scholarly journals The Influence of Fed State Lipolysis Inhibition on the Intraluminal Behaviour and Absorption of Fenofibrate from a Lipid-Based Formulation

Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 119
Author(s):  
Marlies Braeckmans ◽  
Joachim Brouwers ◽  
Danny Riethorst ◽  
Cécile Servais ◽  
Jan Tack ◽  
...  
Keyword(s):  
Drug Absorption ◽  
Lipid Phase ◽  
Proximal Jejunum ◽  
Fenofibric Acid ◽  
Lipophilic Drugs ◽  
Fed State ◽  
Different Levels ◽  
Lipid Based Formulation

The bioavailability of lipophilic drugs may or may not be increased when administered with food due to increased solubilisation in fed state gastrointestinal (GI) fluids. The in vivo interplay between drug solubilisation, lipid phase digestion and drug absorption is complex and remains poorly understood. This study aimed to investigate the role of fed state GI lipolysis on the intraluminal behaviour and absorption of fenofibrate, formulated as the lipid-based formulation Fenogal. Therefore, a crossover study was performed in healthy volunteers using orlistat as lipase inhibitor. Fenofibrate concentrations were determined in the proximal jejunum and linked to simultaneously assessed systemic fenofibric acid concentrations. Inhibition of lipolysis by orlistat resulted in a faster onset of absorption in 4 out of 6 volunteers, reflected by a decrease in systemic Tmax between 20 and 140 min. In addition, the increase of undigested lipids present in the small intestine upon orlistat co-administration sustained drug solubilisation for a longer period, resulting in higher fenofibrate concentrations in the jejunum and improved absorption in 5 out of 6 volunteers (median AUC0–8h 8377 vs. 5832 μM.min). Sustaining drug solubilisation in the lipid phase may thus contribute to the absorption of lipophilic drugs. More research into the different mechanisms underlying lipophilic drug absorption from fed state media at different levels of digestion is warranted.

scholarly journals The role of the NMD factor UPF3B in olfactory sensory neurons

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Kun Tan ◽  
Samantha H Jones ◽  
Blue B Lake ◽  
Jennifer N Dumdie ◽  
Eleen Y Shum ◽  
...  
Keyword(s):  
Human Cognition ◽  
Cell Populations ◽  
Rna Seq ◽  
Wild Type ◽  
Single Cell Rna Sequencing ◽  
Nonsense Mediated Rna Decay ◽  
Different Levels ◽  
Selection Of

The UPF3B-dependent branch of the nonsense-mediated RNA decay (NMD) pathway is critical for human cognition. Here, we examined the role of UPF3B in the olfactory system. Single-cell RNA-sequencing (scRNA-seq) analysis demonstrated considerable heterogeneity of olfactory sensory neuron (OSN) cell populations in wild-type (WT) mice, and revealed that UPF3B loss influences specific subsets of these cell populations. UPF3B also regulates the expression of a large cadre of antimicrobial genes in OSNs, and promotes the selection of specific olfactory receptor (Olfr) genes for expression in mature OSNs (mOSNs). RNA-seq and Ribotag analyses identified classes of mRNAs expressed and translated at different levels in WT and Upf3b-null mOSNs. Integrating multiple computational approaches, UPF3B-dependent NMD target transcripts that are candidates to mediate the functions of NMD in mOSNs were identified in vivo. Together, our data provides a valuable resource for the olfactory field and insights into the roles of NMD in vivo.

scholarly journals Salt-inducible Kinases Are Critical Determinants of Female Fertility

Endocrinology ◽  
2020 ◽  
Vol 161 (7) ◽  
Author(s):  
Marah Armouti ◽  
Nicola Winston ◽  
Osamu Hatano ◽  
Elie Hobeika ◽  
Jennifer Hirshfeld-Cytron ◽  
...  
Keyword(s):  
Ovarian Function ◽  
Follicle Stimulating Hormone ◽  
Female Fertility ◽  
Camp Signaling ◽  
Follicle Development ◽  
Pharmacological Modulation ◽  
Ovarian Granulosa Cells ◽  
Different Levels

Abstract Follicle development is the most crucial step toward female fertility and is controlled mainly by follicle-stimulating hormone (FSH). In ovarian granulosa cells (GCs), FSH activates protein kinase A by increasing 3′,5′-cyclic adenosine 5′-monophosphate (cAMP). Since cAMP signaling is impinged in part by salt-inducible kinases (SIKs), we examined the role of SIKs on the regulation of FSH actions. Here, we report that SIKs are essential for normal ovarian function and female fertility. All SIK isoforms are expressed in human and rodent GCs at different levels (SIK3>SIK2>SIK1). Pharmacological inhibition of SIK activity potentiated the stimulatory effect of FSH on markers of GC differentiation in mouse, rat, and human GCs and estradiol production in rat GCs. In humans, SIK inhibition strongly enhanced FSH actions in GCs of patients with normal or abnormal ovarian function. The knockdown of SIK2, but not SIK1 or SIK3, synergized with FSH on the induction of markers of GC differentiation. SIK inhibition boosted gonadotropin-induced GC differentiation in vivo, while the genomic knockout of SIK2 led to a significant increase in the number of ovulated oocytes. Conversely, SIK3 knockout females were infertile, FSH insensitive, and had abnormal folliculogenesis. These findings reveal novel roles for SIKs in the regulation of GC differentiation and female fertility, and contribute to our understanding of the mechanisms regulated by FSH. Furthermore, these data suggest that specific pharmacological modulation of SIK2 activity could be of benefit to treat ovulatory defects in humans and to increase the propagation of endangered species and farm mammals.

scholarly journals The role of leptin in the regulation of TSH secretion in the fed state: in vivo and in vitro studies

2002 ◽  
Vol 174 (1) ◽  
pp. 121-125 ◽  
Author(s):  
TM Ortiga-Carvalho ◽  
KJ Oliveira ◽  
BA Soares ◽  
CC Pazos-Moura
Keyword(s):  
Fold Increase ◽  
Adult Rats ◽  
Fed State ◽  
Rat Pituitary ◽  
Pituitary Thyroid Axis ◽  
Tsh Secretion ◽  
Thyroid Axis

Leptin has been shown to stimulate the hypothalamus-pituitary-thyroid axis in fasting rodents; however, its role in thyroid axis regulation under physiological conditions is still under investigation. Here it was investigated in freely fed rats whether leptin modulates thyrotroph function in vivo and whether leptin has direct pituitary effects on TSH release. Since leptin is produced in the pituitary, the possibility was also investigated that leptin may be a local regulator of TSH release. TSH was measured by specific RIA. Freely fed adult rats 2 h after being injected with a single s.c. injection of 8 microg leptin/100 g body weight showed a 2-fold increase in serum TSH (P<0.05). Hemi-pituitary explants incubated with 10(-9) and 10(-7) M leptin for 2 h showed a reduced TSH release of 40 and 50% respectively (P<0.05). Conversely, incubation of hemi-pituitary explants with antiserum against leptin, aiming to block the action of locally produced leptin, resulted in higher TSH release (45%, P<0.05). In conclusion, also in the fed state, leptin has an acute stimulatory effect on TSH release in vivo, acting probably at the hypothalamus. However, the direct pituitary effect of leptin is inhibitory and data also provide evidence that in the rat pituitary leptin may act as an autocrine/paracrine inhibitor of TSH release.

scholarly journals Differential CYP 2D6 Metabolism Alters Primaquine Pharmacokinetics

2015 ◽  
Vol 59 (4) ◽  
pp. 2380-2387 ◽  
Author(s):  
Brittney M. J. Potter ◽  
Lisa H. Xie ◽  
Chau Vuong ◽  
Jing Zhang ◽  
Ping Zhang ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Antimalarial Activity ◽  
Wild Type ◽  
Phenolic Metabolites ◽  
Species Specific ◽  
Human And Mouse ◽  
Different Levels ◽  
Cyp 2D6

ABSTRACTPrimaquine (PQ) metabolism by the cytochrome P450 (CYP) 2D family of enzymes is required for antimalarial activity in both humans (2D6) and mice (2D). Human CYP 2D6 is highly polymorphic, and decreased CYP 2D6 enzyme activity has been linked to decreased PQ antimalarial activity. Despite the importance of CYP 2D metabolism in PQ efficacy, the exact role that these enzymes play in PQ metabolism and pharmacokinetics has not been extensively studiedin vivo. In this study, a series of PQ pharmacokinetic experiments were conducted in mice with differential CYP 2D metabolism characteristics, including wild-type (WT), CYP 2D knockout (KO), and humanized CYP 2D6 (KO/knock-in [KO/KI]) mice. Plasma and liver pharmacokinetic profiles from a single PQ dose (20 mg/kg of body weight) differed significantly among the strains for PQ and carboxy-PQ. Additionally, due to the suspected role of phenolic metabolites in PQ efficacy, these were probed using reference standards. Levels of phenolic metabolites were highest in mice capable of metabolizing CYP 2D6 substrates (WT and KO/KI 2D6 mice). PQ phenolic metabolites were present in different quantities in the two strains, illustrating species-specific differences in PQ metabolism between the human and mouse enzymes. Taking the data together, this report furthers understanding of PQ pharmacokinetics in the context of differential CYP 2D metabolism and has important implications for PQ administration in humans with different levels of CYP 2D6 enzyme activity.

scholarly journals AP1 Transcription Factors in Epidermal Differentiation and Skin Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Richard L. Eckert ◽  
Gautam Adhikary ◽  
Christina A. Young ◽  
Ralph Jans ◽  
James F. Crish ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Dominant Negative ◽  
Epidermal Differentiation ◽  
Cancer Development ◽  
Multiple Cells ◽  
Different Levels ◽  
Factor Function

AP1 (jun/fos) transcription factors (c-jun, junB, junD, c-fos, FosB, Fra-1, and Fra-2) are key regulators of epidermal keratinocyte survival and differentiation and important drivers of cancer development. Understanding the role of these factors in epidermis is complicated by the fact that each protein is expressed, at different levels, in multiple cells layers in differentiating epidermis, and because AP1 transcription factors regulate competing processes (i.e., proliferation, apoptosis, and differentiation). Variousin vivogenetic approaches have been used to study these proteins including targeted and conditional knockdown, overexpression, and expression of dominant-negative inactivating AP1 transcription factors in epidermis. Taken together, these studies suggest that individual AP1 transcription factors have different functions in the epidermis and in cancer development and that altering AP1 transcription factor function in the basal versus suprabasal layers differentially influences the epidermal differentiation response and disease and cancer development.

scholarly journals Deciphering the Functional Role of RIPK4 in Melanoma

2021 ◽  
Vol 22 (21) ◽  
pp. 11504
Author(s):  
Ewelina Madej ◽  
Damian Ryszawy ◽  
Anna A. Brożyna ◽  
Malgorzata Czyz ◽  
Jaroslaw Czyz ◽  
...  
Keyword(s):  
Cell Lines ◽  
Time Lapse ◽  
Clinical Samples ◽  
Invasive Potential ◽  
Interacting Protein ◽  
Metastatic Melanoma Cell ◽  
Node Metastasis ◽  
Different Levels

The receptor-interacting protein kinase 4 (RIPK4) plays an important role in the development and maintenance of various tissues including skin, but its role in melanoma has not been reported. Using patient-derived cell lines and clinical samples, we show that RIPK4 is expressed in melanomas at different levels. This heterogenous expression, together with very low level of RIPK4 in melanocytes, indicates that the role of this kinase in melanoma is context-dependent. While the analysis of microarray data has revealed no straightforward correlation between the stage of melanoma progression and RIPK4 expression in vivo, relatively high levels of RIPK4 are in metastatic melanoma cell lines. RIPK4 down-regulation by siRNA resulted in the attenuation of invasive potential as assessed by time-lapse video microscopy, wound-healing and transmigration assays. These effects were accompanied by reduced level of pro-invasive proteins such as MMP9, MMP2, and N-cadherin. Incubation of melanoma cells with phorbol ester (PMA) increased PKC-1β level and hyperphosphorylation of RIPK4 resulting in degradation of RIPK4. Interestingly, incubation of cells with PMA for short and long durations revealed that cell migration is controlled by the NF-κB signaling in a RIPK4-dependent (RIPK4high) or independent (RIPK4low) manner depending on cell origin (distant or lymph node metastasis) or phenotype (mesenchymal or epithelial).

scholarly journals EXTH-09. NEO-ADJUVANT TEMOZOLOMIDE INCREASES THE EFFICACY OF SUBSEQUENT CONCURRENT CHEMORADIATION IN A TRANSGLUTAMINASE-2 DEPENDENT MANNER

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii88-ii88
Author(s):  
Paul Daniel ◽  
Brian Meehan ◽  
Siham Sabri ◽  
George Shenouda ◽  
Jann Sarkaria ◽  
...  
Keyword(s):  
Survival Benefit ◽  
Standard Treatment ◽  
Transglutaminase 2 ◽  
Dependent Manner ◽  
Unique Biology ◽  
Adjuvant Temozolomide ◽  
Different Levels

Abstract Glioblastoma (GBM) is invariably fatal due to failure of current chemoradiation (Stupp) regimes. Biomarkers such as MGMT have proven to predict response to Temozolomide (TMZ). An equivalent biomarker for radiation (RT) has not yet been identified. Transglutaminase-2 (TGM2) has been implicated in driving radiation resistance; but the mechanism is poorly understood. We have investigated how exposure to neoadjuvant TMZ in glioma stem cells (GSCs) with different levels of TGM2 would affect the response to RT. MATERIALS/METHODS: Primary GSCs lines with different TGM2 levels (high: 1123, 83; low: 528, OPK49) were used to explore the role of TGM2 in RT response and modulation of expression by TMZ in vitro and in-vivo. RESULTS: We showed that TGM2 drives radioresistance in GSCs through restriction of p53 mediated repression of RAD51 expression. We demonstrate that exposure of GSCs to TMZ drives rapid downregulation of TGM2 in vitro and this phenomenon is recapitulated in vivo. Interestingly, we confirm that RT is able to drive reciprocal changes in TGM2 and promotes reactivation of TGM2 in TGM2-high tumours but not TGM2-low tumours. Given these observations, we hypothesized that exposure to neoadjuvant TMZ in TGM2-low tumours would increase the efficacy of subsequent RT in these tumours. Comparison of the effect of standard treatment consisting of 3 weeks of concurrent TMZ and RT (Stupp) to a novel regime (neo-Stupp) consisting of 1 week of neoadjuvant TMZ followed by two weeks of TMZ and hypofractionated RT revealed a superior survival benefit of this novel regime in TGM2-low tumours but not in TGM2-high tumours. Utilization of the TGM2 inhibitor GK921 in combination with neo-Stupp prevented rapid relapse previously observed in TGM2-high tumours. CONCLUSION: We provide evidence that TGM2 is a biomarker of RT response and can be used to tailor chemoradiation protocols to the unique biology of each individual GBM patient.

scholarly journals Physiological and Pathological Role of Circadian Hormones in Osteoarthritis: Dose-Dependent or Time-Dependent?

2019 ◽  
Vol 8 (9) ◽  
pp. 1415 ◽  
Author(s):  
Farhad Md. Hossain ◽  
Yunkyung Hong ◽  
Yunho Jin ◽  
Jeonghyun Choi ◽  
Yonggeun Hong
Keyword(s):  
Circadian Clock ◽  
Thyroid Stimulating Hormone ◽  
Cartilage Erosion ◽  
The Relationship ◽  
Dose Dependent ◽  
Different Levels ◽  
Pro Inflammatory Cytokines

Osteoarthritis (OA), the most common form of arthritis, may be triggered by improper secretion of circadian clock-regulated hormones, such as melatonin, thyroid-stimulating hormone (TSH), or cortisol. The imbalance of these hormones alters the expression of pro-inflammatory cytokines and cartilage degenerative enzymes in articular cartilage, resulting in cartilage erosion, synovial inflammation, and osteophyte formation, the major hallmarks of OA. In this review, we summarize the effects of circadian melatonin, TSH, and cortisol on OA, focusing on how different levels of these hormones affect OA pathogenesis and recovery with respect to the circadian clock. We also highlight the effects of melatonin, TSH, and cortisol at different concentrations both in vivo and in vitro, which may help to elucidate the relationship between circadian hormones and OA.

scholarly journals The influence of phosphatidate bilayers on pig heart AMP deaminase. Crucial role of pH-dependent lipid-phase transition

1988 ◽  
Vol 255 (3) ◽  
pp. 977-981 ◽  
Author(s):  
M Woźniak ◽  
E Kossowska ◽  
J Purzycka-Preis ◽  
M M Zydowo
Keyword(s):  
Phase Transition ◽  
Competitive Inhibition ◽  
Saturated Fatty Acids ◽  
Lipid Phase ◽  
Amp Deaminase ◽  
Alkaline Ph ◽  
Lipid Phase Transition ◽  
Inhibited Enzyme

Phosphatidate bilayers composed of dilauroylphosphatidate, dimyristoylphosphatidate, dipalmitoylphosphatidate and dioleoylphosphatidate were prepared. Their interaction with AMP deaminase isolated from pig heart was investigated. Dioleoylphosphatidate bilayers were found to exert non-competitive inhibition on the AMP deaminase with a Ki of 15 x 10(-6) M. This inhibition is three orders of magnitude stronger than that exerted by orthophosphate. The phosphatidate species containing saturated fatty acids were either non-inhibitory or inhibited enzyme activity rather poorly. However, alkalinization of the medium from pH 6.5 to pH 7.9 led to the inhibition of pig heart AMP deaminase by dilauroylphosphatidate bilayers. This was accompanied by the fluidization of the saturated phosphatidate species, i.e. the lowering of their phase transition temperature in alkaline pH, as measured by light-scattering and fluorescence scans. The possible significance of these findings for the regulation of AMP deaminase activity in vivo by natural membranes is discussed.

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