| 1. |
- Augustijns, Patrick, et al.
(författare)
-
Unraveling the behavior of oral drug products inside the human gastrointestinal tract using the aspiration technique : History, methodology and applications
- 2020
-
Ingår i: European Journal of Pharmaceutical Sciences. - : ELSEVIER. - 0928-0987 .- 1879-0720. ; 155
-
Tidskriftsartikel (refereegranskat)abstract
- Fluid sampling from the gastrointestinal (GI) tract has been applied as a valuable tool to gain more insight into the fluids present in the human GI tract and to explore the dynamic interplay of drug release, dissolution, precipitation and absorption after drug product administration to healthy subjects. In the last twenty years, collaborative initiatives have led to a plethora of clinical aspiration studies that aimed to unravel the luminal drug behavior of an orally administered drug product. The obtained drug concentration-time profiles from different segments in the GI tract were a valuable source of information to optimize and/or validate predictive in vitro and in silico tools, frequently applied in the non-clinical stage of drug product development. Sampling techniques are presently not only being considered as a stand-alone technique but are also used in combination with other in vivo techniques (e.g., gastric motility recording, magnetic resonance imaging (MRI)). By doing so, various physiological variables can be mapped simultaneously and evaluated for their impact on luminal drug and formulation behavior. This comprehensive review aims to describe the history, challenges and opportunities of the aspiration technique with a specific focus on how this technique can unravel the luminal behavior of drug products inside the human GI tract by providing a summary of studies performed over the last 20 years. A section `Best practices' on how to perform the studies and how to treat the aspirated samples is described. In the conclusion, we focus on future perspectives concerning this technique.
|
|
| 2. |
- Balgoma, David, et al.
(författare)
-
Anthracyclins Increase PUFAs : Potential Implications in ER Stress and Cell Death
- 2021
-
Ingår i: Cells. - : MDPI. - 2073-4409. ; 10:5
-
Tidskriftsartikel (refereegranskat)abstract
- Metabolic and personalized interventions in cancer treatment require a better understanding of the relationship between the induction of cell death and metabolism. Consequently, we treated three primary liver cancer cell lines with two anthracyclins (doxorubicin and idarubin) and studied the changes in the lipidome. We found that both anthracyclins in the three cell lines increased the levels of polyunsaturated fatty acids (PUFAs) and alkylacylglycerophosphoethanolamines (etherPEs) with PUFAs. As PUFAs and alkylacylglycerophospholipids with PUFAs are fundamental in lipid peroxidation during ferroptotic cell death, our results suggest supplementation with PUFAs and/or etherPEs with PUFAs as a potential general adjuvant of anthracyclins. In contrast, neither the markers of de novo lipogenesis nor cholesterol lipids presented the same trend in all cell lines and treatments. In agreement with previous research, this suggests that modulation of the metabolism of cholesterol could be considered a specific adjuvant of anthracyclins depending on the type of tumor and the individual. Finally, in agreement with previous research, we found a relationship across the different cell types between: (i) the change in endoplasmic reticulum (ER) stress, and (ii) the imbalance between PUFAs and cholesterol and saturated lipids. In the light of previous research, this imbalance partially explains the sensitivity to anthracyclins of the different cells. In conclusion, our results suggest that the modulation of different lipid metabolic pathways may be considered for generalized and personalized metabochemotherapies.
|
|
| 3. |
- Calitz, Carlemi, et al.
(författare)
-
Influence of extracellular matrix composition on tumour cell behaviour in a biomimetic in vitro model for hepatocellular carcinoma
- 2023
-
Ingår i: Scientific Reports. - : NATURE PORTFOLIO. - 2045-2322. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- The tumor micro-environment (TME) of hepatocellular carcinoma (HCC) consists out of cirrhotic liver tissue and is characterized by an extensive deposition of extracellular matrix proteins (ECM). The evolution from a reversible fibrotic state to end-stage of liver disease, namely cirrhosis, is characterized by an increased deposition of ECM, as well as changes in the exact ECM composition, which both contribute to an increased liver stiffness and can alter tumor phenotype. The goal of this study was to assess how changes in matrix composition and stiffness influence tumor behavior. HCC-cell lines were grown in a biomimetic hydrogel model resembling the stiffness and composition of a fibrotic or cirrhotic liver. When HCC-cells were grown in a matrix resembling a cirrhotic liver, they increased proliferation and protein content, compared to those grown in a fibrotic environment. Tumour nodules spontaneously formed outside the gels, which appeared earlier in cirrhotic conditions and were significantly larger compared to those found outside fibrotic gels. These tumor nodules had an increased expression of markers related to epithelial-to-mesenchymal transition (EMT), when comparing cirrhotic to fibrotic gels. HCC-cells grown in cirrhotic gels were also more resistant to doxorubicin compared with those grown in fibrotic gels or in 2D. Therefore, altering ECM composition affects tumor behavior, for instance by increasing pro-metastatic potential, inducing EMT and reducing response to chemotherapy.
|
|
| 4. |
- Cano-Cebrian, Maria-Jose, et al.
(författare)
-
Chemotherapeutics Combined with Luminal Irritants : Effects on Small-Intestinal Mannitol Permeability and Villus Length in Rats
- 2022
-
Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:3
-
Tidskriftsartikel (refereegranskat)abstract
- Chemotherapy causes intestinal mucositis, which includes villous atrophy and altered mucosal barrier function. However, there is an uncertainty regarding how the reduced small-intestinal surface area affects the mucosal permeability of the small marker probe mannitol (MW 188), and how the mucosa responds to luminal irritants after chemotherapy. The aims in this study were to determine (i) the relationship between chemotherapy-induced villus atrophy and the intestinal permeability of mannitol and (ii) how the mucosa regulate this permeability in response to luminal ethanol and sodium dodecyl sulfate (SDS). This was investigated by treating rats with a single intraperitoneal dose of doxorubicin, irinotecan, or 5-fluorouracil. After 72 h, jejunum was single-pass perfused and mannitol permeability determined at baseline and after 15 min luminal exposure to 15% ethanol or 5 mg/mL SDS. Tissue samples for morphological analyses were sampled from the perfused segment. All three chemotherapeutics caused a similar 30% reduction in villus length. Mannitol permeability increased with irinotecan (1.3-fold) and 5-fluorouracil (2.5-fold) and was reduced with doxorubicin (0.5-fold), suggesting that it is not epithelial surface area alone that regulates intestinal permeability to mannitol. There was no additional increase in mannitol permeability induced by luminal ethanol or SDS in the chemotherapy-treated rats compared to controls, which may be related to the relatively high basal permeability of mannitol compared to other common low-permeability probes. We therefore suggest that future studies should focus on elucidating the complex interplay between chemotherapy in combination with luminal irritants on the intestinal permeability of other probes.
|
|
| 5. |
- Dahlgren, David, et al.
(författare)
-
Prevention of Rat Intestinal Injury with a Drug Combination of Melatonin and Misoprostol
- 2020
-
Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 21:18
-
Tidskriftsartikel (refereegranskat)abstract
- A healthy intestinal barrier prevents uptake of allergens and toxins, whereas intestinal permeability increases following chemotherapy and in many gastrointestinal and systemic diseases and disorders. Currently, there are no approved drugs that target and repair the intestinal epithelial barrier while there is a medical need for such treatment in gastrointestinal and related conditions. The objective of this single-pass intestinal perfusion study in rats was to investigate the preventive cytoprotective effect of three mucosal protective drugs-melatonin, misoprostol, and teduglutide-with different mechanisms of action on an acute jejunal injury induced by exposing the intestine for 15 min to the anionic surfactant, sodium dodecyl sulfate (SDS). The effect was evaluated by monitoring intestinal clearance of Cr-51-labeled ethylenediaminetetraacetate and intestinal histology before, during, and after luminal exposure to SDS. Our results showed that separate pharmacological pretreatments with luminal misoprostol and melatonin reduced acute SDS-induced intestinal injury by 47% and 58%, respectively, while their use in combination abolished this injury. This data supports further development of drug combinations for oral treatments of conditions and disorders related to a dysregulated or compromised mucosal epithelial barrier.
|
|
| 6. |
- Dahlgren, David, et al.
(författare)
-
Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat
- 2020
-
Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 12:3
-
Tidskriftsartikel (refereegranskat)abstract
- Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In this rat single-pass intestinal perfusion study, the jejunal and colonic permeability of two low permeability drugs (atenolol and enalaprilat) and two high-permeability ones (ketoprofen and metoprolol) was determined based on plasma appearance. These values were compared to already available corresponding human data from a study conducted in our lab. The colonic effect of four permeation enhancers-sodium dodecyl sulfate, chitosan, ethylenediaminetetraacetic acid (EDTA), and caprate-on drug permeability and transport of chromium EDTA (an established clinical marker for intestinal barrier integrity) was determined. There was no difference in jejunal and colonic permeability determined from plasma appearance data of any of the four model drugs. This questions the validity of the rat single-pass intestinal perfusion model for predicting human regional intestinal permeability. It was also shown that the effect of permeation enhancers on drug permeability in the colon was similar to previously reported data from the rat jejunum, whereas the transport of chromium EDTA was significantly higher (p < 0.05) in the colon than in jejunum. Therefore, the use of permeation enhancers for increasing colonic drug permeability has greater risks than potential medical rewards, as indicated by the higher permeation of chromium EDTA compared to the drugs.
|
|
| 7. |
- Khaled, Jaafar, et al.
(författare)
-
Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma
- 2022
-
Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 11:4
-
Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or-in the case of severe or prolonged ER stress-to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC.
|
|
| 8. |
- Kopsida, Maria, et al.
(författare)
-
Inhibiting the endoplasmic reticulum stress response enhances the effect of doxorubicin by altering the lipid metabolism of liver cancer cells
- 2024
-
Ingår i: Molecular Metabolism. - : Elsevier. - 2212-8778. ; 79
-
Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) is characterized by a low and variable response to chemotherapeutic treatments. One contributing factor to the overall pharmacodynamics is the activation of endoplasmic reticulum (ER) stress pathways. This is a cellular stress mechanism that becomes activated when the cell's need for protein synthesis surpasses the ER's capacity to maintain accurate protein folding, and has been implicated in creating drug-resistance in several solid tumors. Objective: To identify the role of ER-stress and lipid metabolism in mediating drug response in HCC. Methods: By using a chemically-induced mouse model for HCC, we administered the ER-stress inhibitor 4m8C and/or doxorubicin (DOX) twice weekly for three weeks post-tumor initiation. Histological analyses were performed alongside comprehensive molecular biology and lipidomics assessments of isolated liver samples. In vitro models, including HCC cells, spheroids, and patient-derived liver organoids were subjected to 4m8C and/or DOX, enabling us to assess their synergistic effects on cellular viability, lipid metabolism, and oxygen consumption rate. Results: We reveal a pivotal synergy between ER-stress modulation and drug response in HCC. The inhibition of ER-stress using 4m8C not only enhances the cytotoxic effect of DOX, but also significantly reduces cellular lipid metabolism. This intricate interplay culminates in the deprivation of energy reserves essential for the sustenance of tumor cells. Conclusions: This study elucidates the interplay between lipid metabolism and ER-stress modulation in enhancing doxorubicin efficacy in HCC. This novel approach not only deepens our understanding of the disease, but also uncovers a promising avenue for therapeutic innovation. The long-term impact of our study could open the possibility of ER-stress inhibitors and/or lipase inhibitors as adjuvant treatments for HCC-patients. (c) 2023 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
|
|
| 9. |
- Kullenberg, Fredrik, et al.
(författare)
-
The progression of doxorubicin-induced intestinal mucositis in rats
- 2023
-
Ingår i: Naunyn-Schmiedeberg's Archives of Pharmacology. - : Springer Nature. - 0028-1298 .- 1432-1912. ; 396, s. 247-260
-
Tidskriftsartikel (refereegranskat)abstract
- Chemotherapy-induced intestinal mucositis is a severe side effect contributing to reduced quality of life and premature death in cancer patients. Despite a high incidence, a thorough mechanistic understanding of its pathophysiology and effective supportive therapies are lacking. The main objective of this rat study was to determine how 10 mg/kg doxorubicin, a common chemotherapeutic, affected jejunal function and morphology over time (6, 24, 72, or 168 h). The secondary objective was to determine if the type of dosing administration (intraperitoneal or intravenous) affected the severity of mucositis or plasma exposure of the doxorubicin. Morphology, proliferation and apoptosis, and jejunal permeability of mannitol were examined using histology, immunohistochemistry, and single-pass intestinal perfusion, respectively. Villus height was reduced by 40% after 72 h, preceded at 24 h by a 75% decrease in proliferation and a sixfold increase in apoptosis. Villus height recovered completely after 168 h. Mucosal permeability of mannitol decreased after 6, 24, and 168 h. There were no differences in intestinal injury or plasma exposure after intraperitoneal or intravenous doxorubicin dosing. This study provides an insight into the progression of chemotherapy-induced intestinal mucositis and associated cellular mucosal processes. Knowledge from this in vivo rat model can facilitate development of preventive and supportive therapies for cancer patients.
|
|
| 10. |
- Scander, Henrik, 1976-, et al.
(författare)
-
Assessing Commensality in Research
- 2021
-
Ingår i: International Journal of Environmental Research and Public Health. - Basel : MDPI. - 1661-7827 .- 1660-4601. ; 18:5
-
Forskningsöversikt (refereegranskat)abstract
- This scoping review focuses on the assessment of commensality in research and attempts to identify used methods for performing research on commensality. It reflects a multidisciplinary research field and draws on findings from Web of Science Core Collection, up to April 2019. The empirical material consisted of 61 studies, whereof most were qualitative research, and some were of quantitative character, including very few dietary surveys. The findings show nine papers categorized as using quantitative approaches, 52 papers were categorized as qualitative. The results show a wide variety of different ways to try to find and understand how commensality can be understood and identified. There seems to be a shift in the very concept of commensality as well as some variations around the concept. This paper argues the need to further investigate the importance of commensality for health and wellbeing, as well as the need to gather data on health and health-related behaviors, living conditions and sociodemographic data in parallel. The review shows the broad-ranging areas where commensality is researched, from cultural and historical areas to ethnographic or anthropological areas over to dietary assessment. To complement large dietary surveys with methods of assessing who you are eating with in what environment should be a simple way to further our knowledge on the circumstances of meal intake and the importance of commensality. To add 24-h dietary recall to any study of commensality is another way of identifying the importance of commensality for dietary quality. The use of mixed methods research was encouraged by several authors as a good way forward in the assessment of commensality and its importance.
|
|
