Chronotropic actions of bPTH-(1–34) in the right atrium of the rat

1983 ◽  
Vol 61 (10) ◽  
pp. 1162-1167 ◽  
Author(s):  
Thomas E. Tenner Jr. ◽  
Sasanka Ramanadham ◽  
May C. M. Yang ◽  
Peter K. T. Pang
Keyword(s):  
In Vivo Studies ◽  
Hypotensive Activity ◽  
Reflex Tachycardia ◽  
Chronotropic Action ◽  
Chronotropic Effects ◽  
The Right ◽  
Dose Dependent ◽  
Right Atria

Bovine parathyroid hormone and its N-terminal (1–34) peptide fragment (bPTH-(1–34)) are known to possess direct hypotensive activity in the rat. The purpose of the present study was to determine if bPTH-(1–34) possessed a direct chronotropic action as well. In vivo studies revealed that bPTH-(1–34) did produce a chronotropic effect in the rat comprising both a direct component as well as a reflex tachycardia related to its hypotensive actions. In vitro studies of isolated right atria indicated that while bPTH-(1–34) had no positive inotropic effect, it did produce significant chronotropic effects which were direct and dose-dependent. The potency of bPTH-(1–34) was found to be similar to that of isoproterenol, however, it was only one-third as effective as isoproterenol in maximally increasing atrial rate. A slight but significant increase in atrial cyclic AMP was generated prior to the chronotropic actions of bPTH-(1–34).

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

Antinociceptive properties of shikonin: in vitro and in vivo studies

2016 ◽  
Vol 94 (7) ◽  
pp. 788-796 ◽  
Author(s):  
Bhawana Gupta ◽  
Sabyasachi Chakraborty ◽  
Soumya Saha ◽  
Sunita Gulabsingh Chandel ◽  
Atul Kumar Baranwal ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Inhibitory Effect ◽  
Pain Modulation ◽  
In Vivo Studies ◽  
Channel Modulation ◽  
Pain Models ◽  
A Cell ◽  
Dose Dependent

Shikonin possess a diverse spectrum of pharmacological properties in multiple therapeutic areas. However, the nociceptive effect of shikonin is not largely known. To investigate the antinociceptive potential of shikonin, panel of GPCRs, ion channels, and enzymes involved in pain pathogenesis were studied. To evaluate the translation of shikonin efficacy in vivo, it was tested in 3 established rat pain models. Our study reveals that shikonin has significant inhibitory effect on pan sodium channel/N1E115 and NaV1.7 channel with half maximal inhibitory concentration (IC50) value of 7.6 μmol/L and 6.4 μmol/L, respectively, in a cell-based assay. Shikonin exerted significant dose dependent antinociceptive activity at doses of 0.08%, 0.05%, and 0.02% w/v in pinch pain model. In mechanical hyperalgesia model, dose of 10 and 3 mg/kg (intraperitoneal) produced dose-dependent analgesia and showed 67% and 35% reversal of hyperalgesia respectively at 0.5 h. Following oral administration, it showed 39% reversal at 30 mg/kg dose. When tested in first phase of formalin induced pain, shikonin at 10 mg/kg dose inhibited paw flinching by ∼71%. In all studied preclinical models, analgesic effect was similar or better than standard analgesic drugs. The present study unveils the mechanistic role of shikonin on pain modulation, predominantly via sodium channel modulation, suggesting that shikonin could be developed as a potential pain blocker.

Kinetic Studies of Dose-Dependent Metabolism of Alprenolol: In Vitro and In Vivo Studies in Different Species

2009 ◽  
Vol 44 (1) ◽  
pp. 28-35 ◽  
Author(s):  
Inger Skånberg ◽  
Karl Olof Borg ◽  
Erik Fellenius ◽  
Kurt-Jürgen Hoffmann ◽  
Christer Bahr ◽  
...  
Keyword(s):  
Kinetic Studies ◽  
In Vivo Studies ◽  
Dose Dependent

scholarly journals Platelet-Derived Biomaterials Inhibit Nicotine-Induced Intervertebral Disc Degeneration Through Regulating IGF-1/AKT/IRS-1 Signaling Axis

2021 ◽  
Vol 30 ◽  
pp. 096368972110453
Author(s):  
Wen-Cheng Lo ◽  
Chi-Sheng Chiou ◽  
Feng-Chou Tsai ◽  
Chun-Hao Chan ◽  
Samantha Mao ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
In Vivo Studies ◽  
Nicotine Treatment ◽  
Physiological Processes ◽  
Signaling Axis ◽  
Cellular Apoptosis ◽  
Ivd Degeneration ◽  
Dose Dependent

Apart from aging process, adult intervertebral disc (IVD) undergoes various degenerative processes. However, the nicotine has not been well identified as a contributing etiology. According to a few studies, nicotine ingestion through smoking, air or clothing may significantly accumulate in active as well as passive smokers. Since nicotine has been demonstrated to adversely impact various physiological processes, such as sympathetic nervous system, leading to impaired vasculature and cellular apoptosis, we aimed to investigate whether nicotine could induce IVD degeneration. In particular, we evaluated dose-dependent impact of nicotine in vitro to simulate its chronic accumulation, which was later treated by platelet-derived biomaterials (PDB). Further, during in vivo studies, mice were subcutaneously administered with nicotine to examine IVD-associated pathologic changes. The results revealed that nicotine could significantly reduce chondrocytes and chondrogenic indicators (Sox, Col II and aggrecan). Mice with nicotine treatment also exhibited malformed IVD structure with decreased Col II as well as proteoglycans, which was significantly increased after PDB administration for 4 weeks. Mechanistically, PDB significantly restored the levels of IGF-1 signaling proteins, particularly pIGF-1 R, pAKT, and IRS-1, modulating ECM synthesis by chondrocytes. Conclusively, the PDB impart reparative and tissue regenerative processes by inhibiting nicotine-initiated IVD degeneration, through regulating IGF-1/AKT/IRS-1 signaling axis.

scholarly journals Cytotoxic effect of Montivipera bornmuelleri’s venom on cancer cell lines: in vitro and in vivo studies

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9909
Author(s):  
Carol Haddoub ◽  
Mohamad Rima ◽  
Sandrine Heurtebise ◽  
Myriam Lawand ◽  
Dania Jundi ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Cell Lines ◽  
Cytotoxic Effect ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
In Vivo Testing ◽  
Murine Fibrosarcoma ◽  
Dose Dependent

Background Montivipera bornmuelleri’s venom has shown immunomodulation of cytokines release in mice and selective cytotoxicity on cancer cells in a dose-dependent manner, highlighting an anticancer potential. Here, we extend these findings by elucidating the sensitivity of murine B16 skin melanoma and 3-MCA-induced murine fibrosarcoma cell lines to M. bornmuelleri’s venom and its effect on tumor growth in vivo. Methods The toxicity of the venom on B16 and MCA cells was assessed using flow cytometry and xCELLigence assays. For in vivo testing, tumor growth was followed in mice after intratumoral venom injection. Results The venom toxicity showed a dose-dependent cell death on both B16 and MCA cells. Interestingly, overexpression of ovalbumin increased the sensitivity of the cells to the venom. However, the venom was not able to eradicate induced-tumor growth when injected at 100 µg/kg. Our study demonstrates a cytotoxic effect of M. bornmuelleri’s venom in vitro which, however, does not translate to an anticancer action in vivo.

Small Molecule Inhibitor of ITK Disrupts TCR Signaling and Demonstrates Anti-Tumor Efficacy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3932-3932
Author(s):  
Mary Faris ◽  
Uriel M Malyankar ◽  
Qingping Zeng ◽  
Gary A Flynn ◽  
Gerold Feuer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytokine Production ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
T Cell Malignancies ◽  
Dose Dependent ◽  
Leukemias And Lymphomas

Abstract Abstract 3932 ITK (Interluekin-2 Inducible Tyrosine Kinase) is a member of the TEC family of intracellular protein tyrosine kinases. ITK is highly expressed in T cells and NK cells, with expression detected in mast cells. ITK plays a key role in several aspects of T cell biology, including T cell development, differentiation, migration, proliferation and activation. The function of ITK in immunity and allergy is well documented. T cells from ITK knock out mice show several developmental and functional defects, including defective signal transduction, altered CD4+ to CD8+ T cells ratios, reduced Th2 lineage differentiation, diminished IL4 and IL2 production and reduced T cell proliferation. Importantly ITK deficient mice fail to mount an immune response to infection and show reduced allergic asthma reactions. In contrast to its well described role in immune function, ITK's function in cancer biology is still emerging. Recent studies had reported enhanced ITK expression and activation of the ITK pathway in several types of leukemias and lymphomas. In addition, the dependence of T cell malignancies on an ITK-regulated pathway, namely the IL2/IL2R (CD25) pathway, has also been observed. Taken together, this information indicates that ITK is a therapeutic target, with applicability in leukemias and lymphomas. MannKind scientists have developed a series of selective small molecule ITK inhibitors, including the orally available tool compound described within, and evaluated their activity in enzyme, cell-based and in vivo studies. In cellular assays, the compounds showed significant inhibition of the T cell-receptor mediated activation of the ITK pathways and related downstream cytokine production. In addition to inhibiting the phosphorylation of ITK and its downstream mediator, PLCg, our tool compounds inhibited the production of IL2 and expression of CD25 in a dose dependent manner. Importantly, our compound regulated the in vitro growth of tumor T cells but not that of unrelated control cells. In vivo studies revealed that the tool compounds inhibited the growth and progression of patient derived ATL tumors in a xenograft pre-clinical model, and prolonged the survival of treated mice in a dose dependent manner, in addition to regulating cytokine production in vivo. In summary, our team has identified ITK selective compounds with demonstrated on-target and anti-tumor activity in vitro and preclinical T cell tumor models, and validated this pathway relative to T cell malignancies. This effort provides a platform for further compound optimization and evaluation for hematologic malignancies. Disclosures: Faris: MannKind Corp: Employment. Malyankar:MannKind Corp: Employment. Zeng:MannKind Corp: Employment. Kertesz:Mannkind Corporation: Employment, Equity Ownership. Vuga:MannKind Corp.: Employment. Rosario:MannKind Corp: Employment. Bot:MannKind Corp: Employment.

scholarly journals Strong Antifungal Activity of SS750, a New Triazole Derivative, Is Based on Its Selective Binding Affinity to Cytochrome P450 of Fungi

2002 ◽  
Vol 46 (2) ◽  
pp. 308-314 ◽  
Author(s):  
Masaru Matsumoto ◽  
Kazuya Ishida ◽  
Akihiro Konagai ◽  
Kazunori Maebashi ◽  
Takemitsu Asaoka
Keyword(s):  
Cytochrome P450 ◽  
Antifungal Activity ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Strong Affinity ◽  
Dose Dependent ◽  
Potent Inhibitory Activity ◽  
In Vitro Antifungal Activity

ABSTRACT SS750 [(R)-(−)-2-(2,4-difluorophenyl)-1-(ethylsulfonyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol] is a new triazole, and its potential as an antifungal agent was evaluated by in vitro and in vivo studies. In a comparison of the MICs at which 50% of isolates are inhibited (MIC50s) for all strains of Candida species and Cryptococcus neoformans tested, SS750 was four times or more active than fluconazole and had activity comparable to that of itraconazole. The most important advantage of SS750 was that, when the MIC90s were compared, SS750 had 64 and 32 times greater antifungal activities than fluconazole against Candida krusei and Candida glabrata, respectively, which are intrinsically less susceptible to fluconazole. In cyclophosphamide-immunosuppressed mouse models of systemic and pulmonary candidiasis caused by C. albicans, oral SS750 prolonged the number of days of survival of infected animals in a dose-dependent manner and was 4 and ≥64 times more potent than fluconazole and itraconazole, respectively. In a safety profile, SS750, like fluconazole, had less of an affinity for binding to mammalian cytochrome P450 compared with that of ketoconazole, despite its strong affinity for binding to fungal cytochrome P450. The mechanism for the increased in vitro antifungal activity of SS750 against C. krusei is partially due to the potent inhibitory activity (3.7 times versus that of fluconazole) of C. krusei cytochrome P450 sterol 14α-demethylase; SS750 showed a strong affinity for binding to cytochrome P450 of C. krusei, indicating that SS750 acts by inhibiting the cytochrome P450 sterol 14α-demethylase of fungal cells.

scholarly journals New Insights into the Hypotensins from Tityus serrulatus Venom: Pro-Inflammatory and Vasopeptidases Modulation Activities

Toxins ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 846
Author(s):  
Bruno Duzzi ◽  
Cristiane Castilho Fernandes Silva ◽  
Roberto Tadashi Kodama ◽  
Daniela Cajado-Carvalho ◽  
Carla Cristina Squaiella-Baptistão ◽  
...  
Keyword(s):  
Phagocytic Activity ◽  
Clinical Manifestations ◽  
Direct Interaction ◽  
Kinetic Studies ◽  
Pressure Control ◽  
In Vivo Studies ◽  
Hypotensive Activity ◽  
Tityus Serrulatus

The Tityus serrulatus scorpion is considered the most dangerous of the Brazilian fauna due to the severe clinical manifestations in injured victims. Despite being abundant components of the venom, few linear peptides have been characterized so far, such as hypotensins. In vivo studies have demonstrated that hypotensin I (TsHpt-I) exerts hypotensive activity, with an angiotensin-converting enzyme (ACE)-independent mechanism of action. Since experiments have not yet been carried out to analyze the direct interaction of hypotensins with ACE, and to deepen the knowledge about these peptides, hypotensins I and II (TsHpt-II) were studied regarding their modulatory action over the activities of ACE and neprilysin (NEP), which are the peptidases involved in blood pressure control. Aiming to search for indications of possible pro-inflammatory action, hypotensins were also analyzed for their role in murine macrophage viability, the release of interleukins and phagocytic activity. TsHpt-I and -II were used in kinetic studies with the metallopeptidases ACE and NEP, and both hypotensins were able to increase the activity of ACE. TsHpt-I presented itself as an inhibitor of NEP, whereas TsHpt-II showed weak inhibition of the enzyme. The mechanism of inhibition of TsHpt-I in relation to NEP was defined as non-competitive, with an inhibition constant (Ki) of 4.35 μM. Concerning the analysis of cell viability and modulation of interleukin levels and phagocytic activity, BALB/c mice’s naïve macrophages were used, and an increase in TNF production in the presence of TsHpt-I and -II was observed, as well as an increase in IL-6 production in the presence of TsHpt-II only. Both hypotensins were able to increase the phagocytic activity of murine macrophages in vitro. The difference between TsHpt-I and -II is the residue at position 15, with a glutamine in TsHpt-I and a glutamic acid in TsHpt-II. Despite this, kinetic analyzes and cell assays indicated different actions of TsHpt-I and -II. Taken together, these results suggest a new mechanism for the hypotensive effects of TsHpt-I and -II. Furthermore, the release of some interleukins also suggests a role for these peptides in the venom inflammatory response. Even though these molecules have been well studied, the present results suggest a new mechanism for the hypotensive effects of TsHpt-I

scholarly journals Reducing in vitro rumen methanogenesis for two contrasting diets using a series of inclusion rates of different additives

2014 ◽  
Vol 54 (2) ◽  
pp. 141 ◽  
Author(s):  
M. O'Brien ◽  
A. Navarro-Villa ◽  
P. J. Purcell ◽  
T. M. Boland ◽  
P. O'Kiely
Keyword(s):  
Fatty Acids ◽  
Perennial Ryegrass ◽  
Fumaric Acid ◽  
Barley Grain ◽  
Gas Production ◽  
In Vivo Studies ◽  
Grass Silage ◽  
Dose Dependent

Eleven individual additives were incubated with either perennial ryegrass or with grass silage+barley grain (50 : 50) and the in vitro methane output was assessed using the gas production technique (GPT). Additives were: fatty acids (lauric, oleic, linoleic and linolenic acids), halogenated methane analogues (bromoethanesulfonate and bromochloromethane), pyromellitic diimide, statins (mevastatin and lovastatin), a probiotic (Saccharomyces cerevisiae) and an unsaturated dicarboxylic acid (fumaric acid). Each additive was included at a range of concentrations. Effects on methane output per gram of feed dry matter (DM) incubated (CH4/DMi) and disappeared (CH4/DMd), as well as other fermentation variables, were evaluated after 24 h of incubation. The addition of increased concentrations of individual fatty acids, bromoethanesulfonate and pyromellitic diimide caused a dose-dependent decline in methane output (CH4/DMi, CH4/DMd), when incubated with either perennial ryegrass or grass silage+barley grain. No methane output was detected for either feed with the addition of ≥5 µM bromochloromethane. The statins were ineffective inhibitors of methane output regardless of feed type. For perennial ryegrass, S. cerevisiae caused a dose-dependent decline in CH4/DMd and fumaric acid a dose-dependent decline in CH4/DMi and CH4/DMd. The effectiveness of lauric, oleic, linoleic and linolenic acids and bromoethanesulfonate to reduce methane output was more pronounced when incubated with grass silage+barley grain than with perennial ryegrass, and therefore the type of feed is an important component for any future in vitro and in vivo studies to be undertaken with these additives. Thus, incorporating different feed types in the initial in vitro screening protocols of all new additives is recommended.

scholarly journals PF-06869206 is a selective inhibitor of renal Pi transport: evidence from in vitro and in vivo studies

2020 ◽  
Vol 319 (3) ◽  
pp. F541-F551
Author(s):  
Linto Thomas ◽  
Jianxiang Xue ◽  
Viktor N. Tomilin ◽  
Oleh M. Pochynyuk ◽  
Jessica A. Dominguez Rieg ◽  
...  
Keyword(s):  
Collecting Duct ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Open Probability ◽  
Ok Cells ◽  
Increased Risk ◽  
Dose Dependent Increase ◽  
Dose Dependent

Plasma phosphate (Pi) levels are tightly controlled, and elevated plasma Pi levels are associated with an increased risk of cardiovascular complications and death. Two renal transport proteins mediate the majority of Pi reabsorption: Na+-phosphate cotransporters Npt2a and Npt2c, with Npt2a accounting for 70–80% of Pi reabsorption. The aim of the present study was to determine the in vitro effects of a novel Npt2a inhibitor (PF-06869206) in opossum kidney (OK) cells as well as determine its selectivity in vivo in Npt2a knockout (Npt2a−/−) mice. In OK cells, Npt2a inhibitor caused dose-dependent reductions of Na+-dependent Pi uptake (IC50: ~1.4 μmol/L), whereas the unselective Npt2 inhibitor phosphonoformic acid (PFA) resulted in an ~20% stronger inhibition of Pi uptake. The dose-dependent inhibitory effects were present after 24 h of incubation with both low- and high-Pi media. Michaelis-Menten kinetics in OK cells identified an ~2.4-fold higher Km for Pi in response to Npt2a inhibition with no significant change in apparent Vmax. Higher parathyroid hormone concentrations decreased Pi uptake equivalent to the maximal inhibitory effect of Npt2a inhibitor. In vivo, the Npt2a inhibitor induced a dose-dependent increase in urinary Pi excretion in wild-type mice (ED50: ~23 mg/kg), which was completely absent in Npt2a−/− mice, alongside a lack of decrease in plasma Pi. Of note, the Npt2a inhibitor-induced dose-dependent increase in urinary Na+ excretion was still present in Npt2a−/− mice, a response possibly mediated by an off-target acute inhibitory effect of the Npt2a inhibitor on open probability of the epithelial Na+ channel in the cortical collecting duct.

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