MRI Extracellular Volume Fraction in Liver Fibrosis-A Comparison of Different Time Points and Blood Pool Measurements.

BACKGROUND: Extracellular volume (ECV) correlates with the degree of liver fibrosis. PURPOSE: To analyze the performance of liver MRI-based ECV evaluations with different blood pool measurements at different time points. STUDY TYPE: Prospective. SAMPLE: 73 consecutive patients (n = 31 females, mean age 56 years) with histopathology-proven liver fibrosis. FIELD STRENGTH/SEQUENCE: 3T acquisition within 90 days of biopsy, including shortened modified look-locker inversion recovery T1 mapping. ASSESSMENT: Polygonal regions of interest were manually drawn in the liver, aorta, vena cava, and in the main, left and right portal vein on four slices before and after Gd-DOTA administration at 5/10/15 minutes. ECV was calculated 1) on one single slice on portal bifurcation level, and 2) averaged over all four slices. STATISTICAL TESTS: Parameters were compared between patients with fibrosis grades F0-2 and F3-F4 with the Mann-Whitney U and fishers exact test. ROC analysis was used to assess the performance of the parameters to predict F3-4 fibrosis. A P-value <0.05 was considered statistically significant. RESULTS: ECV was significantly higher in F3-4 fibrosis (35.4% [33.1%-37.6%], 36.1% [34.2%-37.5%], and 37.0% [34.8%-39.2%] at 5/10/15 minutes) than in patients with F0-2 fibrosis (33.3% [30.8%-34.8%], 33.7% [31.6%-34.7%] and 34.9% [32.2%-36.0%]; AUC = 0.72-0.75). Blood pool T1 relaxation times in the aorta and vena cava were longer on the upper vs. lower slices at 5 minutes, but not at 10/15 minutes. AUC values were similar when measured on a single slice (AUC = 0.69-0.72) or based on blood pool measurements in the cava or portal vein (AUC = 0.63-0.67 and AUC = 0.65-0.70). DATA CONCLUSION: Liver ECV is significantly higher in F3-4 fibrosis compared to F0-2 fibrosis with blood pool measurements performed in the aorta, inferior vena cava, and portal vein at 5, 10, and 15 minutes. However, a smaller variability was observed for blood pool measurements between slices at 15 minutes. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3.

Anti-Inflammatory Effects of Bioactive Compounds from Seaweeds, Bryozoans, Jellyfish, Shellfish and Peanut Worms.

Inflammation is a defense mechanism of the body in response to harmful stimuli such as pathogens, damaged cells, toxic compounds or radiation. However, chronic inflammation plays an important role in the pathogenesis of a variety of diseases. Multiple anti-inflammatory drugs are currently available for the treatment of inflammation, but all exhibit less efficacy. This drives the search for new anti-inflammatory compounds focusing on natural resources. Marine organisms produce a broad spectrum of bioactive compounds with anti-inflammatory activities. Several are considered as lead compounds for development into drugs. Anti-inflammatory compounds have been extracted from algae, corals, seaweeds and other marine organisms. We previously reviewed anti-inflammatory compounds, as well as crude extracts isolated from echinoderms such as sea cucumbers, sea urchins and starfish. In the present review, we evaluate the anti-inflammatory effects of compounds from other marine organisms, including macroalgae (seaweeds), marine angiosperms (seagrasses), medusozoa (jellyfish), bryozoans (moss animals), mollusks (shellfish) and peanut worms. We also present a review of the molecular mechanisms of the anti-inflammatory activity of these compounds. Our objective in this review is to provide an overview of the current state of research on anti-inflammatory compounds from marine sources and the prospects for their translation into novel anti-inflammatory drugs.

Molecular Docking Identifies 1,8-Cineole (Eucalyptol) as A Novel PPARγ Agonist That Alleviates Colon Inflammation.

Inflammatory bowel disease, comprising Crohn's disease (CD) and ulcerative colitis (UC), is often debilitating. The disease etiology is multifactorial, involving genetic susceptibility, microbial dysregulation, abnormal immune activation, and environmental factors. Currently, available drug therapies are associated with adverse effects when used long-term. Therefore, the search for new drug candidates to treat IBD is imperative. The peroxisome proliferator-activated receptor-γ (PPARγ) is highly expressed in the colon. PPARγ plays a vital role in regulating colonic inflammation. 1,8-cineole, also known as eucalyptol, is a monoterpene oxide present in various aromatic plants which possess potent anti-inflammatory activity. Molecular docking and dynamics studies revealed that 1,8-cineole binds to PPARγ and if it were an agonist, that would explain the anti-inflammatory effects of 1,8-cineole. Therefore, we investigated the role of 1,8-cineole in colonic inflammation, using both in vivo and in vitro experimental approaches. Dextran sodium sulfate (DSS)-induced colitis was used as the in vivo model, and tumor necrosis factor-α (TNFα)-stimulated HT-29 cells as the in vitro model. 1,8-cineole treatment significantly decreased the inflammatory response in DSS-induced colitis mice. 1,8-cineole treatment also increased nuclear factor erythroid 2-related factor 2 (Nrf2) translocation into the nucleus to induce potent antioxidant effects. 1,8-cineole also increased colonic PPARγ protein expression. Similarly, 1,8-cineole decreased proinflammatory chemokine production and increased PPARγ protein expression in TNFα-stimulated HT-29 cells. 1,8-cineole also increased PPARγ promoter activity time-dependently. Because of its potent anti-inflammatory effects, 1,8-cineole may be valuable in treating IBD.

Study protocol for a pilot randomized, double-blind, placebo-controlled trial to investigate the anti-inflammatory effects of Frondanol in adults with inflammatory bowel disease.

Introduction: Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis, is a debilitating condition with a rising incidence globally over recent years. Frondanol, a widely available nutraceutical extract of the edible sea cucumber Cucumaria frondosa has been reported to possess potent anti-inflammatory effects, likely mediated by the inhibition of 5-lipoxygenase and 12-lipoxygenase pathways, whilst showing no signs of toxicity. The potent anti-inflammatory effects of Frondanol in a mouse model of IBD provide encouragement for investigating its effects in human IBD patients. Here we describe the study protocol of a pilot randomized, double-blinded, placebo-controlled trial of Frondanol in patients with mild to moderate IBD who are on standard therapy. Material and methods: One hundred patients will be randomized (1:1) to receive Frondanol or placebo as an adjunct to their standard therapy for the period of six months. Blood and stool samples will be obtained during routine visits at baseline, and after three months and six months of treatment, and tissue samples from colon biopsies will be obtained during clinically indicated colonoscopies at baseline and after six months of treatment. The levels of inflammatory markers will be compared in serum and tissue samples between patients treated with Frondanol and those treated with placebo, and findings will be correlated with clinical and histological parameters. Discussion: If proven beneficial, treatment with Frondanol may increase the likelihood of patients remaining in remission and potentially provide an effective, natural and safe addition/alternative for treatment-naive patients in the future.(Clinical trial registration number: NCT05194007).

ß-Myrcene Mitigates Colon Inflammation by Inhibiting MAP Kinase and NF-κB Signaling Pathways.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders that include Crohn's disease (CD) and ulcerative colitis (UC). The incidence of IBD is rising globally. However, the etiology of IBD is complex and governed by multiple factors. The current clinical treatment for IBD mainly includes steroids, biological agents and need-based surgery, based on the severity of the disease. Current drug therapy is often associated with adverse effects, which limits its use. Therefore, it necessitates the search for new drug candidates. In this pursuit, phytochemicals take the lead in the search for drug candidates to benefit from IBD treatment. ß-myrcene is a natural phytochemical compound present in various plant species which possesses potent anti-inflammatory activity. Here we investigated the role of ß-myrcene on colon inflammation to explore its molecular targets. We used 2% DSS colitis and TNF-α challenged HT-29 adenocarcinoma cells as in vivo and in vitro models. Our result indicated that the administration of ß-myrcene in dextran sodium sulfate (DSS)-treated mice restored colon length, decreased disease activity index (DAI), myeloperoxidase (MPO) enzyme activity and suppressed proinflammatory mediators. ß-myrcene administration suppressed mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) pathways to limit inflammation. ß-myrcene also suppressed mRNA expression of proinflammatory chemokines in tumor necrosis factor-α (TNF-α) challenged HT-29 adenocarcinoma cells. In conclusion, ß-myrcene administration suppresses colon inflammation by inhibiting MAP kinases and NF-κB pathways.

Diagnostic and therapeutic application of thoracic epidural in a child with intractable cardiac arrhythmias: A case report.

A 3-year-old boy presented with episodes of uneasiness and transient loss of consciousness. Atrial tachyarrhythmias with rapid ventricular rate was diagnosed and initially unsuccessfully treated with oral antiarrhythmic drugs. Subsequent Holter monitoring revealed ventricular arrhythmias. Despite pharmacologic treatment, he needed numerous cardioversions. Surgical sympathectomy was planned. Initially, sympathectomy was achieved using a continuous high thoracic epidural block and was performed to ascertain the efficacy of the thoracic sympathectomy. This successfully reduced the ventricular arrhythmias and the need for antiarrhythmic agents. The epidural infusion was also used for pain relief following the subsequent surgical sympathectomy.

α-Bisabolol Mitigates Colon Inflammation by Stimulating Colon PPAR-γ Transcription Factor: In Vivo and In Vitro Study.

The incidence and prevalence of inflammatory bowel disease (IBD, Crohn's disease, and ulcerative colitis) are increasing worldwide. The etiology of IBD is multifactorial, including genetic predisposition, dysregulated immune response, microbial dysbiosis, and environmental factors. However, many of the existing therapies are associated with marked side effects. Therefore, the development of new drugs for IBD treatment is an important area of investigation. Here, we investigated the anti-inflammatory effects of α-bisabolol, a naturally occurring monocyclic sesquiterpene alcohol present in many aromatic plants, in colonic inflammation. To address this, we used molecular docking and dynamic studies to understand how α-bisabolol interacts with PPAR-γ, which is highly expressed in the colonic epithelium: in vivo (mice) and in vitro (RAW264.7 macrophages and HT-29 colonic adenocarcinoma cells) models. The molecular docking and dynamic analysis revealed that α-bisabolol interacts with PPAR-γ, a nuclear receptor protein that is highly expressed in the colon epithelium. Treatment with α-bisabolol in DSS-administered mice significantly reduced Disease Activity Index (DAI), myeloperoxidase (MPO) activity, and colonic length and protected the microarchitecture of the colon. α-Bisabolol treatment also reduced the expression of proinflammatory cytokines (IL-6, IL1ß, TNF-α, and IL-17A) at the protein and mRNA levels. The expression of COX-2 and iNOS inflammatory mediators were reduced along with tissue nitrite levels. Furthermore, α-bisabolol decreased the phosphorylation of activated mitogen-activated protein kinase (MAPK) signaling and nuclear factor kappa B (NFκB) proteins and enhanced colon epithelial PPAR-γ transcription factor expression. However, the PPAR-α and ß/δ expression was not altered, indicating α-bisabolol is a specific stimulator of PPAR-γ. α-Bisabolol also increased the PPAR-γ transcription factor expression but not PPAR-α and ß/δ in pretreated in LPS-stimulated RAW264.7 macrophages. α-Bisabolol significantly decreased the expression of proinflammatory chemokines (CXCL-1 and IL-8) mRNA in HT-29 cells treated with TNF-α and HT-29 PPAR-γ promoter activity. These results demonstrate that α-bisabolol mitigates colonic inflammation by inhibiting MAPK signaling and stimulating PPAR-γ expression.

Using publicly available datasets to identify population-based transcriptomic landscape contributing to the aggressiveness of breast cancer in young women.

Introduction: Although the risk of breast cancer increases with advancing age, some regions have larger number of young breast cancer patients (≤45 years-old), such as the Middle East, Eastern Asia, and North Africa, with more aggressive and poorly differentiated tumors. We aimed to conduct an in-silico analysis in an attempt to understand the aggressive nature of early-onset breast cancer, and to identify potential drivers of early-onset breast cancer using gene expression profiling datasets in a population-dependent manner. Methods: Functional genomics experiments data were acquired from cBioPortal database for cancer genomics, followed by the stratification of patients based on the age at representation of breast cancer and race. Differential gene expression analysis and gene amplification status analysis were carried out, followed by hub gene, transcription factor, and signalling pathway identification. Results: PAM50 subtype analysis revealed that young patients (≤45 years-old) had four-fold more basal tumors and worst progression-free survival (median of 101 months), compared with the 45-65 years group (median of 168 months). Fourteen genes were amplified in more than 14% of patients with an early-onset breast cancer. Interestingly, FREM2, LINC00332, and LINC00366 were exclusively amplified in younger patients. Gene expression data from three different populations (Asian, White, and African) revealed a unique transcriptomic profile of young patients, which was also reflected on the PAM50 subtype analysis. Our data indicates a higher tendency of young African patients to develop basal tumors, while young Asian patients are more prone to developing Luminal A tumors. Most genes that were found to be upregulated in younger patients are involved in important signaling pathways that promote cancer progression and metastasis, such as MAPK pathway, Reelin pathway and the PI3K/Akt pathway. Conclusion: This study provides strong evidence that the molecular profile of tumors derived from young breast cancer patients of different populations is unique and may explain the aggressiveness of these tumors, stressing the need to conduct population- based multi-omic analyses to identify the potential drivers for tumorigenesis and molecular profiles of young breast cancer patients.

Cystic Hepatic Neuroendocrine Tumor: A Rare Entity.

ABSTRACT: A 70-year-old man presented with unspecific abdominal symptoms and weight loss was referred for a sonographic examination. Sonography revealed 3 cystic hepatic masses in an otherwise unremarkable liver. Contrast-enhanced MRI of the liver was performed to characterize the hepatic lesions and elucidate their etiology. The differential diagnosis was primarily parasitic disease or metastases with cystic transformations. 68Ga-DOTATOC PET/CT revealed the neuroendocrine origin of these lesions, confirmed by biopsy. However, the primary site of the neuroendocrine tumor remained unclear, leaving primary hepatic neuroendocrine tumor and neuroendocrine cancer of unknown primary as possible diagnostic options.

Correlation of gastrointestinal perforation location and amount of free air and ascites on CT imaging.

PURPOSE: To analyze the amount of free abdominal gas and ascites on computed tomography (CT) images relative to the location of a perforation. METHODS: We retrospectively included 172 consecutive patients (93:79 = m:f) with GIT perforation, who underwent abdominal surgery (ground truth for perforation location). The volume of free air and ascites were quantified on CT images by 4 radiologists and a semiautomated software. The relation of the perforation location (upper/lower GIT) and amount of free air and ascites was analyzed by the Mann-Whitney test. Furthermore, best volume cutoff for upper and lower GIT perforation, areas under the curve (AUC), and interreader volume agreement were assessed. RESULTS: There was significantly more abdominal ascites with upper GIT perforation (333 ml, range 5 to 2000 ml) than with lower GIT perforation (100 ml, range 5 to 2000 ml, p = 0.022). The highest volume of free air was found with perforations of the stomach, descending colon and sigmoid colon. Significantly less free air was found with perforations of the small bowel and ascending colon compared to the aforementioned. An ascites volume > 333 ml was associated with an upper GIT perforation demonstrating an AUC of 0.63 ± 0.04. CONCLUSION: Using a two-step process based on the volumes of free air and free fluid can help localizing the site of perforation to the upper, middle or lower GI tract.

A case report of a symptomatic right anomalous coronary artery with concomitant atherosclerotic disease: the benefit of a sequential comprehensive non-invasive and invasive diagnostic approach.

BACKGROUND: Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital disease associated with an increased risk of myocardial ischaemia, ventricular arrhythmias, and heart failure. CASE SUMMARY: A 75-year-old Caucasian man was referred for invasive coronary angiography (ICA) due to atypical chest pain. Invasive coronary angiography demonstrated non-significant atherosclerotic disease of the left coronary artery and an anomalous origin of the right coronary artery (RCA); without selective intubation. Coronary computed tomography angiography (CCTA) revealed a right-AAOCA with interarterial and intramural course, and a soft plaque in the distal RCA. Subsequent physical-stress single-photon emissions computed tomography (SPECT) showed exercise-induced inferoapical myocardial ischaemia, giving a Class IC level of evidence for surgical correction of the AAOCA. Repeated ICA with selective R-AAOCA intubation confirmed an 80% distal atherosclerotic stenosis, which was treated with direct stenting. Subsequent invasive physiologic evaluation under maximal dobutamine-volume challenge (gradually increasing dose of dobutamine max. 40 µg/kg per body weight/min, 3000 mL ringer lactate and 1 mg atropine was given until the patient reached a maximum of 145 b.p.m.), revealed a haemodynamically non-relevant anomalous segment with a fractional flow reserve (FFR) of 0.91. A follow-up SPECT was normal, and the patient was completely symptom-free at 1 month. DISCUSSION: We present the sequential diagnostic approach in a symptomatic patient with a right anomalous coronary artery and concomitant atherosclerotic disease. Using this approach, the patient could be deferred from guideline recommended open-heart surgery of the AAOCA, as direct invasive dobutamine/volume FFR revealed haemodynamic non-relevance of the anomalous segment after stenting the concomitant atherosclerotic stenosis in the distal segment within the same coronary artery.

Adult form of Langerhans cell histiocytosis with pulmonary and hepatic involvement mimicking malignancy in a patient with chronic hepatitis C infection.

Langerhans cell histiocytosis (LCH) is a myeloid neoplasm with inflammatory properties. There are few published reports of adult LCH with liver involvement, which is still poorly understood, but shows high morbidity and mortality. We report a case of a 37-year-old woman suffering from hepatitis C showing a LCH affecting the lung as well as the liver. Consistent with histology, we found an early stage of a proliferative/granulomatous phase of hepatobiliary LCH, whereas pulmonary findings showed a nodular stage of adult pulmonary LCH. Although hepatocellular carcinoma is a common malignancy in patients suffering from hepatitis C, it is crucial to keep in mind differential diagnosis for newly appearing liver lesions.

Nerolidol Mitigates Colonic Inflammation: An Experimental Study Using both In Vivo and In Vitro Models.

Nerolidol (NED) is a naturally occurring sesquiterpene alcohol present in various plants with potent anti-inflammatory effects. In the current study, we investigated NED as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were administered 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. Six groups received either vehicle alone or DSS alone or DSS with oral NED (50, 100, and 150 mg/kg body weight/day by oral gavage) or DSS with sulfasalazine. Disease activity index (DAI), colonic histology, and biochemical parameters were measured. TNF-α-treated HT-29 cells were used as in vitro model of colonic inflammation to study NED (25 µM and 50 µM). NED significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue Myeloperoxidase (MPO) concentrations, neutrophil and macrophage mRNA expression (CXCL2 and CCL2), and proinflammatory cytokine content (IL-1ß, IL-6, and TNF-α) both at the protein and mRNA level were significantly reduced by NED. The increase in content of the proinflammatory enzymes, COX-2 and iNOS induced by DSS were also significantly inhibited by NED along with tissue nitrate levels. NED promoted Nrf2 nuclear translocation dose dependently. NED significantly increased antioxidant enzymes activity (Superoxide dismutase (SOD) and Catalase (CAT)), Hemeoxygenase-1 (HO-1), and SOD3 mRNA levels. NED treatment in TNF-α-challenged HT-29 cells significantly decreased proinflammatory chemokines (CXCL1, IL-8, CCL2) and COX-2 mRNA levels. NED supplementation attenuates colon inflammation through its potent antioxidant and anti-inflammatory activity both in in vivo and in vitro models of colonic inflammation.

Ileal Transposition in Rats Reduces Energy Intake, Body Weight, and Body Fat Most Efficaciously When Ingesting a High-Protein Diet.

PURPOSE: Ileal transposition (IT) allows exploration of hindgut effects of bariatric procedures in inducing weight loss and reducing adiposity. Here we investigated the role of dietary macronutrient content on IT effects in rats. METHODS: Male Lewis rats consuming one of three isocaloric liquid diets enriched with fat (HF), carbohydrates (HC), or protein (HP) underwent IT or sham surgery. Body weight, energy intake, energy efficiency, body composition, and (meal-induced) changes in plasma GIP, GLP-1, PYY, neurotensin, and insulin levels were measured. RESULTS: Following IT, HC intake remained highest leading to smallest weight loss among dietary groups. IT in HF rats caused high initial weight loss and profound hypophagia, but the rats caught up later, and finally had the highest body fat content among IT rats. HP diet most efficaciously supported IT-induced reduction in body weight and adiposity, but (as opposed to other diet groups) lean mass was also reduced. Energy efficiency decreased immediately after IT irrespective of diet, but normalized later. Energy intake alone explained variation in post-operative weight change by 80%. GLP-1, neurotensin, and PYY were upregulated by IT, particularly during (0-60 min) and following 17-h post-ingestive intake, with marginal diet effects. Thirty-day post-operative cumulative energy intake was negatively correlated to 17-h post-ingestive PYY levels, explaining 47% of its variation. CONCLUSION: Reduction in energy intake underlies IT-induced weight loss, with highest efficacy of the HP diet. PYY, GLP-1, and neurotensin levels are upregulated by IT, of which PYY may be most specifically related to reduced intake and weight loss after IT.

Phytochemical drug candidates for the modulation of peroxisome proliferator-activated receptor γ in inflammatory bowel diseases.

Plant-based compounds or phytochemicals such as alkaloids, glycosides, flavonoids, volatile oils, tannins, resins, and polyphenols have been used extensively in traditional medicine for centuries and more recently in Western alternative medicine. Extensive evidence suggests that consumption of dietary polyphenolic compounds lowers the risk of inflammatory diseases. The anti-inflammatory properties of several phytochemicals are mediated through ligand-inducible peroxisome proliferator-activated receptors (PPARs), particularly the PPARγ transcription factor. Inflammatory bowel disease (IBD) is represented by ulcerative colitis, which occurs in the mucosa of the colon and rectum, and Crohn's disease (CD) that can involve any segment of gastrointestinal tract. Because of the lack of cost-effective pharmaceutical treatment options, many IBD patients seek and use alternative and unconventional therapies to alleviate their symptoms. PPARγ plays a role in the inhibition of inflammatory cytokine expression and activation of anti-inflammatory immune cells. The phytochemicals reported here are ligands that activate PPARγ, which in turn modulates inflammatory responses. PPARγ is highly expressed in the gut making it a potential therapeutic target for IBDs. This review summarizes the effects of the currently published phytochemicals that modulate the PPARγ pathway and reduce or eliminate colonic inflammation.

1,2,3-Triazolyl ester of ketorolac (15K), a potent PAK1 blocker, inhibits both growth and metastasis of orthotopic human pancreatic cancer xenografts in mice.

More than 90% of human pancreatic cancers carry the oncogenic mutant of Ki-RAS and their growth depends on its downstream kinase PAK1, mainly because PAK1 blocks the apoptosis of cancer cells selectively. We developed a highly cell-permeable PAK1-blocker called 15K from an old pain-killer (ketorolac), that is shown here to inhibit the growth of three pancreatic cancer cell lines with IC50 values ranging 41-88 nM in vitro. The anti-cancer effect of 15K was further investigated in an orthotopic xenograft model with gemcitabine (GEM)-resistant human pancreatic cancer cell lines (AsPC-1 and BxPC-3) expressing luciferase in athymic mice. During 4 weeks, 15K blocks total burden (growth) of both AsPC-1 and BxPC-3 tumors (measured as radians/sec) with the IC50 below daily dose of 0.1 mg/kg, i.p. In a similar manner 15K reduced both their invasion and metastases as well, while it had no effect on either body weight or hematological parameters even at 5 mg/kg/day. To the best of our knowledge, 15K is so far the most potent among synthetic PAK1-blockers in vivo, and could be potentially useful for therapy of GEM-resistant cancers.

Frondanol, a Nutraceutical Extract from Cucumaria frondosa, Attenuates Colonic Inflammation in a DSS-Induced Colitis Model in Mice.

Frondanol is a nutraceutical lipid extract of the intestine of the edible Atlantic sea cucumber, Cucumaria frondosa, with potent anti-inflammatory effects. In the current study, we investigated Frondanol as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were given 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. The colitis group received oral Frondanol (100 mg/kg body weight/per day by gavage) and were compared with a control group and the DSS group. Disease activity index (DAI) and colon histology were scored for macroscopic and microscopic changes. Colonic tissue length, myeloperoxidase (MPO) concentration, neutrophil and macrophage marker mRNA, pro-inflammatory cytokine proteins, and their respective mRNAs were measured using ELISA and real-time RT-PCR. The tissue content of leukotriene B4 (LTB4) was also measured using ELISA. Frondanol significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue MPO concentrations, neutrophil and macrophage mRNA expression (F4/80 and MIP-2), and pro-inflammatory cytokine content (IL-1β, IL-6 and TNF-α) both at the protein and mRNA level were significantly reduced by Frondanol. The increase in content of the pro-inflammatory mediator leukotriene B4 (LTB4) induced by DSS was also significantly inhibited by Frondanol. It was thus found that Frondanol supplementation attenuates colon inflammation through its potent anti-inflammatory activity.

The Anti-Cancer Effects of Frondoside A.

Frondoside A is a triterpenoid glycoside from the Atlantic Sea Cucumber, Cucumariafrondosa. Frondoside A has a broad spectrum of anti-cancer effects, including induction of cellular apoptosis, inhibition of cancer cell growth, migration, invasion, formation of metastases, and angiogenesis. In cell lines and animal models studied to date, the anti-cancer effects of the compound are seen in all solid cancers, lymphomas, and leukemias studied to date. These effects appear to be due to potent inhibition of p21-activated kinase 1 (PAK1), which is up-regulated in many cancers. In mouse models, frondoside A has synergistic effects with conventional chemotherapeutic agents, such as gemcitabine, paclitaxel, and cisplatin. Frondoside A administration is well-tolerated. No side effects have been reported and the compound has no significant effects on body weight, blood cells, or on hepatic and renal function tests after long-term administration. Frondoside A may be valuable in the treatment of malignancies, either as a single agent or in combination with other therapeutic modalities.

A fine balancing act: A delicate kinase-phosphatase equilibrium that protects against chromosomal instability and cancer.

Cancer cells rewire signalling networks to acquire specific hallmarks needed for their proliferation, survival, and dissemination throughout the body. Although this is often associated with the constitutive activation or inactivation of protein phosphorylation networks, there are other contexts when the dysregulation must be much milder. For example, chromosomal instability is a widespread cancer hallmark that relies on subtle defects in chromosome replication and/or division, such that these processes remain functional, but nevertheless error-prone. In this article, we will discuss how perturbations to the delicate kinase-phosphatase balance could lie at the heart of this type of dysregulation. In particular, we will explain how the two principle mechanisms that safeguard the chromosome segregation process rely on an equilibrium between at least two kinases and two phosphatases to function correctly. This balance is set during mitosis by a central complex that has also been implicated in chromosomal instability - the BUB1/BUBR1/BUB3 complex - and we will put forward a hypothesis that could link these two findings. This could be relevant for cancer treatment because most tumours have evolved by pushing the boundaries of chromosomal instability to the limit. If this involves subtle changes to the kinase-phosphatase equilibrium, then it may be possible to exacerbate these defects and tip tumour cells over the edge, whilst still maintaining the viability of healthy cells.