scholarly journals A New Generation Somatostatin-Dopamine Analogue Exerts Potent Antitumoral Actions on Pituitary Neuroendocrine Tumor Cells

2019 ◽  
Vol 110 (1-2) ◽  
pp. 70-82 ◽  
Author(s):  
Mari C. Vázquez-Borrego ◽  
Fernando L-López ◽  
María A. Gálvez-Moreno ◽  
Antonio C. Fuentes-Fayos ◽  
Eva Venegas-Moreno ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Cultures ◽  
Therapeutic Option ◽  
Hormone Secretion ◽  
Somatostatin Analogs ◽  
Therapeutic Effects ◽  
Number Of Patients ◽  
Secretion Expression ◽  
New Generation

Background: Pituitary neuroendocrine tumors (PitNETs) represent approximately 15% of all intracranial tumors and usually are associated with severe comorbidities. Unfortunately, a relevant number of patients do not respond to currently available pharmacological treatments, that is, somatostatin analogs (SSAs) or dopamine-agonists (DA). Thus, novel, chimeric somatostatin/dopamine compounds (dopastatins) that could improve medical treatment of PitNETs have been designed. Objective: This study aims to determine the direct therapeutic effects of a new-generation dopastatin, BIM-065, on primary cell cultures from different PitNETs subtypes. Methods: Thirty-one PitNET-derived cell cultures (9 corticotropinomas, 9 somatotropinomas, 11 nonfunctioning pituitary adenomas [NFPAs], and 2 prolactinomas), were treated with BIM-065, and key functional endpoints were assessed (cell viability, apoptosis, hormone secretion, expression levels of key genes, free cytosolic [Ca2+]i dynamics, etc.). AtT-20 cell line was used to evaluate signaling pathways in response to BIM-065. Results: This chimeric compound decreased cell viability in all corticotropinomas and somatotropinomas tested, but not in NFPAs. BIM-065 reduced ACTH, GH, chromogranin-A and PRL secretion, and increased apoptosis in corticotropinomas, somatotropinomas, and NFPAs. These effects were possibly mediated through modulation of pivotal signaling cascades like [Ca2+]i kinetic and Akt- or ERK1/2-phosphorylation. Conclusions: Our results unveil a robust antitumoral effect in vitro of the novel chimeric compound BIM-065 on the main PitNET subtypes, inform on the mechanisms involved, and suggest that BIM-065 could be an efficacious therapeutic option to be considered in the treatment of PitNETs.

scholarly journals Octreotide and pasireotide (dis)similarly inhibit pituitary tumor cells in vitro

2016 ◽  
Vol 231 (2) ◽  
pp. 135-145 ◽  
Author(s):  
Alejandro Ibáñez-Costa ◽  
Esther Rivero-Cortés ◽  
Mari C Vázquez-Borrego ◽  
Manuel D Gahete ◽  
Luis Jiménez-Reina ◽  
...  
Keyword(s):  
Cell Viability ◽  
Pituitary Adenomas ◽  
Somatostatin Receptor ◽  
Hormone Secretion ◽  
Somatostatin Analogs ◽  
Hormone Release ◽  
Growth Hormone Release ◽  
Molecular Features ◽  
Intracellular Ca

Somatostatin analogs (SSA) are the mainstay of pharmacological treatment for pituitary adenomas. However, some patients escape from therapy with octreotide, a somatostatin receptor 2 (sst2)-preferring SSA, and pasireotide, a novel multi-sst-preferring SSA, may help to overcome this problem. It has been proposed that correspondence between sst1-sst5 expression pattern and SSA-binding profile could predict patient’s response. To explore the cellular/molecular features associated with octreotide/pasireotide response, we performed a parallel comparison of their in vitro effects, evaluating sst1-sst5 expression, intracellular Ca2+ signaling ([Ca2+]i), hormone secretion and cell viability, in a series of 85 pituitary samples. Somatotropinomas expressed sst5>sst2, yet octreotide reduced [Ca2+]i more efficiently than pasireotide, while both SSA similarly decreased growth hormone release/expression and viability. Corticotropinomas predominantly expressed sst5, but displayed limited response to pasireotide, while octreotide reduced functional endpoints. Non-functioning adenomas preferentially expressed sst3 but, surprisingly, both SSA increased cell viability. Prolactinomas mainly expressed sst1 but were virtually unresponsive to SSA. Finally, both SSA decreased [Ca2+]i in normal pituitaries. In conclusion, both SSA act in vitro on pituitary adenomas exerting both similar and distinct effects; however, no evident correspondence was found with the sst1-sst5 profile. Thus, it seems plausible that additional factors, besides the simple abundance of a given sst, critically influence the SSA response.

MiR-485-5p Promotes Neuron Survival through Mediating Rac1/Notch2 Signaling Pathway after Cerebral Ischemia/Reperfusion

2020 ◽  
Vol 17 (3) ◽  
pp. 259-266 ◽  
Author(s):  
Xuan Chen ◽  
Sumei Zhang ◽  
Peipei Shi ◽  
Yangli Su ◽  
Dong Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Viability ◽  
Therapeutic Option ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Small Gtpase ◽  
Luciferase Reporter ◽  
Pathological Feature ◽  
In Cells

Objective: Ischemia-reperfusion (I/R) injury is a pathological feature of ischemic stroke. This study investigated the regulatory role of miR-485-5p in I/R injury. Methods: SH-SY5Y cells were induced with oxygen and glucose deprivation/reoxygenation (OGD/R) to mimic I/R injury in vitro. Cells were transfected with designated constructs (miR-485- 5p mimics, miR-485-5p inhibitor, lentiviral vectors overexpressing Rac1 or their corresponding controls). Cell viability was evaluated using the MTT assay. The concentrations of lactate dehydrogenase, malondialdehyde, and reactive oxygen species were detected to indicate the degree of oxidative stress. Flow cytometry and caspase-3 activity assay were used for apoptosis assessment. Dual-luciferase reporter assay was performed to confirm that Rac family small GTPase 1 (Rac1) was a downstream gene of miR-485-5p. Results: OGD/R resulted in decreased cell viability, elevated oxidative stress, increased apoptosis, and downregulated miR-485-5p expression in SH-SY5Y cells. MiR-485-5p upregulation alleviated I/R injury, evidenced by improved cell viability, decreased oxidative markers, and reduced apoptotic rate. OGD/R increased the levels of Rac1 and neurogenic locus notch homolog protein 2 (Notch2) signaling-related proteins in cells with normal miR-485-5p expression, whereas miR- 485-5p overexpression successfully suppressed OGD/R-induced upregulation of these proteins. Furthermore, the delivery of vectors overexpressing Rac1 in miR-485-5p mimics-transfected cells reversed the protective effect of miR-485-5p in cells with OGD/R-induced injury. Conclusion: This study showed that miR-485-5p protected cells following I/R injury via targeting Rac1/Notch2 signaling suggest that targeted upregulation of miR-485-5p might be a promising therapeutic option for the protection against I/R injury.

scholarly journals Therapeutic effects of Zuojin Pill on Helicobacter pylori-induced chronic atrophic gastritis through JMJD2B/COX-2/VEGF signaling axis

2020 ◽  
Author(s):  
Shihua Wu ◽  
Chunmei Bao ◽  
Ruilin Wang ◽  
Xiaomei Zhang ◽  
Sijia Gao ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Cell Viability ◽  
Atrophic Gastritis ◽  
Chronic Atrophic Gastritis ◽  
Gastric Mucosal Damage ◽  
Therapeutic Effects ◽  
Cox 2 ◽  
H Pylori

Abstract Background: Zuojin Pill (ZJP), a famous Chinese medicinal formula, widely accepted for treatment of chronic atrophic gastritis (CAG) in China. This study aimed to explore the therapeutic effects and mechanisms of ZJP in Helicobacter pylori (H. pylori) - induced chronic atrophic gastritis (CAG) in vivo and in vitro. Methods: CAG rat model was induced by H. pylori. ZJP (0.63, 1.26, and 2.52 g/kg, respectively) was administered orally for four weeks. Therapeutic effects of ZJP were identified by H&E staining and serum indices. In addition, cell viability, morphology and proliferation were detected by cell counting kit-8 (CCK8) and high-content screening assay (HCS), respectively. Moreover, relative mRNA expression and protein expression related to JMJD2B/COX-2/VEGF axis was detected to investigate the potential mechanisms of ZJP in CAG. Results: Results showed the symptoms (weight loss and gastric mucosa damage) of CAG were alleviated, and the contents of TNF-α in serum was markedly decreased after treating with ZJP. Moreover, cell viability, proliferation and morphology changes of GES-1 cells were ameliorated by ZJP intervention. In addition, proinflammatory genes and JMJD2B/COX-2/VEGF axis related genes were suppressed by ZJP administration in vitro and in vivo. Meanwhile, immunohistochemistry (IHC) and western blot confirmed down-regulation of these genes by ZJP intervention. Conclusion: ZJP treatment can alleviate gastric mucosal damage induced by H. pylori via JMJD2B/COX-2/VEGF axis.

Abstract 346: Lipophilic Statins Attenuate Human Atrial Fibroblast Viability In Vitro

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Kiranjit K Sran ◽  
Yun Li ◽  
Saeid Ghavami ◽  
Melanie Ngo ◽  
Rakesh C Arora ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Viability ◽  
Heart Surgery ◽  
Cardiac Fibrosis ◽  
Therapeutic Option ◽  
Open Heart Surgery ◽  
Myocardial Cell ◽  
Dependent Manner ◽  
Vitro Effect

Cardiovascular diseases (CVD) leading to heart failure are associated with myocardial cell loss and cardiac fibrosis. Hydroxymethylglutaryl-Coenzyme-A Reductase (HMGR) inhibitors ("statins") are widely used to limit cardiovascular events in patients with hypercholesterolemia and CVD by altering their lipid profile. HMGR inhibition reduces cholesterol precursor L-mevalonate production, whose depletion induces autophagy, apoptosis, and endoplasmic reticulum stress in various cell types. However it is unclear if this is a class effect or a phenomenon specific to various compounds. We examined the in vitro effect of HMGR inhibition on human atrial fibroblast (hATF) viability with particular reference to hydrophilic vs lipophilic compounds. Hypothesis- Lipophilic statins induce cell death in primary hATF via mevalonate depletion; whereas hydrophilic statins do not have any effect on hATF viability. IRB approval was obtained for collection of hATF from consenting patients undergoing open heart surgery. Cells were treated with atorvastatin, simvastatin or pravastatin (0.1, 1.0 or 10 λM) for 24, 48, 72 or 96 hours. Expression of proteins involved in the regulation of apoptosis and autophagy was assessed using immunoblotting. Cell viability was assessed using MTT assay. Treatment of hATF with 0.1 - 10 λM atorvastatin or simvastatin (lipophilic statins) resulted in progressively reduced cell viability in time and dose-dependent manner. Viability could be rescued by coincubation with mevalonate. Expression of key apoptotic cascade proteins -Bcl2, Bax and cleaved Caspase3 showed a clear induction of apoptosis. Also, there was an increase in Atg5-12 expression at 24h indicating induction of early autophagic response. Pravastatin (hydrophilic statin) did not affect cell viability or autophagy and apoptosis. We conclude that statin-induced cell death is mediated by mevalonate depletion, which activates intrinsic apoptotic pathways in hATF. Lipophilic statins impair the viability of hATFs in vitro, whereas hydrophilic statins have no effect on cell growth and cell viability of hATFs. This may represent an additional pleiotropic effect of statins, and may represent a novel therapeutic option for the prevention and treatment of cardiac fibrosis.

scholarly journals Effects of Circulating HMGB-1 and Histones on Cardiomyocytes–Hemadsorption of These DAMPs as Therapeutic Strategy after Multiple Trauma

2020 ◽  
Vol 9 (5) ◽  
pp. 1421
Author(s):  
Birte Weber ◽  
Ina Lackner ◽  
Meike Baur ◽  
Giorgio Fois ◽  
Florian Gebhard ◽  
...  
Keyword(s):  
Cell Viability ◽  
Ex Vivo ◽  
Therapeutic Option ◽  
Substantial Reduction ◽  
Calcium Handling ◽  
Human Cardiomyocytes ◽  
Multiple Injured ◽  
Extracellular Histones ◽  
Injured Patients

Background and purpose: The aim of the study was to determine the effects of post-traumatically released High Mobility Group Box-1 protein (HMGB1) and extracellular histones on cardiomyocytes (CM). We also evaluated a therapeutic option to capture circulating histones after trauma, using a hemadsorption filter to treat CM dysfunction. Experimental Approach: We evaluated cell viability, calcium handling and mitochondrial respiration of human cardiomyocytes in the presence of HMGB-1 and extracellular histones. In a translational approach, a hemadsorption filter was applied to either directly eliminate extracellular histones or to remove them from blood samples obtained from multiple injured patients. Key results: Incubation of human CM with HMGB-1 or histones is associated with changes in calcium handling, a reduction of cell viability and a substantial reduction of the mitochondrial respiratory capacity. Filtrating plasma from injured patients with a hemadsorption filter reduces histone concentration ex vivo and in vitro, depending on dosage. Conclusion and implications: Danger associated molecular patterns such as HMGB-1 and extracellular histones impair human CM in vitro. A hemadsorption filter could be a therapeutic option to reduce high concentrations of histones.

scholarly journals SCIDOT-46. MicroRNA NANOCELL THERAPY FOR GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi281-vi281
Author(s):  
Muhammad Babar Khan ◽  
Rosamaria Ruggieri ◽  
Nhan Tran ◽  
Jann Sarkaria ◽  
Jennifer MacDiarmid ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cell Cultures ◽  
Radiation Treatment ◽  
The Cancer Genome Atlas ◽  
Therapeutic Resistance ◽  
Therapeutic Effects ◽  
Resistance Proteins ◽  
Phosphorylated Akt

Abstract Therapeutic resistance stemming from inter and intra-tumoral heterogeneity is a significant impediment towards development of effective therapeutics for glioblastoma. We hypothesized that microRNAs can potentially counteract resistance emanating from such heterogeneity as they simultaneously modulate the expression of multiple proteins. We identified microRNA-34a as a unique microRNA which modulates multiple oncoproteins in GBM using two different in silico approaches. We investigated the therapeutic effects of microRNA-34a in three primary patient-derived xenografts (PDX) representing classical (GBM6), proneural (GBM118) and mesenchymal (GBM118) subtypes; four established cell lines (T98G, U251, A172, LN229) and two cell lines with acquired resistance to temozolomide (A172-TR, LN229-TR) in vitro. Glioblastoma cell cultures showed variable responses to temozolomide but microRNA-34a inhibited proliferation in all cell cultures. Furthermore, microRNA-34a also sensitized all tested cell lines to temozolomide (combination index < 0.8, p=.03) and radiation treatment (dose enhancement factor 1.7–2.2, p=0.02). Mechanistically, microRNA 34a down-regulates at least six distinct therapeutic resistance proteins. Importantly, these resistance proteins are expressed in distinct spatial niches and are prognostic for patient survival based on our analysis of the cancer genome atlas (TCGA) data. For in vivo delivery of microRNA-34a, we utilized nanocells which are derived from genetically modified bacteria, loaded with microRNA-34a and tagged with a bispecific antibody targeting EGFR. Nanocells were injected intravenously while temozolomide was administered by oral gavage in an orthotopic PDX model. We confirmed delivery of microRNA-34a to tumor by observing down-regulation of cMet and phosphorylated Akt in treated mice. Importantly, microRNA-34a nanocells resulted in significant reduction in tumor growth (p=0.021), increased survival (p<0.001) with microRNA-34a monotherapy and synergy in combination with temozolomide in vivo. Taken together, our results suggest that delivery of miR-34a may be a powerful new adjuvant for the treatment of glioblastoma in combination with temozolomide that can mitigate both inter- and intra-tumor heterogeneity.

scholarly journals Anti-Inflammatory Potential of Complex Extracts of Ligularia stenocephala Matsum. & Koidz. and Secale cereale L. Sprout in Chronic Gingivitis: In Vitro Investigation and Randomized Clinical Trial

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1586
Author(s):  
Inpyo Hong ◽  
Jin-Young Park ◽  
Yoo-Hun Noh ◽  
Su-Hee Jeon ◽  
Jeong-Won Paik ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cell Viability ◽  
Secale Cereale ◽  
Test Group ◽  
Number Of Patients ◽  
In Vitro Investigation ◽  
Secale Cereale L ◽  
Anti Inflammatory ◽  
Ligularia Stenocephala

Complex extracts of Ligularia stenocephala Matsum. & Koidz. (LSE) and Secale cereale L. sprout (SCSE) (TEES-10®) were prepared. The purposes of the study were to evaluate anti-inflammatory activities of TEES-10® in vitro and to observe resolution of gingivitis in human with oral administration of TEES-10®. The effects of TEES-10® on normal periodontal ligament (PDL) cell viability, lipopolysaccharide (LPS) induced PDL cell viability and the changes of inflammatory mediator expression were evaluated in vitro. In the clinical trial, 150 mg of TEES-10® powder containing capsule was administered twice daily to the test group, while the control group administered placebos in a total 100 participants with gingivitis. Probing depth (PD), bleeding on probing (BOP), clinical attachment loss, gingival index (GI) and plaque index (PI) were measured at baseline and 4 weeks. Administering TEES-10® showed significant increase in PDL cell viability compared to administering LSE or SCSE alone. In addition, treating TEES-10® to LPS induced PDL cell significantly increased PDL cell viability compared to control. TEES-10® suppressed expression of NF-κB, p-ERK, ERK, COX-2, c-Fos and p-STAT and promoted expression of PPARγ in LPS induced PDL cells. In the clinical trial, significant improvement of GI and BOP was observed in the test group at 4 weeks. In addition, the number of patients diagnosed with gingivitis was significantly reduced in the test group at 4 weeks. Salivary MMP-8 and MMP-9 was also significantly decreased compared to placebo group. Within the limitations of this study, the TEES-10® would have an anti-inflammatory potential clinically in the chronic gingivitis patients.

scholarly journals Efficacy, Efficiency and Security of Urea Treatment in the Syndrome of Inappropiate Antidiuretic Hormone Secretion

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A627-A627
Author(s):  
Eva Perelló Camacho ◽  
Francisco José Pomares Gómez ◽  
Luis López Penabad ◽  
Rosa María Mirete López ◽  
María Rosa Pinedo Esteban ◽  
...  
Keyword(s):  
Antidiuretic Hormone ◽  
Therapeutic Option ◽  
Hormone Secretion ◽  
Cost Effective ◽  
Plasma Sodium ◽  
Duration Of Treatment ◽  
Inappropriate Antidiuretic Hormone Secretion ◽  
Antidiuretic Hormone Secretion ◽  
Number Of Patients ◽  
Effective Option

Abstract Introduction: In the present times, several strategies have been proposed for the treatment of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Urea has demonstrated to be an effective treatment but its use has not been extended. Our work analyzes our experience with urea in the treatment of SIADH. Material and Methods: Observational retrospective analysis of 39 patients with SIADH in which urea has been used in our hospital with pre- and post-analysis of plasmatic sodium concentrations. Results: We included 39 patients with SIADH win a mean age of 76,4 ± 15,8 years. The plasma sodium nadir was 120,0 ± 5,1 mmoL/L and at the initiation of treatment 125,2 ± 4,1 mmoL/L. Total time of treatment was 2,42 ± 3,86 months being the treatment still active in 4 patients. We observed an improvement of sodium in all patients with a mean sodium at the end of treatment of 134.3 + - 5.0 mmol/L being this values statistically significant compared to the initial sodium (p&lt;0.01). As a matter of fact we found significant differences at one week of treatment (p&lt;0.01), keeping sodium stable levels around 135 mmol/L during the treatment period. The treatment was stopped in 3 cases (7.7 %) by the patient, one for mild digestive symptomatology and two for limited palatability. Of them two were treated with tolvaptan and the other did not need any further treatment. There were no adverse events in the rest of the patients. From the economic perspective and considering the duration of treatment, if we compare this to the cost of tolvaptan during the same period and the same number of patients, there was a reduction of cost of 87.9 % in comparison with treatment with tolvaptan. Conclusions: In our experience urea has shown to be a safe and cost effective option in the treatment of hyponatremia caused by SIADH showing improvement in sodium levels from the first week of treatment in all patients. We think it should be considered a valid therapeutic option.

scholarly journals Aloe Vera/Collagen Mixture Induces Integrin α1β1 and PECAM-1Genes Expression in Human Adipose-Derived Stem Cells

2019 ◽  
Vol 9 (4) ◽  
pp. 662-667 ◽  
Author(s):  
Faraz Sigaroodi ◽  
Hajar Shafaei ◽  
Mohammad Karimipour ◽  
Mohammad Amin Dolatkhah ◽  
Abbas Delazar
Keyword(s):  
Tissue Engineering ◽  
Stem Cells ◽  
Cell Viability ◽  
Real Time ◽  
Cell Attachment ◽  
Aloe Vera ◽  
Therapeutic Effects ◽  
Adipose Derived Stem Cells ◽  
Genes Expression

Purpose: Natural biomaterials are a key base in tissue engineering, and collagen, as the maincontent of the extracellular matrix (ECM), is frequently used in tissue engineering. Aloe verahas some therapeutic effects on ulcers, therefore, the use of this natural resource has alwaysbeen considered for improving collagen function. We aimed to evaluate the effect of Aloe vera/Collagen blended on cell viability, cell attachment, and angiogenic potential by determining ofintegrin α1β1 and platelet endothelial cell adhesion molecule (PECAM-1) genes expression inhuman adipose-derived stem cells (hASCs).Methods: In this study, hASCs after harvesting of adipose tissues from abdominal subcutaneousadipose tissue and isolation, were cultured in four groups of control, collagen gel, Aloe veragel, and Aloe vera/collagen blended in vitro environment at 24h and then cell viability wasassessed by MTT (3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium) assay. Integrin α1β1 andPECAM-1 genes expression were evaluated by real-time RT-PCR.Results: The results of MTT showed that the combination of Aloe vera/collagen was retained thecell viability at the normal range and improved it. In real-time RT-PCR results, integrin α1β1 andPECAM-1 gene expression were increased in the Aloe vera/collagen blended group comparedto the control group.Conclusion: For tissue engineering purposes, Aloe vera improves collagen properties in theculture of hASCs by increasing the expression of the integrin α1β1 and PECAM-1 genes.<br />

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