cancers. Methods CWR22Rv1 cells, a castrate-resistant prostate cancer cell line, were treated with Zyflamend and the expression of class I and II histone deacetylases, along with their downstream target the tumor suppressor gene p21, was investigated. Involvement of p21 was confirmed with siRNA knockdown and over expression experiments. Results Zyflamend down-regulated the expression of all class I and II histone deacetylases where Chinese goldthread and baikal skullcap (two of its components) appear to be primarily responsible for these results. In addition, Zyflamend up regulated the histone acetyl transferase complex CBP/p300, potentially contributing to the increase in histone 3 acetylation. Expression of the tumor suppressor gene p21, a known downstream target of histone deacetylases and CBP/p300, was increased by Zyflamend treatment and the effect on p21 was, in part, mediated through Erk1/2. Knockdown of p21 with siRNA technology attenuated Zyflamend-induced growth inhibition. Over expression of p21 inhibited cell growth and concomitant treatment with Zyflamend enhanced this effect. Conclusions Our results suggest that the extracts of this polyherbal combination increase histone 3 acetylation, inhibit the expression of class I and class II histone deacetylases, increase the activation of CBP/p300 and inhibit cell proliferation, in part, by up regulating p21 expression

n3 and n6 polyunsaturated fatty acids differentially modulate prostaglandin E secretion but not markers of lipogenesis in adipocytes

A dramatic rise in the incidence of obesity in the U.S. has accelerated the search for interventions that may impact this epidemic. One recently recognized target for such intervention is adipose tissue, which secretes a variety of bioactive substances including prostaglandins. Prostaglandin E2 (PGE2) has been shown to decrease lipolysis in adipocytes, but limited studies have explored alternative mechanisms by which PGE2 might impact obesity, such as adipogenesis or lipogenesis. Studies conducted on ApcMin/+ mice indicated that selective inhibition of the cyclooxygenase (COX)-2 enzyme led to significant reductions in fatty acid synthase (FAS) activity in adipose tissue suggesting lipogenic effects of PGE2. To further investigate whether these lipid mediators directly regulate lipogenesis, we used 3T3-L1 adipocytes to determine the impact of eicosapentaenoic acid (EPA) and celecoxib on PGE2 formation and FAS used as a lipogenic marker. Both arachidonic acid (AA) and EPA dose-dependently increased PGE secretion from adipocytes. AA was expectedly more potent and exhibiting at 150 uM dose a 5-fold increase in PGE2 secretion over EPA. Despite higher secretion of PGE by EPA and AA compared to control, neither PUFA significantly altered FAS activity. By contrast both AA and EPA significantly decreased FAS mRNA levels. Addition of celecoxib, a selective COX-2 inhibitor, significantly decreased PGE2 secretion (p < 0.05) versus control, and also significantly decreased FAS activity (p < 0.05). Unexpectedly, the combination of exogenous PGE2 and celecoxib further decreased the FAS activity compared to PGE2 alone or untreated controls. In conclusion, EPA-mediated inhibition of AA metabolism did not significantly alter FAS activity while both AA and EPA significantly decreased FAS mRNA expression. COX-2 inhibition significantly decreased PGE2 production resulting in a decrease in FAS activity and expression that was not reversed with the addition of exogenous PGE2, suggesting an additional mechanism that is independent of COX-2

Head and neck sarcomas: A single institute series

BACKGROUND: Sarcomas are tumours of mesenchymal origin, accounting for 1% of all malignancies. METHODS: This is a retrospective analysis of 107 head and neck sarcoma cases, treated over a period of thirteen years. RESULTS: Fifty-four patients had with craniofacial bone sarcomas (BSs) (male: 33; female: 21) with high grade osteosarcoma being the most predominant type. The soft tissue sarcomas (STS) (53 patients; male: 28, female: 25) were histologically diverse with rhabdomyosarcomas and myxofibrosarcomas being the predominant types. The majority of BSs were managed with neoadjuvant chemotherapy followed by surgery, whereas in STSs treatment included predominantly surgery followed by radiotherapy. Overall survival estimates were 79% at 2years and 64% at 5years (mean follow-up period was 48months). CONCLUSIONS: The mesenchymal origin of sarcomas, the pattern of disease spread and the different extent of cancellous bone infiltration in contrast to epithelial tumours, dictate distinct principles for surgical clearance

Volume 42, Number 4, December 2022 OLAC Newsletter

Digitized December 2022 issue of the OLAC Newsletter

Volume 43, Number 3, September 2023 OLAC Newsletter

Digitized September 2023 issue of the OLAC Newsletter