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Communications Biology May 2024Cell stiffness is regulated by dynamic interaction between ras-related C3 botulinum toxin substrate 1 (Rac1) and p21 protein-activated kinase 1 (PAK1) proteins, besides...
Cell stiffness is regulated by dynamic interaction between ras-related C3 botulinum toxin substrate 1 (Rac1) and p21 protein-activated kinase 1 (PAK1) proteins, besides other biochemical and molecular regulators. In this study, we investigated how the Placental Growth Factor (PlGF) changes endometrial mechanics by modifying the actin cytoskeleton at the maternal interface. We explored the global effects of PlGF in endometrial stromal cells (EnSCs) using the concerted approach of proteomics, atomic force microscopy (AFM), and electrical impedance spectroscopy (EIS). Proteomic analysis shows PlGF upregulated RhoGTPases activating proteins and extracellular matrix organization-associated proteins in EnSCs. Rac1 and PAK1 transcript levels, activity, and actin polymerization were significantly increased with PlGF treatment. AFM further revealed an increase in cell stiffness with PlGF treatment. The additive effect of PlGF on actin polymerization was suppressed with siRNA-mediated inhibition of Rac1, PAK1, and WAVE2. Interestingly, the increase in cell stiffness by PlGF treatment was pharmacologically reversed with pravastatin, resulting in improved trophoblast cell invasion. Taken together, aberrant PlGF levels in the endometrium can contribute to an altered pre-pregnancy maternal microenvironment and offer a unifying explanation for the pathological changes observed in conditions such as pre-eclampsia (PE).
Topics: Female; rac1 GTP-Binding Protein; Humans; Pre-Eclampsia; Pregnancy; Endometrium; Placenta Growth Factor; Signal Transduction; Stromal Cells; p21-Activated Kinases; Microscopy, Atomic Force
PubMed: 38704457
DOI: 10.1038/s42003-024-06220-7 -
Biomedicine & Pharmacotherapy =... Jun 2024Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative...
Transmembrane drug transporters can be important determinants of the pharmacokinetics, efficacy, and safety profiles of drugs. To investigate the potential cooperative and/or counteracting interplay of OATP1A/1B/2B1 uptake transporters and ABCB1 and ABCG2 efflux transporters in physiology and pharmacology, we generated a new mouse model (Bab12), deficient for Slco1a/1b, Slco2b1, Abcb1a/1b and Abcg2. Bab12 mice were viable and fertile. We compared wild-type, Slco1a/1b/2b1, Abcb1a/1b;Abcg2 and Bab12 strains. Endogenous plasma conjugated bilirubin levels ranked as follows: wild-type = Abcb1a/1b;Abcg2 << Slco1a/1b/2b1 < Bab12 mice. Plasma levels of rosuvastatin and fexofenadine were elevated in Slco1a/1b/2b1 and Abcb1a/1b;Abcg2 mice compared to wild-type, and dramatically increased in Bab12 mice. Although systemic exposure of larotrectinib and repotrectinib was substantially increased in the separate multidrug transporter knockout strains, no additive effects were observed in the combination Bab12 mice. Significantly higher plasma exposure of fluvastatin and pravastatin was only found in Slco1a/1b/2b1-deficient mice. However, noticeable transport by Slco1a/1b/2b1 and Abcb1a/1b and Abcg2 across the BBB was observed for fluvastatin and pravastatin, respectively, by comparing Bab12 mice with Abcb1a/1b;Abcg2 or Slco1a/1b/2b1 mice. Quite varying behavior in plasma exposure of erlotinib and its metabolites was observed among these strains. Bab12 mice revealed that Abcb1a/1b and/or Abcg2 can contribute to conjugated bilirubin elimination when Slco1a/1b/2b1 are absent. Our results suggest that the interplay of Slco1a/1b/2b1, Abcb1a/1b, and Abcg2 could markedly affect the pharmacokinetics of some, but not all drugs and metabolites. The Bab12 mouse model will represent a useful tool for optimizing drug development and clinical application, including efficacy and safety.
Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 2; Bilirubin; Mice; ATP Binding Cassette Transporter, Subfamily B; Mice, Knockout; Organic Anion Transporters; Liver-Specific Organic Anion Transporter 1; Terfenadine; Male; Biological Transport; Rosuvastatin Calcium; Mice, Inbred C57BL
PubMed: 38692057
DOI: 10.1016/j.biopha.2024.116644 -
Biomacromolecules May 2024Autosomal dominant polycystic kidney disease (ADPKD) is a complex disorder characterized by uncontrolled renal cyst growth, leading to kidney function decline. The...
Autosomal dominant polycystic kidney disease (ADPKD) is a complex disorder characterized by uncontrolled renal cyst growth, leading to kidney function decline. The multifaceted nature of ADPKD suggests that single-pathway interventions using individual small molecule drugs may not be optimally effective. As such, a strategy encompassing combination therapy that addresses multiple ADPKD-associated signaling pathways could offer synergistic therapeutic results. However, severe off-targeting side effects of small molecule drugs pose a major hurdle to their clinical transition. To address this, we identified four drug candidates from ADPKD clinical trials, bardoxolone methyl (Bar), octreotide (Oct), salsalate (Sal), and pravastatin (Pra), and incorporated them into peptide amphiphile micelles containing the RGD peptide (GRGDSP), which binds to the basolateral surface of renal tubules via integrin receptors on the extracellular matrix. We hypothesized that encapsulating drug combinations into RGD micelles would enable targeting to the basolateral side of renal tubules, which is the site of disease, via renal secretion, leading to superior therapeutic benefits compared to free drugs. To test this, we first evaluated the synergistic effect of drug combinations using the 20% inhibitory concentration for each drug (IC) on renal proximal tubule cells derived from mice. Next, we synthesized and characterized the RGD micelles encapsulated with drug combinations and measured their therapeutic effects via a 3D PKD growth model. Upon both IV and IP injections , RGD micelles showed a significantly higher accumulation in the kidneys compared to NT micelles, and the renal access of RGD micelles was significantly reduced after the inhibition of renal secretion. Specifically, both Bar+Oct and Bar+Sal in the RGD micelle treatment showed enhanced therapeutic efficacy in ADPKD mice () with a significantly lower KW/BW ratio and cyst index as compared to PBS and free drug-treated controls, while other combinations did not show a significant difference. Hence, we demonstrate that renal targeting through basolateral targeting micelles enhances the therapeutic potential of combination therapy in genetic kidney disease.
Topics: Animals; Micelles; Mice; Drug Delivery Systems; Humans; Polycystic Kidney, Autosomal Dominant; Oligopeptides; Polycystic Kidney Diseases
PubMed: 38652072
DOI: 10.1021/acs.biomac.3c01397 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Feb 2024This paper aims to study the therapeutic effect of Massa Medicata Fermentata on hyperlipidemia model rats and investigate its mechanism of hypolipidemic effect with the...
This paper aims to study the therapeutic effect of Massa Medicata Fermentata on hyperlipidemia model rats and investigate its mechanism of hypolipidemic effect with the help of non-targeted metabolomics. The mixed hyperlipidemia model rats were constructed by giving high-fat chow. After successful modeling, the rats were divided into the model group, pravastatin sodium group(4.4 mg·kg~(-1)), lipotropic group(0.1 g·kg~(-1)), high-dose group(2.4 g·kg~(-1)), medium-dose group(1.2 g·kg~(-1)), and low-dose group(0.6 g·kg~(-1)) of Massa Medicata Fermentata, and they were administered for four weeks once daily. An equal volume of ultrapure water was given to the blank group and model group. Serum lipid level and liver hematoxylin-eosin(HE) staining were used as indicators to estimate the intervention effect of Massa Medicata Fermentata on mixed hyperlipidemia, and the changes in metabolites in plasma of mixed hyperlipidemia model rats were analyzed by non-targeted metabolomics. The mechanism of the hypolipidemic effect of Massa Medicata Fermentata was analyzed through metabolite pathway enrichment. The results showed that compared with the model group, the Massa Medicata Fermentata administration group, especially the high-dose group, could significantly reduce the content of total cholesterol(TC), triglyceride(TG), and low-density lipoprotein cholesterol(LDL-c)(P<0.05 or P<0.01), and liver HE staining revealed that the number of adipocytes in the high-dose group was reduced to some extent. The potential biomarkers obtained by non-targeted metabolomics screening included glycerol 3-phosphate, sphingomyelin, sphingosine 1-phosphate, and deoxyuridine, which were mainly involved in the sphingolipid metabolism process, glycerophospholipid metabolism process, glycerol ester metabolism pathway, and pyrimidine metabolism pathway, totaling four possible metabolic pathways related to lipid metabolism. This study provides a reference for an in-depth investigation of the hypolipidemic mechanism of Massa Medicata Fermentata, which is of great significance for further promoting the clinical application of Massa Medicata Fermentata and increasing the indications.
Topics: Rats; Animals; Drugs, Chinese Herbal; Liver; Hyperlipidemias; Metabolomics; Cholesterol; Diet, High-Fat
PubMed: 38621881
DOI: 10.19540/j.cnki.cjcmm.20231019.401 -
AAPS PharmSciTech Apr 2024The common disorders irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) can modify the drugs' pharmacokinetics via their induced pathophysiological...
The Effect of Inflammatory Bowel Disease and Irritable Bowel Syndrome on Pravastatin Oral Bioavailability: In vivo and in silico evaluation using bottom-up wbPBPK modeling.
The common disorders irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) can modify the drugs' pharmacokinetics via their induced pathophysiological changes. This work aimed to investigate the impact of these two diseases on pravastatin oral bioavailability. Rat models for IBS and IBD were used to experimentally test the effects of IBS and IBD on pravastatin pharmacokinetics. Then, the observations made in rats were extrapolated to humans using a mechanistic whole-body physiologically-based pharmacokinetic (wbPBPK) model. The rat in vivo studies done herein showed that IBS and IBD decreased serum albumin (> 11% for both), decreased PRV binding in plasma, and increased pravastatin absolute oral bioavailability (0.17 and 0.53 compared to 0.01) which increased plasma, muscle, and liver exposure. However, the wbPBPK model predicted muscle concentration was much lower than the pravastatin toxicity thresholds for myotoxicity and rhabdomyolysis. Overall, IBS and IBD can significantly increase pravastatin oral bioavailability which can be due to a combination of increased pravastatin intestinal permeability and decreased pravastatin gastric degradation resulting in higher exposure. This is the first study in the literature investigating the effects of IBS and IBD on pravastatin pharmacokinetics. The high interpatient variability in pravastatin concentrations as induced by IBD and IBS can be reduced by oral administration of pravastatin using enteric-coated tablets. Such disease (IBS and IBD)-drug interaction can have more drastic consequences for narrow therapeutic index drugs prone to gastric degradation, especially for drugs with low intestinal permeability.
Topics: Humans; Animals; Rats; Irritable Bowel Syndrome; Pravastatin; Inflammatory Bowel Diseases; Research Design
PubMed: 38605192
DOI: 10.1208/s12249-024-02803-z -
Drug Metabolism and Disposition: the... May 2024Extrapolating in vivo hepatic clearance from in vitro uptake data is a known challenge, especially for organic anion-transporting polypeptide transporter (OATP)...
Using the Dynamic Well-Stirred Model to Extrapolate Hepatic Clearance of Organic Anion-Transporting Polypeptide Transporter Substrates without Assuming Albumin-Mediated Hepatic Drug Uptake.
Extrapolating in vivo hepatic clearance from in vitro uptake data is a known challenge, especially for organic anion-transporting polypeptide transporter (OATP) substrates, and the well-stirred model (WSM) commonly yields systematic underpredictions for those anionic drugs, hypothetically due to "albumin-mediated hepatic drug uptake". In the present study, we demonstrate that the WSM incorporating the dynamic free fraction ( ), a measure of drug protein binding affinity, performs reasonably well in predicting hepatic clearance of OATP substrates. For a selection of anionic drugs, including atorvastatin, fluvastatin, pravastatin, rosuvastatin, pitavastatin, cerivastatin, and repaglinide, this dynamic well-stirred model (dWSM) correctly predicts hepatic plasma clearance within 2-fold error for six out of seven OATP substrates examined. The geometric mean of clearance ratios between the predicted and the observed values falls in the range of 1.21-1.38. As expected, the WSM with unbound fraction ( ) systematically underpredicts hepatic clearance with greater than 2-fold error for five out of seven drugs, and the geometric mean of clearance ratios between the predicted and the observed values is in the range of 0.20-0.29. The results suggest that, despite its simplicity, the dWSM operates well for transporter-mediated uptake clearance, and that clearance under-prediction of OATP substrates may not necessarily be associated with the chemical class of the anionic drugs, nor is it a result of albumin-mediated hepatic drug uptake as currently hypothesized. Instead, the superior prediction power of the dWSM confirms the utility of the dynamic free fraction in clearance prediction and the importance of drug plasma binding kinetics in hepatic uptake clearance. SIGNIFICANCE STATEMENT: The traditional well-stirred model (WSM) consistently underpredicts organin anion-transporting polypeptide transporter (OATP)-mediated hepatic uptake clearance, hypothetically due to the albumin-mediated hepatic drug uptake. In this manuscript, we apply the dynamic WSM to extrapolate hepatic clearance of the OATP substrates, and our results show significant improvements in clearance prediction without assuming albumin-mediated hepatic drug uptake.
Topics: Organic Anion Transporters; Liver; Models, Biological; Humans; Albumins; Biological Transport; Metabolic Clearance Rate; Protein Binding; Pharmaceutical Preparations; Animals
PubMed: 38604729
DOI: 10.1124/dmd.124.001645 -
Neurocritical Care Apr 2024There are knowledge gaps regarding the relative efficacy of statins for aneurysmal subarachnoid hemorrhage (aSAH). This study aims to examine the comparative...
BACKGROUND
There are knowledge gaps regarding the relative efficacy of statins for aneurysmal subarachnoid hemorrhage (aSAH). This study aims to examine the comparative effectiveness and determine the ranking of different statins with network meta‑analysis in patients with aSAH.
METHODS
MEDLINE, Embase, Pubmed, and Cochrane Central Register of Controlled Trials were searched from database inception until December 15, 2022. Outcomes included delayed cerebral ischemia (DCI), functional recovery, and mortality. Relative risk (RRs) ratios and associated 95% confidence intervals (CIs) were estimated. The values derived from surface under the cumulative ranking curve were obtained to rank the treatment hierarchy in the analysis.
RESULTS
We identified 13 trials involving 1,885 patients. Atorvastatin 20 mg (RR 0.68, 95% CI 0.53-0.86), pravastatin 40 mg (RR 0.51, 95% CI 0.31-0.77), and simvastatin 80 mg (RR 0.54, 95% CI 0.40-0.70) were superior to the placebo in preventing DCI. Additionally, simvastatin 80 mg (RR 0.60, 95% CI 0.42-0.84) and pravastatin 40 mg (RR 0.56, 95% CI 0.32-0.93) were associated with a decreased risk of DCI than simvastatin 40 mg. Comparisons across treatment durations suggested that short-term (RR 0.62, 95% CI 0.50-0.76) statin therapy reduced risk of DCI.
CONCLUSIONS
Simvastatin 80 mg might be the most effective intervention in reducing DCI. Additionally, short-term therapy might provide more benefits. Further research with longer follow-up is warranted to validate the current findings in patients with aSAH who are at high risk of DCI.
PubMed: 38565835
DOI: 10.1007/s12028-024-01957-9 -
Acta Pharmaceutica (Zagreb, Croatia) Mar 2024Statin treatment may increase the risk of diabetes; there is insufficient data on how statins affect glucose regulation and glycemic control and the effects of statins...
Statin treatment may increase the risk of diabetes; there is insufficient data on how statins affect glucose regulation and glycemic control and the effects of statins on liver enzymes related to carbohydrate metabolism have not been fully studied. Therefore, we aimed to compare the effects of the statin derivatives, pravastatin, and rosuvastatin, on carbohydrate metabolism in an experimental diabetic rat model. Female Wistar albino rats were used and diabetes was induced by intraperitoneal injection of streptozotocin. Thereafter, 10 and 20 mg kg day doses of both pravastatin and rosuvastatin were administered by oral gavage to the diabetic rats for 8 weeks. At the end of the experiment, body masses, the levels of fasting blood glucose, serum insulin, insulin resistance (HOMA-IR), liver glycogen, and liver enzymes related to carbohydrate metabolism were measured. Both doses of pravastatin significantly in creased the body mass in diabetic rats, however, rosuvastatin, especially at the dose of 20 mg kg day reduced the body mass signi ficantly. Pravastatin, especially at a dose of 20 mg kg day, caused significant increases in liver glycogen synthase and glucose 6-phosphate dehydrogenase levels but significant decreases in the levels of glycogen phosphorylase, lactate dehydrogenase, and glucose-6-phosphatase. Hence, pravastatin partially ameliorated the adverse changes in liver enzymes caused by diabetes and, especially at the dose of 20 mg kg day, reduced the fasting blood glucose level and increased the liver glycogen content. However, rosuvastatin, especially at the dose of 20 mg kg day, significantly reduced the liver glycogen synthase and pyruvate kinase levels, but increased the glycogen phosphorylase level in diabetic rats. Rosuvastatin, 20 mg kg day dose, caused significant decreases in the body mass and the liver glycogen content of diabetic rats. It can be concluded that pravastatin, especially at the dose of 20 mg kg day is more effective in ameliorating the negative effects of diabetes by modulating carbohydrate metabolism.
Topics: Female; Rats; Animals; Blood Glucose; Rats, Wistar; Rosuvastatin Calcium; Pravastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemic Agents; Diabetes Mellitus, Experimental; Glycogen Synthase; Liver Glycogen; Glycated Hemoglobin; Glucose; Carbohydrate Metabolism; Glycogen Phosphorylase; Liver; Insulin
PubMed: 38554383
DOI: 10.2478/acph-2024-0001 -
Molecular Pharmaceutics May 2024Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3, encoded by the gene family of the solute carrier superfamily, are involved in the disposition of many...
Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3, encoded by the gene family of the solute carrier superfamily, are involved in the disposition of many exogenous and endogenous compounds. Preclinical rodent models help assess risks of pharmacokinetic interactions, but interspecies differences in transporter orthologs and expression limit direct clinical translation. An OATP1B transgenic mouse model comprising a rodent gene cluster knockout and human and gene insertions provides a potential physiologically relevant preclinical tool to predict pharmacokinetic interactions. Pharmacokinetics of exogenous probe substrates, pitavastatin and pravastatin, and endogenous OATP1B biomarkers, coproporphyrin-I and coproporphyrin-III, were determined in the presence and absence of known OATP/Oatp inhibitors, rifampin or silymarin (an extract of milk thistle []), in wild-type FVB mice and humanized OATP1B mice. Rifampin increased exposure of pitavastatin (4.6- and 2.8-fold), pravastatin (3.6- and 2.2-fold), and coproporphyrin-III (1.6- and 2.1-fold) in FVB and OATP1B mice, respectively, but increased coproporphyrin-I AUC only (1.8-fold) in the OATP1B mice. Silymarin did not significantly affect substrate AUC, likely because the silymarin flavonolignan concentrations were at or below their reported IC values for the relevant OATPs/Oatps. Silymarin increased the of pitavastatin 2.7-fold and pravastatin 1.9-fold in the OATP1B mice. The data of the OATP1B mice were similar to those of the pitavastatin and pravastatin clinical data; however, the FVB mice data more closely recapitulated pitavastatin clinical data than the data of the OATP1B mice, suggesting that the OATP1B mice are a reasonable, though costly, preclinical strain for predicting pharmacokinetic interactions when doses are optimized to achieve clinically relevant plasma concentrations.
Topics: Animals; Rifampin; Mice; Liver-Specific Organic Anion Transporter 1; Mice, Transgenic; Humans; Silymarin; Pravastatin; Solute Carrier Organic Anion Transporter Family Member 1B3; Drug Interactions; Quinolines; Coproporphyrins; Male; Organic Anion Transporters
PubMed: 38529622
DOI: 10.1021/acs.molpharmaceut.3c01088 -
Comparative Biochemistry and... Jun 2024Statins, widely prescribed for cholesterol management by inhibiting HMG-CoA reductase in the cholesterol biosynthesis pathway, may also influence vertebrate development....
Statins, widely prescribed for cholesterol management by inhibiting HMG-CoA reductase in the cholesterol biosynthesis pathway, may also influence vertebrate development. In this study, we investigated the developmental effects of two widely used statins, atorvastatin (ATO) and pravastatin (PRA), on zebrafish offspring. For ATO, we administered doses classified as low (1 μM), medium (5 μM), and high (10 μM), while for PRA, the corresponding concentrations were set at low (18 μM), medium (180 μM), and high (270 μM). Our results showed significant reductions in birth and hatching rates, along with decreased body length in offspring at all ATO concentrations and medium to high PRA concentrations. A notable increase in malformation rates, especially in the spine and heart, was observed across all ATO treatments and in medium and high PRA groups. Additionally, we observed reduced heart contraction rates, decreased heart size, lower bone volumes, and diminished expression of mRNA osteogenic markers. Elevated venous sinus-artery bulb (SV-BA) ratios, increased thoracic area, and abnormal cartilage development were also prominent in all ATO-treated groups. Transcriptome analysis revealed alterations in genes predominantly associated with ion channels. These findings provide insights into the potential impacts of specific concentrations of statins on offspring development and highlight potential gene interactions with statins.
Topics: Animals; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Zebrafish; Transcriptome; Pravastatin; Atorvastatin; Ion Channels
PubMed: 38522713
DOI: 10.1016/j.cbpc.2024.109905