Okara is a major agro-waste, generated as a byproduct from the soymilk and tofu industry. Since okara has a high nutritive value, reusing it as a substrate for solid state biofermentation is an ...economical and environmental friendly option. Rhizopus oligosporus and Lactobacillus plantarum were the probiotic FDA-approved food-grade cultures used in this study. The study revealed that biofermenting okara improves its nutritional composition. It was found that the metabolomic composition (by GC-MS analysis) and antioxidant activity (by DPPH test) improved after the microbial fermentations. Of the two, okara fermented with R. oligosporus showed better results. Further, the metabolites were traced back to their respective biosynthesis pathways, in order to understand the biochemical reactions being triggered during the fermentation processes. The findings of this entire work open up the possibility of employing fermented okara as a potential functional food for animal feed.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
Extracts were extricated from raw okara and okara fermented with Rhizopus oligosporus using a clean, green protocol; water was used as the extraction solvent and coupled with ultrasound assistance ...for enhanced extraction. In vitro anti-oxidant analyses for antioxidant potential and capacity, superoxide scavenging activity, and nitric oxide scavenging activity validated that fermented okara yielded superior bioactive performance compared to raw okara. Fermented okara extracts showed no toxicity to erythrocytes and successfully prevented induced haemolysis. After 48 h incubation at the highest tested concentration (100 mg/mL), fermented okara extracts could inhibit HepG2 cells by 48.47 ± 5.28%, which was significantly different from their effects on NIH 3T3 cells. Gas chromatography–mass spectrometry characterization of extracts validated amino acids to be the chief fraction responsible for the detected bioactivity of the fermented okara extract. The results derived in this study open up the possibility that biofermented okara extract may be a potential novel sustainable nutraceutical.
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The rates of primary laparoscopic adjustable gastric banding (LAGB) have declined in the last 5 years due to band removal secondary to complications and the subsequent weight regain that requires ...revisional procedures.
This study aimed to present medium-term weight loss results and the safety profile of converting LAGB to Roux-en-Y gastric bypass in patients with body mass index (BMI) <35.0 kg/m
who presented with LAGB intolerance or complications. Many health services do not permit such procedures on low BMI patients.
Single-surgeon series, including public and private practice, Brisbane, Australia.
A prospectively maintained database was reviewed and retrospectively analyzed for LAGB patients with a BMI <35.0 kg/m
who underwent conversion to Roux-en-Y gastric bypass by a single surgeon. Indications for conversion, weight loss data, and early (30 d postoperative) and late complications were recorded with follow-up out to 5 years.
One hundred thirty-two adult patients with a BMI <35.0 kg/m
underwent conversion from 2009 to 2016. The main indications for conversion were reflux and band complications. Median BMI at bypass was 32.8 kg/m
(23.1-35.0). Median percentage excess weight loss was 77%, 90%, 73%, 47%, 49%, and 44% at 1, 2, 3, 4, and 5 years, respectively among patients who were eligible and present at follow-up. Median BMI was <30.0 kg/m
(29.1-40.9) at 5 years with only 1 subject exceeding >35.0 kg/m
. Mortality was 0%. Early morbidity occurred in 31.8% of patients. The most common late complication was gastrojejunostomy stricture requiring endoscopic dilation.
In combination with our 2014 study showing morbidity data in the short-term period being comparable to patients with BMI >35.0 kg/m
, our study demonstrates that converting LABG to Roux-en-Y gastric bypass in low BMI patients is a feasible and safe option that avoids weight regain and maintains adequate weight loss at 5 years, with acceptable morbidity and no mortality.
Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) that stimulate oncogenic signaling in TEC. In this study, we ...evaluated the cross-talk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mut p53-induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGFβ signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, nonproliferative state. TEC exposed to media conditioned by drug-treated CAFs exhibited a decrease in oncogenic signaling, as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGFβ. Given promising early clinical studies with Minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma cross-talk may offer a viable strategy to treat pancreatic cancer.
In an established mouse model of pancreatic cancer, administration of the promising experimental drug Minnelide was found to actively deplete reactive stromal fibroblasts and to trigger tumor regression, with implications for stromal-based strategies to attack this disease.
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Pancreatic ductal adenocarcinoma (PDAC) is considered to be a highly immunosuppressive and heterogenous neoplasm. Despite improved knowledge regarding the genetic background of the tumor and better ...understanding of the tumor microenvironment, immune checkpoint inhibitor therapy (targeting CTLA4, PD1, PDL1) has not been very successful against PDAC. The robust desmoplastic stroma, along with an extensive extracellular matrix (ECM) that is rich in hyaluronan, plays an integral role in this immune evasion. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on the one hand and influence the hyaluronan synthesis in the ECM on the other. The rate-limiting enzyme of the pathway, glutamine-fructose amidotransferase 1 (GFAT1), uses glutamine and fructose 6-phosphate to eventually synthesize uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). In the current manuscript, we targeted this glutamine-utilizing enzyme by a small molecule glutamine analog (6-diazo-5-oxo-l-norleucine DON). Our results showed that DON decreased the self-renewal potential and metastatic ability of tumor cells. Further, treatment with DON decreased hyaluronan and collagen in the tumor microenvironment, leading to an extensive remodeling of the ECM and an increased infiltration of CD8+ T cells. Additionally, treatment with DON sensitized pancreatic tumors to anti-PD1 therapy, resulting in tumor regression and prolonged survival.
Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) signaling have been shown to be dysregulated in multiple cancer types. Glucose regulatory protein 78 (GRP78), the master ...regulator of the UPR, plays a role in proliferation, invasion, and metastasis in cancer. Cancer stem cells (CSCs) make up a crucial component of the tumor heterogeneity in pancreatic cancer, as well as other cancers. "Stemness" in pancreatic cancer defines a population of cells within the tumor that have increased therapeutic resistance as well as survival advantage. In the current study, we investigated how GRP78 was responsible for maintaining "stemness" in pancreatic cancer thereby contributing to its aggressive biology. We determined that GRP78 downregulation decreased clonogenicity and self-renewal properties in pancreatic cancer cell lines in vitro. In vivo studies resulted in delayed tumor initiation frequency, as well as smaller tumor volume in the shGRP78 groups. Additionally, downregulation of GRP78 resulted in dysregulated fatty acid metabolism in pancreatic tumors as well as the cells. Further, our results showed that shGRP78 dysregulates multiple transcriptomic and proteomic pathways that involve DNA damage, oxidative stress, and cell death, that were reversed upon treatment with a ROS inhibitor, N-acetylcysteine. This study thus demonstrates for the first time that the heightened UPR in pancreatic cancer may be responsible for maintenance of the "stemness" properties in these cells that are attributed to aggressive properties like chemoresistance and metastasis.
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with an immunosuppressive microenvironment that is resistant to most therapies. IL17 is involved in pancreatic tumorigenesis, but ...its role in invasive PDAC is undetermined. We hypothesized that IL17 triggers and sustains PDAC immunosuppression. We inhibited IL17/IL17RA signaling using pharmacological and genetic strategies alongside mass cytometry and multiplex immunofluorescence techniques. We uncovered that IL17 recruits neutrophils, triggers neutrophil extracellular traps (NETs), and excludes cytotoxic CD8 T cells from tumors. Additionally, IL17 blockade increases immune checkpoint blockade (PD-1, CTLA4) sensitivity. Inhibition of neutrophils or Padi4-dependent NETosis phenocopies IL17 neutralization. NMR spectroscopy revealed changes in tumor lactate as a potential early biomarker for IL17/PD-1 combination efficacy. Higher expression of IL17 and PADI4 in human PDAC corresponds with poorer prognosis, and the serum of patients with PDAC has higher potential for NETosis. Clinical studies with IL17 and checkpoint blockade represent a novel combinatorial therapy with potential efficacy for this lethal disease.
The extracellular matrix (ECM) has remained an enigmatic component of the tumor microenvironment. It drives metastasis via its interaction with the integrin signaling pathway, contributes to tumor ...progression and confers therapy resistance by providing a physical barrier around the tumor. The complexity of the ECM lies in its heterogeneous composition and complex glycosylation that can provide a support matrix as well as trigger oncogenic signaling pathways by interacting with the tumor cells. In this review, we attempt to dissect the role of the ECM in enriching for the treatment refractory cancer stem cell population and how it may be involved in regulating their metabolic needs. Additionally, we discuss how the ECM is instrumental in remodeling the tumor immune microenvironment and the potential ways to target this component in order to develop a viable therapy.
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Tumor-initiating cells (TIC) have been implicated in pancreatic tumor initiation, progression, and metastasis. Among different markers that define this cell population within the tumor, the CD133
...cancer stem cell (CSC) population has reliably been described in these processes. CD133 expression has also been shown to functionally promote metastasis through NF-κB activation in this population, but the mechanism is unclear. In the current study, overexpression of CD133 increased expression and secretion of IL1β (IL1B), which activates an autocrine signaling loop that upregulates NF-κB signaling, epithelial-mesenchymal transition (EMT), and cellular invasion. This signaling pathway also induces CXCR4 expression, which in turn is instrumental in imparting an invasive phenotype to these cells. In addition to the autocrine signaling of the CD133 secreted IL1β, the tumor-associated macrophages (TAM) also produced IL1β, which further activated this pathway in TICs. The functional significance of the TIC marker CD133 has remained elusive for a very long time; the current study takes us one step closer to understanding how the downstream signaling pathways in these cells regulate the functional properties of TICs.
This study demonstrates the important role of tumor- and macrophage-derived IL1β stimulation in pancreatic cancer. IL1 signaling is increased in cells with CD133 expression, leading to increased NF-kB activity, EMT induction, and invasion. Increased invasiveness via IL1β stimulation is mediated by the upregulation of CXCR4 expression. The study highlights the importance of IL1-mediated signaling in TICs.
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