scholarly journals The effects of selected inhibitors on human fetal adrenal steroidogenesis differs under basal and ACTH-stimulated conditions

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Cecilie Melau ◽  
Malene Lundgaard Riis ◽  
John E. Nielsen ◽  
Signe Perlman ◽  
Lene Lundvall ◽  
...  
Keyword(s):  
Treatment Effects ◽  
Ex Vivo ◽  
Abiraterone Acetate ◽  
Clinical Effects ◽  
Inhibitory Effects ◽  
Acth Stimulation ◽  
Therapeutic Drugs ◽  
Adrenal Steroidogenesis ◽  
Culture Model ◽  
The Impact

Abstract Background Disordered fetal adrenal steroidogenesis can cause marked clinical effects including virilization of female fetuses. In postnatal life, adrenal disorders can be life-threatening due to the risk of adrenal crisis and must be carefully managed. However, testing explicit adrenal steroidogenic inhibitory effects of therapeutic drugs is challenging due to species-specific characteristics, and particularly the impact of adrenocorticotropic hormone (ACTH) stimulation on drugs targeting steroidogenesis has not previously been examined in human adrenal tissue. Therefore, this study aimed to examine the effects of selected steroidogenic inhibitors on human fetal adrenal (HFA) steroid hormone production under basal and ACTH-stimulated conditions. Methods This study used an established HFA ex vivo culture model to examine treatment effects in 78 adrenals from 50 human fetuses (gestational weeks 8–12). Inhibitors were selected to affect enzymes critical for different steps in classic adrenal steroidogenic pathways, including CYP17A1 (Abiraterone acetate), CYP11B1/2 (Osilodrostat), and a suggested CYP21A2 inhibitor (Efavirenz). Treatment effects were examined under basal and ACTH-stimulated conditions in tissue from the same fetus and determined by quantifying the secretion of adrenal steroids in the culture media using liquid chromatography-tandem mass spectrometry. Statistical analysis was performed on ln-transformed data using one-way ANOVA for repeated measures followed by Tukey’s multiple comparisons test. Results Treatment with Abiraterone acetate and Osilodrostat resulted in potent inhibition of CYP17A1 and CYP11B1/2, respectively, while treatment with Efavirenz reduced testosterone secretion under basal conditions. ACTH-stimulation affected the inhibitory effects of all investigated drugs. Thus, treatment effects of Abiraterone acetate were more pronounced under stimulated conditions, while Efavirenz treatment caused a non-specific inhibition on steroidogenesis. ACTH-stimulation prevented the Osilodrostat-mediated CYP11B1 inhibition observed under basal conditions. Conclusions Our results show that the effects of steroidogenic inhibitors differ under basal and ACTH-stimulated conditions in the HFA ex vivo culture model. This could suggest that in vivo effects of therapeutic drugs targeting steroidogenesis may vary in conditions where patients have suppressed or high ACTH levels, respectively. This study further demonstrates that ex vivo cultured HFAs can be used to evaluate steroidogenic inhibitors and thereby provide novel information about the local effects of existing and emerging drugs that targets steroidogenesis.

Inhibitory effects of gossypol on adrenal function

1991 ◽  
Vol 124 (6) ◽  
pp. 672-678 ◽  
Author(s):  
Yan-Wan Wu ◽  
Constance L. Chik ◽  
Barry D. Albertson ◽  
W. Marston Linehan ◽  
Richard A. Knazek
Keyword(s):  
Adrenal Function ◽  
Dependent Manner ◽  
Inhibitory Effects ◽  
Acth Stimulation ◽  
Adrenal Steroidogenesis ◽  
Cortisol Responses ◽  
Corticosterone Response ◽  
High Doses ◽  
Dose Dependent

Abstract. Gossypol, an antifertility agent, has inhibitory actions on many membrane-associated enzymes, suggesting that this agent might have a generalized effect on cell membranes. This hypothesis was examined in the present study using membranes and dispersed cells prepared from human and rat adrenal glands. Four parameters were determined: microviscosity as measured by fluorescence polarization of human adrenal microsomal- and mitochondrial-enriched membranes, adrenal steroidogenic enzymes; and cAMP and cortisol responses to ACTH. It was found that gossypol increased the polarization constants of microsomes and mitochondria in a dose-dependent manner. Of the three adrenal enzymes tested, both 3β-hydroxysteroid dehydrogenase Δ5-Δ4 isomerase and 11-hydroxylase were inhibited by gossypol, but not 21-hydroxylase. Using intact human adrenocortical cells, high doses of gossypol also inhibited the ACTH-stimulated cAMP and cortisol levels. The in vivo corticosterone response to ACTH in rats subjected to chronic gossypol treatment was also found to be reduced. These findings suggest that gossypol has multiple effects on adrenal function. Its effects on membrane microviscosity, adrenal steroidogenesis, cAMP and corticosterone responses to ACTH stimulation probably occur through a generalized membrane effect.

scholarly journals Establishment of a Robust and Simple Corneal Organ Culture Model to Monitor Wound Healing

2021 ◽  
Vol 10 (16) ◽  
pp. 3486
Author(s):  
Sandra Schumann ◽  
Eva Dietrich ◽  
Charli Kruse ◽  
Salvatore Grisanti ◽  
Mahdy Ranjbar
Keyword(s):  
Wound Healing ◽  
Organ Culture ◽  
Mitomycin C ◽  
Ex Vivo ◽  
Corneal Tissue ◽  
Dependent Manner ◽  
Toxicological Studies ◽  
Culture Model ◽  
The Impact

The use of in vitro systems to investigate the process of corneal wound healing offers the opportunity to reduce animal pain inflicted during in vivo experimentation. This study aimed to establish an easy-to-handle ex vivo organ culture model with porcine corneas for the evaluation and modulation of epithelial wound healing. Cultured free-floating cornea disks with a punch defect were observed by stereomicroscopic photo documentation. We analysed the effects of different cell culture media and investigated the impact of different wound sizes as well as the role of the limbus. Modulation of the wound healing process was carried out with the cytostatic agent Mitomycin C. The wound area calculation revealed that after three days over 90% of the lesion was healed. As analysed with TUNEL and lactate dehydrogenase assay, the culture conditions were cell protecting and preserved the viability of the corneal tissue. Wound healing rates differ dependent on the culture medium used. Mitomycin C hampered wound healing in a concentration-dependent manner. The porcine cornea ex vivo culture ideally mimics the in vivo situation and allows investigations of cellular behaviour in the course of wound healing. The effect of substances can be studied, as we have documented for a mitosis inhibitor. This model might aid in toxicological studies as well as in the evaluation of drug efficacy and could offer a platform for therapeutic approaches based on regenerative medicine.

HBOT Application at Cases of Gingival Inflammation

2019 ◽  
Author(s):  
Ilma Robo
Keyword(s):  
Root Resorption ◽  
Periodontal Diseases ◽  
Therapeutic Effects ◽  
Clinical Effects ◽  
Gingival Inflammation ◽  
Beneficial Effects ◽  
New Therapeutic Approaches ◽  
Short Period ◽  
Mechanical Therapy ◽  
The Impact

The treatment of periodontal diseases, mainly of their origin, with the most common clinical manifestation in form of gingival inflammation, is manifold and powerful, including: mechanical therapy, antibiotic, antiseptic and various approaches to treatment, which are recommended to be used within a short period of time. New therapeutic approaches have been proven as alternative treatment to conventional therapy, or in combination with conventional therapies, to reduce the number of periodontopathic pathogens in gingival sulcus. HBOT has a detrimental effect on periodontal microorganisms, as well as beneficial effects on the healing of periodontal tissue, increasing oxygen pressure in gingival pockets. Our study is aimed at reviewing the current published literature on hyperbaric oxygen therapy and focuses on role of HBOT as a therapeutic measure for the individual with periodontal disease in general and for the impact on the recovery of gingival inflammation. HBOT and periodontal treatment together, reduce up to 99% of the gram-negative anaerobic load of subgingival flora. HBOT, significantly reduces subgingival anaerobic flora. Clinical effects in 2-year follow-up of treated patients are sensitive. Reduction of gingival hemorrhage indexes, depth of peritoneum, plaque index, occurs in cases of combination of HBOT and detraction. Reduced load persists up to 2 months after therapy. The significant increase in connective tissue removal starts at the end of 2nd week, to achieve the maximum in week 3-6 of application. HBOT used for re-implantation, stimulates the healing of periodontal membrane, pulp, prevents root resorption, healing of periodontal lining tissues. HBOT, significantly reduces the hemorrhage index with 1.2 value difference, 0.7mm probe depth, reduces gingival fluid by 2. HGH exposure is increased by gingival blood flow, with a difference of 2 in measured value. The therapeutic effects of HBOT in the value of the evaluation index can be saved up to 1-year post treatment.

scholarly journals The Caspase-1/IL-18 Axis of the Inflammasome in Tumor Cells: A Modulator of the Th1/Tc1 Response of Tumor-Infiltrating T Lymphocytes in Colorectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 189
Author(s):  
Linda Bilonda Mutala ◽  
Cécile Deleine ◽  
Matilde Karakachoff ◽  
Delphine Dansette ◽  
Kathleen Ducoin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Lymphocytes ◽  
Tumor Cells ◽  
Ex Vivo ◽  
Explant Culture ◽  
T Cell Response ◽  
Mrna Levels ◽  
Innate And Adaptive Immunity ◽  
Caspase 1 ◽  
Culture Model

In colorectal cancer (CRC), a high density of T lymphocytes represents a strong prognostic marker in subtypes of CRC. Optimized immunotherapy strategies to boost this T-cell response are still needed. A good candidate is the inflammasome pathway, an emerging player in cancer immunology that bridges innate and adaptive immunity. Its effector protein caspase-1 matures IL-18 that can promote a T-helper/cytotoxic (Th1/Tc1) response. It is still unknown whether tumor cells from CRC possess a functional caspase-1/IL-18 axis that could modulate the Th1/Tc1 response. We used two independent cohorts of CRC patients to assess IL-18 and caspase-1 expression by tumor cells in relation to the density of TILs and the microsatellite status of CRC. Functional and multiparametric approaches at the protein and mRNA levels were performed on an ex vivo CRC explant culture model. We show that, in the majority of CRCs, tumor cells display an activated and functional caspase-1/IL-18 axis that contributes to drive a Th1/Tc1 response elicited by TILs expressing IL-18Rα. Furthermore, unsupervised clustering identified three clusters of CRCs according to the caspase-1/IL-18/TIL density/interferon gamma (IFNγ) axis and microsatellite status. Together, our results strongly suggest that targeting the caspase-1/IL-18 axis can improve the anti-tumor immune response in subgroups of CRC.

scholarly journals 231 Impact of Brachyspira hyodysentariae on intestinal function and integrity

2020 ◽  
Vol 98 (Supplement_3) ◽  
pp. 116-116
Author(s):  
Emma T Helm ◽  
Susanne J Lin ◽  
Nicholas Gabler ◽  
Eric R Burrough
Keyword(s):  
Ex Vivo ◽  
Potato Starch ◽  
Nutrient Digestibility ◽  
High Morbidity ◽  
Post Inoculation ◽  
Intestinal Function ◽  
Treatment Groups ◽  
Intestinal Integrity ◽  
Beet Pulp ◽  
The Impact

Abstract Swine dysentery (SD) induced by Brachyspira hyodysentariae (Bhyo) causes colitis and mucohemorrhagic diarrhea in grow-finish pigs, however little is known about the physiological changes that occur to the gastrointestinal tract during Bhyo infection. Thus, the objective of this study was to evaluate the impact of a Bhyo challenge on intestinal function and integrity of pigs fed two divergent diets. A total of 36 Bhyo negative gilts (24.3 ± 3.6 kg BW) were selected and assigned to one of three treatment groups (n=12 pigs/trt): 1) Bhyo negative, 20% DDGS diet (CON), 2) Bhyo challenged, 20% DDGS diet (DDGS), and 3) Bhyo challenged, 10% DDGS, 5% beet pulp and 5% resistant potato starch diet (RS). Pigs were fed diets 21 days prior to challenge and on days post inoculation (dpi) 0 and 1, pigs were inoculated with Bhyo or sham. Fecal samples were collected for ATTD and pigs were euthanized for colon collection within 72 hours of initial observation of clinical SD, or at the end of the study (dpi 10-16). Tissues were assessed for ex vivo measures of intestinal integrity and mitochondrial function. The challenge resulted in high morbidity, with 88% of DDGS and RS pigs developing clinical SD. Colon transepithelial resistance was increased in DDGS pigs compared with CON and RS pigs (P=0.005), and colon macromolecule permeability was reduced in both DDGS and RS pigs compared with CON pigs (P=0.006), likely due to mucoid discharge. Colonic mitochondrial oxygen consumption was not impacted by treatment (P >0.10). Further, ATTD of DM, OM, N, and GE were reduced in DDGS pigs compared with CON pigs (P< 0.001), whilst nutrient digestibility was not reduced in RS pigs. Taken together, these data show Bhyo does not appear to reduce ex vivo colonic integrity. Further, the RS diet may reduce severity of a Bhyo challenge.

scholarly journals Histological, Biomechanical, and Biological Properties of Genipin-Crosslinked Decellularized Peripheral Nerves

2021 ◽  
Vol 22 (2) ◽  
pp. 674
Author(s):  
Óscar Darío García-García ◽  
Marwa El Soury ◽  
David González-Quevedo ◽  
David Sánchez-Porras ◽  
Jesús Chato-Astrain ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Nerve Repair ◽  
Wistar Rat ◽  
Biomechanical Properties ◽  
Biological Properties ◽  
Suitable Alternative ◽  
Promising Alternative ◽  
Histological Pattern ◽  
The Impact

Acellular nerve allografts (ANGs) represent a promising alternative in nerve repair. Our aim is to improve the structural and biomechanical properties of biocompatible Sondell (SD) and Roosens (RS) based ANGs using genipin (GP) as a crosslinker agent ex vivo. The impact of two concentrations of GP (0.10% and 0.25%) on Wistar rat sciatic nerve-derived ANGs was assessed at the histological, biomechanical, and biocompatibility levels. Histology confirmed the differences between SD and RS procedures, but not remarkable changes were induced by GP, which helped to preserve the nerve histological pattern. Tensile test revealed that GP enhanced the biomechanical properties of SD and RS ANGs, being the crosslinked RS ANGs more comparable to the native nerves used as control. The evaluation of the ANGs biocompatibility conducted with adipose-derived mesenchymal stem cells cultured within the ANGs confirmed a high degree of biocompatibility in all ANGs, especially in RS and RS-GP 0.10% ANGs. Finally, this study demonstrates that the use of GP could be an efficient alternative to improve the biomechanical properties of ANGs with a slight impact on the biocompatibility and histological pattern. For these reasons, we hypothesize that our novel crosslinked ANGs could be a suitable alternative for future in vivo preclinical studies.

scholarly journals Phytotoxicity of Silver Nanoparticles on Tobacco Plants: Evaluation of Coating Effects on Photosynthetic Performance and Chloroplast Ultrastructure

Nanomaterials ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 744
Author(s):  
Petra Peharec Štefanić ◽  
Karla Košpić ◽  
Daniel Mark Lyons ◽  
Lara Jurković ◽  
Biljana Balen ◽  
...  
Keyword(s):  
Silver Nanoparticles ◽  
Cetyltrimethylammonium Bromide ◽  
Photosynthetic Apparatus ◽  
Chloroplast Ultrastructure ◽  
Photosynthetic Performance ◽  
Pigment Content ◽  
Inhibitory Effects ◽  
Tobacco Plants ◽  
Agriculture And Food ◽  
The Impact

Silver nanoparticles (AgNPs) are the most exploited nanomaterial in agriculture and food production, and their release into the environment raises concern about their impact on plants. Since AgNPs are prone to biotransformation, various surface coatings are used to enhance their stability, which may modulate AgNP-imposed toxic effects. In this study, the impact of AgNPs stabilized with different coatings (citrate, polyvinylpyrrolidone (PVP), and cetyltrimethylammonium bromide (CTAB)) and AgNO3 on photosynthesis of tobacco plants as well as AgNP stability in exposure medium have been investigated. Obtained results revealed that AgNP-citrate induced the least effects on chlorophyll a fluorescence parameters and pigment content, which could be ascribed to their fast agglomeration in the exposure medium and consequently weak uptake. The impact of AgNP-PVP and AgNP-CTAB was more severe, inducing a deterioration of photosynthetic activity along with reduced pigment content and alterations in chloroplast ultrastructure, which could be correlated to their higher stability, elevated Ag accumulation, and surface charge. In conclusion, intrinsic properties of AgNP coatings affect their stability and bioavailability in the biological medium, thereby indirectly contributing changes in the photosynthetic apparatus. Moreover, AgNP treatments exhibited more severe inhibitory effects compared to AgNO3, which indicates that the impact on photosynthesis is dependent on the form of Ag.

scholarly journals Impact of pretreatment anemia on upfront abiraterone acetate therapy for metastatic hormone-sensitive prostate cancer: a multicenter retrospective study

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Teppei Okamoto ◽  
Daisuke Noro ◽  
Shingo Hatakeyama ◽  
Shintaro Narita ◽  
Koji Mitsuzuka ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Factor ◽  
Abiraterone Acetate ◽  
Tumor Burden ◽  
Hazard Ratio ◽  
Historical Cohort ◽  
High Tumor Burden ◽  
Significant Difference ◽  
Hormone Sensitive ◽  
The Impact

Abstract Background Anemia has been a known prognostic factor in metastatic hormone-sensitive prostate cancer (mHSPC). We therefore examined the effect of anemia on the efficacy of upfront abiraterone acetate (ABI) in patients with mHSPC. Methods We retrospectively evaluated 66 mHSPC patients with high tumor burden who received upfront ABI between 2018 and 2020 (upfront ABI group). We divided these patients into two groups: the anemia-ABI group (hemoglobin < 13.0 g/dL, n = 20) and the non-anemia-ABI group (n = 46). The primary objective was to examine the impact of anemia on the progression-free survival (PFS; clinical progression or PC death before development of castration resistant PC) of patients in the upfront ABI group. Secondary objectives included an evaluation of the prognostic significance of upfront ABI and a comparison with a historical cohort (131 mHSPC patients with high tumor burden who received androgen deprivation therapy (ADT/complete androgen blockade [CAB] group) between 2014 and 2019). Results We found that the anemia-ABI group had a significantly shorter PFS than the non-anemia-ABI group. A multivariate Cox regression analysis showed that anemia was an independent prognostic factor of PFS in the upfront ABI group (hazard ratio, 4.66; P = 0.014). Patients in the non-anemia-ABI group were determined to have a significantly longer PFS than those in the non-anemia-ADT/CAB group (n = 68) (P < 0.001). However, no significant difference was observed in the PFS between patients in the anemia-ABI and the anemia-ADT/CAB groups (n = 63). Multivariate analyses showed that upfront ABI could significantly prolong the PFS of patients without anemia (hazard ratio, 0.17; P < 0.001), whereas ABI did not prolong the PFS of patients with anemia. Conclusion Pretreatment anemia was a prognostic factor among mHSPC patients who received upfront ABI. Although the upfront ABI significantly improved the PFS of mHSPC patients without anemia, its efficacy in patients with anemia might be limited.

scholarly journals Gut-Ex-Vivo system as a model to study gluten response in celiac disease

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Mara Gagliardi ◽  
Nausicaa Clemente ◽  
Romina Monzani ◽  
Luca Fusaro ◽  
Eleonora Ferrari ◽  
...  
Keyword(s):  
Celiac Disease ◽  
Intestinal Epithelium ◽  
Complex Disease ◽  
Ex Vivo ◽  
Dynamic Condition ◽  
Model Systems ◽  
In Vivo Models ◽  
Effective Manner ◽  
Junction Protein ◽  
The Impact

AbstractCeliac disease (CD) is a complex immune-mediated chronic disease characterized by a consistent inflammation of the gastrointestinal tract induced by gluten intake in genetically predisposed individuals. Although initiated by the interaction between digestion-derived gliadin, a gluten component, peptides, and the intestinal epithelium, the disorder is highly complex and involving other components of the intestine, such as the immune system. Therefore, conventional model systems, mainly based on two- or three-dimension cell cultures and co-cultures, cannot fully recapitulate such a complex disease. The development of mouse models has facilitated the study of different interacting cell types involved in the disorder, together with the impact of environmental factors. However, such in vivo models are often expensive and time consuming. Here we propose an organ ex vivo culture (gut-ex-vivo system) based on small intestines from gluten-sensitive mice cultivated in a dynamic condition, able to fully recapitulate the biochemical and morphological features of the mouse model exposed to gliadin (4 weeks), in 16 h. Indeed, upon gliadin exposure, we observed: i) a down-regulation of cystic fibrosis transmembrane regulator (CFTR) and an up-regulation of transglutaminase 2 (TG2) at both mRNA and protein levels; ii) increased intestinal permeability associated with deregulated tight junction protein expression; iii) induction and production of pro-inflammatory cytokines such as interleukin (IL)-15, IL-17 and interferon gamma (IFNγ); and iv) consistent alteration of intestinal epithelium/villi morphology. Altogether, these data indicate that the proposed model can be efficiently used to study the pathogenesis of CD, test new or repurposed molecules to accelerate the search for new treatments, and to study the impact of the microbiome and derived metabolites, in a time- and cost- effective manner.

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