Epithelial-mesenchymal transition-related signaling pathways in gastric Cancer cells distinctively respond to long-term experimental ketosis.

BACKGROUND: The interrelationship between cellular metabolism and the epithelial-to-mesenchymal transition (EMT) process has made it an interesting topic to investigate the adjuvant effect of therapeutic diets in the treatment of cancers. However, the findings are controversial. In this study, the effects of glucose limitation along and with the addition of beta-hydroxybutyrate (bHB) were examined on the expression of specific genes and proteins of EMT, Wnt, Hedgehog, and Hippo signaling pathways, and also on cellular behavior of gastric cancer stem-like (MKN-45) and non-stem-like (KATO III) cells. METHODS AND RESULTS: The expression levels of chosen genes and proteins studied in cancer cells gradually adopted a low-glucose condition of one-fourth, along and with the addition of bHB, and compared to the unconditioned control cells. The long-term switching of the metabolic fuels successfully altered the expression profiles and behaviors of both gastric cancer cells. However, the results for some changes were the opposite. Glucose limitation along and with the addition of bHB reduced the CD44+ population in MKN-45 cells. In KATO III cells, glucose restriction increased the CD44+ population. Glucose deprivation alleviated EMT-related signaling pathways in MKN-45 cells but stimulated EMT in KATO III cells. Interestingly, bHB enrichment reduced the beneficial effect of glucose starvation in MKN-45 cells, but also alleviated the adverse effects of glucose restriction in KATO III cells. CONCLUSIONS: The findings of this research clearly showed that some controversial results in clinical trials for ketogenic diet in cancer patients stemmed from the different signaling responses of various cells to the metabolic changes in a heterogeneous cancer mass.

Efficacy of triamcinolone acetonide-impregnated Gelfoam nasal pack in management of chronic sinusitis with nasal polyps following endoscopic sinus surgery: a perfectly matched, placebo-controlled trial study.

PURPOSE: This perfectly matched, double-blinded, placebo-controlled trial study was performed to investigate the efficacy of triamcinolone acetonide (TAA)-impregnated Gelfoam nasal pack in management of different endotypes of chronic rhinosinusitis with nasal polyps (CRSwNP) following endoscopic sinus surgery (ESS). METHODS: One hundred and four patients with bilateral CRSwNP undergoing ESS were selected and randomized to receive TAA-soaked nasal packing in one nostril and saline-impregnated dressing contra-laterally. Validated Perioperative Sinus Endoscopy (POSE) scoring system was used to assess the participants' condition at postoperative months 1, 3, 6, 12, and 18. RESULTS: The treatment side of eosinophilic CRSwNP (EosCRSwNP) group had significantly better endoscopic scores than the contralateral control side in all follow-up visits (P < 0.05 for all comparisons) except for the first postoperative month. No significant difference was detected between the TAA- and saline-treated nostrils in the non-eosinophilic CRSwNP (nonEosCRSwNP) subgroup during the follow-up period. Intergroup comparisons revealed a borderline better POSE score for the treatment side of the EosCRSwNP group compared with the treatment nostril of the nonEosCRSwNP group at months 12 (P = 0.041) and 18 (P = 0.044). At the end of the study period, the treatment side of the EosCRSwNP group demonstrated better clinical response than the saline-treated side in terms of the total POSE scores (P = 0.019), middle turbinate synechia (P = 0.008), middle meatal narrowing (P = 0.010), ethmoid polypoid changes (P = 0.039), ethmoid polyposis (P = 0.027), ethmoid cavity secretions (P = 0.042), and sphenoid severity (P = 0.018). CONCLUSION: TAA-soaked Gelfoam dressing following bilateral ESS was found to be an effective method for treating CRSwNP particularly for the eosinophilic endotype of the disease.

Starvation promotes histone lysine butyrylation in the liver of male but not female mice.

AIMS: Post-translational modifications (PTMs) of histones are regulated by the availability of their respective acyl-CoAs. Among these histone PTMs, the metabolic origin of histone butyrylation (Kbu) is still poorly understood. MATERIAL AND METHODS: The impact of starvation on the levels of Kbu was determined by western blotting on histones extracted from the liver of fed and fasted C57BL/6 mice and immunohistochemistry on liver paraffin sections. KEY FINDINGS: Using animal model we provide evidence that the stimulation of ketogenesis following starvation, in addition to histone beta-hydroxybutyrylation (Kbhb), also leads to an increase in histone butyrylation (Kbu). Using an immunohistochemistry (IHC) approach we report first that hepatocytes contained butyrylated histones with important cell-to-cell heterogeneity. More importantly, our investigations based on western blotting and IHC also proposed that the basal levels of Kbu differ between male and female mice, with female mouse hepatocytes containing higher levels of butyrylated histones. Starvation enhanced solely histone Kbu levels in the liver of males but not females. SIGNIFICANCE: This is the first demonstration of a sex-dependent large-scale stimulation of histone acylation. Our data also point to different basal metabolic conditions of the male and female liver cells with a sex-dependent impact on the hepatocytes' epigenome.

Histone Butyrylation/ Acetylation Remains Unchanged in Triple Negative Breast Cancer Cells after a Long Term Metabolic Reprogramming.

BACKGROUND: Altered metabolism is one of the hallmarks of the cancer cells which reciprocally interrelate with epigenetic processes, such as post-translational histone modifications to maintain their desired gene expression profiles. The role of beta-hydroxybutyrate as a ketone body in cancer cell biology and histone modifications are reported. The present study aimed to evaluate the impacts of long-term metabolic reprogramming via glucose restriction and beta-hydroxybutyrate treatment on histone acetylation and butyrylation in MDA-MB231 cells as a model of triple negative stem-like breast cancer. METHODS: For long-term treatment, cells were set up in three groups receiving DMEM with restricted glucose (250 mg/L), DMEM with restricted glucose but enriched with five millimolar beta-hydroxybutyrate and DMEM with standard glucose (1gL) and investigated for a month. Histone modifications, including H3 acetylation and butyrylation, were investigated by immunoblotting after an acid extraction of the histone proteins. RESULTS AND CONCLUSION: Neither beta-hydroxybutyrate enrichment nor glucose restriction elicited a significant effect on the butyrylation or acetylation level of histone H3 upon a long-term treatment. Metabolic plasticity of cancer cells, mainly stem-like triple negative breast cancer cells alleviate or neutralize the impact of long-term metabolic reprogramming via restriction of glucose and histone modifications enrichment. These results shed new light upon the mechanism of controversial efficacy of ketogenic diets in clinical trials.

A Systematic and Mechanistic Review on the Phytopharmacological Properties of Alhagi Species.

Alhagi species are well known in Iran (locally known as Khar Shotor) and other parts of Asia as a popular folk medicine. Recent research has shown extensive pharmacological effects of these species. This paper is a comprehensive review of the phytopharmacological effects and traditional uses of Alhagi species and their active constituents with special attention to the responsible mechanisms, effective dosages and routes of administration. The Alhagi species studied in this paper include: A. maurorum, A. camelorum, A. persarum, A. pseudoalhagi, and A. kirgisorum. In order to include all the up to date data, the authors went through several databases including the Web of Science, Embase, etc. The findings were critically reviewed and sorted on the basis of relevance to the topic. Tables have been used to clearly present the ideas and discrepancies were settled through discussion. Alhagi species have significant biomedical properties which can be exploited in clinical use. Proantocyanidin isolated from A. pseudoalhagi has significant biochemical effects on blood factors. Among Alhagi species, A. camelorum and A. maurorum possess the highest anti-microbial activity. Most of the effects observed with A. maurorum are dose-dependent. This paper indicates with emphasis that Alhagi species are safe and rich sources of biologically active compounds with low toxicity. Since DNA damage has been observed following the ingestion of specific concentrations of A. pseudalhagi, care should be taken during administration of the plant for therapeutic use. Further studies are required to confirm the safety and quality of these plants to be used by clinicians as therapeutic agents.