Increased glucose availability sensitizes pancreatic cancer to chemotherapy.

Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose.

Targeting wild-type IDH1 enhances chemosensitivity in pancreatic cancer.

Pancreatic cancer (PC) is one of the most aggressive types of cancer, with a five-year overall survival rate of 11% among all-comers. Current systemic therapeutic options are limited to cytotoxic chemotherapies which have limited clinical efficacy and are often associated with development of drug resistance. Analysis of The Cancer Genome Atlas showed that wild-type isocitrate dehydrogenase (wtIDH1) is overexpressed in pancreatic tumors. In this study, we focus on the potential roles of wtIDH1 in pancreatic cancer chemoresistance. We found that treatment of pancreatic cancer cells with chemotherapy induced expression of wtIDH1, and this serves as a key resistance factor. The enzyme is protective to cancer cells under chemotherapy-induced oxidative stress by producing NADPH and alpha-ketoglutarate to maintain redox balance and mitochondrial function. An FDA-approved mutant IDH1 inhibitor, ivosidenib (AG-120), is actually a potent wtDH1 inhibitor under a nutrient-deprived microenvironment, reflective of the pancreatic cancer microenvironment. Suppression of wtIDH1 impairs redox balance, results in increased ROS levels, and enhances chemotherapy induced apoptosis in pancreatic cancer vis ROS damage in vitro. In vivo experiments further revealed that inhibiting wtIDH1 enhances chemotherapy anti-tumor effects in patient-derived xenografts and murine models of pancreatic cancer. Pharmacologic wtIDH1 inhibition with ivosidenib represents an attractive option for combination therapies with cytotoxic chemotherapy for patients with pancreatic cancer. Based on these data, we have initiated phase Ib trial combining ivosidenib and multi-agent chemotherapy in patients with pancreatic cancer (NCT05209074).

Lactobacillus fermentum MCC2760 abrogate high-fat induced perturbations in the enterohepatic circulation of bile acids in rats.

AIM: This study in hyperlipidemic rats elucidated the effect of Lactobacillus fermentum MCC2760 on intestinal bile acid (BA) uptake, hepatic BA synthesis, and enterohepatic BA transporters. MAIN METHODS: Diets rich in saturated fatty acids [coconut oil (CO)] and omega-6 fatty acids [sunflower oil (SFO)] at 25 g fat/100 g diet were fed to rats with or without MCC2760 (109 cells/kg body weight). After 60 days of feeding, intestinal BA uptake and expression of Asbt, Osta/b mRNA and protein, and hepatic expression of Ntcp, Bsep, Cyp7a1, Fxr, Shp, Lrh-1, and Hnf4a mRNA were measured. Hepatic expression of HMG-CoA reductase protein and its activity and total BAs in serum, liver, and feces were assessed. KEY FINDINGS: Hyperlipidaemic groups (HF-CO and HF-SFO) had: 1) increased intestinal BA uptake, Asbt and Osta/b mRNA expression, and ASBT staining 2) increased BA in serum, 3) decreased hepatic expression of Ntcp, Bsep, and Cyp7a1 mRNA, and NTCP staining 4) increased activity of HMG-CoA reductase, 5) increased hepatic expression of Fxr and Shp mRNA, 6) decreased hepatic expression of Lrh-1 and Hnf4a mRNA, and 7) decreased BA in Feces when compared to their respective controls (N-CO and N-SFO) and experimental groups (HF-CO + LF and HF-SFO + LF). Immunostaining revealed increased intestinal Asbt and hepatic Ntcp protein expression in the HF-CO and HF-SFO groups compared to control and experimental groups. SIGNIFICANCE: Incorporating probiotics like MCC2760 abrogated hyperlipidemia-induced changes in the intestinal uptake, hepatic synthesis, and enterohepatic transporters of BA in rats. Probiotic MCC2760 can be used to modulate lipid metabolism in high-fat-induced hyperlipidemic conditions.

IDO1 Is a Therapeutic Target for Pancreatic Cancer-Associated Depression.

Metabolites of tryptophan degradation are known to alter mood. Their effects have only been superficially examined in the context of pancreatic cancer. Herein, we study the role of indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme important in the conversion of tryptophan to kynurenine, in a murine model of pancreatic cancer-associated depression. Behavioral tests (open field, forced swim, tail suspension, and elevated plus maze) and biochemical assays (LC-MS metabolomics) were used to characterize a depressive-phenotype in tumor-bearing mice (relative to non-tumor-bearing mice). In addition, we determine whether pharmacologic blockade of IDO1 affects mood in tumor-bearing mice. Immunocompetent mice bearing orthotopic pancreatic tumors exhibit depressive-like behavior relative to non-tumor-bearing mice. Pancreatic tumors strongly express IDO1. Consequently, serum kynurenine levels in tumor-bearing mice are elevated relative to non-tumor-bearing mice. Tumor-bearing mice treated with epacadostat, an IDO1 inhibitor, exhibited improved mood relative to mice receiving vehicle. There was a 95% reduction in serum kynurenine levels in mice receiving epacadostat relative to mice treated with vehicle. As confirmatory evidence of on-target activity, tumors of mice treated with epacadostat exhibited a compensatory increase in IDO1 protein levels. Escitalopram, an approved antidepressant, was ineffective at improving mood in tumor-bearing mice as measured by behavioral assays and did not affect kynurenine levels. Neither epacadostat, nor escitalopram, affected overall survival relative to vehicle. Mice with pancreatic cancer exhibit depressive-like behavior. Epacadostat was effective as an antidepressant for pancreatic cancer-associated depression in mice. These data offer a rationale to consider IDO1 inhibition as a therapeutic strategy to mitigate depressive symptoms in patients with pancreatic cancer.

Wild-type IDH1 inhibition enhances chemotherapy response in melanoma.

BACKGROUND: Alternative treatment strategies in melanoma beyond immunotherapy and mutation-targeted therapy are urgently needed. Wild-type isocitrate dehydrogenase 1 (wtIDH1) has recently been implicated as a metabolic dependency in cancer. The enzyme protects cancer cells under metabolic stress, including nutrient limited conditions in the tumor microenvironment. Specifically, IDH1 generates NADPH to maintain redox homeostasis and produces α-ketoglutarate to support mitochondrial function through anaplerosis. Herein, the role of wtIDH1 in melanoma is further explored. METHODS: The expression of wtIDH1 was determined by qRT-PCR, and Western blot in melanoma cell lines and the effect of wtIDH1 on metabolic reprogramming in melanoma was interrogated by LC-MS. The impact of wtIDH1 inhibition alone and in combination with chemotherapy was determined in cell culture and mouse melanoma models. RESULTS: Melanoma patients express higher levels of the wtIDH1 enzyme compared to normal skin tissue, and elevated wtIDH1 expression portends poor patient survival. Knockdown of IDH1 by RNA interference inhibited cell proliferation and migration under low nutrient levels. Suppression of IDH1 expression in melanoma also decreased NADPH and glutathione levels, resulting in increased reactive oxygen species. An FDA-approved inhibitor of mutant IDH1, ivosidenib (AG-120), exhibited potent anti-wtIDH1 properties under low magnesium and nutrient levels, reflective of the tumor microenvironment in natura. Thus, similar findings were replicated in murine models of melanoma. In light of the impact of wtIDH1 inhibition on oxidative stress, enzyme blockade was synergistic with conventional anti-melanoma chemotherapy in pre-clinical models. CONCLUSIONS: These results demonstrate the clinical potential of wtIDH1 inhibition as a novel and readily available combination treatment strategy for patients with advanced and refractory melanoma. Schematic shows increased wild-type IDH1 expression and activity as an adaptive response to metabolic stress induced by chemotherapy.

Studies on the partial characterization of extracted glycosaminoglycans from fish waste and its potentiality in modulating obesity through in-vitro and in-vivo.

Glycosaminoglycans (GAGs) are bioactive polysaccharides or glycoconjugates found in the fish waste having significant health impacts. In the present study it has been attempted to extract GAGs from mackerel fish waste through chemical and enzymatic methods. Further, the extracted GAGs (e-GAGs) were analyzed for their composition (uronic acid, total sugar & sulfate), chemical characterization was carried out through techniques of scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR) & Proton NMR. Further, probable major GAGs present was identified by enzymatic digestion. The biological potential of the extracted glycoconjugate was assessed further through in-vitro and in-vivo studies. In-vitro biological activity showed good lipase inhibition (IC50, 2.6 mg/mL) and bile acid binding properties (dose-dependent). Lipid accumulation lowered in the e-GAGs differentiated 3T3L1 preadipocyte cells have also been observed. The high fat fed animal (in-vivo) study showed ameliorative effect via reducing blood sugar∼1.28↓, lipid profile↓, plasma insulin∼3.5↓, improved glucose tolerance, and homeostatic model assessment for insulin resistance (HOMA-IR, ∼3.0↓). Furthermore, elimination of bile acid (BA) due to GAG-BA binding properties resultant in removal of elevated fecal triglyceride and cholesterol suggesting its lipid lowering activity. Regulation of various proteins linked to carbohydrate and lipid metabolism including fatty acid synthase (FAS), low density lipoproteins receptor (LDL-R), 7α-hydroxylase, glucose transporter-4 (GLUT4) and Peroxisome proliferator- activated receptor gamma (PPAR-γ) were significant (p < 0.05) with e-GAGs treatment when compared to HFD group. Thus, the e-GAGs showed potential hypolipidemic activity through elimination of bile acid binding property together with regulating the specific protein related to obesity and its associated complications.

Modulation of obesity associated metabolic dysfunction by novel lipophilic fraction obtained from Agaricus bisporus.

AIM: The present study aimed to prepare a novel lipophilic fraction rich in fat soluble bioactive from Agaricus bisporus and investigated its impact through in vitro and in vivo assessments since the prospective biological activities of fat soluble components from mushrooms are limited. METHODS: Ergosterol concentrate fraction (ECF) preparation followed by subsequent characterization of the extract using various analytical techniques (HPLC-UV, Mass spectroscopy, NMR). Furthermore, the fraction has been evaluated for antioxidant activity, DNA protection ability, hypolipidemic properties by in vitro specific enzyme inhibition and in vivo animal model (C57BL/6). KEY FINDINGS: The fraction majorly contains ergosterol (504 mg/100 g dw) and linoleic acid (71.92 %). In vitro studies showed that the fraction limited free radicals induced DNA damage, exhibited significant free radical scavenging activities (IC50 of DPPH 15.64; ABTS 8.28 mg/ml), and inhibited HMG-CoA reductase activity (IC50 5.03 mg/ml). Further, in vivo study showed that ECF treatment significantly (p < 0.05) improved insulin sensitivity (reduced plasma glucose & insulin, increased adiponectin) and reduced inflammatory markers (CRP & TNF-α) in comparison to high fat fed mice. Furthermore, ECF has significantly reduced plasma lipid profile and accumulation of lipids in liver. This could be due to down regulation of mRNA expression of lipogenic transcription factors such as SREBP-1c and SREBP-2, and key lipogenic enzyme ACC. Moreover, ECF treatment has suppressed protein expression of FAS, induced cholesterol clearance by enhancing LDL-R protein expression. SIGNIFICANCE: The present work for the first time evaluated the synergistic potential of ergosterol and linoleic acid to improve antioxidant defense system and ameliorate obesity associated metabolic dysfunction.

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

Prodromal depression and anxiety are associated with worse treatment compliance and survival among patients with pancreatic cancer.

OBJECTIVE: To determine the frequency of depression or anxiety preceding a diagnosis of pancreatic cancer (PC). Further, to examine the association of PC-associated depression or anxiety with treatment compliance and survival. METHODS: 856 patients with PC from a single institution were identified using International Classification of Diseases (ICD) codes. For each case, two non-cancer age- and sex-matched controls were included. Dates of depression or anxiety diagnosis identified using ICD codes were compared to the date of PC diagnosis. The medical record was queried to further explore psychiatric symptoms. Multivariable analyses were performed to examine if prediagnosis depression or anxiety was associated with receipt of treatment or survival. RESULTS: A greater proportion of patients with PC experienced depression or anxiety in the year preceding diagnosis than the overall frequency in controls (4.6% vs. 2.6%, p = 0.005) based on ICD codes. Patients with PC exhibited signs of prodromal depression or anxiety based on ICD codes, clinical documentation of psychiatric symptoms, or initiation of new psychiatric medications more often than controls (20.7% vs. 6.7%, p < 0.001). Prediagnosis depression or anxiety was associated with a reduced likelihood of receiving chemotherapy (OR = 0.58, p = 0.04). There was an associated decrease in overall survival among patients with metastatic disease who experienced depression or anxiety before PC diagnosis (HR = 1.32, p = 0.04). CONCLUSIONS: The frequency of depression or anxiety among patients with PC was higher than the general population. Prediagnosis psychiatric symptoms were associated with reduced chemotherapy utilization and worse overall survival. Thus, timely identification and treatment of these symptoms may improve outcomes.

Clinical development of IDH1 inhibitors for cancer therapy.

Isocitrate dehydrogenase 1 (IDH1) has been investigated as a promising therapeutic target in select cancers with a mutated version of the enzyme (mtIDH1). With only one phase III trial published to date and two indications approved for routine clinical use by the FDA, we reviewed the entire clinical trial portfolio to broadly understand mtIDH1 inhibitor activity in patients. We queried PubMed.gov and ClinicalTrials.gov to identify published and ongoing clinical trials related to IDH1 and cancer. Progression-free survival (PFS), overall survival (OS), 2-hydroxyglutarate levels, and adverse events were summarized. To date, ten clinical trials investigating mtIDH1 inhibitors among patients with diverse malignancies (cholangiocarcinoma, acute myeloid leukemia, chondrosarcoma, glioma) have been published. Almost every trial (80%) has investigated ivosidenib. In multiple phase I trials, ivosidenib treatment resulted in promising radiographic and biochemical responses with improved survival outcomes (relative to historic data) among patients with both solid and hematologic mtIDH1 malignancies. Among patients enrolled in a phase III trial with advanced cholangiocarcinoma, ivosidenib resulted in a PFS rate of 32% at 6 months, as compared to 0% with placebo. There was a 5.2 month increase in OS with ivosidenib relative to placebo, after considering crossover. The treatment-specific grade ≥3 adverse event rate of ivosidenib was 2%-26% among all patients, and was just 3.6% among 284 patients who had a solid tumor across four trials. Although <1% of malignancies harbor IDH1 mutations, small molecule mtIDH1 inhibitors, namely ivosidenib, appear to be biologically active and well tolerated in patients with solid and hematologic mtIDH1 malignancies.

Liver Endothelium Microenvironment Promotes HER3-mediated Cell Growth in Pancreatic Ductal Adenocarcinoma.

~90% metastatic pancreatic ductal adenocarcinoma (mPDAC) occurs in the liver, and the 5-year survival rate for patients with mPDAC is only at 3%. The liver has a unique endothelial cell (EC)-rich microenvironment, and preclinical studies showed that ECs promote cancer cell survival pathways by secreting soluble factors in a paracrine fashion in other types of cancer. However, the effects of liver ECs on mPDAC have not been elucidated. In this study, we used primary liver ECs and determined that liver EC-secreted factors containing conditioned medium (CM) increased PDAC cell growth, compared to control CM from PDAC cells. Using an unbiased receptor tyrosine kinase array, we identified human epidermal growth factor receptor 3 (HER3, also known as ErbB3) as a key mediator of liver EC-induced growth in PDAC cells with HER3 expression (HER3 +ve). We found that EC-secreted neuregulins activated the HER3-AKT signaling axis, and that depleting neuregulins from EC CM or blocking HER3 with an antibody, seribantumab, attenuated EC-induced functions in HER3 +ve PDAC cells, but not in cells without HER3 expression. Furthermore, we determined that EC CM increased PDAC xenograft growth in vivo, and that seribantumab blocked EC-induced growth in xenografts with HER3 expression. These findings elucidated a paracrine role of liver ECs in promoting PDAC cell growth, and identified the HER3-AKT axis as a key mediator in EC-induced functions in HER3 +ve PDAC cells. As over 70% mPDAC express HER3, this study highlights the potential of using HER3-targeted therapies for treating patients with HER3 +ve mPDAC.

Dietary n-3 but not n-6 fatty acids modulate anthropometry and fertility indices in high-fat diet fed rats: a two-generation study.

The present study assessed the modulatory potentials of dietary n-3 [α-linolenic acid (ALA, 18:3n-3, eicosapentaenoic acid (EPA, 20:5n-3 + docosahexaenoic acid (DHA) 22:6n-3), and n-6 fatty acid (LA, 18:2n-6)] on anthropometric parameters and fertility indices in high-fat-fed rats. Weanling female Wistar rats were fed with control diet (7% lard), high-fat diet (35% lard, HFL), high-fat with fish oil (21% fish oil + 14% lard, HFF), high-fat with canola oil (21% canola oil + 14% lard, HFC) and high-fat with sunflower oil (21% sunflower oil + 14% lard, HFS) for 2 months, mated and continued on their diets during pregnancy. At gestation day 18-20, the intra-uterine environment was examined in representative rats, and the rest were allowed for delivering pups. The pups after lactation were subjected to mating and feeding trials as above. Growth parameters (body weight, body length (BL), abdominal circumference (AC), thoracic circumference (TC), and Lee index and fertility parameters (litter size and sex ratio) were studied. Feeding HFL diet increased BL (16%), AC (33%) and TC (21%) compared to control (p < 0.05). Adipose tissue accumulation was 11% higher in the HFL group compared to control and was lowered with n-3 fatty acid incorporation in the diet. HFL group exhibited a lower percentage of fertility, pregnancy, and delivery indices. Litter size was decreased by 20%, and litter weight was increased by 23% in HFL group compared to control with more male pups. Our study indicated that n-3 to a larger extent than n-6 fatty acids modulated high-fat induced changes in the anthropometric parameters and fertility indices.

Role of n-3 Fatty Acids on Bile Acid Metabolism and Transport in Dyslipidemia: A Review.

Dietary n-3 fatty acids, especially of marine origin, eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3), have always been lauded for their profound effects on regulating the risk factors for major metabolic disorders. Yet, their consumption rate is poor compared to n-6 fatty acids [linoleic acid (18:2n-6)], which are predominantly consumed. Hence, the skewed n-6 to n-3 fatty acid ratio may have a bearing on the risk factors of various diseases, including dyslipidemia. Dyslipidemia and other lifestyle diseases associated with it, such as diabetes, obesity, hypertension, are a growing concern in both developed and developing countries. A common strategy for addressing dyslipidemia involves bile acid (BA) sequestration, to interrupt the enterohepatic circulation of BA, resulting in the modulation of lipid absorption in the intestine, thereby normalizing the levels of circulating lipids. The BA homeostasis is under the tight control of hepatic and enteric BA transporters. Many investigations have reported the effects of dietary constituents, including certain fatty acids on the reabsorption and transport of BA. However, a critical review of the effects of n-3 fatty acids on BA metabolism and transport is not available. The present review attempts to explore certain unmapped facets of the n-3 fatty acids on BA metabolism and transport in dyslipidemia, and their interplay with biological processes involving lipid rafts and gut microbiome.

Nuclear Receptor 4A2 (NR4A2/NURR1) Regulates Autophagy and Chemoresistance in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis and chemotherapy with gemcitabine has limited effects and is associated with development of drug resistance. Treatment of Panc1 and MiaPaca2 pancreatic cancer cells with gemcitabine induced expression of the orphan nuclear receptor 4A2 (NURR1) and analysis of the cancer genome atlas indicated the NURR1 is overexpressed in pancreatic tumors and is a negative prognostic factor for patient survival. Results of NURR1 knockdown or treatment with the NURR1 antagonist 1,1-bis(3΄-indolyl)-1-(p-chlorophenyl)methane (C-DIM 12) demonstrated that NURR1 was pro-oncogenic in pancreatic cancer cells and regulated cancer cell and tumor growth and survival. NURR1 is induced by gemcitabine and serves as a key drug-resistance factor and is also required for gemcitabine-induced cytoprotective autophagy. NURR1 regulated genes were determined by RNA sequencing of mRNAs expressed in MiaPaCa2 cells expressing NURR1 and in CRISPR/Cas9 gene edited cells for NURR1 knockdown and KEGG enrichment analysis of the differentially expressed genes showed that autophagy was the major pathway regulated by NURR1. Moreover, NURR1 regulated expression of two major autophagic genes ATG7 and ATG12 which are also overexpressed in pancreatic tumors and like NURR1 are negative prognostic factors for patient survival. Thus, gemcitabine-induced cytoprotective autophagy is due to the NURR1 - ATG7/ATG12 axis and this can be targeted and disrupted by NURR1 antagonist C-DIM12 demonstrating the potential clinical applications for combination therapies with gemcitabine and NURR1 antagonists.

Ginger and turmeric lipid-solubles attenuate heated oil-induced cardio-hepatic oxidative stress via the up-regulation of nuclear factor erythroid 2-related factor 2 and decrease blood pressure in rats.

Deep-fried vegetable oils are reused multiple times to save costs, and their chronic consumption may cause organ dysfunction. In this study, we assessed the modulatory effects of lipid-solubles from ginger and turmeric that may migrate to oils during heating, on the cardio-hepatic antioxidant defence response and blood pressure in rats. Male Wistar rats were fed with: (1) control (native rapeseed (N-CNO) or native sunflower (N-SFO)) oil, (2) heated (heated rapeseed (H-CNO) or heated sunflower (H-SFO)) oil and (3) heated oil with ginger or turmeric (heated rapeseed oil with ginger (H-CNO + GI) or heated rapeseed oil with turmeric (H-CNO + TU), heated sunflower oil with ginger (H-SFO + GI) or heated sunflower oil with turmeric (H-SFO + TU)) for 120 d. Oxidative stress (OS) markers, antioxidant enzymes, nitric oxide synthase-2 (NOS-2), intercellular adhesion molecule-1 (ICAM-1), nuclear factor erythroid 2-related factor 2 (NRF-2), markers of hepatic and cardiac function and blood pressure were assessed. Feeding heated oils (H-CNO or H-SFO) (1) increased OS markers, NOS-2 and ICAM-1 expression; (2) decreased antioxidant enzyme activity and NRF-2 level; (3) increased marker enzymes of hepatic and cardiac function and (4) increased systolic and diastolic blood pressure significantly (P < 0·05), when compared with respective native oils (N-CNO or N-SFO). However, feeding oils heated with ginger or turmeric positively countered the changes induced by heated oils. Consumption of repeatedly heated oil causes cardio-hepatic dysfunction by inducing OS through NRF-2 down-regulation. Lipid-solubles from ginger and turmeric that may migrate to oil during heating prevent the oxidative stress and blood pressure triggered by heated oils in rats.

Ginger and turmeric lipid-solubles attenuate heated oil-induced hepatic inflammation via the downregulation of NF-kB in rats.

PURPOSE: Reusing deep-fried vegetable oils multiple times is a common practice to save costs, and their chronic consumption may cause hepatic dysfunction. In this investigation, we assessed the modulatory effects of ginger and turmeric lipid-solubles that may migrate to oils during heating on the hepatic inflammatory response in rats. METHODS: Male Wistar rats were fed with; 1) control {native canola (N-CNO) or native sunflower (N-SFO)} oil, 2) heated (heated canola {(H-CNO) or heated sunflower (H-SFO)} oil, and 3) heated oil with ginger or turmeric {heated canola with ginger (H-CNO + GI) or heated canola oil with turmeric (H-CNO + TU), heated sunflower oil with ginger (H-SFO + GI) or heated sunflower oil with turmeric (H-SFO + TU)} for 120 days. Hepatic inflammatory response comprising eicosanoids, cytokines, and NF-kB were assessed. RESULTS: Compared to respective controls, feeding heated oils significantly (p < 0.05); 1) increased eicosanoids (PGE2, LTB4, and LTC4) and cytokines (TNF-α, MCP-1, IL-1ß, and IL-6), 2) increased nuclear translocation of NF-kB in the liver, and 3) increased the hepatic expression of 5-LOX, COX-2, BLT-1, and EP-4. However, feeding oils heated with ginger or turmeric positively countered the changes induced by consumption of heated oils. CONCLUSIONS: Consumption of repeatedly heated oil may cause hepatic dysfunction by inducing inflammatory stress through NF-kB upregulation. Lipid-solubles from ginger and turmeric that may migrate to oil during heating prevent the hepatic inflammatory response triggered by heated oils in rats.

Ginger and turmeric lipid-solubles attenuate heated oil-induced oxidative stress in the brain via the upregulation of NRF2 and improve cognitive function in rats.

In this study, we elucidated the modulatory potentials of lipid-solubles from ginger and turmeric that may migrate to oils during heating on the brain antioxidant defense and cognitive response in rats. Male Wistar rats were fed with control diet [including native canola oil (N-CNO), and native sunflower oil (N-SFO)], or experimental diets [including heated canola oil (H-CNO), heated sunflower oil (H-SFO), heated canola oil with ginger (H-CNO + GI), heated canola oil with turmeric (H-CNO + TU), heated sunflower oil with ginger (H-SFO + GI), heated sunflower oil with turmeric (H-SFO + TU)] for 90 days. Memory parameters [Morris water maze, elevated plus maze, novel object recognition test, T-maze (spontaneous alteration)], locomotor skills (open field test and rotarod test), antioxidant defense enzymes, reactive oxygen species, NOS2, ICAM-1, and NRF-2 level in the brain were assessed. Compared to their respective controls, heated oil-fed rats, but not those fed oils heated with ginger or turmeric, showed significant (p < 0.05) reduction in the memory, motor coordination skills, antioxidant defense enzymes, and NRF-2 activation in the brain. Compared to their respective controls, the brain NOS-2 and ICAM-1 were significantly (p < 0.05) increased in heated oil-fed rats, but not those fed oils heated with ginger or turmeric. Chronic intake of repeatedly heated oil causes brain dysfunction by inducing oxidative stress through NRF-2 downregulation. Lipid-solubles from ginger and turmeric that may migrate to oil during heating prevent the oxidative stress and cognitive dysfunction triggered by heated oils in rats.

Improving vascular imaging with co-planar mutually guided photoacoustic and diffuse optical tomography: a simulation study.

Diffuse optical tomography (DOT) and photoacoustic tomography (PAT) are functional imaging modalities that provide absorption coefficient maps of the tissue. Spatial resolution of DOT is relatively low due to light scattering characteristics of the tissue. On the other hand, although PAT can resolve regions of different absorptions with a high spatial resolution, measuring the absolute value of optical absorptions using PAT is challenging due to unknown light fluence distribution in the tissue. Development of image guidance techniques using a priori information of imaging target structure has been shown to increase the accuracy of DOT. PAT is one such method that can be used as a complementary modality to serve as a guide for DOT image reconstruction. On the other hand, estimated fluence map provided by DOT can be used to quantitatively correct PAT images. In this study we introduce a mutually-guided imaging system for fast and simultaneous optical and photoacoustic measurements of tissue absorption map, where DOT is guided by the PAT image and vice versa. Using the obtained absorption map of the tissue, we then estimate the tissue scattering map. We conducted this study using a series of simulations on digital phantoms and demonstrated the effectiveness of the proposed method.

Natural bioactive 4-Hydroxyisophthalic acid (4-HIPA) exhibited antiproliferative potential by upregulating apoptotic markers in in vitro and in vivo cancer models.

There is tremendous scope for identifying novel anti-cancer molecules from the unexplored reserves of plant kingdom. The application of dietary supplementation or medicine derived from such sources is a promising approach towards treatment of cancer. In the present study we have evaluated the antiproliferative potential of 4-hydroxyisophthalic acid (4-HIPA), which is a novel antioxidant compound isolated from the roots of the aqueous extract of Decalepis hamiltonii. 4-HIPA was screened in vitro against human breast cancer cell lines MCF-7, MDA-MB-468 and normal human breast epithelial cell MCF-10, and demonstrated that human breast cancer cell lines, in contrast to MCF-10, are sensitive to 4-HIPA .4-HIPA showed marked reduction in cell viability and short-term proliferation assays in these cells. Results of the long-term colony formation and scratch assay further reaffirmed that 4-HIPA inhibited the growth and proliferation in breast cancer cells. We further conducted in vivo studies using murine Ehrlich Ascites Tumor (EAT) cell model. Our in vivo results established that treatment with 4-HIPA reduced the tumorigenesis by promoting apoptosis in EAT-bearing mice. The results of our molecular docking predictions further warranted our claim. This study is valuable as 4-HIPA exhibits antiproliferative potential that can be exploited in the development of anticancer drugs.

Cysteinyl leukotriene receptor antagonism: a promising pharmacological strategy for lowering the severity of arthritis.

BACKGROUND AND AIMS: Though cyclooxygenase inhibitors are employed in rheumatoid arthritis treatment, modulators of leukotrienes are underexplored. We investigated the therapeutic potential of montelukast, a known cysteinyl leukotriene receptor-1 (CysLT1) inhibitor in an experimental rat model of arthritis. METHODS: Arthritis was induced in rats, and montelukast (5 mg/kg body wt.) was administered prophylactically (PAM) and therapeutically (TAM) through oral route. RESULTS AND DISCUSSION: Blood and joint tissue markers of oxidative stress (lipid peroxidation, protein carbonyls, and nitric oxides) were significantly (p < 0.05) reduced in montelukast administered rats. Paw inflammation, RA markers (RF and CRP), eicosanoids (PGE2, LTB4, and LTC4), cytokines (IL-1ß and MCP-1), activity of hydrolytic enzymes (collagenase, elastase, and hyaluronidase), expression of matrix metalloproteinases (MMP), and EP-4 receptor were significantly (p < 0.05) reduced in montelukast administered rats. This study established that leukotriene inhibition through montelukast lowered the severity of arthritis and thus a potential strategy for reducing the severity of arthritis.