Search

Feline infectious peritonitis (FIP) is one of the most common infectious diseases in cats that is fatal when untreated. So far, there is no legally available effective treatment in Germany. Treatment options include only symptomatic treatment (e. g. glucocorticoids, propentofylline), immunomodulatory approaches (e. g. interferons, polyprenyl immunostimulant), and antiviral chemotherapy with protease inhibitors (e. g. GC376) or nucleoside analogues (e. g. GS-441524, remdesivir). Symptomatic treatment does not cure FIP but may lead to a short-term improvement of clinical signs in a subset of cats. Immunomodulatory treatment has also not shown to be very promising. In contrary, the antiviral compounds GS-441524 and GC376 exhibited significant efficacy in several studies and their use saved the lives of many cats suffering from FIP. However, both agents are currently not licensed and thus cannot be legally administered by veterinarians in Germany. Legally, cats may only be legally treated with GS-441524 in a few countries (e.g. Great Britain and Australia). In other countries, GS-441524 is imported by cat owners via the black market and administered on their own. This article provides an overview of the available treatment options and an outlook on the legal use of effective antiviral drugs., Competing Interests: Das Präparat Xraphconn® zur oralen Therapie der FIP wurde vom Hersteller Mutian (Mutian Life Sciences Limited, Nantong, China) kostenlos zur Verfügung gestellt., (Thieme. All rights reserved.)

Tackling the ancient infectious foe of malaria, Xie et al. (2022) uncover a novel class of nucleoside analogs that selectively hijack and inhibit the tyrosine tRNA synthase of the parasite. With high potency, good oral bioavailability, and minimal host cell toxicity, these inhibitors show promise as next-generation antimalarials., Competing Interests: Declaration of interests Dr. John is on the scientific advisory board of Pluton Biosciences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To investigate the therapeutic effect of Sishen Wan (, SSW) on ulcerative colitis (UC) induced by dinitrobenzene sulfonic acid and its effect on toll-like receptor 2/interleukin-1 receptor-associated kinase-4/nuclear factor-κB (TLR2/IRAK4/NF-κB) sig-naling pathway in colonic tissue., Methods: In this study, 120 Sprague-Dawley rats were randomly divided into blank and model groups. The experimental UC model in rats was established by subcutaneous injection of hydrocortisone + senna gavage for 21 d + dinitrobenzene sulfonic acid (DNBS)/ ethanol solution enema. The successful model rats were randomly divided into the model group; mesalazine (0.36 g/kg) group; and high-, medium-, and low- dose SSW (24, 12, and 6 g/kg) groups. The model and blank groups were gavaged with equal volumes of distilled water once a day for 21 d. The general condition of the rats was observed, and the body mass, fecal properties, and occult blood were recorded for calculating the disease activity index (DAI) score. The colonic tissue of the rats was collected, and its general morphology and pathological form were noted for obtaining the colonic mucosal injury index (CMDI) score. Hematoxylin-eosin staining was used to view the pathological changes of the colon tissue in each group, apoptosis of the cells was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, and quantitative real-time polymerase chain reaction was used to measure the expressions of TLR2, myeloid differentiation primary response gene 88 (MyD88), IRAK4, and NF-κB p65 mRNA in the colon tissue. The expressions of TLR2, MyD88, IRAK4, and NF-κB p65 protein were detected using western blotting and immunohistochemistry assay, and the levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the colon tissue were determined using enzyme linked immunosorbent assay., Results: Compared with the blank group, the general condition of the model group was relatively poor. The DAI and CMDI scores of the model group increased significantly (< 0.01), the glands and intestinal mucosa disappeared partially, and several inflammatory cells infiltrated and gathered in the mucosal layer and base layer of the rats in the model group. Furthermore, the cell apoptosis and expression levels of TLR2, MyD88, IRAK4, and NF-κB p65 mRNA and protein in the colon tissue of rats in the model group increased significantly (< 0.01). The levels of IL-1β and TNF-α increased significantly in the colon tissue of rats in the model group (< 0.01). After treatment with SSW, compared with the model group, the general condition of the UC rats improved. Moreover, the DAI and CMDI scores of the UC rats decreased significantly (< 0.05), and the pathological changes in the colon tissue of the UC rats tended to be normal. The cell apoptosis and expression levels of TLR2, MyD88, IRAK4, and NF-κB p65 mRNA and protein in the colon tissue of the UC rats decreased gradually ( < 0.01), and the levels of IL-1β and TNF-α decreased significantly (< 0.01)., Conclusion: SSW can improve the general condition and alleviate the intestinal mucosal injury of UC model rats. Additionally, SSW can inhibit the TLR2/IRAK4/ NF-κB signaling pathway, but further studies are required to confirm it.

Hypertension significantly increases the risk of cardiovascular disease. Currently, effective standard pharmacological treatment is available in the form of diuretics, ACE inhibitors, angiotensin II receptor blockers and calcium channel blockers. These all help to decrease blood pressure in hypertensive patients, each with their own mechanism. Recently, firibastat, a new first-in-class antihypertensive drug has been developed. Firibastat is a prodrug that when crossing the blood-brain barrier, is cleaved into two active EC33 molecules. EC33 is the active molecule that inhibits the enzyme aminopeptidase A. Aminopeptidase A converts angiotensin II to angiotensin III. Angiotensin III usually has three central mechanisms that increase blood pressure, so by inhibiting this enzyme activity, a decrease in blood pressure is seen. Firibastat is an antihypertensive drug that affects the brain renin angiotensin system by inhibiting aminopeptidase A. Clinical trials with firibastat have been performed in animals and humans. No severe adverse effects related to firibastat treatment have been reported. Results from studies show that firibastat is generally well tolerated and safe to use in hypertensive patients. The aim of this review is to investigate the current knowledge about firibastat in the treatment of hypertension.

Background & Aims: TOB1 is an anti-proliferative protein of Tob/BTG family and typically involved in the tumorigenesis and T cell activation. Although TOB1 is associated with T helper 17 cell-related autoimmunity, its role in modulating T cell-mediated immune responses in IBD remains poorly understood. Here, we explored its expression and the underlying mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD)., Methods: TOB1 and ID2 expression in IBD patients was examined by quantitative real time polymerase chain reaction and immunohistochemistry. IBD CD4 + T cells were transfected with lentivirus expressing TOB1, ID2, TOB1 short hairpin RNA and ID2 short hairpin RNA, respectively, and Tob1 -/- CD4 + T cells were transfected with lentivirus expressing Id2. Experimental colitis was established in Tob1 -/- mice by trinitrobenzene sulfonic acid enema and in Rag1 -/- mice reconstituted with Tob1 -/- CD45RB high CD4 + T cells to further explore the role of Tob1 in intestinal mucosal inflammation. Splenic CD4 + T cells of Tob1 -/- mice were sorted to determine transcriptome differences by RNA sequencing., Results: TOB1 expression was decreased in inflamed mucosa and peripheral blood CD4 + T cells of IBD patients compared with healthy subjects. Overexpression of TOB1 downregulated IBD CD4 + T cells to differentiate into Th1/Th17 cells compared with control subjects. Severe colitis was observed in Tob1 -/- mice through trinitrobenzene sulfonic acid enema or in Rag1 -/- mice reconstituted with Tob1 -/- CD45RB high CD4 + T cells, compared with control animals. RNA sequencing analysis revealed ID2 as functional target of TOB1 to inhibit IBD CD4 + T cell differentiation into Th1/Th17 cells. Mechanistically, TOB1 was associated with Smad4/5 to induce ID2 expression and restrain Th1/Th17 cell differentiation., Conclusions: TOB1 restrains intestinal mucosal inflammation through suppressing Th1/Th17 cell-mediated immune responses via the Smad4/5-ID2 pathway. It may serve as a novel therapeutic target for treatment of human IBD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Many pentacyclic triterpenoids show anti-cancer and anti-inflammatory properties. Recently, we detected a pronounced cytotoxicity and radiosensitivity of two betulinyl sulfamates in human breast cancer cells. Besides betulinic acid scaffold (BSBA-S), we synthesized several new sulfamate-coupled scaffolds from oleanolic acid (OSBA-S), ursolic acid (USBA-S), platanic acid (PSBA-S) and maslinic acid (MSBA-S). Highest cytotoxicity was monitored in breast cancer cell lines after MSBA-S treatment showing in SRB assays IC 50 values between 3.7 μM and 5.8 μM. Other sulfamate/triterpene conjugates, however, were less cytotoxic holding IC 50 values between 6.6 μM and >50 µM, respectively. MSBA-S-treated breast cancer cells displayed significantly reduced clonogenic survival and an increased rate of apoptosis as compared to the other conjugates. In addition, MSBA-S in combination with irradiation resulted in effects on radiosensitivity in MDA-MB-231 cells (DMF 10  = 1.14). In particular, ROS formation was strongly assessed in MSBA-S-treated breast cancer cells. Our findings suggest that the sulfamate derivative of maslinic acid MSBA-S might be a new option for the radiation therapy in breast cancer cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Purpose: Probiotics have been shown to exert beneficial effects in IBD although their exact mechanisms are not completely understood. The aim of the present study was to assess the intestinal anti-inflammatory activity of different probiotics (Lactobacillus fermentum CECT5716, Lactobacillus salivarius CECT5713, Escherichia coli Nissle 1917, Saccharomyces boulardii CNCMI-745 in the dinitrobenzene sulfonic acid (DNBS) model of mouse colitis and correlate it with the modifications of the gut microbiota and the immune response, focusing on miRNA expression., Methods: The probiotics were daily administered orally for 25 days. On day 19 colitis was induced by rectal installation of DNBS. At the end of the treatment, mice were sacrificed and the colonic damage was assessed biochemically by analysing the expression of different markers involved in the immune response, including miRNAs; and the colonic microbiota by pyrosequencing. Probiotics properties were also evaluated in vitro in different immune cell types (CMT-93 intestinal epithelial cells and bone marrow-derived macrophages), where the expression of different mRNAs and miRNAs was examined., Results: All the probiotics displayed intestinal anti-inflammatory effects but slightly different, especially regarding miRNAs expression. Likewise, the probiotics ameliorated the colitis-associated dysbiosis, although showing differences in the main bacterial groups affected., Conclusion: Among the probiotics assayed, Lactobacillus fermentum CECT5716 and Escherichia coli Nissle 1917 appear to present the best intestinal anti-inflammatory effects, being the latter one of the few probiotics with reputed efficacy in human IBD. Therefore, Lactobacillus fermentum CECT5716 could be considered as a complementary nutritional strategy for IBD treatment., (© 2020. Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Receptor-type vascular endothelial protein tyrosine phosphatase (VE-PTP) dephosphorylates Tie-2 as well as CD31, VE-cadherin, and vascular endothelial growth factor receptor 2 (VEGFR2). The latter form a signal transduction complex that mediates the endothelial cell response to shear stress, including the activation of the endothelial nitric oxide (NO) synthase (eNOS). As VE-PTP expression is increased in diabetes, we investigated the consequences of VE-PTP inhibition (using AKB-9778) on blood pressure in diabetic patients and the role of VE-PTP in the regulation of eNOS activity and vascular reactivity., Methods and Results: In diabetic patients AKB-9778 significantly lowered systolic and diastolic blood pressure. This could be linked to elevated NO production, as AKB increased NO generation by cultured endothelial cells and elicited the NOS inhibitor-sensitive relaxation of endothelium-intact rings of mouse aorta. At the molecular level, VE-PTP inhibition increased the phosphorylation of eNOS on Tyr81 and Ser1177 (human sequence). The PIEZO1 activator Yoda1, which was used to mimic the response to shear stress, also increased eNOS Tyr81 phosphorylation, an effect that was enhanced by VE-PTP inhibition. Two kinases, i.e. abelson-tyrosine protein kinase (ABL)1 and Src were identified as eNOS Tyr81 kinases as their inhibition and down-regulation significantly reduced the basal and Yoda1-induced tyrosine phosphorylation and activity of eNOS. VE-PTP, on the other hand, formed a complex with eNOS in endothelial cells and directly dephosphorylated eNOS Tyr81 in vitro. Finally, phosphorylation of eNOS on Tyr80 (murine sequence) was found to be reduced in diabetic mice and diabetes-induced endothelial dysfunction (isolated aortic rings) was blunted by VE-PTP inhibition., Conclusions: VE-PTP inhibition enhances eNOS activity to improve endothelial function and decrease blood pressure indirectly, through the activation of Tie-2 and the CD31/VE-cadherin/VEGFR2 complex, and directly by dephosphorylating eNOS Tyr81. VE-PTP inhibition, therefore, represents an attractive novel therapeutic option for diabetes-induced endothelial dysfunction and hypertension., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO-TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.

In this work, an anionic conjugated polyelectrolyte (PCP-SO3K), in which the backbone contains alternating 4,4-bis-alkyl-4H-cyclopenta-[2,1-b;3,4-b']-dithiophene and benzene structural units and the charges are provided by pendant sulfonate groups, was synthesized. The ionic nature of PCP-SO3K renders it soluble in water, and PCP-SO3K aqueous solution exhibits good photostability, with two main absorbance bands centered at 490 nm and 837 nm before and after laser irradiation. Its NIR absorption in water, negligible photoluminescence and insignificant intersystem crossing endow PCP-SO3K with efficient photothermal therapy performance, and an effective photothermal conversion efficiency of 56.7% was realized. Thus, PCP-SO3K aqueous solution can be used as an effective photothermal agent for in vivo applications as its photoactivity can be triggered by NIR light and can convert laser energy into thermal energy in a water environment. Of particular importance is the fact that complete tumor remission without recurrence in 4T1 tumor-bearing mice was realized after intravenous injection of PCP-SO3K aqueous solution and laser irradiation (2.0 W cm-2, 808 nm). The results indicate that the application of anionic conjugated polyelectrolytes as photothermal agents in photothermal therapy provides a new platform for the design of photothermal agents for clinical cancer treatment.

Aspartate/asparagine β‑hydroxylase (AspH) is a type II transmembrane protein that catalyzes the post‑translational hydroxylation of definite aspartyl and asparaginyl residues in epidermal growth factor‑like domains of substrates. In the last few decades, accumulating evidence has indicated that AspH expression is upregulated in numerous types of human malignant cancer and is associated with poor survival and prognosis. The AspH protein aggregates on the surface of tumor cells, which contributes to inducing tumor cell migration, infiltration and metastasis. However, small‑molecule inhibitors targeting hydroxylase activity can markedly block these processes, both in vitro and in vivo. Immunization of tumor‑bearing mice with a phage vaccine fused with the AspH protein can substantially delay tumor growth and progression. Additionally, AspH antigen‑specific CD4+ and CD8+ T cells were identified in the spleen of tumor‑bearing mice. Therefore, these agents may be used as novel strategies for cancer treatment. The present review summarizes the current progress on the underlying mechanisms of AspH expression in cancer development.

Post-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries. Currently, no effective treatment is available. In this study, we showed that inhibition of the acute stage chondrocyte death is a promising strategy to mitigate the development of PTOA. Namely, we examined efficacies of Kyoto University Substance (KUS) 121, a valosin-containing protein modulator, for PTOA as well as its therapeutic mechanisms. In vivo, in a rat PTOA model by cyclic compressive loading, intra-articular treatments of KUS121 significantly improved the modified Mankin scores and reduced damaged-cartilage volumes, as compared to vehicle treatment. Moreover, KUS121 markedly reduced the numbers of TUNEL-, CHOP-, MMP-13-, and ADAMTS-5-positive chondrocytes in the damaged knees. In vitro, KUS121 rescued human articular chondrocytes from tunicamycin-induced cell death, in both monolayer culture and cartilage explants. It also significantly downregulated the protein or gene expression of ER stress markers, proinflammatory cytokines, and extracellular-matrix-degrading enzymes induced by tunicamycin or IL-1β. Collectively, these results demonstrated that KUS121 protected chondrocytes from cell death through the inhibition of excessive ER stress. Therefore, KUS121 would be a new, promising therapeutic agent with a protective effect on the progression of PTOA.

Equine sarcoid (ES) is the most prevalent skin tumor in equids worldwide. Additionally, aging grey horses frequently suffer from equine malignant melanoma (EMM). Current local therapies targeting these skin tumors remain challenging. Therefore, more feasible topical treatment options should be considered. In order to develop a topical therapy against ES and EMM, betulinyl-bis-sulfamate and NVX-207, derivatives of the naturally occurring betulin and betulinic acid, respectively, were evaluated for their antiproliferative (crystal violet staining assay), cytotoxic (MTS assay) and apoptotic (AnnexinV staining, cell cycle investigations) effects on primary ES cells, EMM cells and equine dermal fibroblasts in vitro. The more potent derivative was assessed for its in vitro penetration and permeation on isolated equine skin within 30 min and 24 h using Franz-type diffusion cells and HPLC analysis. Betulinyl-bis-sulfamate and NVX-207 inhibited the proliferation and metabolism in ES cells, EMM cells and fibroblasts significantly (p < 0.001) in a time- and dose-dependent manner. NVX-207 had superior anticancer effects compared to betulinyl-bis-sulfamate. Both compounds led to the externalization of phosphatidylserines on the cell membrane and DNA fragmentation, demonstrating that the effective mode of action was apoptosis. After 48 h of treatment with NVX-207, the number of necrotic cells was less than 2% in all cell types. Detected amounts of NVX-207 in the different skin layers exceeded the half-maximal inhibitory concentrations calculated by far. Even though data obtained in vitro are auspicious, the results are not unconditionally applicable to the clinical situation. Consequently, in vivo studies are required to address the antitumoral effects of topically applied NVX-207 in ES and EMM patients., Competing Interests: The authors declare that no competing interests exist. The affiliation "BioSolutions Halle GmbH” of Dr. Jutta Kalbitz does not alter our adherence to PLOS ONE policies on sharing data and materials. As described in the Funding Statement, BioSolutions Halle GmbH is not a commercial funder, but an equal partner in the TopiDrugHorse project.

Our previous study showed that propane-2-sulfonic acid octadec-9-enyl-amide (N15), a novel peroxisome proliferator-activated receptor α and γ (PPARα/γ) dual agonist, inhibits inflammatory responses in tumor necrosis factor alpha (TNFα)-induced vascular endothelial cells or lipopolysaccharide (LPS)-induced human myeloid leukemia mononuclear cells-1. However, little is known about whether N15 applies to other pathological or neuroinflammatory conditions. In the present study, we detected the effect of N15 on the LPS-induced neuroinflammatory response in mice and further investigated whether the effect of N15 on neuroinflammation and neuronal cells survival was related to PPARα/γ dual pathways. We found that N15 decreased the mRNA expression of the proinflammatory cytokines IL-1β, IL-6, TNFα, inducible nitric oxide synthase and cyclooxygenase-2; inhibited microglial activation; and ameliorated neuronal apoptosis in the hippocampus and cortex of LPS-induced mice. In addition, PPARα antagonist MK886 or PPARγ antagonist T0070907 partially eliminated the effect of N15. These results demonstrate that N15 exerts an anti-inflammatory effect, at least in part, by enhancing PPARα/γ dual signaling. Our study reveals that N15 may be a promising neuronal protective drug for the treatment of neuroinflammatory diseases.

Our previous reports demonstrated that the novel peroxisome proliferator-activated receptors α and γ (PPARα/γ) dual agonist propane-2-sulfonic acid octadec-9-enyl-amide (N15) alleviates cognitive ability in the chronic phase of ischemic stroke. However, the potential effects of N15 on Alzheimer's disease (AD) animal models have not been elucidated. In the present study, we investigated the effects of N15 on scopolamine-induced cognitive dysfunction and cholinergic system ability. N15 (50, 100 or 200 mg/kg) was administered to mice via oral gavage for 21 days, and spatial cognitive dysfunction was induced via an intraperitoneal injection of scopolamine (4 mg/kg) for 6 days. We found that N15 pretreatment markedly ameliorated scopolamine-induced spatial cognitive impairment and enhanced cholinergic system reactivity in the hippocampus. N15 pretreatment also significantly increased the expression levels of growth-associated protein-43, synaptophysin, brain-derived neurotrophic factor and neurotrophin-3 in the hippocampus. Our data demonstrate that N15 has an anti-amnesic effect, which may be mediated by enhancing cholinergic activity and synaptic plasticity. These findings support N15 as a potent neuropharmacological drug against AD., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier Inc.)

The pathophysiology of heart failure (HF) and hypertension are thought to involve brain renin-angiotensin system (RAS) hyperactivity. Angiotensin III, a key effector peptide in the brain RAS, provides tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme responsible for generating brain angiotensin III, constitutes a potential therapeutic target for hypertension treatment. We focus here on studies of RB150/firibastat, the first prodrug of the specific and selective APA inhibitor EC33 able to cross the blood-brain barrier. We consider its development from therapeutic target discovery to clinical trials of the prodrug. After oral administration, firibastat crosses the gastrointestinal and blood-brain barriers. On arrival in the brain, it is cleaved to generate EC33, which inhibits brain APA activity, lowering BP in various experimental models of hypertension. Firibastat was clinically and biologically well tolerated, even at high doses, in phase I trials conducted in healthy human subjects. It was then shown to decrease BP effectively in patients of various ethnic origins with hypertension in phase II trials. Brain RAS hyperactivity leads to excessive sympathetic activity, which can contribute to HF after myocardial infarction (MI). Chronic treatment with oral firibastat (4 or 8 weeks after MI) has been shown to normalize brain APA activity in mice. This effect is accompanied by a normalization of brain RAS and sympathetic activities, reducing cardiac fibrosis and hypertrophy and preventing cardiac dysfunction. Firibastat may therefore represent a novel therapeutic advance in the clinical management of patients with hypertension and potentially with HF after MI., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Selective estrogen receptor modulators (SERMs) are a class of structurally diverse compounds, which have been extensively used to treat hormone-responsive cancers due to their unique partially agonistic and antagonistic properties toward estrogen receptors. Our previous studies have identified a three-dimensional SERM, oxabicycloheptene sulfonate (OBHS), as an estrogen receptor α (ERα) ligand, which is effective for the prevention and treatment of estrogen-dependent endometriosis in vivo. Here, using genome-wide ChIP-seq and RNA-seq analysis, we report that OBHS rapidly induces genome-wide ERα occupancy and acts as a partial agonist and antagonist for ERα. Interestingly, OBHS downregulates the homologous recombination and repair (HRR) modules, resulting in increased DNA damage, apoptosis and cell cycle arrest, inducing synthetic lethality with poly (ADP-ribose) polymerase (PARP) inhibitor olaparib through ERα antagonism. Mechanistically, OBHS impairs the RNA polymerase II (Pol II) loading at the promoters of estrogen-responsive HRR genes. Furthermore, combination therapy of OBHS with olaparib significantly reduces the tumour burden and delays the progression of breast cancer in vivo. Together, our studies not only characterise a novel SERM which uniquely targets the homologous recombination and repair programmes through ERα antagonism but also propose a synthetic lethal strategy by combining OBHS with PARP inhibitor olaparib for ERα-responsive cancers., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells/tissues. Upregulation of the CAIX/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal structure of the catalytic domains of CAIX/XII provided the basis for the generation of CAIX/XII selective inhibitors based on the sulfonamide, sulfamate and coumarins chemical structures. Ureido-substituted benzenesulfonamide CAIX/XII inhibitors have shown significant potential, with U-104 (SLC-0111) currently present in clinical Phase I/II. Ureido-substituted sulfamate CAIX/XII inhibitors have received less attention despite encouraging preclinical test results. In triple-negative breast cancer (TNBC), ureidosulfamates revealed a significant antitumour (FC9-398A) and antimetastatic potential (S4). In small cell lung cancer (SCLC), a cancer cell type very sensitive to a dysregulation in CAIX signaling, S4 treatment was particularly effective when combined with cisplatin with no evidence of acquired cisplatin-resistance. These successful anticancer strategies should provide a solid basis for future studies on ureido-substituted sulfamates.

Administration of interleukin (IL)-2 has led to a durable response in patients with advanced renal cancer and melanoma but is restricted for clinical application because of adverse effects, including the vascular leak syndrome (VLS). VLS is associated with increased circulating levels of the Tie2 antagonist ligand, angiopoietin 2, and decreased Tie2 receptor phosphorylation and downstream signaling in endothelial cells (ECs). Given that vascular endothelial protein tyrosine phosphatase (VE-PTP) is a specific membrane phosphatase in ECs that dephosphorylates Tie2, the effects of targeting VE-PTP by a selective inhibitor AKB-9778 (AKB) in terms of VLS and antitumor efficacy were examined in this study. The authors found, by targeting VE-PTP, that the antitumor effects induced by IL-2 were augmented [tumor-free 44% (IL-2 alone) vs. 87.5% (IL-2+AKB)], associated with enhanced immune cell infiltrate (90% increase for CD8 T cells and natural killer cells). In addition, the side effects of IL-2 therapy were lessened, as demonstrated by diminished lung weight (less vascular leakage) as well as reduced cytokine levels (serum HMGB1 from 137.04±2.69 to 43.86±3.65 pg/mL; interferon-γ from 590.52±90.52 to 31.37±1.14 pg/mL). The authors further sought to determine the potential mechanism of the action of AKB-9778. The findings suggest that AKB-9778 may function through reducing serum angiopoietin 2 level and regulating EC viability. These findings provide insights into the targeting VE-PTP to improve tolerance and efficacy of IL-2 therapy and highlight the clinical potential of AKB-9778 for treating patients with VLS and cancer.

Reduced adenosine triphosphate (ATP) levels in ischemic stroke constitute an upstream contributor to neuronal cell death. We have recently created a small chemical, named Kyoto University Substance 121 (KUS121), which can reduce cellular ATP consumption. In this study, we examined whether KUS121 has neuroprotective effects in rodent cerebral ischemia models. We evaluated cell viability and ATP levels in vitro after oxygen glucose deprivation (OGD) in rat cortical primary neuronal cultures incubated with or without KUS121. We found that KUS121 protected neurons from cell death under OGD by preventing ATP depletion. We also used in vivo ischemic stroke models of transient distal middle cerebral artery occlusion in C57BL/6 and B-17 mice. Administration of KUS121 in these models improved functional deficits and reduced brain infarction volume after transient focal cerebral ischemia in both C57BL/6 and B-17 mice. These results indicate that KUS121 could be a novel type of neuroprotective drug for ischemic stroke.

Objectives: We conducted a pilot multicenter double-blind randomized placebo-controlled crossover pharmacodynamic study to evaluate the blood pressure (BP) and the hormonal effects of firibastat, a first-in-class aminopeptidase A inhibitor prodrug, in patients with hypertension., Methods: Thirty-four patients with daytime ambulatory BP of at least 135/85 mmHg and less than 170/105 mmHg, after a 2-week run-in period were randomly assigned to receive either firibastat (250 mg b.i.d. for 1 week uptitrated to 500 mg b.i.d. for 3 weeks) and then placebo for 4 weeks each or vice versa, with a 2-week washout period on placebo., Results: At 4 weeks, daytime ambulatory systolic BP (SBP) decreased by 2.7 mmHg (95% confidence interval -6.5 to +1.1 mmHg) with firibastat versus placebo (P = 0.157). Office SBP decreased by 4.7 mmHg (95% confidence interval -11.1 to +1.8 mmHg) with firibastat versus placebo (P = 0.151). However, more the basal daytime ambulatory SBP was elevated, more the firibastat-induced BP decrease was marked. Firibastat did not influence 24h-ambulatory heart rate. Firibastat had no effect on plasma renin, aldosterone, apelin and copeptin concentrations. No major adverse events occurred. There was one episode of reversible skin allergy with facial edema., Conclusion: In patients with hypertension, a 4-week treatment with firibastat, tended to decrease daytime SBP relative to placebo. Firibastat did not modify the activity of the systemic renin-angiotensin system These results have justified designing a larger, powered trial of longer duration to fully assess its safety and effectiveness., Clinical Trial Registration: http://www.clinicaltrials.gov. NCT02322450.

Diabetic nephropathy is the commonest cause of end-stage renal disease and affects between 30 and 45% of patients with diabetes mellitus. There is no cure for diabetic nephropathy and the current management of this condition includes glycaemic control, blockade of the renin-angiotensin aldosterone system and lifestyle changes. However, many patients eventually progress to end-stage renal disease. The exact pathogenesis of diabetic nephropathy is still being researched, and recent advances have led to the development of several novel potential therapeutic targets. There are a number of different experimental therapies that are currently being assessed. Generally, these can be separated into drugs targeting vasculature/haemodynamic effects, drugs targeting inflammation and drugs targeting oxidative stress. Drugs targeting the vasculature include Tie-2 activators, -sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists. Anti-inflammatory therapies include inflammatory cytokines inhibitors, pentoxifylline, as well as anti-transforming growth factor α/-epiregulin therapies. Finally, anti-oxidative stress therapies include nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors and allopurinol. Many new trials are providing promising results and it is likely that some of these therapies will be available for clinical use within the next decade. This article will seek to outline the main advancements in each of these experimental therapies for diabetic nephropathy. Results: Abnormal vascular remodelling, inflammation and oxidative stress seem to be the 3 main sources from which future new drugs for diabetic kidney disease will originate., (© 2018 S. Karger AG, Basel.)

Peroxisome proliferator-activated receptor alpha/gamma (PPARα/γ) agonists have emerged as important pharmacological agents for improving insulin action. Propane-2-sulfonic acid octadec-9-enyl-amide (N15) is a novel PPARα/γ dual agonist synthesized in our laboratory. The present study investigates the efficacy and safety of N15 on insulin resistance regulation in high fat diet (HFD)-and streptozotocin (STZ)-induced diabetic mice and in palmitic acid (PA)-induced HepG2 cells. Our results showed that N15 remarkably ameliorated insulin resistance and dyslipidemia in vivo, as well as rectified the glucose consumption and gluconeogenesis in vitro. Moreover, the glucose-lowering effect of N15 was associated with PPARγ mediated up-regulation of hepatic glucose consumption and down-regulation of gluconeogenesis. Meanwhile, N15 exerted advantageous effects on glucose and lipid metabolism without triggering weight gain and hepatotoxicity in mice. In conclusion, our data demonstrated that by alleviating glucose and lipid abnormalities, N15 could be used as a potential prophylactic and therapeutic agent against type 2 diabetes and related metabolic disorders., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Objective: Hyperactivity of the brain renin-angiotensin (Ang) system has been implicated in the development and maintenance of hypertension. AngIII, one of the main effector peptides of the brain renin-Ang system, exerts a tonic stimulatory control over blood pressure (BP) in hypertensive rats. Aminopeptidase A (APA), the enzyme generating brain AngIII, represents a new therapeutic target for the treatment of hypertension. We developed RB150, a prodrug of the specific and selective APA inhibitor, EC33. When given orally in acute treatment in hypertensive rats, RB150 crosses the gastrointestinal and blood-brain barriers, enters the brain, inhibits brain APA activity and decreases BP. We investigate, here, the antihypertensive effects of chronic oral RB150 (50 mg/kg per day) treatment over 24 days in alert hypertensive deoxycorticosterone acetate-salt rats., Methods: We measured variations in Brain APA enzymatic activity, SBP, plasma arginine vasopressin levels and metabolic parameters after RB150 chronic administration., Results: This resulted in a significant decrease in SBP over the 24-day treatment period showing that no tolerance to the antihypertensive RB150 effect was observed throughout the treatment period. Chronic RB150 treatment also significantly decreased plasma arginine vasopressin levels and increased diuresis, which participate to BP decrease by reducing the size of fluid compartment. Interestingly, we observed an increased natriuresis without modifying both plasma sodium and potassium levels., Conclusion: Our results strengthen the interest of developing RB150 as a novel central-acting antihypertensive agent and evaluating its efficacy in salt-sensitive hypertension.

Direct-acting antivirals (DAAs), which target hepatitis C virus (HCV) proteins, have exhibited impressive efficacy in the management of chronic hepatitis C. However, the concerns regarding high costs, drug resistance mutations and subsequent unexpected side effects still call for the development of host-targeting agents (HTAs) that target host factors involved in the viral life cycle and exhibit pan-genotypic antiviral activity. Given the close relationship between lipid metabolism and the HCV life cycle, we investigated the anti-HCV activity of a series of lipid-lowering drugs that have been approved by government administrations or proven safety in clinical trials. Our results showed that avasimibe, an inhibitor of acyl coenzyme A:cholesterol acyltransferase (ACAT), exhibited marked pan-genotypic inhibitory activity and superior inhibition against HCV when combined with DAAs. Moreover, avasimibe significantly impaired the assembly of infectious HCV virions. Mechanistic studies demonstrated that avasimibe induced downregulation of microsomal triglyceride transfer protein expression, resulting in reduced apolipoprotein E and apolipoprotein B secretion. Therefore, the pan-genotypic antiviral activity and clinically proven safety endow avasimibe exceptional potential as a candidate for combination therapy with DAAs. In addition, the discovery of the antiviral properties of ACAT inhibitors also suggests that inhibiting the synthesis of cholesteryl esters might be an additional target for the therapeutic intervention for chronic HCV infection., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Atypical protein kinase Cs (aPKC) are involved in cell cycle progression, tumorigenesis, cell survival and migration in many cancers. We believe that aPKCs play an important role in cell motility of melanoma by regulating cell signaling pathways and inducing epithelial to mesenchymal transition (EMT). We have investigated the effects of two novel aPKC inhibitors; 2-acetyl-1,3-cyclopentanedione (ACPD) and 3,4-diaminonaphthalene-2,7-disulfonic acid (DNDA) on cell proliferation, apoptosis, migration and invasion of two malignant melanoma cell lines compared to normal melanocytes. Molecular docking data suggested that both inhibitors specifically bind to protein kinase C-zeta (PKC-ζ) and PKC-iota (PKC-ι) and kinase activity assays were carried out to confirm these observations. Both inhibitors decreased the levels of total and phosphorylated PKC-ζ and PKC-ι. Increased levels of E-cadherin, RhoA, PTEN and decreased levels of phosphorylated vimentin, total vimentin, CD44, β-catenin and phosphorylated AKT in inhibitor treated cells. This suggests that inhibition of both PKC-ζ and PKC-ι using ACPD and DNDA downregulates EMT and induces apoptosis in melanoma cells. We also carried out PKC-ι and PKC-ζ directed siRNA treatments to prove the above observations. Immunoprecipitation data suggested an association between PKC-ι and vimentin and PKC-ι siRNA treatments confirmed that PKC-ι activates vimentin by phosphorylation. These results further suggested that PKC-ι is involved in signaling pathways which upregulate EMT and which can be effectively suppressed using ACPD and DNDA. Our results summarize that melanoma cells proliferate via aPKC/AKT/NF-κB mediated pathway while inducing the EMT via PKC-ι/Par6/RhoA pathway. Overall, results show that aPKCs are essential for melanoma progression and metastasis, suggesting that ACPD and DNDA can be effectively used as potential therapeutic drugs for melanoma by inhibiting aPKCs.

Objective: Advanced/metastatic or recurrent endometrial cancer has a poor prognosis. Malignant endometrial tissue has high steroid sulphatase (STS) activity. The aim of this study was to evaluate STS as a therapeutic target in patients with endometrial cancer., Methods: This was a phase 2, multicenter, international, open-label, randomized (1:1), 2-arm study of the STS inhibitor oral irosustat 40 mg/d versus oral megestrol acetate 160 mg/d in women with advanced/metastatic or recurrent estrogen receptor-positive endometrial cancer. The primary end point was the proportion of patients without progression or death 6 months after start of treatment. Secondary end points included progression-free survival, time to progression, overall survival, and safety., Results: Seventy-one patients were treated (36 with irosustat, 35 with megestrol acetate). The study was prematurely stopped after futility analysis. Overall, 36.1% and 54.1% of patients receiving irosustat or megestrol acetate had not progressed or died at 6 months, respectively. There were no statistically significant differences between irosustat and megestrol acetate in response and overall survival rates. Irosustat patients had a median progression-free survival of 16 weeks (90% confidence interval, 9.0-31.4) versus 40 weeks (90% confidence interval, 16.3-64.0) in megestrol acetate patients. Treatment-related adverse events occurred in 20 (55.6%) and 13 (37.1%) patients receiving irosustat or megestrol, respectively. Most adverse events in both groups were grade 1 or 2., Conclusions: Although irosustat monotherapy did not attain a level of activity sufficient for further development in patients with advanced/recurrent endometrial cancer, this study confirms the activity of hormonal treatment (megestrol acetate) for this indication.

Tie2 is a tyrosine kinase receptor located predominantly on vascular endothelial cells that plays a central role in vascular stability. Angiopoietin-1 (Angpt1), produced by perivascular cells, binds, clusters, and activates Tie2, leading to Tie2 autophosphorylation and downstream signaling. Activated Tie2 increases endothelial cell survival, adhesion, and cell junction integrity, thereby stabilizing the vasculature. Angiopoietin-2 (Angpt2) and vascular endothelial-protein tyrosine phosphatase (VE-PTP) are negative regulators increased by hypoxia; they inactivate Tie2, destabilizing the vasculature and increasing responsiveness to vascular endothelial growth factor (VEGF) and other inflammatory cytokines that stimulate vascular leakage and neovascularization. AKB-9778 is a small-molecule antagonist of VE-PTP which increases phosphorylation of Tie2 even in the presence of high Angpt2 levels. In preclinical studies, AKB-9778 reduced VEGF-induced leakage and ocular neovascularization (NV) and showed additive benefit when combined with VEGF suppression. In two clinical trials in diabetic macular edema (DME) patients, subcutaneous injections of AKB-9778 were safe and provided added benefit to VEGF suppression. Preliminary data suggest that AKB-9778 monotherapy improves diabetic retinopathy. These data suggest that Tie2 activation may be a valuable strategy to treat or prevent diabetic retinopathy.

Our group synthesized propane-2-sulfonic acid octadec-9-enyl-amide (N15), a novel peroxisome proliferator activated receptor alpha (PPARα) agonist. Because PPARα activation is associated with inflammation control, we hypothesize that N15 may have anti-inflammatory effects. We investigated the effect of N15 on the regulation of inflammation in THP-1 cells stimulated with lipopolysaccharide (LPS). In particular, we assessed the production of chemokines, adhesion molecules and proinflammatory cytokines, three important types of cytokines that are released from monocytes and are involved in the development of atherosclerosis. The results showed that N15 remarkably reduced the mRNA expression of chemokines, such as monocyte chemotactic protein 1 (MCP-1 or CCL2), interleukin-8 (IL-8) and interferon-inducible protein-10 (IP-10 or CXCL10), and proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6). N15 also decreased the protein expression of vascular cell adhesion molecule (VCAM) and matrix metalloproteinase (MMP) 2 and 9. The reduction in the expression of cytokine mRNAs observed following N15 treatment was abrogated in THP-1 cells treated with PPARα siRNA, indicating that the anti-inflammatory effects of N15 are dependent on PPARα activation. Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) inhibition, which are dependent on PPARα activation, were also involved in the mechanism underlying the anti-inflammatory effects of N15. In conclusion, the novel PPARα agonist, N15, exerts notable anti-inflammatory effects, which are mediated via PPARα activation and TLR4/NF-κB and STAT3 inhibition, in LPS-stimulated THP-1 cells. In our study, N15 exhibits promise for the treatment of atherosclerosis., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: To assess the effect of AKB-9778 alone or in combination with ranibizumab in subjects with diabetic macular edema (DME)., Design: A phase IIa, randomized, placebo- and sham injection-controlled, double-masked clinical trial., Participants: Subjects (n = 144) with decreased vision from DME and central subfield thickness (CST) ≥325 μm measured by spectral-domain optical coherence tomography (SD OCT) enrolled at 36 sites., Methods: Subjects were randomized to (1) AKB-9778 monotherapy: subcutaneous AKB-9778 15 mg twice per day (BID) + monthly sham intraocular injections; (2) combination therapy: subcutaneous AKB-9778 15 mg BID + monthly 0.3 mg ranibizumab; or (3) ranibizumab monotherapy: subcutaneous placebo injections BID + monthly 0.3 mg ranibizumab. Best-corrected visual acuity (BCVA) and CST were measured at baseline and every 4 weeks., Main Outcome Measures: Primary outcome measure was mean change from baseline CST at week 12. Other outcomes included BCVA, safety assessments, and Diabetic Retinopathy Severity Score (DRSS)., Results: At week 12, mean change from baseline CST was significantly greater in the combination group (-164.4±24.2 μm) compared with the ranibizumab monotherapy group (-110.4±17.2 μm; P = 0.008) and was 6.2±13.0 μm in the AKB-9778 monotherapy group. Mean CST at week 12 and percentage of eyes with resolved edema was 340.0±11.2 μm and 29.2%, respectively, in the combination group versus 392.1±17.1 μm and 17.0%, respectively, in the ranibizumab monotherapy group. Mean change from baseline BCVA (letters) was 6.3±1.3 in the combination group, 5.7±1.2 in the ranibizumab monotherapy group, and 1.5±1.2 in the AKB-9778 monotherapy group. The percentage of study eyes that gained ≥10 or ≥15 letters was 8.7% and 4.3%, respectively, in the AKB-9778 monotherapy group, 29.8% and 17.0%, respectively, in the ranibizumab monotherapy group, and 35.4% and 20.8%, respectively, in the combination group. Improvements in DRSS in study eyes were similar across groups, and the percentage of qualified fellow eyes with a ≥2-step change was 11.4% in all AKB-9778-treated subjects compared with 4.2% in the ranibizumab monotherapy group. AKB-9778 was well tolerated, with no clear by-treatment differences in adverse events., Conclusions: Activation of Tie2 by subcutaneous injections of AKB-9778 combined with suppression of vascular endothelial growth factor (VEGF) causes a significantly greater reduction in DME than that seen with suppression of VEGF alone., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

A series of alkyl nitrohydroxytyrosyl ether derivatives has been synthesized from free hydroxytyrosol (HT), the natural olive oil phenol, in order to increase the assortment of compounds with potential neuroprotective activity in Parkinson's disease. In this work, the antioxidant activity of these novel compounds has been evaluated using Ferric Reducing Antioxidant Power (FRAP), 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), and Oxygen Radical Scavenging Capacity (ORAC) assays compared to that of nitrohydroxytyrosol (NO₂HT) and free HT. New compounds showed variable antioxidant activity depending on the alkyl side chain length; compounds with short chains (2-4 carbon atoms) maintained or even improved the antioxidant activity compared to NO₂HT and/or HT, whereas those with longer side chains (6-8 carbon atoms) showed lower activity than NO₂HT but higher than HT.

One new alkyl sulfonic acid derivative, sulfotanone (1), and the known panosialin wA (2) were isolated from the methanolic extract of mycelium of Streptomyces sp. 11694. The structure of the new compound (1) was established by a combination of spectroscopic techniques, including HRESIMS, IR, 1D and 2D NMR measurements. Compound 1 (40 µM) in combination with TRAIL showed synergistic activity in sensitizing TRAIL-resistance in human gastric adenocarcinoma cell lines.

CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

We report herein the design and optimization of a novel series of sulfamides and sulfamates derived from amino esters with anticonvulsant properties. The structures were designed based on the pharmacophoric pattern previously proposed, with the aim of improving the anticonvulsant action. The compounds were obtained by a new synthetic procedure with microwave assisted heating and the use of adsorbents in the isolation process. All the derivatives showed protection against the maximal electroshock seizure test (MES test) in mice at the lowest dose tested (30 mg/kg) but they did not show significant protection against the chemical induced convulsion by pentylenetetrazole. These results verify the ability of the computational model for designing new anticonvulsants structures with anti-MES activity. Additionally, we evaluated the capacity of the synthesized structures to bind to the benzodiazepine binding site (BDZ-bs) of the γ-aminobutiric acid receptor (GABAA receptor). Some of them showed medium to low affinity for the BDZ-bs., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Introduction: Carbonic anhydrase inhibitors (CAIs) of the sulfonamide and sulfamate type are clinically used drugs as diuretics, antiglaucoma, antiepileptic, antiobesity and anti-high altitude disease agents. Anticancer agents based on CAIs are also in clinical development for the management of hypoxic, metastatic tumors. Acetazolamide, methazolamide, dichlorophenamide, dorzolamide and brinzolamide are mainly used as antiglaucoma drugs, sulthiame, topiramate and zonisamide as antiepileptic/antiobesity agents, celecoxib and polmacoxib are dual carbonic anhydrase/cycloxygenase inhibitors. Girentuximab, a monoclonal antibody and SLC-0111, a sulfonamide inhibitor, are in clinical trials as anticancer agents., Areas Covered: The drug interactions with many classes of pharmacological agents are reviewed. Some of these drugs, such as acetazolamide, topiramate and celecoxib show a large number of interactions with non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, antiepileptics, immunosupressants, anticholinesterase drugs, β-blockers, anesthetics, oral contraceptives, anticancer agents, antifungals, anti-mycobacterials, lithium, metformin and clopidogrel., Expert Opinion: The multiple drug interactions in which CAIs are involved should be carefully considered when such drugs are used in combination with the drug classes mentioned above, as the risks of developing toxicity and serious side effects if the dosages are not adjusted are high. There are also synergistic effects between CAIs and some NSAIDs, anticancer agents and benzodiazepines for the management of cystoid macular edema, some tumor types and neuropathic pain, respectively.

Introduction: Acetylcholinesterase inhibitors (neostigmine, edrophonium) and encapsulating agents (sugammadex and calabadion) can be used to reverse residual neuromuscular blockade (NMB)., Areas Covered: This review provides information about efficacy, effectiveness, and side effects of drugs (acetylcholinesterase inhibitors and encapsulating agents) used to reverse neuromuscular blocking agents (NMBAs)., Expert Opinion: The therapeutic range of acetylcholinesterase-inhibitors is narrow and effectiveness studies demonstrate clinicians don't use these unspecific reversal agents effectively to increase postoperative respiratory safety. The encapsulating drugs sugammadex and calabadion reverse all levels of NMB, and complete recovery of muscle strength can be achieved almost immediately after administration. For this reason encapsulating agents can be used as a solution for "cannot intubate cannot ventilate"- situations. Poor binding selectivity of encapsulating agents carries the risk of displacement of the NMBA by a competitively binding drug, which may lead to recurarization. In order to avoid side-effects, related to unspecific binding of endogenous proteins and drugs administered perioperatively it is prudent to titrate the dose of reversal agents to the minimal effective dose, depending on the depth of neuromuscular transmission block identified by neuromuscular transmission monitoring. Calabadions provide a diversified (increased binding selectivity) and expanded (reversal of benzylisoquinolines) spectrum of possible indications.

Background: The aim of this study was to evaluate the effect of morin-5'-sulfonic acid sodium salt (NaMSA) on cyclophosphamide-induced gastrointestinal changes in rats., Methods: Rats received intragastrically 0.9% saline (group C), cyclophosphamide (15 mg/kg) (group CX), NaMSA (100 mg/kg) (group M) or cyclophosphamide (15 mg/kg) with NaMSA (100 mg/kg) (group M-CX), respectively, for 10 days., Results: No histological lesions were observed in the liver and the large intestine in the control group and group receiving NaMSA. In the cyclophosphamide-treated group, a generalized blurred trabecular structure, hepatocyte apoptosis, focal and diffuse necrosis were noticed in the liver and atypia of epithelial cells or adenoma were noticed in the large intestine. In the group receiving both cyclophosphamide and NaMSA, hepatocyte apoptosis in the liver was observed less frequently. Histological examination of the small intestine revealed: low-grade dysplasia adenoma in the C, M, CX and M-CX group (in 44%, 0%, 100%, and 55.6% of specimens, respectively) with adenocarcinoma in 55.6% of specimens in the cyclophosphamide-receiving group only. Adenoma with high-grade dysplasia was observed in the control and NaMSA-receiving group with a similar frequency (22%). In addition to the histological evaluation, blood cell count parameters, as well as total protein concentration, blood glucose level, amylase, ALT, AST and GGTP activities were evaluated. Cyclophosphamide impaired weight gain, decreased blood cell count parameters and total protein concentration, and increased the GGTP activity. Those changes were not reversed by NaMSA., Conclusions: Summing up, NaMSA may protect against some cyclophosphamide-induced histological abnormalities in the gastrointestinal tract, including intestinal neoplasia in rats., (Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Following ischemic stroke, blood-brain barrier (BBB) is disrupted and is further aggravated with the corresponding incidence of hyperlipidemia. BBB breakdown promotes inflammation infiltration into the brain, which exacerbates cerebral ischemic injury as a result. Here, we report that 10-O-(N,N-dimethylaminoethyl)-ginkgolide B methanesulfonate (XQ-1H), a novel analog of ginkgolide B, alleviates BBB breakdown in hyperlipidemic rats and protects endothelial cells against inflammatory response. Middle cerebral artery occlusion (MCAO) modeled ischemic stroke in rats. Before surgery, these rats were fed a cholesterol-rich diet to induce an experimental hyperlipidemic condition. Additionally, lipopolysaccharide (LPS) incubation with rat brain microvessel endothelial cells (rBMECs) was applied to mimic hyperlipidemia-induced inflammatory injury of BBB. The results indicated more severe infarct size, increased BBB permeability, excessive secretion of pro-inflammatory cytokines, and exaggerated inflammation infiltration of the brain in hyperlipidemic rats following MCAO when compared to rats fed with normal diet. XQ-1H protected BBB integrity, lessoned brain edema and inflammation penetration, downregulated MMP-9 and VCMA-1 expressions, and extenuated ischemic infarction. XQ-1H alleviated LPS-induced inflammatory response in rBMECs, characterized by promoting cell viability, inhibiting TNF-α, IL-1β, and IL-6 releasing, and downregulating NF-κB inflammatory signal and downstream proteins, such as VCAM-1 and iNOS. In conclusion, the present study shows that XQ-1H stabilizes BBB function following ischemic stroke in hyperlipidemic rats, and the possible mechanisms may be related to inflammation inhibition.

Patients with Alzheimer's disease (AD) display amyloidopathy and tauopathy. In mouse models of AD, pharmacological inhibition using small molecule enzyme inhibitors or genetic inactivation of acyl-coenzyme A (Acyl-CoA):cholesterol acyltransferase 1 (ACAT1) diminished amyloidopathy and restored cognitive deficits. In microglia, ACAT1 blockage increases autophagosome formation and stimulates amyloid β peptide1-42 degradation. Here, we hypothesize that in neurons ACAT1 blockage augments autophagy and increases autophagy-mediated degradation of P301L-tau protein. We tested this possibility in murine neuroblastoma cells ectopically expressing human tau and in primary neurons isolated from triple transgenic AD mice that express mutant forms of amyloid precursor protein, presenilin-1, and human tau. The results show that ACAT1 blockage increases autophagosome formation and decreases P301L-tau protein content without affecting endogenous mouse tau protein content. In vivo, lacking Acat1 decreases P301L-tau protein content in the brains of young triple transgenic AD mice but not in those of old mice, where extensive hyperphosphorylations and aggregation of P301L-tau take place. These results suggest that, in addition to ameliorating amyloidopathy in both young and old AD mice, ACAT1 blockage may benefit AD by reducing tauopathy at early stage., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: to analyze the meanings of leprosy for people treated during the sulfonic and multidrug therapy periods., Method: qualitative nature study based on the Vigotski's historical-cultural approach, which guided the production and analysis of data. It included eight respondents who have had leprosy and were submitted to sulfonic and multidrug therapy treatments. The participants are also members of the Movement for Reintegration of People Affected by Leprosy., Results: the meanings were organized into three meaning cores: spots on the body: something is out of order; leprosy or hanseniasis? and leprosy from the inclusion in the Movement for Reintegration of People Affected by Leprosy., Conclusion: the meanings of leprosy for people submitted to both regimens point to a complex construction thereof, indicating differences and similarities in both treatments. Health professionals may contribute to the change of the meanings, since these are socially constructed and the changes are continuous.

Purpose: Irosustat is the 'first-in-class' irreversible potent steroid sulphatase inhibitor with lack of oestrogenic activity. The objective of this work was to develop a population model characterizing simultaneously the pharmacokinetic profiles of irosustat in plasma and whole blood., Methods: This clinical study was an open label, multicentre, phase I multiple cohort dose escalation trial conducted in 35 postmenopausal women with oestrogen-receptor positive breast cancer. Patients received 1, 5, 20, 40, or 80 mg oral doses. Irosustat was administered as a single oral dose to each patient followed by an observation period of 7 days. On day 8 each patient received once daily oral administration until day 34. Concentrations of irosustat in both blood and plasma were obtained and pharmacokinetic analyses were performed with NONMEM 7.2., Results and Conclusions: Irosustat showed non-linear disposition characteristics modelled as maximum binding capacity into the red blood cells. Plasma concentration corresponding to half of the maximum capacity was 32.79 ng/mL. The value of the blood to plasma concentration ratio in linear conditions was 419, indicating very high affinity for the red blood cells. Apparent plasma and blood clearances were estimated in 1199.52 and 3.90 L/day, respectively. Pharmacokinetics of irosustat showed low-moderate inter-subject variability, and neither the demographics (e.g., age, or weight) nor the phenotypes for CYP2C9, CYP2C19, and CYP3A5 enzymes showed statistically significant effects. Relative bioavailability was decreased as the administered dose was augmented. The model predicted a 47% decrease in relative bioavailability in the 40 mg with respect to the 1 mg dose.

A novel zinc(II) phthalocyanine bearing octa-sulphonates has been prepared, which is non-aggregated in water, highly photoactive and low dark-toxic. More interestingly, it exhibits specific affinity to macrophages via the scavenger receptor-A, and can selectively accumulate in tumour sites.

Background: Clostridium difficile infection (CDI) is a common complication of antibiotic therapy that is treated with antibiotics, contributing to ongoing disruption of the colonic microbiota and CDI recurrence. Two multinational trials were conducted to compare the efficacy of tolevamer, a nonantibiotic, toxin-binding polymer, with vancomycin and metronidazole., Methods: Patients with CDI were randomly assigned in a 2:1:1 ratio to oral tolevamer 9 g (loading dose) followed by 3 g every 8 hours for 14 days, vancomycin 125 mg every 6 hours for 10 days, or metronidazole 375 mg every 6 hours for 10 days. The primary endpoint was clinical success, defined as resolution of diarrhea and absence of severe abdominal discomfort for more than 2 consecutive days including day 10., Results: In a pooled analysis, 563 patients received tolevamer, 289 received metronidazole, and 266 received vancomycin. Clinical success of tolevamer was inferior to both metronidazole and vancomycin (P < .001), and metronidazole was inferior to vancomycin (P = .02; 44.2% [n = 534], 72.7% [n = 278], and 81.1% [n = 259], respectively). Clinical success in patients with severe CDI who received metronidazole was 66.3% compared with vancomycin, which was 78.5%. (P = .059). A post-hoc multivariate analysis that excluded tolevamer found 3 factors that were strongly associated with clinical success: vancomycin treatment, treatment-naive status, and mild or moderate CDI severity. Adverse events were similar among the treatment groups., Conclusions: Tolevamer was inferior to antibiotic treatment of CDI, and metronidazole was inferior to vancomycin. Trial Registration. clinicaltrials.gov NCT00106509 and NCT00196794., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Hypertension affects one-third of the adult population and is a growing problem due to the increasing incidence of obesity and diabetes. Brain RAS (renin-angiotensin system) hyperactivity has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We have identified in the brain RAS that APA (aminopeptidase A) and APN (aminopeptidase N), two membrane-bound zinc metalloproteases, are involved in the metabolism of AngII (angiotensin II) and AngIII (angiotensin III) respectively. The present review summarizes the main findings suggesting that AngIII plays a predominant role in the brain RAS in the control of BP (blood pressure). We first explored the organization of the APA active site by site-directed mutagenesis and molecular modelling. The development and the use in vivo of specific and selective APA and APN inhibitors EC33 and PC18 respectively, has allowed the demonstration that brain AngIII generated by APA is one of the main effector peptides of the brain RAS, exerting a tonic stimulatory control over BP in conscious hypertensive rats. This identified brain APA as a potential therapeutic target for the treatment of hypertension, which has led to the development of potent orally active APA inhibitors, such as RB150. RB150 administered orally in hypertensive DOCA (deoxycorticosteroneacetate)-salt rats or SHRs (spontaneously hypertensive rats) crosses the intestinal, hepatic and blood-brain barriers, enters the brain, generates two active molecules of EC33 which inhibit brain APA activity, block the formation of brain AngIII and normalize BP for several hours. The decrease in BP involves two different mechanisms: a decrease in vasopressin release into the bloodstream, which in turn increases diuresis resulting in a blood volume reduction that participates in the decrease in BP and/or a decrease in sympathetic tone, decreasing vascular resistance. RB150 constitutes the prototype of a new class of centrally acting antihypertensive agents and is currently being evaluated in a Phase Ib clinical trial.

Several studies have shown that HDL has altered antioxidant and anti-inflammatory effects in chronic uremia, either by the reduction in its antioxidant enzymes or by the impairment of their activity. Systemic oxidative stress, which is highly prevalent in chronic kidney disease (CKD) patients, has been shown to decrease antioxidant and anti-inflammatory effects of HDL and even transform it into a pro-oxidant and pro-inflammatory agent. For this reason, we believe that the propensity for accelerated cardiovascular disease in CKD is facilitated by a few key features of this disease, namely, oxidative stress, inflammation, hypertension, and disorders of lipid metabolism. In a nutshell, oxidative stress and inflammation enhance atherosclerosis leading to increased cardiovascular mortality and morbidity in this population. In this detailed review, we highlight the current knowledge on HDL dysfunction and impairment in chronic kidney disease as well as the available therapy.

Misfolded protein amyloid-beta protein (Aβ) and tau protein are two high hallmarks of Alzheimer's disease (AD), representing significant targets in treating AD. Researches on mechanisms of the two proteins inducing neuron dysfunctions provide therapeutic strategies of AD, including inhibition of Aβ production and aggregation, acceleration of Aβ clearance as well as reduction of tau hyperphosphorylation. Proteoglycans (PGs) consist of a core protein and glycosaminoglycans (GAGs) chains, with enormous structural diversity due to variation in the core protein, the number of GAGs chains as well as extent and position of sulfation. Considerable evidences have indicated that PGs and GAGs play important roles in Aβ and tau processing. Numbers of GAGs and analogues have potential therapeutic function in AD. In this Review, we focus on the relationship of PGs and GAGs with misfolded proteins in AD and their potential therapeutic implications.

Targeting tumour associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII is now considered as a pertinent approach for the development of new cancer therapeutics against hypoxic tumours. In the last period, with the help of X-ray crystallography, much progress has been achieved for the drug-design of selective CA IX inhibitors, by considering the three main structural elements that govern both potency and selectivity, that is, a zinc binding group (ZBG), an organic scaffold, and one or more side chains substituting the scaffold. The use of sugar moiety in the structure of sulfonamide-based CA inhibitors (CAIs), has allowed the discovery of very potent CA IX inhibitors able to impair the growth of both primary tumors and metastases. The search for specific CA IX inhibitors by using the sugar approach has become an important research field, leading to sulfonamides, sulfamates, sulfamides and coumarins with excellent in vitro activity and relevant potency in vivo, in animal models of cancer. This paper will review the latest development in this hot topic., (Copyright © 2012 Elsevier Ltd. All rights reserved.)