Polystyrene nanoplastics with different functional groups and charges have different impacts on type 2 diabetes.

BACKGROUND: Increasing attention is being paid to the environmental and health impacts of nanoplastics (NPs) pollution. Exposure to nanoplastics (NPs) with different charges and functional groups may have different adverse effects after ingestion by organisms, yet the potential ramifications on mammalian blood glucose levels, and the risk of diabetes remain unexplored. RESULTS: Mice were exposed to PS-NPs/COOH/NH2 at a dose of 5 mg/kg/day for nine weeks, either alone or in a T2DM model. The findings demonstrated that exposure to PS-NPs modified by different functional groups caused a notable rise in fasting blood glucose (FBG) levels, glucose intolerance, and insulin resistance in a mouse model of T2DM. Exposure to PS-NPs-NH2 alone can also lead the above effects to a certain degree. PS-NPs exposure could induce glycogen accumulation and hepatocellular edema, as well as injury to the pancreas. Comparing the effect of different functional groups or charges on T2DM, the PS-NPs-NH2 group exhibited the most significant FBG elevation, glycogen accumulation, and insulin resistance. The phosphorylation of AKT and FoxO1 was found to be inhibited by PS-NPs exposure. Treatment with SC79, the selective AKT activator was shown to effectively rescue this process and attenuate T2DM like lesions. CONCLUSIONS: Exposure to PS-NPs with different functional groups (charges) induced T2DM-like lesions. Amino-modified PS-NPs cause more serious T2DM-like lesions than pristine PS-NPs or carboxyl functionalized PS-NPs. The underlying mechanisms involved the inhibition of P-AKT/P-FoxO1. This study highlights the potential risk of NPs pollution on T2DM, and provides a new perspective for evaluating the impact of plastics aging.

Targeting a xenobiotic transporter to ameliorate vincristine-induced sensory neuropathy.

Vincristine is a widely used chemotherapeutic drug for the treatment of multiple malignant diseases that causes a dose-limiting peripheral neurotoxicity. There is no clinically effective preventative treatment for vincristine-induced sensory peripheral neurotoxicity (VIPN), and mechanistic details of this side effect remain poorly understood. We hypothesized that VIPN is dependent on transporter-mediated vincristine accumulation in dorsal root ganglion neurons. Using a xenobiotic transporter screen, we identified OATP1B3 as a neuronal transporter regulating the uptake of vincristine. In addition, genetic or pharmacological inhibition of the murine orthologue transporter OATP1B2 protected mice from various hallmarks of VIPN - including mechanical allodynia, thermal hyperalgesia, and changes in digital maximal action potential amplitudes and neuronal morphology - without negatively affecting plasma levels or antitumor effects of vincristine. Finally, we identified α-tocopherol from an untargeted metabolomics analysis as a circulating endogenous biomarker of neuronal OATP1B2 function, and it could serve as a companion diagnostic to guide dose selection of OATP1B-type transport modulators given in combination with vincristine to prevent VIPN. Collectively, our findings shed light on the fundamental basis of VIPN and provide a rationale for the clinical development of transporter inhibitors to prevent this debilitating side effect.

The effect and a mechanistic evaluation of polystyrene nanoplastics on a mouse model of type 2 diabetes.

Nanoplastics have become ubiquitous in the global environment and have attracted increasing attention. However, whether there is an influence between exposure to nanoplastics and diabetes is unclear. To determine the effects of exposure to Polystyrene nanoplastics (PS-NPs) and evaluate the underlying mechanisms, mice were orally exposed to PS-NPs at dosages of 1, 10, 30 mg/kg/day for 8 weeks, alone or combined with a high fat diet and streptozocin (STZ) injection. Our data showed that exposure to 30 mg/kg/day PS-NPs alone induced a significant increase in blood glucose, glucose intolerance and insulin resistance. Combined with a high fat diet and STZ injection, PS-NPs exposure markedly aggravated oxidative stress, glucose intolerance, insulin tolerance and insulin resistance, and induced lesions in the liver and pancreas. PS-NPs exposure could decrease the phosphorylation of AKT and GSK3ß, and treatment with SC79, a selective AKT activator, could increase the level of AKT and GSK3ß phosphorylation, effectively alleviating the increase in ROS levels in the liver or pancreas, and slightly attenuating the increase in fasting blood glucose levels and insulin resistance induced by PS-NPs exposure. This showed that exposure to PS-NPs aggravated type 2 diabetes and the underlying mechanism partly involved in the inhibition of AKT/GSK3ß phosphorylation.

Formaldehyde causes an increase in blood pressure by activating ACE/AT1R axis.

Previous studies suggest some link between formaldehyde exposure and harmful cardiovascular effects. But whether exposure to formaldehyde can cause blood pressure to rise, and if so, what the underlying mechanism is, remains unclear. In this study, C57BL/6 male mice were exposed to 0.1, 0.5, 2.5 mg/m3 of gaseous formaldehyde for 4 h daily over a three-week period. The systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP) and heart rate (HR) of the mice were measured by tail-cuff plethysmography, and any histopathological changes in the target organs of hypertension were investigated. The results showed that exposure to formaldehyde did cause a significant increase in blood pressure and heart rate, and resulted in varying degrees of damage to the heart, aortic vessels and kidneys. To explore the underlying mechanism, a specific inhibitor of angiotensin converting enzyme (ACE) was used to block the ACE/AT1R axis. We observed the levels of ACE and angiotensin II type 1 receptor (AT1R), as well as the bradykinin (BK) in cardiac cytoplasm. The data suggest that exposure to formaldehyde induced an increase in the expression of ACE and AT1R, and decreased the levels of BK. Strikingly, treatment with 5 mg/kg/d ACE inhibitor can attenuate the increase in blood pressure and the pathological changes caused by formaldehyde exposure. This result has improved our understanding of whether, and how, formaldehyde exposure affects the development of hypertension.

Current advancements and future perspectives of long noncoding RNAs in lipid metabolism and signaling.

BACKGROUND: The investigation of lncRNAs has provided a novel perspective for elucidating mechanisms underlying diverse physiological and pathological processes. Compelling evidence has revealed an intrinsic link between lncRNAs and lipid metabolism, demonstrating that lncRNAs-induced disruption of lipid metabolism and signaling contribute to the development of multiple cancers and some other diseases, including obesity, fatty liver disease, and cardiovascular disease. AIMOF REVIEW: The current review summarizes the recent advances in basic research about lipid metabolism and lipid signaling-related lncRNAs. Meanwhile, the potential and challenges of targeting lncRNA for the therapy of cancers and other lipid metabolism-related diseases are also discussed. KEY SCIENTIFIC CONCEPT OF REVIEW: Compared with the substantial number of lncRNA loci, we still know little about the role of lncRNAs in metabolism. A more comprehensive understanding of the function and mechanism of lncRNAs may provide a new standpoint for the study of lipid metabolism and signaling. Developing lncRNA-based therapeutic approaches is an effective strategy for lipid metabolism-related diseases.

Comparing the effects of polystyrene microplastics exposure on reproduction and fertility in male and female mice.

Microplastics (MPs) may have an impact on the reproductive development of humans and mammals. However, any effects of MPs exposure on male and female reproductive systems and fertility are still ambiguous. In this study, male and female C57BL/6 mice were exposed to saline or 0.1 mg/d polystyrene microplastics (PS-MPs) for 30 days or 44 days to determine the effects of MPs on reproductive systems, following which some of the mice were caged for 10 days to mate to test fertility. Another group of mice were given fluorescent PS-MPs to determine the accumulation of MPs. The results show that PS-MPs exposure resulted in more significant accumulation and oxidative stress in the ovary than in the testis. In male mice, the number of viable epididymis sperm and spermatogenic cells in the testes after PS-MPs exposure was significantly reduced, and the rate of sperm deformity increased. In female mice, PS-MPs exposure induced a decrease in ovary size and number of follicles. After exposure to PS-MPs, the levels of Follicle stimulating hormone, Luteinizing hormone and testosterone were reduced, and the estradiol levels increased in the serum of male mice, while the changes in these hormone levels of female mice was the opposite. The mice exposed to PS-MPs had a reduced pregnancy rate and produced fewer embryos. These findings suggest that exposure to PS-MPs damaged the testes and ovaries, induced oxidative stress, altered the serum hormone levels, and induced changes in reproduction and fertility. Female mice appear to be more susceptible to MPs in reproduction and fertility than male mice.

Phenanthrene induces autism-like behavior by promoting oxidative stress and mTOR pathway activation.

Autism is thought to be associated with both environmental and genetic factors. Phenanthrene (Phe) makes up a relatively high proportion of the low-ring polycyclic aromatic hydrocarbons. However, the association between exposure to Phe and Autism remain unclear. In this study, the effect and mechanisms of phenanthrene exposure on autistic behavior were investigated. Three-week-old male Kunming mice were exposed to doses of 5, 50, or 500 µg/kg/d Phe for 22 days. Exposure to phenanthrene induced a marked decrease in the activity of the mice in the central area in the open field test, and caused a significant decrease in communication with unfamiliar mice in the three-chambered social test. The hippocampus of the mice exposed to high concentrations of Phe showed pathological changes. Exposure to phenanthrene induced an increase in the levels of ROS and a decrease in levels of glutathione, and caused a significant decrease in the expression of Shank3 and Beclin1. This also led to an increase in the phosphorylation levels of Akt and mTOR. However, administering Rapamycin or vitamin E, inhibited the oxidative stress and activation of the mTOR pathway induced by Phe exposure, effectively alleviating the above-mentioned autistic-like anxious social behaviors. These results indicate that exposure to phenanthrene will lead to autism-like behavior. The underlying mechanism involves oxidative stress and the mTOR pathway.

Regulation of OATP1B1 Function by Tyrosine Kinase-mediated Phosphorylation.

PURPOSE: OATP1B1 (SLCO1B1) is the most abundant and pharmacologically relevant uptake transporter in the liver and a key mediator of xenobiotic clearance. However, the regulatory mechanisms that determine OATP1B1 activity remain uncertain, and as a result, unexpected drug-drug interactions involving OATP1B1 substrates continue to be reported, including several involving tyrosine kinase inhibitors (TKI). EXPERIMENTAL DESIGN: OATP1B1-mediated activity in overexpressing HEK293 cells and hepatocytes was assessed in the presence of FDA-approved TKIs, while rosuvastatin pharmacokinetics in the presence of an OATP1B1 inhibiting TKI were measured in vivo. Tyrosine phosphorylation of OATP1B1 was determined by LC/MS-MS-based proteomics and transport function was measured following exposure to siRNAs targeting 779 different kinases. RESULTS: Twenty-nine of 46 FDA-approved TKIs studied significantly inhibit OATP1B1 function. Inhibition of OATP1B1 by TKIs, such as nilotinib, is predominantly noncompetitive, can increase systemic concentrations of rosuvastatin in vivo, and is associated with reduced phosphorylation of OATP1B1 at tyrosine residue 645. Using genetic screens and functional validation studies, the Src kinase LYN was identified as a potential regulator of OATP1B1 activity that is highly sensitive to inhibition by various TKIs at clinically relevant concentrations. CONCLUSIONS: A novel kinase-dependent posttranslational mechanism of OATP1B1 activation was identified and interference with this process by TKIs can influence the elimination of a broad range of xenobiotic substrates.

Androgen receptor signalling impairs docetaxel efficacy in castration-resistant prostate cancer.

Androgen receptor (AR) signalling drives neoplastic growth and therapy resistance in prostate cancer. Recent clinical data show that docetaxel combined with androgen deprivation therapy improves outcome in hormone-sensitive disease. We studied whether testosterone and AR signalling interferes with docetaxel treatment efficacy in castration-resistant prostate cancer (CRPC). We found that testosterone supplementation significantly impaired docetaxel tumour accumulation in a CRPC model, resulting in decreased tubulin stabilisation and antitumour activity. Furthermore, testosterone competed with docetaxel for uptake by the drug transporter OATP1B3. Irrespective of docetaxel-induced tubulin stabilisation, AR signalling by testosterone counteracted docetaxel efficacy. AR-pathway activation could also reverse long-term tumour regression by docetaxel treatment in vivo. These results indicate that to optimise docetaxel efficacy, androgen levels and AR signalling need to be suppressed. This study lends evidence for continued maximum suppression of AR signalling by combining targeted therapeutics with docetaxel in CRPC.

Exposure to formaldehyde at low temperatures aggravates allergic asthma involved in transient receptor potential ion channel.

Studies have indicated that formaldehyde and low temperature are considered to be the factors associated with several respiratory diseases. However, the effect of co-exposure to formaldehyde and low temperature on allergic asthma, and the potential mechanisms, are unknown. In this study, an allergic asthma mouse model was built and mice were exposed to 0.8 mg/m3 formaldehyde and/or subjected to low temperatures of 16 °C. The data showed that exposure to either low temperature or formaldehyde did not induce a significant aggravation on allergic asthma. However, simultaneous exposure to formaldehyde and low temperature was shown to aggravate mucus hypersecretion and inflammation in the lung, lead to an exacerbation of allergic asthma. After blocking the TRPM8 and TRPA1 ion channels, the levels of inflammatory factors reduced. These results demonstrated that co-exposure to formaldehyde and low temperature exacerbate allergic asthma, and that TRPM8 and TRPA1 are involved in this process.

lncRNA TUG1 promotes endometrial fibrosis and inflammation by sponging miR-590-5p to regulate Fasl in intrauterine adhesions.

Intrauterine adhesion (IUA) is one of the most common reproductive system diseases in women worldwide. The role of lncRNAs in multiple diseases has been confirmed, but the role and mechanism of lncRNA taurine upregulated gene 1 (TUG1) in the progression of IUA need to be elucidated further. Here, we found that lncRNA TUG1 was upregulated in the endometrial tissues of IUA and TGF-ß1-treated human embryonic stem cells (hESCs). Moreover, lncRNA TUG1-silenced alleviated TGF-ß1-induced the proliferation and migration abilities of hESCs and enhanced inflammatory cytokines secretion in vitro. In vivo experiments showed that inhibition of lncRNA TUG1 promoted endometrium regeneration in IUA rats through downregulating inflammatory response and epithelial-to-mesenchymal transition (EMT) process. Mechanistically, lncRNA TUG1 suppression attenuated EMT process and inflammation through competitively binding miR-590-5p to downregulate Fasl expression. Collectively, our findings provide vital theoretical evidence for explaining the mechanisms of the lncRNA TUG1/miR-590-5p/Fasl axis in the progression of IUA, and may provide a new biomarker for the treatment of IUA patients.

Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice.

Peripheral neurotoxicity is a debilitating condition that afflicts up to 90% of patients with colorectal cancer receiving oxaliplatin-containing therapy. Although emerging evidence has highlighted the importance of various solute carriers to the toxicity of anticancer drugs, the contribution of these proteins to oxaliplatin-induced peripheral neurotoxicity remains controversial. Among candidate transporters investigated in genetically engineered mouse models, we provide evidence for a critical role of the organic cation transporter 2 (OCT2) in satellite glial cells in oxaliplatin-induced neurotoxicity, and demonstrate that targeting OCT2 using genetic and pharmacological approaches ameliorates acute and chronic forms of neurotoxicity. The relevance of this transport system was verified in transporter-deficient rats as a secondary model organism, and translational significance of preventive strategies was demonstrated in preclinical models of colorectal cancer. These studies suggest that pharmacological targeting of OCT2 could be exploited to afford neuroprotection in cancer patients requiring treatment with oxaliplatin.

Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions.

The organic anion transporting polypeptide (OATP)2B1 is localized on the basolateral membrane of hepatocytes and is expressed in enterocytes. Based on its distribution pattern and functional similarity to OATP1B-type transporters, OATP2B1 might have a role in the absorption and disposition of a range of xenobiotics. Although several prescription drugs, including hydroxymethylglutaryl-coenzyme A-CoA reductase inhibitors (statins) such as fluvastatin, are OATP2B1 substrates in vitro, evidence supporting the in vivo relevance of this transporter remains limited, and most has relied on substrate-inhibitor interactions resulting in altered pharmacokinetic properties of the victim drugs. To address this knowledge deficit, we developed and characterized an Oatp2b1-deficient mouse model and evaluated the impact of this transporter on the absorption and disposition of fluvastatin. Consistent with the intestinal localization of Oatp2b1, we found that the genetic deletion or pharmacological inhibition of Oatp2b1 was associated with decreased absorption of fluvastatin by 2- to 3-fold. The availability of a viable Oatp2b1-deficient mouse model provides an opportunity to unequivocally determine the contribution of this transporter to the absorption and drug-drug interaction potential of drugs. SIGNIFICANCE STATEMENT: The current investigation suggests that mice deficient in Oatp2b1 provide a valuable tool to study the in vivo importance of this transporter. In addition, our studies have identified novel potent inhibitors of OATP2B1 among the class of tyrosine kinase inhibitors, a rapidly expanding class of drugs used in various therapeutic areas that may cause drug-drug interactions with OATP2B1 substrates.

Exposure to polystyrene microplastics causes reproductive toxicity through oxidative stress and activation of the p38 MAPK signaling pathway.

Microplastics (MP) are receiving increased attention as a harmful environmental pollutant, however information on the reproduction toxicity of MP in terrestrial animals, especially mammals, is limited. In this experiment, we investigated the impact of polystyrene microplastics (micro-PS) on the reproductive system of male mice. Healthy Balb/c mice were exposed to saline or to different doses of micro-PS for 6 weeks. The results showed that micro-PS exposure resulted in a significant decrease in the number and motility of sperm, and a significant increase in sperm deformity rate. We also detected a decrease in the activity of the sperm metabolism-related enzymes, succinate dehydrogenase (SDH) and lactate dehydrogenase (LDH), and a decrease in the serum testosterone content in the micro-PS exposure group. We found that micro-PS exposure caused oxidative stress and activated JNK and p38 MAPK. In addition, we found that when N-acetylcysteine (NAC) scavenges ROS, and when the p38 MAPK-specific inhibitor SB203580 inhibits p38MAPK, the micro-PS-induced sperm damage is alleviated and testosterone secretion improves. In conclusion, our findings suggest that micro-PS induces reproductive toxicity in mice through oxidative stress and activation of the p38 MAPK signaling pathways.

Sorafenib Activity and Disposition in Liver Cancer Does Not Depend on Organic Cation Transporter 1.

Systemic therapy of advanced hepatocellular carcinoma (HCC) with the small-molecule multikinase inhibitor sorafenib is associated with large interindividual pharmacokinetic variability and unpredictable side effects potentially requiring dose reduction or treatment termination. Organic cation transporter (OCT1; gene SLC22A1) has been proposed as a clinical biomarker of HCC response. Because proof is lacking that OCT1 transports sorafenib, we used a combinatorial approach to define how OCT1 contributes to sorafenib transport. Overexpression of functional OCT1 protein in Xenopus laevis oocytes and mammalian cell lines did not facilitate sorafenib transport. Otherwise, sorafenib considerably accumulated in liver cancer cell lines despite negligible OCT1 mRNA and protein levels. Sorafenib pharmacokinetics was independent of OCT1 genotype in mice. Finally, SLC22A1 mRNA expression was significantly reduced by DNA methylation in The Cancer Genome Atlas HCC cohort. These results clearly demonstrate OCT1-independent cellular sorafenib uptake indicating that OCT1 is apparently not a valid biomarker of sorafenib response in HCC.

Exposure to both formaldehyde and high relative humidity exacerbates allergic asthma by activating the TRPV4-p38 MAPK pathway in Balb/c mice.

Some studies have indicated that formaldehyde, a ubiquitous environmental pollutant, can induce or aggravate allergic asthma. Epidemiological studies have also shown that the relative humidity indoors may be an independent and a key factor associated with the aggravation of allergic asthma. However, the synergy of humidity and formaldehyde on allergic asthma and the mechanism underlying this effect remain largely unknown. In this study, we aim to determine the effect of high relative humidity and/or formaldehyde exposure on allergic asthma and explore the underlying mechanisms. Male Balb/c mice were modeled with ovalbumin (OVA) and exposure to 0.5 mg/m3 formaldehyde and/or different relative humidity (60%/75%/90%). Histopathological changes, pulmonary function, Th1/Th2 balance, the status of mucus hypersecretion and the levels of inflammatory factors were detected to assess the exacerbation of allergic asthma. The levels of the transient receptor potential vanilloid 4 (TRPV4), calcium ion and the activation of p38 mitogen-activated protein kinases (p38 MAPK) were detected to explore the underlying mechanisms. The results showed that exposure to high relative humidity or to 0.5 mg/m3 formaldehyde alone had a slight, but not significant, affect on allergic asthma. However, the pathological response and airway hyperresponsiveness (AHR) were greatly aggravated by simultaneous exposure to 0.5 mg/m3 formaldehyde and 90% relative humidity. Blocking TRPV4or p38 MAPK using HC-067047 and SB203580 respectively, effectively alleviated the exacerbation of allergic asthma induced by this simultaneous exposure to formaldehyde and high relative humidity. The results show that when formaldehyde and high relative humidity are present this can enhance the activation of the TRPV4 ion channel in the lung leading to the aggravation of the p38 MAPK activation, resulting in the exacerbation of inflammation and hypersecretion of mucus in the airways.

Supramolecular micellar drug delivery system based on multi-arm block copolymer for highly effective encapsulation and sustained-release chemotherapy.

Poly(phosphoester)-based biomaterials have great potential in drug delivery systems (DDSs) because of their multifunctional adjustability, stealth effect, excellent biodegradability, and biocompatibility. To further increase the drug loading efficiency (DLE) and sustained release ability, a multi-arm block copolymer, poly(amido amine)-b-poly(2-butenyl phospholane)-b-poly(2-methoxy phospholane) conjugated with folic acid (abbreviated as PAMAM-PBEP-PMP-FA), was designed and prepared. Compared to the traditional linear copolymers, this multi-arm phosphoester block copolymer integrates a balanced combination of unique features. As an advanced DDS, the PAMAM-PBEP-PMP-FA based supramolecular micelle provides good architectural stability, low protein adsorption, extremely high DLE, and sustained drug release for chemotherapy and abundant surface chemistry for target engineering. Benefitting from these novel functions, the supramolecular micellar drug delivery system exhibits great performances both in in vitro and in vivo evaluations. Doxorubicin (DOX)-loaded supramolecular micelles PAMAM-PBEP-PMP-FA/DOX are fast taken up by HepG2 cells and inhibit the tumor growth effectively in HepG2-tumor-bearing nude mice without obvious system toxicity. This work not only suggests a targeted sustained release DDS for effective chemotherapy but also enlightens, through a delicate design at the molecular scale, the brilliance of multifunctional PPE-based nanomaterials towards versatile bio-applications.

Injectable and Near-Infrared-Responsive Hydrogels Encapsulating Dopamine-Stabilized Gold Nanorods with Long Photothermal Activity Controlled for Tumor Therapy.

Gold nanorods (AuNRs) are confirmed to have excellent and repeated photothermal properties under near-infrared (NIR)-light irradiation above 780 nm. However, AuNRs easily leaked out from local pathological tissues and circulated in the body, reducing photothermal therapy (PTT) efficacy. By complexing AuNRs with a scaffold via interactions, AuNRs might be dispersed in the scaffold and fixed in the tumor site. Thus, based on the mussel-mimetic adhesion concept, AuNRs were designed to be coated with polydopamine (PDA), and then the prepared polydopamine-coated AuNRs (AuNR-PDA) were incorporated into a thermosensitive injectable hydrogel composed of ß-glycerophosphate-bound chitosan (CGP) and dopamine-modified alginate (Alg-DA) efficiently. Due to the strong interactions between PDA and polymers, AuNR-PDA could be immobilized stably and evenly into the obtained CGP/Alg-DA/AuNR composite hydrogel, which can avoid overheating locally or leaking out. The sol-gel transition temperature of the composite hydrogel was adjusted to the body temperature at around 37 °C to be conveniently injectable in vivo. With NIR irradiation at 808 nm of wavelength, the composite hydrogel was locally heated quickly to over 50 °C depending on controlling the irradiation powers and times. Moreover, the in vitro cytotoxicity test of the composite hydrogel showed good biocompatibility to normal cells but obvious suppression to tumor cells' growth under multiple times of photothermal therapy. Furthermore, the in vivo antitumor test demonstrated the obvious suppression to tumor growth of the CGP/Alg-DA/AuNR composite hydrogel under multiple PTTs. Therefore, the injectable CGP/Alg-DA/AuNR hydrogel could be a promising candidate for the long-term repeated photothermal treatment of tumors.

Interaction Between Sex and Organic Anion-Transporting Polypeptide 1b2 on the Pharmacokinetics of Regorafenib and Its Metabolites Regorafenib-N-Oxide and Regorafenib-Glucuronide in Mice.

Regorafenib, a multikinase inhibitor used in the treatment of various solid tumors, undergoes extensive uridine 5'-diphosphate glucuronosyltransferase (Ugt)1a9-mediated glucuronidation to form regorafenib-N-ß-glucuronide (M7; RG), but the contribution of hepatic uptake transporters, such as organic anion-transporting polypeptide (Oatp)1b2, to the pharmacokinetics of regorafenib remains poorly understood. Using NONMEM-based, population-based, parent-metabolite modeling, we found that Oatp1b2 and sex strongly impact the systemic exposure to RG in mice receiving oral regorafenib. Metabolic studies revealed that the liver microsomal expression of cytochrome P450 (Cyp)3a11 is twofold lower in female mice, whereas Ugt1a9 levels and function are not sex dependent. This finding is consistent with the metabolism of regorafenib occurring via two competing pathways, and the lack of Oatp1b2 results in decreased clearance of RG. The described model provides mechanistic insights into the in vivo disposition of regorafenib.

Comparing the effects of diethylhexyl phthalate and dibutyl phthalate exposure on hypertension in mice.

Epidemiological studies have shown that high molecular weight phthalates (HMW) such as diethylhexyl phthalate (DEHP), are associated with hypertension in humans, while low molecular weight phthalates (LMW) such as dibutyl phthalate (DBP), have hardly any impact on the elevation of blood pressure. However, the molecular mechanisms responsible for this difference are not completely understood. In this experiment, mice were exposed to 0.1/1/10 mg/kg/day DEHP and 0.1/1/10 mg/kg/day DBP for 6 weeks, and their blood pressure was monitored using the tail pressure method. The results showed that exposure to DEHP dosages of 1 or 10 mg/kg/day resulted in a sharp increase in blood pressure, while exposure to DBP did not induce any significant changes in blood pressure. Investigating the renin-angiotensin-aldosterone system (RAAS) and NO pathway in mice exposed to DEHP, we found that levels of angiotensin-converting enzyme (ACE) and angiotensin II (AngII) increased with increasing exposure to DEHP, and the expression of nitric oxide synthase (eNOS) and the level of NO decreased. Treatment with ACE inhibitor (ACEI) to block the ACE pathway inhibited the enhancement of RAAS expression, inhibited the increase in blood pressure, and inhibited the decrease in NO levels induced by DEHP. However, the expression of ACE, AngII, AT1R, and eNOS in the DBP treatment groups showed no significant changes. When examining estradiol in vivo, we found that exposure to DBP resulted in a significant increase in the level of estradiol, while exposure to DEHP did not lead to a significant change. When ICI182780 was used to block the estradiol receptors, any increase in the level of NO induced by DBP exposure, was inhibited. These results indicate that exposure to DEHP induces an increase in mouse blood pressure through RAAS, and the different effects of DEHP and DBP on blood pressure are partly due to the different estradiol levels induced by DEHP and DBP.