Possible role of the systemic inflammatory reaction in defining tumor responder vs. nonresponder in cancer macrobead therapy.

572 Background: Peritoneal implantation of mouse renal adenocarcinoma cell-containing (RENCA) Macrobead (MB) represents a cell-system-based approach to the treatment of advanced, mCRC that has been evaluated to date in Phase IIa trials. The data indicate that there are “responders” (R) and “non-responders”(NR) as reflected in overall survival (OS), where “response” is defined as a >20% decrease in either/both CEA or CA19-9 during the first 30 days after MB implantation. We analyzed whether the “response” is due to a post-implant systemic inflammatory response (SIR) or rather a direct inhibitory effect of the MB. Methods: Thirty-four treatment-resistant mCRC patients (pts) were implanted laparoscopically at least once with RENCA MB. Pts were considered R (n=25), or NR (n=9), based on tumor marker responses within the first 30 days. CRP, IL-6, TNF-alpha, and ESR, as measures of SIR, were measured at Day 14 and 30. Results: All 34 pts showed SIR to MB implantation, as indicated by transient rises in CRP, IL-6, TNF-a, and ESR. Baseline CRP values (R, mean 3.24+/-4.39 vs. NR, 2.96+/-3.43; t-test, p=0.86), Day 14 CRP values (R, mean 20.97 +/- 7.21 vs. NR, 14.5+/-8.78; t-test, p=0.04), Day 30 CRP values (R, mean 8.21+/-5.43 vs. NR, 10.76+/-6.92; t-test, p=0.27) and mean changes in IL-6 (baseline p=0.28; Day 14 p=0.36; Day 30 p=0.54), TNF-a (baseline p=0.37; Day 14 p=0.32; Day 30 p=0.29) did not show statistically significant differences between R and NR groups. Conclusions: Data suggest that early tumor marker decreases in R of RENCA MB are likely not due to the induced SIR, but rather a possibly direct anti-tumor-cell effect by factors released by MB. This supports the importance of the MB-induced changes in the MEF-2 pathway in the target colorectal cancer cell/tumor reported previously. Studies of clinical efficacy of MB continue in a Phase IIb clinical trial. Clinical trial information: NCT01053013.

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Role of endothelial cells in regulating hemoglobin-induced changes in lymphatic pumping

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1992.263.6.h1880 ◽

1992 ◽

Vol 263 (6) ◽

pp. H1880-H1887 ◽

Cited By ~ 1

Author(s):

R. M. Elias ◽

J. Eisenhoffer ◽

M. G. Johnston

Keyword(s):

Endothelial Cells ◽

Smooth Muscle ◽

Inhibitory Effect ◽

Direct Inhibitory Effect ◽

Induced Changes ◽

Lymphatic Pumping ◽

Pumping Activity

Studies with a sheep isolated duct preparation in vivo demonstrated that the route of administration of hemoglobin was important in demonstrating its inhibitory effect on lymphatic pumping. With autologous oxyhemoglobin administered intravenously (final plasma concentration 5 x 10(-5) M), pumping was not inhibited. However, the addition of oxyhemoglobin (5 x 10(-5) M) into the reservoir (lumen of the duct) resulted in > 95% inhibition of pumping. The extraluminal administration of oxyhemoglobin (10(-5) M) to bovine mesenteric lymphatics in vitro resulted in a 40% inhibition of pumping, whereas the introduction of oxyhemoglobin (10(-5) M) into the lumen of the vessels suppressed pumping 95%. In vessels mechanically denuded of endothelium, intraluminal oxyhemoglobin inhibited pumping 50%. These results suggested that oxyhemoglobin depressed pumping through an effect on both smooth muscle and endothelium. Once pumping was inhibited with oxyhemoglobin administration, stimulation of the duct with elevations in transmural pressure restored pumping activity when endothelial cells were present. However, in the absence of endothelium, pumping decreased with increases in distending pressures. We conclude that oxyhemoglobin has a direct inhibitory effect on lymphatic smooth muscle. The ability of oxyhemoglobin to alter the pressure range over which the lymph pump operates appears to be dependent on an intact endothelium.

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Somatostatin and dopamine receptor expression in lung carcinoma cells and effects of chimeric somatostatin-dopamine molecules on cell proliferation

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00209.2005 ◽

2005 ◽

Vol 289 (6) ◽

pp. E1044-E1050 ◽

Cited By ~ 26

Author(s):

Diego Ferone ◽

Marica Arvigo ◽

Claudia Semino ◽

Philippe Jaquet ◽

Alexandru Saveanu ◽

...

Keyword(s):

Cell Proliferation ◽

Cell Growth ◽

Inhibitory Effect ◽

Cell System ◽

Receptor Expression ◽

Suitable Model ◽

Independent Manner ◽

Lung Carcinoma Cells ◽

Cancer Line ◽

Direct Inhibitory Effect

To study somatostatin/dopamine (SS/D) synergy in a human cell system constitutively expressing SS and D receptors (SSR and DR, respectively), we characterized the expression of SSR and DR subtypes in the non-small-cell lung cancer line Calu-6, and then we evaluated the effect on cell proliferation of SS/D chimeric molecules (BIM-23A387 and BIM-23A370), which bind with high affinity both sst2 and D2R, and compared the results with those obtained by using SS-14 and subtype-selective SS analogs (SSA) and D agonists (DA). Because Calu-6 cells produce insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) peptides, which play a role in the autocrine/paracrine control of cell growth, we also investigated the effects of chimeric compounds on secretion and expression of IGF system components. Relative high levels of sst2 and the long isoform of the D2R were detected by real-time RT-PCR and Western blot in Calu-6, together with sst5 and to a lesser extent sst3 and D4R. BIM-23A387 and BIM-23A370 significantly inhibited growth of Calu-6, whereas IGF-IGFBP secretion or expression was unaffected, suggesting a direct inhibitory effect. The inhibition of cell growth, measured by both [3H]thymidine incorporation and cell count, was significantly lower when individual SSA and DA control peptides or subtype-specific SSA and DA were tested. BIM-23A370 was more potent than BIM-23A387 ( P < 0.001). These findings show that SS/D chimeras can inhibit Calu-6 proliferation in an IGF-independent manner and suggest that this enhanced potency might be because of the induction of SSR/DR dimerization. The Calu-6 cell line, constitutively expressing SSR and DR, provides a suitable model to elucidate the mechanism of action of SSA and DA on regulation of cell growth and to characterize the interaction between SSR and DR.

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Suppression of Damping-Off Disease in Host Plants by the Rhizoplane Bacterium Lysobacter sp. Strain SB-K88 Is Linked to Plant Colonization and Antibiosis against Soilborne Peronosporomycetes

Applied and Environmental Microbiology ◽

10.1128/aem.71.7.3786-3796.2005 ◽

2005 ◽

Vol 71 (7) ◽

pp. 3786-3796 ◽

Cited By ~ 139

Author(s):

Md. Tofazzal Islam ◽

Yasuyuki Hashidoko ◽

Abhinandan Deora ◽

Toshiaki Ito ◽

Satoshi Tahara

Keyword(s):

Sugar Beet ◽

Microscopic Analysis ◽

Inhibitory Effect ◽

Root Surface ◽

Plant Colonization ◽

Damping Off ◽

Electron Microscopic ◽

Aphanomyces Cochlioides ◽

Direct Inhibitory Effect ◽

A Cell

ABSTRACT We previously demonstrated that xanthobaccin A from the rhizoplane bacterium Lysobacter sp. strain SB-K88 suppresses damping-off disease caused by Pythium sp. in sugar beet. In this study we focused on modes of Lysobacter sp. strain SB-K88 root colonization and antibiosis of the bacterium against Aphanomyces cochlioides, a pathogen of damping-off disease. Scanning electron microscopic analysis of 2-week-old sugar beet seedlings from seeds previously inoculated with SB-K88 revealed dense colonization on the root surfaces and a characteristic perpendicular pattern of Lysobacter colonization possibly generated via development of polar, brush-like fimbriae. In colonized regions a semitransparent film apparently enveloping the root and microcolonies were observed on the root surface. This Lysobacter strain also efficiently colonized the roots of several plants, including spinach, tomato, Arabidopsis thaliana, and Amaranthus gangeticus. Plants grown from both sugar beet and spinach seeds that were previously treated with Lysobacter sp. strain SB-K88 displayed significant resistance to the damping-off disease triggered by A. cochlioides. Interestingly, zoospores of A. cochlioides became immotile within 1 min after exposure to a SB-K88 cell suspension, a cell-free supernatant of SB-K88, or pure xanthobaccin A (MIC, 0.01 μg/ml). In all cases, lysis followed within 30 min in the presence of the inhibiting factor(s). Our data indicate that Lysobacter sp. strain SB-K88 has a direct inhibitory effect on A. cochlioides, suppressing damping-off disease. Furthermore, this inhibitory effect of Lysobacter sp. strain SB-K88 is likely due to a combination of antibiosis and characteristic biofilm formation at the rhizoplane of the host plant.

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Protein kinase C inhibits Na(+)-K(+)-2Cl- cotransporter activity in cultured rabbit nonpigmented ciliary epithelium

AJP Cell Physiology ◽

10.1152/ajpcell.1994.267.6.c1553 ◽

1994 ◽

Vol 267 (6) ◽

pp. C1553-C1560 ◽

Cited By ~ 14

Author(s):

J. Dong ◽

N. A. Delamere

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Inhibitory Effect ◽

Ciliary Epithelium ◽

Sodium Potassium ◽

Kinase C ◽

A Cell ◽

Induced Changes ◽

Pkc Activation ◽

Nonpigmented Ciliary Epithelium

We examined the regulation of Na(+)-K(+)-2Cl- transporter activity by protein kinase C (PKC) in a cell line derived from rabbit nonpigmented ciliary epithelium. Na(+)-K(+)-2Cl- cotransporter activity was measured as the rate of bumetanide-sensitive potassium (86Rb) transport. Phorbol 12,13-dibutyrate (PBDu) was used to activate PKC. PBDu inhibited bumetanide-sensitive potassium (86Rb) uptake, with a half-maximal inhibitory concentration of approximately 0.1 microM. The inhibitory effect of PBDu on potassium uptake by the N(+)-K(+)-2Cl- cotransporter was abolished by PCK downregulation and diminished by 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, a PKC inhibitor. PBDu inhibited Na(+)-K(+)-2Cl- cotransporter-mediated inward potassium (86Rb) transport by approximately 26% in control cells and by 40% in cells pretreated with ouabain. PKC activation also reduced the rate of bumetanide-sensitive potassium (86Rb) efflux in ouabain-treated cells but not in control (no oubain) cells. PBDu caused little change of intracellular sodium, potassium, or chloride, suggesting that an alteration of cytoplasmic ion composition is not responsible for the observed PBDu-induced changes in the rate of either inward or outward potassium movement mediated by the Na(+)-K(+)-2Cl- cotransporter.

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Effects of oestradiol benzoate (OeB) and human chorionic gonadotrophin (hCG) on the testes and accessory sex glands of the rat

Acta Endocrinologica ◽

10.1530/acta.0.0960273 ◽

1981 ◽

Vol 96 (2) ◽

pp. 273-280 ◽

Cited By ~ 1

Author(s):

Mridula Chowdhury ◽

Robert Tcholakian ◽

Emil Steinberger

Keyword(s):

Treated Group ◽

Inhibitory Effect ◽

Male Rats ◽

Plasma Testosterone ◽

Control Group ◽

Intact Male ◽

Intact Control ◽

Testosterone Levels ◽

Oestradiol Benzoate ◽

Direct Inhibitory Effect

Abstract. It has been suggested that treatment of intact male rats with oestradiol benzoate (OeB) causes an interference with testosterone (T) production by the testes by a direct inhibitory effect on steroidogenesis. To test this hypothesis, different doses (5, 10 or 25 IU) of hCG were administered concomitantly with 50 μg of OeB to adult intact or hypophysectomized male rats. The testicular and plasma testosterone, and serum hCG levels were determined. The sex accessory weights were recorded. In the intact OeB-treated group of animals, hCG stimulated both the secondary sex organs and plasma testosterone levels above the intact control group. However, in hypophysectomized animals, although plasma testosterone levels increased above that of intact controls, their secondary sex organ weights did not. Moreover, inspite of high circulating hCG levels, the testicular testosterone content and concentration remained suppressed in OeB-treated animals. The reason for such dichotomy of hCG action on OeB-treated animals is not clear at present.

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Identification of the vaccinia hemagglutinin polypeptide from a cell system yielding large amounts of extracellular enveloped virus.

Journal of Virology ◽

10.1128/jvi.31.1.147-155.1979 ◽

1979 ◽

Vol 31 (1) ◽

pp. 147-155 ◽

Cited By ~ 78

Author(s):

L G Payne

Keyword(s):

Cell System ◽

Enveloped Virus ◽

A Cell

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A Direct Inhibitory Effect of Botulinum Toxin Type A on Antral Circular Muscle Contractility of Guinea Pig

Yonsei Medical Journal ◽

10.3349/ymj.2012.53.5.968 ◽

2012 ◽

Vol 53 (5) ◽

pp. 968 ◽

Cited By ~ 2

Author(s):

Jung Ho Park ◽

EunJoo Choi ◽

Hyojin Park ◽

Yong Ho Lee

Keyword(s):

Botulinum Toxin ◽

Guinea Pig ◽

Botulinum Toxin Type A ◽

Circular Muscle ◽

Type A ◽

Botulinum Toxin Type ◽

Inhibitory Effect ◽

Muscle Contractility ◽

Direct Inhibitory Effect

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Inhibitory Effects of Secondary Metabolites from the Lichen Stereocaulon evolutum on Protein Tyrosine Phosphatase 1B

Planta Medica ◽

10.1055/a-1334-4480 ◽

2021 ◽

Author(s):

Birgit Waltenberger ◽

Françoise Lohézic-Le Dévéhat ◽

Thi Huyen Vu ◽

Olivier Delalande ◽

Claudia Lalli ◽

...

Keyword(s):

Protein Tyrosine Phosphatase ◽

Inhibitory Activity ◽

Tyrosine Phosphatase ◽

Inhibitory Effect ◽

Positive Control ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine ◽

Ic50 Values ◽

A Cell

AbstractProtein tyrosine phosphatase 1B plays a significant role in type 2 diabetes mellitus and other diseases and is therefore considered a new drug target. Within this study, an acetone extract from the lichen Stereocaulon evolutum was identified to possess strong protein tyrosine phosphatase 1B inhibition in a cell-free assay (IC50 of 11.8 µg/mL). Fractionation of this bioactive extract led to the isolation of seven known molecules belonging to the depsidones and the related diphenylethers and one new natural product, i.e., 3-butyl-3,7-dihydroxy-5-methoxy-1(3H)-isobenzofurane. The isolated compounds were evaluated for their inhibition of protein tyrosine phosphatase 1B. Two depsidones, lobaric acid and norlobaric acid, and the diphenylether anhydrosakisacaulon A potently inhibited protein tyrosine phosphatase 1B with IC50 values of 12.9, 15.1, and 16.1 µM, respectively, which is in the range of the protein tyrosine phosphatase 1B inhibitory activity of the positive control ursolic acid (IC50 of 14.4 µM). Molecular simulations performed on the eight compounds showed that i) a contact between the molecule and the four main regions of the protein is required for inhibitory activity, ii) the relative rigidity of the depsidones lobaric acid and norlobaric acid and the reactivity related to hydrogen bond donors or acceptors, which interact with protein tyrosine phosphatase 1B key amino acids, are involved in the bioactivity on protein tyrosine phosphatase 1B, iii) the cycle opening observed for diphenylethers decreased the inhibition, except for anhydrosakisacaulon A where its double bond on C-8 offsets this loss of activity, iv) the function present at C-8 is a determinant for the inhibitory effect on protein tyrosine phosphatase 1B, and v) the more hydrogen bonds with Arg221 there are, the more anchorage is favored.

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Discovery of SARS-CoV-2-E channel inhibitors as antiviral candidates

Acta Pharmacologica Sinica ◽

10.1038/s41401-021-00732-2 ◽

2021 ◽

Author(s):

Yi Wang ◽

Sui Fang ◽

Yan Wu ◽

Xi Cheng ◽

Lei-ke Zhang ◽

...

Keyword(s):

High Throughput Screening ◽

Antiviral Drug ◽

Binding Pocket ◽

Inhibitory Effect ◽

Inhibitory Effects ◽

Cell Protection ◽

Host Cell Death ◽

A Cell ◽

Protection Activity ◽

Molecular Modeling And Docking

AbstractLack of efficiency has been a major problem shared by all currently developed anti-SARS-CoV-2 therapies. Our previous study shows that SARS-CoV-2 structural envelope (2-E) protein forms a type of cation channel, and heterogeneously expression of 2-E channels causes host cell death. In this study we developed a cell-based high throughput screening (HTS) assay and used it to discover inhibitors against 2-E channels. Among 4376 compounds tested, 34 hits with cell protection activity were found. Followed by an anti-viral analysis, 15 compounds which could inhibit SARS-CoV-2 replication were identified. In electrophysiological experiments, three representatives showing inhibitory effect on 2-E channels were chosen for further characterization. Among them, proanthocyanidins directly bound to 2-E channel with binding affinity (KD) of 22.14 μM in surface plasmon resonance assay. Molecular modeling and docking analysis revealed that proanthocyanidins inserted into the pore of 2-E N-terminal vestibule acting as a channel blocker. Consistently, mutations of Glu 8 and Asn 15, two residues lining the proposed binding pocket, abolished the inhibitory effects of proanthocyanidins. The natural product proanthocyanidins are widely used as cosmetic, suggesting a potential of proanthocyanidins as disinfectant for external use. This study further demonstrates that 2-E channel is an effective antiviral drug target and provides a potential antiviral candidate against SARS-CoV-2.

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