Maltol Promotes Mitophagy and Inhibits Oxidative Stress via the Nrf2/PINK1/Parkin Pathway after Spinal Cord Injury.

Spinal cord injury (SCI), a fatal disease in the central nervous system, is characteristic of weak neuronal regeneration ability and complex pathological progress. Activation of oxidative stress (OS) and apoptosis-mediated cell death significantly contributes to the progression of SCI. Current evidence suggests that maltol exerts natural antioxidative properties via obstructing OS and apoptosis. However, the significant effect of maltol on SCI treatment has never been evaluated yet. In our current study, we explored maltol administration that could trigger the expression of Nrf2 and promote the retranslocation of Nrf2 from the cytosol to the nucleus, which can subsequently obstruct OS signal and apoptosis-mediated neuronal cell death after SCI. Furthermore, we found that maltol treatment enhances PINK1/Parkin-mediated mitophagy in PC12 cells, facilitating the recovery of mitochondrial functions. Our findings propose that maltol could be a promising therapeutic candidate for the treatment and management of SCI.

Long-Term Effectiveness of Oral Ferric Maltol vs Intravenous Ferric Carboxymaltose for the Treatment of Iron-Deficiency Anemia in Patients With Inflammatory Bowel Disease: A Randomized Controlled Noninferiority Trial.

BACKGROUND: Iron-deficiency anemia is common in inflammatory bowel disease, requiring oral or intravenous iron replacement therapy. Treatment with standard oral irons is limited by poor absorption and gastrointestinal toxicity. Ferric maltol is an oral iron designed for improved absorption and tolerability. METHODS: In this open-label, phase 3b trial (EudraCT 2015-002496-26 and NCT02680756), adults with nonseverely active inflammatory bowel disease and iron-deficiency anemia (hemoglobin, 8.0-11.0/12.0 g/dL [women/men]; ferritin, <30 ng/mL/<100 ng/mL with transferrin saturation <20%) were randomized to oral ferric maltol 30 mg twice daily or intravenous ferric carboxymaltose given according to each center's standard practice. The primary endpoint was a hemoglobin responder rate (≥2 g/dL increase or normalization) at week 12, with a 20% noninferiority limit in the intent-to-treat and per-protocol populations. RESULTS: For the intent-to-treat (ferric maltol, n = 125/ferric carboxymaltose, n = 125) and per-protocol (n = 78/88) analyses, week 12 responder rates were 67% and 68%, respectively, for ferric maltol vs 84% and 85%, respectively, for ferric carboxymaltose. As the confidence intervals crossed the noninferiority margin, the primary endpoint was not met. Mean hemoglobin increases at weeks 12, 24, and 52 were 2.5 vs 3.0 g/dL, 2.9 vs 2.8 g/dL, and 2.7 vs 2.8 g/dL with ferric maltol vs ferric carboxymaltose. Treatment-emergent adverse events occurred in 59% and 36% of patients, respectively, and resulted in treatment discontinuation in 10% and 3% of patients, respectively. CONCLUSIONS: Ferric maltol achieved clinically relevant increases in hemoglobin but did not show noninferiority vs ferric carboxymaltose at week 12. Both treatments had comparable long-term effectiveness for hemoglobin and ferritin over 52 weeks and were well tolerated.

Antioxidative and Anti-inflammatory Effects of Kojic Acid in Aß-Induced Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a common cause of dementia that is clinically characterized by the loss of memory and cognitive functions. Currently, there is no specific cure for the management of AD, although natural compounds are showing promising therapeutic potentials because of their safety and easy availability. Herein, we evaluated the neuroprotective properties of kojic acid (KA) in an AD mouse model. Intracerebroventricular injection (i.c.v) of Aß1-42 (5 µL/5 min/mouse) into wild-type adult mice induced AD-like pathological changes in the mouse hippocampus by increasing oxidative stress and neuroinflammation, affecting memory and cognitive functions. Interestingly, oral treatment of kojic acid (50 mg/kg/mouse for 3 weeks) reversed the AD pathology by reducing the expression of amyloid-beta (Aß) and beta-site amyloid precursor protein cleaving enzyme1 (BACE-1). Moreover, kojic acid reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (Nrf2) and heme oxygenase 1 (HO1). Also, kojic acid reduced the lipid peroxidation and reactive oxygen species in the Aß + kojic acid co-treated mice brains. Moreover, kojic acid decreased neuroinflammation by inhibiting Toll-like receptor 4, phosphorylated nuclear factor-κB, tumor necrosis factor-alpha, interleukin 1-beta (TLR-4, p-NFκB, TNFα, and IL-1ß, respectively), and glial cells. Furthermore, kojic acid enhanced synaptic markers (SNAP-23, SYN, and PSD-95) and memory functions in AD model mice. Additionally, kojic acid treatment also decreased Aß expression, oxidative stress, and neuroinflammation in vitro in HT-22 mouse hippocampal cells. To the best of our knowledge, this is the first study to show the neuroprotective effects of kojic acid against an AD mouse model. Our findings could serve as a favorable and alternative strategy for the discovery of novel drugs to treat AD-related neurodegenerative conditions.

Interventions for treating iron deficiency anaemia in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease affects approximately seven million people globally. Iron deficiency anaemia can occur as a common systemic manifestation, with a prevalence of up to 90%, which can significantly affect quality of life, both during periods of active disease or in remission. It is important that iron deficiency anaemia is treated effectively and not be assumed to be a normal finding of inflammatory bowel disease. The various routes of iron administration, doses and preparations present varying advantages and disadvantages, and a significant proportion of people experience adverse effects with current therapies. Currently, no consensus has been reached amongst physicians as to which treatment path is most beneficial. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of the interventions for the treatment of iron deficiency anaemia in people with inflammatory bowel disease. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two other databases on 21st November 2019. We also contacted experts in the field and searched references of trials for any additional trials. SELECTION CRITERIA: Randomised controlled trials investigating the effectiveness and safety of iron administration interventions compared to other iron administration interventions or placebo in the treatment of iron deficiency anaemia in inflammatory bowel disease. We considered both adults and children, with studies reporting outcomes of clinical, endoscopic, histologic or surgical remission as defined by study authors. DATA COLLECTION AND ANALYSIS: Two review authors independently conducted data extraction and 'Risk of bias' assessment of included studies. We expressed dichotomous and continuous outcomes as risk ratios and mean differences with 95% confidence intervals. We assessed the certainty of the evidence using the GRADE methodology. MAIN RESULTS: We included 11 studies (1670 randomised participants) that met the inclusion criteria. The studies compared intravenous iron sucrose vs oral iron sulphate (2 studies); oral iron sulphate vs oral iron hydroxide polymaltose complex (1 study); oral iron fumarate vs intravenous iron sucrose (1 study); intravenous ferric carboxymaltose vs intravenous iron sucrose (1 study); erythropoietin injection + intravenous iron sucrose vs intravenous iron sucrose + injection placebo (1 study); oral ferric maltol vs oral placebo (1 study); oral ferric maltol vs intravenous ferric carboxymaltose (1 study); intravenous ferric carboxymaltose vs oral iron sulphate (1 study); intravenous iron isomaltoside vs oral iron sulphate (1 study); erythropoietin injection vs oral placebo (1 study). All studies compared participants with CD and UC together, as well as considering a range of disease activity states. The primary outcome of number of responders, when defined, was stated to be an increase in haemoglobin of 20 g/L in all but two studies in which an increase in 10g/L was used. In one study comparing intravenous ferric carboxymaltose and intravenous iron sucrose, moderate-certainty evidence was found that intravenous ferric carboxymaltose was probably superior to intravenous iron sucrose, although there were responders in both groups (150/244 versus 118/239, RR 1.25, 95% CI 1.06 to 1.46, number needed to treat for an additional beneficial outcome (NNTB) = 9). In one study comparing oral ferric maltol to placebo, there was low-certainty evidence of superiority of the iron (36/64 versus 0/64, RR 73.00, 95% CI 4.58 to 1164.36). There were no other direct comparisons that found any difference in the primary outcomes, although certainty was low and very low for all outcomes, due to imprecision from sparse data and risk of bias varying between moderate and high risk. The reporting of secondary outcomes was inconsistent. The most common was the occurrence of serious adverse events or those requiring withdrawal of therapy. In no comparisons was there a difference seen between any of the intervention agents being studied, although the certainty was very low for all comparisons made, due to risk of bias and significant imprecision due to the low numbers of events. Time to remission, histological and biochemical outcomes were sparsely reported in the studies. None of the other secondary outcomes were reported in any of the studies. An analysis of all intravenous iron preparations to all oral iron preparations showed that intravenous administration may lead to more responders (368/554 versus 205/373, RR 1.17, 95% CI 1.05 to 1.31, NNTB = 11, low-certainty due to risk of bias and inconsistency). Withdrawals due to adverse events may be greater in oral iron preparations vs intravenous (15/554 versus 31/373, RR 0.39, 95% CI 0.20 to 0.74, low-certainty due to risk of bias, inconsistency and imprecision). AUTHORS' CONCLUSIONS: Intravenous ferric carboxymaltose probably leads to more people having resolution of IDA (iron deficiency anaemia) than intravenous iron sucrose. Oral ferric maltol may lead to more people having resolution of IDA than placebo. We are unable to draw conclusions on which of the other treatments is most effective in IDA with IBD (inflammatory bowel disease) due to low numbers of studies in each comparison area and clinical heterogeneity within the studies. Therefore, there are no other conclusions regarding the treatments that can be made and certainty of all findings are low or very low. Overall, intravenous iron delivery probably leads to greater response in patients compared with oral iron, with a NNTB (number needed to treat) of 11. Whilst no serious adverse events were specifically elicited with any of the treatments studied, the numbers of reported events were low and the certainty of these findings very low for all comparisons, so no conclusions can be drawn. There may be more withdrawals due to such events when oral is compared with intravenous iron delivery. Other outcomes were poorly reported and once again no conclusions can be made as to the impact of IDA on any of these outcomes. Given the widespread use of many of these treatments in practice and the only guideline that exists recommending the use of intravenous iron in favour of oral iron, research to investigate this key issue is clearly needed. Considering the current ongoing trials identified in this review, these are more focussed on the impact in specific patient groups (young people) or on other symptoms (such as fatigue). Therefore, there is a need for studies to be performed to fill this evidence gap.

Ferric Maltol: A New Oral Iron Formulation for the Treatment of Iron Deficiency in Adults.

OBJECTIVE: To review the pharmacology, efficacy, and safety of ferric maltol (FM), an oral iron formulation, for iron deficiency anemia (IDA). DATA SOURCES: A MEDLINE/PubMed and EMBASE (January 1, 1985, to June 19, 2020) literature search was performed using the terms ferric maltol, accrufer, feraccru, iron maltol, ferric trimaltol, iron deficiency, iron deficiency anemia, inflammatory bowel disease, and chronic kidney disease. Additional data sources included prescribing information, abstracts, and the National Institutes of Health Clinical Trials Registry. STUDY SELECTION/DATA EXTRACTION: English language literature evaluating FM pharmacology, pharmacokinetics, efficacy, or safety in the treatment of IDA were reviewed. DATA SYNTHESIS: FM is a ferric, non-salt-based oral iron formulation demonstrating improved tolerance in patients with previous intolerance to other iron formulations. Phase 3 trials demonstrated significant improvements in anemia and serum iron parameters in patients with inflammatory bowel disease (IBD) and chronic kidney disease (CKD). Common adverse effects were gastrointestinal intolerance. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: FM is an effective and well-tolerated alternative to oral iron salts for patients with IBD or CKD and IDA. Emerging data suggest that FM is noninferior to intravenous (IV) ferric carboxymaltose in patients with IBD and IDA. Prior to selecting FM over IV iron products, consideration should be given to time to normalization of Hb, ease of administration, cost, and tolerability. CONCLUSION: FM is a relatively safe, effective oral iron therapy that may be better tolerated than other oral iron formulations. FM may be an effective alternative to IV iron in patients with IBD.

(3E,5E)-3,5-Bis(pyridin-3-methylene)-tetrahydrothiopyran-4-one enhances the inhibitory effect of gemcitabine on pancreatic cancer cells.

Gemcitabine (GEM) is a commonly used treatment for advanced pancreatic cancer. However, chemoresistance and toxic side effect limits its clinical success. In an earlier study, our laboratory found that the curcumin analogue, (3E,5E)-3,5-Bis(pyridin-3-methylene)-tetrahydrothiopyran-4-one (FN2) had strong inhibitory effect on human pancreatic cancer cells. In the present study, we investigated the effects of FN2 in combination with GEM on growth inhibition and apoptosis in human pancreatic cancer Panc-1 cells. The results showed that the combination of FN2 and GEM synergistically inhibited the growth of Panc-1 cells. Panc-1 cells survived the GEM treatment became partially resistant to the drug. Treatment with FN2 in combination with GEM strongly inhibited the growth and stimulated apoptosis in the GEM resistant Panc-1 cells. Mechanistic studies showed that inhibition of cell growth and induction of apoptosis in the GEM resistant Panc-1 cells were associated with decreases in activation of NF-κB and Akt. FN2 in combination with GEM also decreased the level of Bcl-2 and increased the level of Bax. Results of the present study indicate that GEM in combination with FN2 may represent an effective strategy for improving the efficacy of GEM and decreasing the resistance of pancreatic cancer to GEM chemotherapy.

Oral Dosing of Dihydromethysticin Ahead of Tobacco Carcinogen NNK Effectively Prevents Lung Tumorigenesis in A/J Mice.

Our early studies demonstrated an impressive chemopreventive efficacy of dihydromethysticin (DHM), unique in kava, against tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis in A/J mice in which DHM was supplemented in the diet. The current work was carried out to validate the efficacy, optimize the dosing schedule, and further elucidate the mechanisms using oral bolus dosing of DHM. The results demonstrated a dose-dependent chemopreventive efficacy of DHM (orally administered 1 h before each of the two NNK intraperitoneal injections, 1 week apart) against NNK-induced lung adenoma formation. Temporally, DHM at 0.8 mg per dose (∼32 mg per kg body weight) exhibited 100% lung adenoma inhibition when given 3 and 8 h before each NNK injection and attained >93% inhibition when dosed at either 1 or 16 h before each NNK injection. The simultaneous treatment (0 h) or 40 h pretreatment (-40 h) decreased lung adenoma burden by 49.8% and 52.1%, respectively. However, post-NNK administration of DHM (1-8 h after each NNK injection) was ineffective against lung tumor formation. In short-term experiments for mechanistic exploration, DHM treatment reduced the formation of NNK-induced O6-methylguanine (O6-mG, a carcinogenic DNA adduct in A/J mice) in the target lung tissue and increased the urinary excretion of NNK detoxification metabolites as judged by the ratio of urinary NNAL-O-gluc to free NNAL, generally in synchrony with the tumor prevention efficacy outcomes in the dose scheduling time-course experiment. Overall, these results suggest DHM as a potential chemopreventive agent against lung tumorigenesis in smokers, with O6-mG and NNAL detoxification as possible surrogate biomarkers.

Mycobacterium tuberculosis exploits host ATM kinase for survival advantage through SecA2 secretome.

(Mtb) produces inflections in the host signaling networks to create a favorable milieu for survival. The virulent Mtb strain, Rv caused double strand breaks (DSBs), whereas the non-virulent Ra strain triggered single-stranded DNA generation. The effectors secreted by SecA2 pathway were essential and adequate for the genesis of DSBs. Accumulation of DSBs mediated through Rv activates ATM-Chk2 pathway of DNA damage response (DDR) signaling, resulting in altered cell cycle. Instead of the classical ATM-Chk2 DDR, Mtb gains survival advantage through ATM-Akt signaling cascade. Notably, in vivo infection with Mtb led to sustained DSBs and ATM activation during chronic phase of tuberculosis. Addition of ATM inhibitor enhances isoniazid mediated Mtb clearance in macrophages as well as in murine infection model, suggesting its utility for host directed adjunct therapy. Collectively, data suggests that DSBs inflicted by SecA2 secretome of Mtb provides survival niche through activation of ATM kinase.

Plocabulin Displays Strong Cytotoxic Activity in a Personalized Colon Cancer Patient-Derived 3D Organoid Assay.

Plocabulin is a novel microtubule-disrupting antitumor agent of marine origin that is currently undergoing phase II clinical trials. Plocabulin has potent antiproliferative and antiangiogenic actions in carcinoma cell lines and has antitumor activity in xenografted mice. Here, we used three-dimensional (3D) tumor organoids derived from three colorectal cancer (CRC) patients to study the effect of plocabulin in a personalized assay system that ensures dose dependence and high reproducibility. The cytotoxicity of plocabulin was an order of magnitude higher than that of the active irinotecan derivative SN38 (7-ethyl-10-hydroxy-camptothecin) in tumor organoids at different passages. Moreover, plocabulin maintained its strong cytotoxic activity in wash-out experiments, in which a short pulse treatment of tumor organoids was as efficient as continuous treatment. Our data show that plocabulin has a very potent cytotoxic action in CRC patient-derived tumor organoids, supporting ongoing clinical trials with plocabulin and the use of organoid assays to provide personalized validation of antitumor drugs.

Novel Oral Iron Therapies for Iron Deficiency Anemia in Chronic Kidney Disease.

Iron deficiency anemia (IDA) is a frequent complication of chronic kidney disease (CKD) and is associated with adverse outcomes in these patients. Patients with CKD and IDA remain largely undertreated. Conventional oral iron agents are insufficiently effective due to poor absorption and cause gastrointestinal side effects; thus, novel oral iron preparations are needed. This article covers current treatment guidelines for patients with anemia and CKD and clinical trial data for iron-repletion agents currently in use, as well as for novel oral iron therapies in development. Ferric citrate, a novel oral iron-repletion agent approved for patients with non-dialysis-dependent CKD and IDA, demonstrated improvements in hemoglobin levels and iron parameters, with good tolerability in patients with non-dialysis-dependent CKD. When used as a phosphate binder, ferric citrate also improves hemoglobin and iron parameters in dialysis-dependent CKD, but additional trials are needed to evaluate its efficacy as an iron-repletion agent in this setting. Other novel oral iron preparations in development for IDA in patients with CKD include ferric maltol, which is approved in Europe and the United States for IDA in adult patients, and sucrosomial iron, which has been evaluated in IDA associated with CKD and several other clinical settings.

Maltol (3-Hydroxy-2-methyl-4-pyrone) Slows d-Galactose-Induced Brain Aging Process by Damping the Nrf2/HO-1-Mediated Oxidative Stress in Mice.

Maltol, a maillard reaction product from ginseng (Panax ginseng C. A. Meyer), has been confirmed to inhibit oxidative stress in several animal models. Its beneficial effect on oxidative stress related brain aging is still unclear. In this study, the mouse model of d-galactose (d-Gal)-induced brain aging was employed to investigate the therapeutic effects and potential mechanisms of maltol. Maltol treatment significantly restored memory impairment in mice as determined by the Morris water maze tests. Long-term d-Gal treatment reduced expression of cholinergic regulators, i.e., the cholineacetyltransferase (ChAT) (0.456 ± 0.10 vs 0.211 ± 0.03 U/mg prot), the acetylcholinesterase (AChE) (36.4 ± 5.21 vs 66.5 ± 9.96 U/g). Maltol treatment prevented the reduction of ChAT and AChE in the hippocampus. Maltol decreased oxidative stress levels by reducing levels of reactive oxygen species (ROS) and malondialdehyde (MDA) production in the brain and by elevating antioxidative enzymes. Furthermore, maltol treatment minimized oxidative stress by increasing the phosphorylation levels of phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt), nuclear factor-erythroid 2-related factor 2 (Nrf2), and hemeoxygenase-1 (HO-1). The above results clearly indicate that supplementation of maltol diminishes d-Gal-induced behavioral dysfunction and neurological deficits via activation of the PI3K/Akt-mediated Nrf2/HO-1 signaling pathway in brain. Maltol might become a potential drug to slow the brain aging process and stimulate endogenous antioxidant defense capacity. This study provides the novel evidence that maltol may slow age-associated brain aging.

Maltol Mitigates Thioacetamide-induced Liver Fibrosis through TGF-ß1-mediated Activation of PI3K/Akt Signaling Pathway.

Our previous study has confirmed that maltol can attenuate alcohol-induced acute hepatic damage and prevent oxidative stress in mice. Therefore, maltol might have the capacity to improve thioacetamide (TAA)-induced liver fibrosis. The purpose of this work was to explore the antifibrotic efficacy and underlying mechanisms of maltol for TAA-treated mice. Progressive liver fibrosis was established with a dose-escalating protocol in which the mice received TAA intraperitoneal three times a week for a total duration of 9 weeks. The injection doses of TAA were 50 mg/kg for the first week, 100 mg/kg for the second and third weeks, and 150 mg/kg for the rest of the injections. Maltol with doses of 50 and 100 mg/kg was given by gavage after 4 weeks of intraperitoneal injection of TAA, respectively, once daily for 5 weeks. Results indicated that TAA intraperitoneal injection significantly increased serum activities of alanine aminotransferase (ALT) (52.93 ± 13.21 U/L vs 10.22 ± 3.36 U/L) and aspartate aminotransferase (AST) (67.58 ± 25.84 U/L vs 39.34 ± 3.89 U/L); these elevations were significantly diminished by pretreatment with maltol. Additionally, maltol ameliorated TAA-induced oxidative stress with attenuation in MDA ( p < 0.05 or p < 0.01) content; evident elevation in the GSH levels, GSH/GSSG ratio ( p < 0.05 or p < 0.01), and superoxide dismutase (SOD) ( p < 0.01); and restored liver histology accompanied by a decrease of α-smooth muscle actin (α-SMA) expression. Furthermore, maltol significantly suppressed the transforming growth factor-ß1 (TGF-ß1) expression and the PI3K/Akt pathway. This study suggested that maltol alleviated experimental liver fibrosis by suppressing the activation of HSCs and inducing apoptosis of activated HSCs through TGF-ß1-mediated PI3K/Akt signaling pathway. These findings further clearly suggested that maltol is a potent therapeutic candidate for the alleviation of liver fibrosis.

First-in-human phase I study of the microtubule inhibitor plocabulin in patients with advanced solid tumors.

Background Plocabulin (PM060184) is a novel marine-derived microtubule inhibitor that acts as an antitumor agent. This first-in-human study evaluated dose-limiting toxicities (DLT) to define the maximum tolerated dose (MTD) and phase II recommended dose (RD) of plocabulin given as a 10-min infusion on Day (D) 1, D8 and D15 every four weeks. Patients and methods Forty-four patients with advanced solid tumors received plocabulin following an accelerated titration design. Results Plocabulin was escalated from 1.3 mg/m2 to 14.5 mg/m2, which was defined as the MTD. No RD was confirmed, because frequent dose delays and omissions resulted in low relative dose intensity (66%) at the 12.0 mg/m2 expansion cohort. The main DLT was grade 3 peripheral sensory neuropathy (PSN); other DLTs were grade 4 tumor lysis syndrome, grade 4 cardiac failure and grade 3 myalgia. Toxicities were mainly mild to moderate, and included abdominal pain, myalgia, fatigue, nausea, and vomiting. Myelosuppression was transient and manageable. Plocabulin had a half-life of ~4 h and a wide diffusion to peripheral tissues. Antitumor response was observed in cervix carcinoma and heavily pretreated metastatic non-small cell lung cancer patients, and disease stabilization (≥3 months) in patients with colorectal, thymic, gastrointestinal stromal and breast tumors, among others. The clinical benefit rate was 33%. Conclusion The main DLT of plocabulin was PSN, as anticipated for a tubulin-binding agent. Since encouraging antitumor activity was observed, efforts to improve toxicity and to find the RD were planned in other trials evaluating D1&D8 and D1-D3 plus D15-D17 schedules.

Combination Effects of Hispidin and Gemcitabine via Inhibition of Stemness in Pancreatic Cancer Stem Cells.

BACKGROUND/AIM: Natural products extracted from plants can be potent for developing pharmaceutical products. Hispidin, a polyphenolic compound mainly derived from the medicinal mushroom Phellinus linteus, has been shown to have a therapeutic potential against cancer cells. Pancreatic cancer is one of the most aggressive solid malignancies with high resistance to existing drugs. Cancer stem cells (CSCs) are responsible for chemoresistance. The present study aimed to evaluate the anticancer effects of hispidin on pancreatic CSCs. MATERIALS AND METHODS: The cytotoxic effects of hispidin on BxPC-3 and AsPC-1 pancreatic cancer cells and BxPC-3 CD44+ CSCs and the synergistic effects of gemcitabine and hispidin on CSCs were evaluated by a series of in vitro experiments including the 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), fluorescence-activated cell sorting, colony forming, Transwell assay, immunocytochemistry, sphere-forming, and western blot assays. RESULTS: Hispidin exerted antitumor effects against both BxPC-3 pancreatic cancer cells and CSCs. Furthermore, it was found that hispidin sensitized pancreatic CSCs to gemcitabine and promoted the therapeutic efficacy of gemcitabine. CONCLUSION: Hispidin might be a novel chemosensitizer for gemcitabine and a potential synergistic agent for increasing the therapeutic index of gemcitabine as a treatment for pancreatic cancer.

Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners.

(+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3'-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of ß-tubulin insufficiently occupied by (+)-discodermolide, thereby conferring improved ligand-target interaction. It was recently demonstrated, however, that the C-3'-phenyl side chain occupied a different space, instead extending toward the M-loop of ß-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+)-discodermolide. Since (+)-discodermolide is a potent inducer of accelerated senescence, a fate that contributes to drug resistance, congeners were also screened for senescence induction. Flow cytometric and transcriptional analysis revealed that the hybrids largely retained the senescence-inducing properties of (+)-discodermolide. In taxol-sensitive cell models, the congeners had improved dose-response parameters relative to (+)-discodermolide and, in some cases, were superior to taxol. However, in cells susceptible to senescence, EMax increased without concomitant improvements in EC50 such that overall dose-response profiles resembled that of (+)-discodermolide.

Management of inflammatory bowel disease-related anemia and iron deficiency with specific reference to the role of intravenous iron in current practice.

INTRODUCTION: Anemia is a common extraintestinal manifestation in patients with inflammatory bowel disease, impacting disease prognosis, morbidity, hospitalization rates and time lost from work. While iron deficiency anemia and anemia of chronic inflammation predominate, combinations of hematimetric and biochemical markers facilitate the diagnosis and targeted therapy of other etiologies according to their underlying pathophysiological causes. Intravenous iron replacement is currently recommended in IBD patients with moderate to severe anemia or intolerance to oral iron. Areas covered: This review examines the impact, pathophysiology and diagnostics of iron deficiency and anemia, compares the characteristics and safety profiles of available oral and intravenous iron preparations, and highlights issues which require consideration in decision making for therapy administration and monitoring. Expert opinion: Modern intravenous iron formulations have been shown to be safe and effective in IBD patients, allowing rapid anemia correction and repletion of iron stores. While traditional oral iron preparations are associated with increased inflammation, negative effects on the microbiome, and poor tolerance and compliance, first clinical trial data indicate that newer oral compounds such as ferric maltol and sucrosomial iron offer improved tolerability and may thus offer a viable alternative for the future.

Synergistic Antitumor Effect of Sorafenib in Combination with ATM Inhibitor in Hepatocellular Carcinoma Cells.

Background: Currently, sorafenib is the only systemic chemotherapy drug for advanced stage Hepatocellular carcinoma (HCC). However, emerging data from some clinical HCC patients indicate that sorafenib alone has only moderate antitumor efficacy, and could not inhibit disease metastasis and progression. KU-55933 is a specific ATM inhibitor, which has pro-apoptotic effect on tumor cells. In this study, we analyzed the synergistic effect of sorafenib and KU-55933 on the proliferation of HCC cell lines. Methods: Three HCC cell lines were treated with sorafenib and KU-55933 alone or combination in vitro to investigate inhibitory effect by MTT and wound healing assay. Epithelial to mesenchymal transition (EMT) phenotype change was investigated after sorafenib and KU-55933 treatment by microscopy. Akt signaling pathway proteins including p-Akt, p-mTOR and p-p70S6K were examined by western blot. In addition, cleaved PARP and autophage-related proteins LC3A/B were detected by western blot. Results: KU-55933 can enhance the effect of sorafenib in inhibiting cell proliferation and migration, overcoming EMT, inducing cell apoptosis via inactivating Akt signaling pathway and inducing autophage. The combination treatment with sorafenib and KU-55933 resulted in a strong synergistic effect in vitro. Conclusion: Our results demonstrate that sorafenib combined with KU-55933 treatment does effectively inhibit proliferation of HCC cell lines synergistically. These data suggests that KU-55933 may be a promising chemosensitizer to sorafenib in the treatment of HCC.

Exposure to chronic hyperglycemic conditions results in Ras-related C3 botulinum toxin substrate 1 (Rac1)-mediated activation of p53 and ATM kinase in pancreatic ß-cells.

Chronic hyperglycemia (HG) promotes pancreatic islet dysfunction which leads to the onset of T2DM. This study is aimed at defining regulatory roles of Rac1, a small G-protein, in the activation of p53 and ATM kinase in pancreatic ß-cells, under the duress of HG conditions. We report significant stimulatory effects of HG (20 mM; 24 h) on p53 activation in INS-1 832/13 cells, normal rodent and human islets. Pharmacological inhibition of Rac1 (EHT1864 or NSC23766) significantly suppressed HG-induced p53 activation in INS-1 832/13 cells and rat islets, suggesting novel roles for this small G-protein in the activation of p53. Inhibition of Rac1 geranylgeranylation with simvastatin or GGTI-2147, significantly attenuated HG-induced p53 activation, suggesting requisite roles for this signaling step in HG-mediated effects on ß-cells. HG-induced p53 activation was also suppressed by SB203580, a known inhibitor of p38MAPK. Additionally, we observed increased activation of ATM kinase under HG conditions, which was blocked in presence of EHT1864. Furthermore, pharmacological inhibition of ATM kinase (KU55933) reduced activation of ATM kinase, but not p53, suggesting that HG-mediated activation of p53 and ATM could represent independent pro-apoptotic events. In conclusion, these data indicate that sustained activation of Rac1-p38MAPK signaling axis leads to activation of p53 leading to ß-cell dysfunction under the duress of chronic hyperglycemic conditions.

Toxicity Studies of Ethyl Maltol and Iron Complexes in Mice.

Ethyl maltol and iron complexes are products of ethyl maltol and the iron found in the cooking pots used to prepare the Chinese dish, hot-pot. Because their safety is undocumented, the toxicity study of ethyl maltol and iron complexes was conducted in male and female Kunming (KM) mice. The animal study was designed based on the preliminary study conducted to determine the median lethal dose (LD50). The doses used in the study were 0, 1/81, 1/27, 1/9, and 1/3 of the LD50 (mg kg body weight (BW)-1 day-1) dissolved in the water. The oral LD50 of the ethyl maltol and iron complexes was determined to be 743.88 mg kg BW-1 in mice. The ethyl maltol and iron complexes targeted the endocrine organs including the liver and kidneys following the 90 D oral exposure. Based on the haematological data, the lowest-observed-adverse-effect level (LOAEL) of the ethyl maltol and iron complexes was determined to be 1/81 LD50 (9.18 mg kg BW-1 day-1) in both male and female mice. Therefore, we suggest that alternative strategies for preparing the hot-pot, including the use of non-Fe-based cookware, need to be developed and encouraged to avoid the formation of the potentially toxic complexes.

Randomized Open-Label Phase 1 Study of the Pharmacokinetics of Ferric Maltol in Inflammatory Bowel Disease Patients with Iron Deficiency.

BACKGROUND: Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD). Oral ferric maltol improves and normalizes hemoglobin (Hb) in patients with IBD. AIM: This open-label, randomized Phase 1 study evaluated the pharmacokinetics of ferric maltol and its effect on iron indices in IBD patients with iron deficiency (with or without anemia). METHODS: Iron deficient adult IBD patients received ferric maltol 30, 60, or 90 mg twice daily during an 8-day period. Pharmacokinetics and iron uptake were assessed on days 1 and 8. RESULTS: Twenty-four patients were included: 13 with Crohn's disease and 11 with ulcerative colitis (mean age 39 years; 67 % female, mean Hb 13.0 g/dL; mean reticulocyte Hb content (CHr) 31.9 pg; mean ferritin 13.9 µg/L). Plasma maltol and maltol glucuronide increased rapidly at all doses, reaching maximum plasma concentration (C max) 1.0-1.5 h post-dose and declining to baseline after 3-6 h. Maltol and maltol glucuronide exposure (area under the concentration-time curve; AUC) appeared dose proportional with twice-daily dosing, with higher exposure to maltol glucuronide vs. maltol. Mean day 8/day 1 ratios for C max and AUC0-t indicated no accumulation after 7 days of twice-daily dosing. Serum iron and transferrin saturation (TSAT) increased with all doses (maximum values at 1.5-3.0 h post-dose). Serum ferritin and CHr increased by day 8, with greater improvements with 60 and 90 mg twice-daily doses than with 30 mg twice-daily doses. CONCLUSIONS: The key constituents of ferric maltol showed predictable pharmacokinetics, with no accumulation over 7 days and increased iron uptake and storage over time at 30-90 mg twice-daily doses.