Xenobiotic-Induced Hepatocyte Proliferation Enhanced by Pregnane X Receptor Activation in Mice
Xenobiotic-responsive nuclear receptors such as pregnane X receptor (PXR), constitutive active/androstane receptor (CAR), and peroxisome proliferator-activated receptor alpha (PPARα) play critical roles in hepatic metabolism, including xenobiotic detoxification and energy homeostasis. While activation of CAR or PPARα has been linked to hepatocyte proliferation and hepatocarcinogenesis in rodents, the role of PXR in this context remains unclear. This study investigated whether PXR activation modulates xenobiotic-induced hepatocyte proliferation in mice, particularly in conjunction with CAR or PPARα activation.
Male C57BL/6 mice were treated intraperitoneally with either 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or phenobarbital (PB), known activators of CAR, or Wy-14643, a PPARα ligand, alone or in combination with the PXR agonist pregnenolone 16α-carbonitrile (PCN).Cyclopentane-1,3-dicarboxylic acid site Liver-to-body weight ratios increased significantly following TCPOBOP or PB treatment, indicating hepatomegaly. Immunohistochemical analysis revealed a marked increase in Ki-67-positive nuclei in livers from mice treated with TCPOBOP or PB, confirming enhanced cell proliferation.2-Benzoylbenzoic acid Autophagy However, PCN treatment alone did not induce significant changes in liver weight or Ki-67 expression.PMID:34820984 Notably, co-treatment with PCN and TCPOBOP or PB resulted in a substantial further increase in both liver weight and the percentage of Ki-67-positive cells, suggesting synergistic enhancement of proliferation.
This effect was absent in PXR-deficient mice, where PCN co-treatment failed to augment the proliferative response induced by TCPOBOP. Similarly, when Wy-14643 was used to activate PPARα, PCN co-treatment significantly amplified hepatocyte proliferation, as evidenced by increased Ki-67 positivity and elevated mRNA levels of cell cycle markers such as Mcm2, Ccna2, and Ccnb1. Despite these effects, PCN did not enhance the expression of canonical target genes of CAR (Cyp2b10) or PPARα (Cyp4a10), indicating that PXR’s role is not through direct transcriptional upregulation of these pathways.
Flow cytometry analysis revealed that PCN treatment increased RNA content in hepatocytes without altering DNA content, suggesting a shift from quiescent G0 phase into early G1 phase. This was accompanied by downregulation of key cyclin-dependent kinase inhibitors, Cdkn1b (p27) and Rbl2 (p130), which normally restrain G0/G1 transition. These findings imply that PXR activation primes hepatocytes for cell cycle entry by reducing inhibitory signals.
In summary, while PXR activation alone does not initiate hepatocyte proliferation in mice, it potently enhances proliferation driven by CAR or PPARα activators. This effect appears to be mediated through facilitation of the G0/G1 transition rather than direct stimulation of mitotic machinery. The results suggest a novel, non-redundant role for PXR as a modulator of hepatocyte hyperplasia under xenobiotic exposure, potentially acting as an amplifier in chemical carcinogenesis. This insight underscores the importance of considering PXR status in assessing the safety of drugs and environmental chemicals that may promote liver tumor development via nongenotoxic mechanisms.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
Severe blast exposures are frequently complicated by fatal intracranial hemorrhages. However, many individuals sustain low-level blasts without detectable tissue damage via conventional brain imaging. To investigate the effects of nonlethal blast exposure on thrombin-related biomarkers, rats were subjected to two distinct types of head-directed blast: 1) moderate “composite” blast involving strong head acceleration, or 2) moderate primary blast without head acceleration. Thrombin generation (TG) ex vivo following blast was assessed using calibrated automated thrombography (CAT). In parallel, key microvascular and inflammatory markers were evaluated in the same blood samples, including integrin α/β, soluble endothelial selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), and matrix metalloproteinases MMP-2, MMP-8, and MMP-13.
Blast exposure significantly altered all TG parameters. In animals exposed to composite blast, TGmax peaked at 6 hours post-blast—approximately 4.5-fold higher than control levels—and remained elevated at day 1 (3.8-fold increase), before declining to a 2-fold elevation by day 7. In contrast, primary blast also induced a sharp rise in TGmax to 4.2-fold of control at 6 hours, followed by a drop to 1.7-fold at day 1, with a mild secondary increase to 2-fold at day 7. No significant differences were observed between the two blast types regarding t-start, t-peak, or t-mean times.
Concomitant changes in biomarkers mirrored TG dynamics. Integrin α/β and sICAM-1 levels rose significantly after both blast types at 6 hours, day 1, and day 7. sE-selectin remained near baseline after composite blast but increased markedly at day 7 post-primary blast.ZIF-9(Co) Purity MMP-2, MMP-8, and MMP-13 showed only slight elevations after composite blast but exhibited substantial increases—2- to 4-fold—following primary blast exposure.Fenirofibrate impurity 4 Epigenetics These findings suggest that primary blast induces more pronounced systemic vascular and inflammatory activation despite the absence of mechanical head acceleration.PMID:34962318
In summary, CAT offers a sensitive, quantitative method for detecting blast-induced alterations in thrombin generation potential. When combined with a panel of microvascular and inflammatory biomarkers, it may serve as a valuable diagnostic tool for identifying subtle, clinically relevant injuries in individuals exposed to low-to-moderate blast forces—particularly those without overt structural brain injury visible on standard imaging. This approach holds promise for early triage and monitoring in military and civilian blast trauma scenarios.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
Asymmetric membrane capsules (AMCs) represent an advanced osmotic-controlled drug delivery system capable of sustained and precise release of therapeutic agents. In this study, a novel semiautomatic benchtop manufacturing model was developed to fabricate AMCs using cellulose acetate butyrate (CAB) as the polymeric shell material and metformin hydrochloride as the model drug. The process was designed to enhance reproducibility, consistency, and scalability in capsule production. A hydraulic-assisted robotic arm system was engineered to perform key operations including dipping, spinning, flipping, quenching, and drying—critical steps in the phase inversion method. The equipment featured a vertical and horizontal arm connected via syringe-driven hydraulic pressure, enabling controlled two-dimensional motion. Mold pins made from Teflon were used to ensure smooth demolding without lubrication, with dimensions set at 35 × 9.85 mm for caps and 55 × 9.5 mm for bodies. The mold plate allowed for six-pin rotation via two diagonal knobs, facilitating uniform coating during spinning.
The AMCs were prepared by dip-coating the mold pins into a solution of CAB in acetone:ethanol (3:7 v/v), followed by air-drying for 30 seconds and quenching in a 5% aqueous propylene glycol (PG) bath for 3 minutes. This process induced asymmetric membrane formation with a dense outer layer and a porous inner structure. Different concentrations of CAB (10–16% w/v) and PG (10–20% v/v) were tested. Physical characterization revealed that increasing PG concentration reduced both thickness and weight of the capsules due to enhanced plasticity and spreading efficiency, while higher CAB levels improved mechanical strength but caused rigidity issues. Formulation CAB-12% with 15% PG emerged as optimal based on balanced mechanical integrity and flexibility.
Scanning electron microscopy confirmed the presence of a thin dense skin supported by a thick porous substructure, essential for osmotic control. Osmotic release studies demonstrated dye release only in distilled water, not in high-osmolarity sodium chloride solution, confirming the osmotic mechanism. FTIR analysis showed shifts in –OH and C=O stretching frequencies in asymmetric membranes, indicating intramolecular hydrogen bonding due to phase inversion. Water vapor transmission rate (WVTR) increased with PG content, reflecting greater porosity. In vitro drug release profiles from metformin-loaded AMCs, evaluated using a 2³ full factorial design, indicated that PG concentration and osmogent levels (potassium chloride and fructose) significantly influenced release kinetics. Higher PG and osmogent levels accelerated release, primarily through diffusion and osmosis.
Statistical modeling using Design-Expert software identified potassium chloride and fructose as major contributors to release time, with PG playing a secondary role.Firibastat MedChemExpress The optimized formulation (OPT) achieved complete drug release within 13 hours following zero-order kinetics (R² = 0.99). Release was independent of pH (1.Berotralstat web 2–7.PMID:34619210 4) and agitation intensity (50–150 rpm), confirming the dominance of osmotic pressure over environmental variables. Studies in different osmotic environments further validated that drug release was driven by osmotic gradient, with significantly higher rates in distilled water compared to magnesium sulfate solution.
This semiautomatic process offers a reliable, cost-effective, and industrially feasible approach for producing high-quality AMCs. It enables consistent capsule shells with minimal variability, making it ideal for early-stage formulation development and potential scale-up. The successful application of this system with metformin hydrochloride demonstrates its versatility for other water-soluble drugs requiring controlled release. Future work may focus on extending the platform to include multiple active ingredients and evaluating in vivo performance.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
Obesity is a major risk factor for type 2 diabetes, characterized by a paradoxical state where insulin secretion increases while its metabolic actions diminish across key tissues such as liver, skeletal muscle, and adipose tissue. This condition, known as insulin resistance, is defined by a reduced response to insulin at the cellular level or impaired glucose-lowering capacity of circulating insulin at the organismal level. Despite decades of research, the precise sequence of events during the development of obesity and diabetes remains controversial. A central debate centers on whether insulin resistance precedes hyperinsulinemia or vice versa. Recent studies in both mouse models and human subjects suggest that fasting hyperinsulinemia often emerges before detectable changes in blood glucose, indicating it may be an early driver rather than a secondary consequence.
The traditional view posits that insulin resistance arises first due to nutrient excess, leading to impaired glucose uptake and increased hepatic glucose production. This triggers compensatory hyperinsulinemia to maintain normoglycemia. However, emerging evidence challenges this paradigm. In mice fed a high-fat diet (HFD), fasting insulin levels rise within one day—before any significant change in fasting glucose occurs. Similar findings are observed in humans undergoing short-term overfeeding, where hyperinsulinemia appears without concurrent hyperglycemia. These observations support the hypothesis that hyperinsulinemia may initiate metabolic dysfunction, rather than merely respond to it.
One proposed mechanism involves chronic insulin exposure impairing downstream signaling pathways independently of Akt activation. For instance, in skeletal muscle, insulin resistance can occur despite normal Akt phosphorylation, suggesting defects lie further downstream in glucose transport regulation. Similarly, in adipocytes, insulin-stimulated GLUT4 translocation is blunted even when Akt activity remains intact. These findings imply that insulin resistance is not solely due to upstream signaling failure but also stems from disruptions in post-Akt metabolic fluxes.
Moreover, hyperinsulinemia itself contributes to systemic inflammation and oxidative stress, particularly in adipose tissue. Elevated insulin levels promote macrophage infiltration and cytokine release, which further impair insulin sensitivity. Genetic models demonstrate that reducing insulin levels—through partial deletion of insulin genes—prevents diet-induced obesity and improves insulin sensitivity, even without altering food intake.Chlorambucil (Standard) Autophagy These mice exhibit increased energy expenditure, adipose browning, and enhanced mitochondrial function, underscoring insulin’s role in promoting fat storage and suppressing thermogenesis.Voriconazole In stock
Another critical pathway involves the disruption of adipocyte lipid metabolism.PMID:34089365 Under HFD conditions, insulin fails to suppress lipolysis effectively, leading to excessive free fatty acid release into circulation. These fatty acids are taken up by the liver, where they activate gluconeogenic enzymes through allosteric mechanisms and increase substrate availability for glucose production. Concurrently, de novo lipogenesis is suppressed in adipocytes, partly due to feedback inhibition by NADPH and reduced activity of transcription factors like ChREBP. This suppression impairs triglyceride storage capacity, contributing to ectopic fat deposition and lipotoxicity in liver and muscle.
The interplay between liver and adipose tissue creates a vicious cycle: adipose-derived fatty acids drive hepatic glucose overproduction, which in turn exacerbates insulin demand. Meanwhile, hyperinsulinemia promotes lipogenesis in the liver via mTORC1-SREBP-1c signaling, leading to VLDL overproduction and hypertriglyceridemia. This dual dysregulation—increased glucose output and lipid overproduction—defines the metabolic phenotype of obesity and type 2 diabetes.
In conclusion, the temporal sequence of metabolic changes following nutrient overload suggests that hyperinsulinemia may act as an initial trigger, setting off a cascade of downstream effects including inflammation, impaired glucose handling, and altered lipid metabolism. While insulin resistance is clearly involved, its origins may lie beyond classical receptor signaling defects and instead reflect broader disruptions in cellular metabolism and interorgan communication. Understanding these dynamics offers new avenues for therapeutic intervention—such as targeting adipose browning, modulating insulin secretion, or restoring metabolic flexibility—potentially breaking the cycle before irreversible damage occurs.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
Our previous studies demonstrated that the cell culture-grown hepatitis C virus of genotype 2a (HCVcc) uses apolipoprotein E (apoE) to mediate its attachment to the surface of human hepatoma Huh-7.5 cells. ApoE mediates HCV attachment by binding to the cell surface heparan sulfate (HS), which is covalently attached to the core proteins of proteoglycans (HSPGs). In the present study, we further determined the physiological importance of apoE and HSPGs in the HCV attachment using a clinical HCV of genotype 1b (HCV1b) obtained from hepatitis C patients and human embryonic stem cell-differentiated hepatocyte-like cells (DHHs). DHHs were found to resemble primary human hepatocytes. Similar to HCVcc, HCV1b was found to attach to the surface of DHHs by the apoE-mediated binding to the cell surface HSPGs. The apoE-specific monoclonal antibody, purified HSPGs, and heparin were all able to efficiently block HCV1b attachment to DHHs. Similarly, the removal of heparan sulfate from cell surface by treatment with heparinase suppressed HCV1b attachment to DHHs. More significantly, HCV1b attachment was potently inhibited by a synthetic peptide derived from the apoE receptor-binding region as well as by an HSPG-binding peptide. Likewise, the HSPG-binding peptide prevented apoE from binding to heparin in a dose-dependent manner, as determined by an in vitro heparin pull-down assay. Collectively, these findings demonstrate that HSPGs serve as major HCV attachment receptors on the surface of human hepatocytes to which the apoE protein ligand on the HCV envelope binds.
Hepatitis C virus (HCV) chronically infects 170 million people worldwide, resulting in hepatitis, cirrhosis, and hepatocellular carcinoma. The current optimal care of hepatitis C is a combination therapy with pegylated interferon-a (IFN-a), ribavirin, and one of the HCV NS3 protease inhibitors boceprevir and telaprevir. However, both IFN-a and ribavirin cause severe side effects, limiting their clinical benefits because of the toxicity-associated intolerance among many hepatitis C patients. A number of novel HCV-specific inhibitors targeting NS3 protease, NS5A protein, and NS5B RNA-dependent RNA polymerase were discovered and have advanced to late stages of clinical studies. It is anticipated that some of the HCV-specific antiviral drugs will be approved for treatment of hepatitis C in coming years. Ideally, future therapies for hepatitis C shall combine HCV-specific antiviral drugs targeting different viral proteins independently of IFN. HCV is the prototype member of the hepacivirus genus in the Flaviviridea family. It is an enveloped RNA virus containing a single positive-sense RNA genome. Upon translation, the HCV polyprotein precursor of 3,000 amino acids is cleaved by cellular and viral proteases, resulting in individual structural (C, E1, and E2), p7, and nonstructural (NS) proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B). The NS3/4A, NS4B, NS5A, and NS5B are known to be the minimal set of viral proteins essential for HCV RNA replication. The viral structural and NS proteins play important roles in HCV morphogenesis although the underlying mechanism of NS proteins in HCV virion assembly has not been defined. The untranslated regions (UTRs) flanked at both the 5′ and 3′ ends of the HCV RNA genome function as cis-acting RNA elements required for the initiation of HCV protein translation as well as viral RNA replication. Besides viral proteins, many cellular proteins were identified to be critical for the HCV life cycle and/or viral pathogenesis.
Substantial evidence derived from our previous studies suggests that the cellular protein apolipoprotein E (apoE) plays important roles in both HCV infection and virion assembly. Initially, apoE was found to be enriched in infectious HCV particles and correlated very nicely with the HCV infectivity. Our studies also suggested that apoE is a structural component of HCV virions as determined by co-immunoprecipitation (co-IP) of HCV virions with an apoE monoclonal antibody and its sensitivity to trypsin digestion. The structural nature of apoE was further confirmed by immunogold electronic microscopy studies which visualized apoE on the HCV envelope. Additionally, we have demonstrated that the apoE binds HCV NS5A and the apoE-NS5A interaction is important for HCV virion assembly and production. Through deletion and site-specific mutagenesis studies, the C-terminal α-helical domain of apoE was found to be important for NS5A binding and HCV virion assembly. Consistent with these findings, apoE was recently shown to be the only apolipoprotein required for HCV production when expressed in nonhepatic 293T cells. The importance of apoE in HCV infection was confirmed by recent findings that the apoE peptides derived from its receptor-binding domain potently inhibited HCV attachment to the cell surface. Our recent work also demonstrated that apoE on HCV virions mediates the HCV attachment via binding to the cell surface heparin sulfate (HS), which was previously found important for HCV infection. In this study, we further determined the physiological importance of apoE and HSPGs in HCV attachment using clinical HCV of genotype 1b derived from hepatitis C patients and human embryonic stem cell-differentiated hepatocyte-like cells (DHHs). Results obtained from our experiments demonstrate that apoE mediates the attachment of clinical HCV of genotype 1b to the surface of DHHs, suggesting its importance in HCV infection in vivo.
Human embryonic stem cell (hESCs) line WA09 (H9) was obtained from WiCell Research Institute and maintained on Geltrex coated culture plates in Stem Pro medium (Invitrogen, Carlsbad, CA). The Huh-7, Huh-7.5, and HEK293 cells were maintained in Dulbecco’s modified Eagle’s medium (Hyclone) supplemented with 10% fetal bovine serum (Germini), 0.1 mM nonessential amino acids, 100 U/ml penicillin, and 100 mg/ml streptomycin at 37°C in 5% CO₂ incubator. The differentiation of hESCs into hepatocytes has been described previously. Briefly, the base defined medium (DM) consists of DMEM/F12 containing 10% Probumin, 0.2% β-Mercaptoethanol, 1% L-Alanyl-L-Glutamine and 2% hESC supplements. Confluent cells were harvested with Accutase and then plated into culture dishes (Costar; Corning Life Sciences) precoated with Geltrex (1:200 dilution in DMEM/F-12) in Stem Pro medium at a confluence level of 30–40%. The next day, culture medium was changed to medium A (DM+100 ng/ml Activin-A+8 ng/ml b-FGF+25 ng/ml Wnt-3A) for 24 hrs, followed by three days in medium B (DM+100 ng/ml Activin-A+8 ng/ml b-FGF). To induce hepatic differentiation, we then cultured cells in the presence of medium C (DM+50 ng/ml FGF10) for three days and then in the presence of medium D (DM+50 ng/ml FGF-10+0.1 mM RA+1 mM SB431542) for three more days.N‐Nitrosociprofloxacin Autophagy The immature hepatocyte-like cells were then split 1:2 and grown in medium E (DM+30 ng/ml FGF-4+50 ng/ml EGF+50 ng/ml HGF) for 10 days with changes to fresh medium E every two to three days.
Cell culture plates were coated with either Geltrex (1:200 dilution in DMEM/F-12) or 0.1 mg/ml of poly-L-lysine (Sigma-Aldrich). The hESCs differentiated human hepatocytes (DHHs) or Huh-7.5 cells in 12-well cell culture plates were incubated with HCV1b or HCVcc in the absence or presence of indicated peptides at 4°C (on ice) for 2 hours (hrs). The unbound HCV was removed by aspiration and washing cells with PBS for three times. The virion RNA (vRNA) of cell-bound HCV was isolated with a Trizol Reagent (Invitrogen) or RNAzol Reagent (Molecular Research Center). The levels of HCV vRNA were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) method.
DHHs in a 12-well cell culture plate were washed with DPBS and then incubated with various concentrations of heparinase I in a buffer containing 20 mM Tris-HCl (pH 6.8), 50 mM NaCl, 4 mM CaCl₂ and 0.01% bovine serum albumin at 37°C for 1 hr. The heparinase-containing buffer was removed, and cells were washed three times with PBS. The heparinase-treated DHHs were incubated with HCV1b on ice for 2 hrs. The unbound HCV was removed, and the cells were washed three times with DPBS. The vRNA of the cell-bound HCV was extracted with Trizol Reagent (Invitrogen) and quantified by qRT-PCR using the StepOnePlus real-time PCR system.
The patient serum containing HCV of genotype 1b (HCV1b) was obtained from a commercial supplier (Teragenix, Ft. Lauderdale, FL). ApoE-specific monoclonal antibody 23 (mAb23) and WuE4 (ATCC) were produced in the lab as previously described. Horseradish peroxidase-conjugated goat anti-mouse IgG and heparin-conjugated beads were from Pierce. ApoE peptides of 21 amino acids are derived from the receptor-binding region from amino acid residue 130 to 150. Both hEP and hEPm peptides derived from apoE were described previously. The HSPG-binding peptide was obtained from the exon 6a-encoding domain of the vascular endothelial cell growth factor (VEGF). Peptides were synthesized by Biomatik with a purity of 95%. Heparinase I, HSPG (isolated from basement membrane of Engelbreth-Holm-Swarm mouse sarcoma), and Heparin (ammonium salt from porcine intestinal mucosa) were purchased from Sigma-Aldrich.
To determine whether heparin or GAGs inhibits HCV attachment to DHHs or Huh7.5 cells, infectious HCV reacted with different concentrations of heparin or GAGs in a final volume of 0.5 ml/well at 4°C (on ice) for 1 hr was added onto cells in 12-well plates at 4°C (on ice) for 2 hrs to allow binding.IR-775 site The unbound HCV was removed by aspiration and washing cells with PBS three times.PMID:34786623 The virion RNA (vRNA) of cell-bound HCV was isolated with a Trizol Reagent (Invitrogen) or RNAzol Reagent (Molecular Research Center). The levels of HCV vRNA were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) method.
Total RNAs were extracted from the HCV-infected cells using a Trizol Reagent (Invitrogen) or RNAzol Reagent (Molecular Research Center). The level of HCV1b vRNA was quantified by a one-step real-time RT-PCR method using SuperScript® III Platinum® SYBR® Green One-Step qPCR Kit w/ROX (Invitrogen). The oligonucleotide primers were NS3 1b-F (5′GTCGTGCTGGCCACCGCTAC-3′) and NS3 1b-R (5′CCTCCCCCCCTTGATGGTCTC-3′). Reactions were run in a StepOnePlus real-time PCR system (Applied Biosystems) using the cycle conditions provided by the qPCR kit. An endogenous gene GAPDH was also determined using Hu-GAPDH primer/probe mix containing vic-TAMRA (Applied Biosystems). The levels of HCV vRNA were normalized to the level of GAPDH.
Protein concentration of cell lysate was determined using a protein assay reagent (Bio-Rad). Equal amount of total protein for each sample was analyzed by electrophoresis in 10% SDS-PAGE. Separated proteins were transferred onto a polyvinylidene difluoride (PVDF) membrane using a semidry blotter. After blocking with 5% dry milk, immunoblot analysis of apoE was done using apoE-specific mAb WuE4 and an enhanced chemiluminescence kit (Pierce).
Heparin-immobilized beads (Pierce) were pre-equilibrated with PBS and then incubated with 500 ml of cell culture medium from Huh-7.5 cells in the absence or presence of HSPG peptides. After 2 hrs incubation at room temperature, apoE-bound beads were spin down, while the supernatant was collected and used for detection of unbound apoE protein. The apoE-bound beads in pellet were washed with 1 ml of PBS for three times. Heparin-bound and unbound apoE proteins were detected by Western blotting using the WuE4 monoclonal antibody.
Our previous studies found that the apoE-blocking monoclonal antibody mAb23 could efficiently inhibit the binding of the cell culture-grown HCV of genotype 2a (HCVcc) to the surface of Huh-7.5 cells, suggesting that apoE mediates HCV attachment to cell surface receptors. To further corroborate the physiological importance of apoE in the mediation of HCV attachment, we carried out HCV binding studies using a clinical HCV of genotype 1b obtained from hepatitis C patients together with human embryonic stem cell-differentiated hepatocyte-like cells (DHHs). DHH was previously shown to resemble primary human hepatocytes in many aspects, including its permissiveness to infection of clinical HCV isolates. Similar to its neutralizing activity against HCVcc attachment, mAb23 potently blocked the attachment of HCV1b to the surface of DHHs in a dose-dependent manner (Fig. 1). In contrast to normal mouse IgG1, 10 mg/ml of mAb23 resulted in over 70% reduction of HCV1b vRNA (Fig. 1). These results demonstrate that apoE is not only important for HCVcc attachment to Huh-7.5 cells but more importantly also for the attachment of HCV1b to the surface of DHHs. It is most likely that apoE mediates HCV attachment to human hepatocytes in vivo.
Several previous studies suggested that HSPGs play an important role in HCV absorption and uptake through interactions with the HCV E2 protein. Removal of the cell surface heparan sulfate (HS) by pretreatment of cells with heparinases resulted in an inhibition of HCV infection. Additionally, our recent studies demonstrated that apoE anchored on the HCV envelope actually mediates the attachment of HCVcc to Huh-7.5 cells by binding to the cell surface heparan sulfate (HS). To validate the role and underlying mechanism of HSPGs in HCV infection, we determined the effects of purified HSPGs, heparin, and removal of HS by heparinase treatment on HCV1b attachment to DHHs. Results derived from these experiments show that purified HSPGs did inhibit the attachment of HCV1b to DHHs in a dose-dependent manner, lowering the HCV1b vRNA by 60% at 40 mg/ml (Fig. 2A). Similarly, the HCV1b cell attachment was suppressed by increasing concentrations of heparin, which resulted in >70% decrease of HCV1b vRNA at 10 U/ml (Fig. 2B). Consistent with findings derived from studies with HCVcc, removal of HS from the surface of DHHs by pretreatment with varying concentrations of heparinase I also proportionally blocked HCV1b attachment (Fig. 3). Taken together, these results demonstrate that HSPGs are important for HCV attachment to the cell surface and also suggest that HSPGs act as receptors for HCV attachment to hepatocytes in vivo.
To further confirm the importance of apoE and HSPGs in HCV1b attachment to DHHs, we sought to determine the effects of a synthetic apoE-derived peptide and an HSPG-binding peptide on HCV1b attachment. It was previously found that a synthetic peptide of 21 amino acids derived from the apoE receptor-binding domain (residues 130–150) specifically inhibited HCVcc attachment to Huh-7.5 cells. This finding was independently confirmed by using longer peptides derived from the receptor- and lipid-binding domains of apoE. Therefore, we first determined the effect of the apoE-derived peptide (E3/21C) on HCV1b attachment to DHHs. A mutant peptide (E3/21Cm) containing lysine to glutamic acid mutations at apoE residues 143 and 146 was used as a control (Fig. 4A). Similar to HCVcc, HCV1b attachment to DHHs was proportionally inhibited by increasing concentrations of E3/21C peptide, resulting in about 80% reduction of HCV1b vRNA at 60 mM concentration. However, the mutant E3/21Cm peptide had no effect on HCV1b attachment to DHHs (Fig. 4B). Next, we examined an HSPG-binding peptide 6a-P corresponding to the exon 6a-encoded domain of vascular endothelial cell growth factor (VEGF) using HCV1b attachment assay (Fig. 4A). It was previously shown that 6a-P peptide bound strongly to heparin and prevented VEGF binding to HSPGs on the surface of different cell types. Compared to E3/21Cm peptide (Fig. 4B), 6a-P peptide similarly suppressed the binding of HCV1b to DHHs, reducing 75% of HCV1b vRNA at 60 mM concentration (Fig. 4C). These results suggest that apoE on the viral envelope and HSPGs on the cell surface are important for HCV1b attachment, consistent with our earlier findings that apoE mediates HCVcc attachment via binding to HSPGs on the surface of Huh-7.5 cells.
HSPG is one of the apoE receptors. We have previously demonstrated that the receptor-binding domain of apoE is responsible for HSPG-binding and HCV infection. Mutations within the apoE receptor-binding region, which impaired HCV infectivity, resulted in inability of apoE to bind heparin in vitro. To provide additional direct evidence on the apoE and HSPG interaction, we used a heparin pull-down assay to determine the effects of apoE peptide and the HSPG-binding peptide 6a-P on the apoE-heparin interaction. The apoE-containing supernatant of Huh-7.5 cells was incubated with heparin-immobilized beads in the presence or absence of peptides. In the absence of any peptide, apoE was efficiently precipitated by heparin-immobilized beads. However, hEP and 6a-P peptides potently blocked the binding of apoE to heparin beads (Fig. 5A). The blockade of the apoE-heparin interaction was proportional to increasing concentrations of peptides (Fig. 5B). These results suggest that the apoE receptor-binding domain mediates specific interactions with HSPG and therefore HCV attachment to the cell surface of hepatocytes in vivo. It is also possible that HCV infection may be prophylactically preventable by inhibitors of the apoE-HSPG interaction.
To validate apoE and HSPG interaction in the mediation of HCV attachment, we determined the effects of apoE mAb23 (Fig. 1) and the HSPG-binding peptide 6a-P (Fig. 4 and Fig. 5) on the binding of apoE to Huh-7 cells. The endogenous apoE expression in Huh-7 cells was silenced by transfection with an apoE-specific siRNA as previously described. The apoE-containing lipoproteins secreted to the supernatant of Huh-7 cells were used as ligands. The apoE-containing supernatant of Huh-7 cells (Huh7Sup) was incubated with the siRNA-transfected Huh-7 cells in the presence of apoE-specific monoclonal antibody (mAb23), normal mouse IgG (mIgG), the HSPG-binding peptide 6a-P, or the control peptide 6a-Pm, respectively (Fig. 6). Consistent with the blockade of apoE and heparin interaction by the peptide 6a-P (Fig. 5), both apoE mAb23 and peptide 6a-P efficiently suppressed the binding of apoE to Huh-7 cells. In contrast, the idiotype-matched normal mouse IgG (mIgG) and a mutant peptide 6a-Pm did not affect the binding of apoE to Huh-7 cells (Fig. 6). These findings further support the conclusion that apoE mediates HCV attachment by binding to HSPGs on the surface of hepatocytes.
HSPGs are localized on the cell surface and act as ubiquitous protein ligands, including serving as attachment receptors for many different viruses. In the case of HCV, HSPGs were previously found to be important for HCV infection although the molecular mechanism underlying HSPGs in HCV infection was not defined. Our recent studies with a cell culture-grown HCVcc of genotype 2a (JFH1) suggested that HSPGs function as HCV attachment receptors on the surface of hepatocytes and that apoE on the virus envelope serves as a protein ligand mediating the initial binding of HCV to the cell surface HSPGs. The physiological importance of apoE, HSPGs, and their interactions in vivo are further supported by several lines of evidence obtained from the present study with HCV of genotype 1b derived from hepatitis C patients in conjunction with DHHs which resemble primary human hepatocytes. First of all, the attachment of a clinical HCV isolate of genotype 1b to DHHs was efficiently blocked by an apoE-specific monoclonal antibody (Fig. 1), similar to our previous findings obtained from the studies with HCVcc. Also, the HCV1b attachment to DHHs was potently inhibited by heparin and purified HSPGs (Fig. 2) as well as by heparinase treatment which removes heparan sulfate (HS) from the cell surface (Fig. 3). Additionally, HCV attachment could be blocked by 2-, 3-, and 6-sulfated glucosamines (data not shown). More significantly, the peptide derived from the apoE receptor-binding domain and the HSPG-binding peptide from VEGF prevented HCV1b from binding to DHHs (Fig. 4), suggesting that both apoE on the HCV envelope and the HSPGs on the cell surface are important for HCV attachment. The molecular interaction between apoE and HSPGs was previously suggested by findings obtained from heparin-pull down assay and mutagenesis analysis of the apoE receptor-binding domain. In this study, it was further demonstrated that both apoE-derived peptide and the HSPG-binding peptide potently blocked apoE and heparin interaction in vitro (Fig. 5). The suppression of apoE binding to Huh-7 cells by mAb23 and peptide 6a-P further demonstrates that apoE interacts with HSPGs on the surface of hepatocytes (Fig. 6). Collectively, these findings demonstrate that HSPGs on the hepatocyte surface serve as major receptors for apoE binding, resulting in HCV attachment to the surface of human hepatocytes.
HSPGs were found to serve as receptors for initial attachment of many different viruses, including but not limited to herpes simplex virus type 1 (HSV1), cytomegalovirus, adeno-associated virus, human papillomavirus, vaccinia virus, respiratory syncytial virus, dengue virus, filovirus, and hepatitis B, C, and E viruses. The question arose how HSPGs act as attachment receptors for so many diverse viruses. We believe that the tropism of initial attachment of different viruses to their target cell types is likely determined by molecular interactions between viral envelope protein and the cell surface HSPG receptor with distinct structure. HSPG is composed of a core protein and heparin sulfate glycosaminoglycan (GAGs) chains, resulting in a large mix of structurally heterogeneous HSPGs. The heterogeneity of HSPGs is the result of different core proteins, the length of polysaccharides, and numbers and positions of sulfation. Based on their core proteins, HSPGs can be divided into three subfamilies: the membrane-spanning proteoglycans like syndecans (1, 2, 3, and 4), the glycophosphatidylinositol (GPI)-linked proteoglycans such as glypicans (1, 2, 3, 4, 5, and 6), and the extracellular matrix proteoglycans including agrin and perlecan. The numbers of GAGs attached to core proteins also vary depending on HSPG core protein. For instance, syndecan-1 contains three GAG attachment sites within its ectodomain although GAG may be attached to these three sites individually or in different combinations among different cell types. Additionally, sulfation at different positions (e.g., 2-, 3-, and 6-O-sulfation) adds another complexity to HSPGs. Therefore, the structures of HSPGs synthesized by different cell types would be highly heterogeneous, resulting in various HSPG receptors for different viruses. The proof-of-concept of HSPG structure important for virus attachment came from an elegant study demonstrating that 3-O-sulfation of specific glucosamine residues in HS determines specific interaction with HSV1 gD protein. Additionally, a number of studies found that HSPG core protein syndecans 1–4 preferentially determine the susceptibility of cells to initial attachment of different viruses. Future studies are warranted to determine the nature and structure of the specific HSPG utilized by HCV for its initial attachment to hepatocytes during virus infection. It is also possible that the initial HCV attachment mediated by apoE binding to HSPG is stabilized by the subsequent interactions between viral envelopment proteins (E1 and E2) and their receptors (e.g., CD81, claudin, occludin, SR-BI, and others). These later interactions may also contribute to the tropism of HCV infection.
The interaction between protein ligands on the viral envelope and their HSPG receptors is largely electrostatic. Thus, it is possible that initial virus attachment mediated by HSPG receptors may not be highly specific. The specificity of virus attachment to target cells may also be determined by interactions of viral envelope protein(s) with other cell surface receptor(s). In the case of HCV, the binding of apoE on the HCV envelope to the cell surface HSPG receptor initiates HCV attachment. The subsequent interactions between E2 and other cell surface receptors and/or co-receptors, including CD81, claudin, occludin, and SR-BI, probably stabilize HCV attachment and therefore result in specific infection of hepatocytes. This argument is in line with a recent finding that nonhepatic 293 cells could be infected with HCV only when they expressed the aforementioned four key receptors and/or co-receptors. However, the importance and underlying molecular mechanism of the cell surface receptors in HCV attachment and entry to cells are not well understood. HSPGs as virus attachment receptors could serve as potential antiviral targets. As discussed above, HSV1 attachment to cells requires 3-O-sulfated glucosamine residues in HSPG. Based on this knowledge, Hu et al. synthesized two 3-O-sulfonated heparan sulfate octasaccharides as antiviral compounds. Interestingly, these sulfated sugars potently blocked HSV1 infection in vitro and in mice, demonstrating the feasibility of HSPGs as antiviral targets. The structural determination of the specific HSPG receptors used by different viruses will facilitate rational design of potent antiviral inhibitors which can be developed as specific drugs to control various virus infections.
We are grateful to Charlie Rice (Rockefeller University) for providing Huh7.5 cell line, Stephen Dalton (University of Georgia) for supplements used for differentiation of DHHs, and Tianyi Wang (University of Pittsburgh) for peptides hEP and hEPm. Conceived and designed the experiments: GL. Performed the experiments: JJ XW. Analyzed the data: GL JJ XW HT. Contributed reagents/materials/analysis tools: HT. Wrote the paper: GL JJ.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
ATP-dependent chromatin remodeling enzymes are essential regulators of DNA-dependent processes in eukaryotic cells. Despite their high abundance, these enzymes act selectively at specific genomic loci, raising the question of how they achieve such precise targeting. While direct recruitment by sequence-specific transcription factors (TFs) is a known mechanism, its genome-wide scope remains unclear. This study reveals that a major targeting pathway for the Isw2 chromatin remodeling enzyme involves TF-dependent DNA looping.Tozorakimab Inhibitor Using genome-wide ChIP-chip analysis, we found that Isw2 is recruited to numerous loci without canonical TF binding sites. Surprisingly, this recruitment is dependent on both the general transcription factor TFIIB and the repressor Ume6. Chromosome conformation capture (3C) assays confirmed that physical DNA loops form between distal regions harboring Ume6 binding sites and distant ectopic targets lacking such sites. These loops require TFIIB function, as evidenced by the loss of looping in the sua7-1 mutant. Furthermore, Ume6 is essential for loop formation, indicating that a transcriptional repressor actively participates in chromatin architecture.CSK Antibody Technical Information The absence of Isw2 or the catalytically inactive Isw2-K215R mutant does not affect looping, suggesting that chromatin remodeling occurs downstream of loop establishment. Functionally, Ume6-dependent looping correlates with chromatin remodeling and transcriptional repression at ectopic sites, demonstrating a novel role for DNA looping in gene regulation.PMID:34748805 Our findings define a previously unrecognized mechanism for targeting chromatin remodelers—via three-dimensional chromatin architecture—and reveal that DNA looping can mediate long-range regulatory functions beyond gene looping. This work underscores the importance of spatial genome organization in directing chromatin dynamics and gene expression across the yeast genome.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
Acute myeloid leukemia (AML) remains a challenging hematologic malignancy with limited therapeutic options. Current treatment strategies rely heavily on intensive chemotherapy, yet relapse rates remain high and long-term survival is poor. This study investigates the synergistic anti-leukemic effects of dasatinib, a multi-targeted tyrosine kinase inhibitor, combined with valproic acid (VPA), a class I histone deacetylase inhibitor. The research focuses on elucidating the molecular mechanisms underlying their combined action in AML cell lines, including HL60, Kasumi-1, and NB4, as well as primary cells from AML patients.
The combination of dasatinib and VPA significantly inhibits proliferation and induces apoptosis in AML cells in a dose-dependent manner. While either drug alone had minimal effect at low concentrations, their combination led to a marked reduction in cell viability—down to 46% in HL60 cells—indicating strong synergy. This effect was specific to AML cells, as non-leukemic cell lines such as HepG2, Hep3B, and MCF-7 showed no significant response or even increased proliferation under the same conditions.
Mechanistically, the combination treatment induced G1 phase cell cycle arrest. Flow cytometry analysis revealed that the percentage of cells in G0/G1 phase increased dramatically, reaching up to 90% after 72 hours of treatment. This arrest was associated with upregulation of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1, which inhibit CDK activity. Western blotting confirmed a 59-fold and 55-fold increase in p21Cip1 and p27Kip1 expression, respectively, following combination therapy. Concurrently, expression of key G1 regulatory proteins—including CDK2, CDK4, CDK6, cyclin D1, and cyclin E—was markedly reduced, confirming disruption of the G1/S transition machinery.δ-Dodecalactone Anti-infection
Apoptosis induction was further validated by multiple assays.Isosulfan blue Description Annexin V/PI staining demonstrated a substantial increase in apoptotic cells, particularly in the combination group. Nuclear fragmentation, visualized via DRAQ5 staining, confirmed morphological hallmarks of apoptosis. Intracellular detection of cleaved PARP and caspase-3 revealed robust activation of the apoptotic cascade. Time-course experiments showed progressive cleavage of procaspase-3, -7, and -9, indicating activation of both intrinsic and extrinsic pathways.
Importantly, caspase inhibition experiments proved that apoptosis was dependent on caspase activation. Pretreatment with caspase-3 or caspase-9 inhibitors significantly attenuated cell death, confirming the central role of these proteases. Moreover, MEK/ERK and p38 MAPK inhibitors effectively suppressed apoptosis, suggesting that these kinases act as upstream regulators of the apoptotic pathway in this context.PMID:34969349
In primary AML samples from two patients, the combination also induced significant apoptosis, with blast cells showing increased sensitivity compared to cell lines. These findings confirm the clinical relevance of the observed synergy.
Collectively, these results demonstrate that dasatinib potentiates VPA-induced apoptosis in AML cells by promoting G1 cell cycle arrest and activating caspase-dependent apoptotic pathways. The regulation of differentiation capacity through modulation of MEK/ERK and p38 MAPK signaling further contributes to the anti-leukemic effect. This study provides strong preclinical evidence supporting the potential of combining dasatinib and VPA as a novel therapeutic strategy for AML.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
The human malaria parasite *Plasmodium falciparum* harbors a relict, nonphotosynthetic plastid of algal origin known as the apicoplast. Despite advances in understanding its metabolic functions, knowledge about the lipid composition and biogenesis of its four surrounding membranes remains limited. This study presents an efficient method for isolating highly purified apicoplasts from blood-stage parasites using transgenic lines expressing an epitope-tagged triosephosphate transporter, followed by immunopurification on magnetic beads. Comprehensive lipidomic analysis via gas and liquid chromatography coupled with mass spectrometry revealed significant differences between apicoplast lipids and those of whole parasites. Notably, apicoplasts were enriched in phosphatidylinositol (PI), suggesting a potential role for phosphoinositides in vesicular trafficking to the organelle.CD200 Antibody In stock The PI and other phospholipids in the apicoplast were also enriched in saturated fatty acids, likely due to limited acyl exchange with other membranes or specific physical requirements for membrane stability.FITC-inulin custom synthesis Unexpectedly, atypical lipids such as sphingomyelins, ceramides, and cholesterol were detected—lipids not typically associated with plastids.PMID:34710745 Cholesterol’s presence was confirmed through filipin staining of isolated apicoplasts, indicating integration into one or more membranes. In contrast, galactoglycerolipids—dominant in plant and algal plastids—were absent, implying their loss during the evolution of parasitism. These findings suggest that apicoplasts possess a unique lipid profile derived from both host scavenging and parasite-specific remodeling. Stable isotope labeling demonstrated that some apicoplast lipids are synthesized de novo, indicating residual biosynthetic capacity. Together, these results highlight the apicoplast’s complex lipid metabolism, shaped by evolutionary adaptation, and underscore its dependence on both salvage and endogenous synthesis pathways for membrane biogenesis.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
Breast cancer survivors often face persistent physical and psychological challenges long after treatment ends. Chronic pain and depressive symptoms are among the most common, significantly impacting quality of life and overall well-being. Research has consistently shown that lower levels of social support are associated with worse mental and physical health outcomes across various medical populations, including cancer survivors. This study aimed to investigate how social support at diagnosis predicts changes in pain, depressive symptoms, and inflammation over time in breast cancer survivors.
A longitudinal design was employed with 164 women diagnosed with early-stage breast cancer (stages 0–IIIA). Participants completed assessments before any treatment and again six months after completing surgery, radiation, or chemotherapy—the last treatment modality received. At each visit, they provided self-reported data on social support, pain severity, and depressive symptoms using validated instruments such as the ENRICHD Social Support Instrument, the CES-D scale, and the RAND-36 pain subscale. Blood samples were collected to measure serum interleukin-6 (IL-6), a key marker of systemic inflammation.
Results revealed that women with lower social support prior to treatment reported significantly higher levels of both pain and depressive symptoms at the six-month follow-up, even after controlling for baseline levels of these outcomes. These findings suggest that social support acts as a protective factor during the transition from diagnosis to recovery. Furthermore, lower pretreatment social support was linked to elevated IL-6 levels over time.Tetracosanoyl-L-carnitine Autophagy Although higher IL-6 did not predict increased pain, it marginally predicted greater increases in depressive symptoms, indicating a potential biological pathway through which low social support may influence emotional health.1,2-Dimethylimidazole supplier
Importantly, the relationships remained significant after adjusting for multiple covariates including age, BMI, education, comorbidities, cancer stage, and treatment type.PMID:35102801 Reverse causality analyses showed no evidence that pain, depression, or IL-6 at baseline predicted changes in social support or inflammation later on, supporting a unidirectional model where social support influences immune and psychological outcomes rather than vice versa.
These findings highlight the critical role of social support in shaping long-term survivorship experiences. Early identification of low social support during the diagnostic phase could enable timely interventions—such as peer support programs, family counseling, or community integration initiatives—that may reduce risk for chronic pain, depression, and inflammation. Given the strong links between inflammation and mood disorders, targeting psychosocial factors early may help break the cycle of distress and poor health. Future research should explore whether sustained social support interventions can lead to measurable improvements in biomarkers and clinical outcomes. Overall, this study underscores the importance of integrating psychosocial care into standard oncology practice to enhance both survival and quality of life.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
**Background**
The long chain free fatty acid (LCFA) receptor 4, also known as FFA4 or GPR120, is a G protein-coupled receptor primarily expressed in immune cells and adipocytes. Activation of FFA4 plays a critical role in regulating glucose homeostasis and exerting anti-inflammatory effects, making it a significant target for the treatment of metabolic disorders and inflammatory diseases. Understanding the pharmacology of this receptor is essential for developing therapeutic agents that can mimic the beneficial effects of endogenous ligands like $\alpha$-linolenic acid. In this context, we will introduce a potent and selective agonist of FFA4 – TUG-891.
**Definition**
TUG-891 is a potent and selective agonist for the long chain free fatty acid receptor 4 (FFA4/GPR120) with a molecular weight of 364.41 and the chemical formula $\text{C}_{23}\text{H}_{21}\text{FO}_3$.
**In Vitro Studies**
According to the TUG-891 description, this compound exhibits signaling properties at human FFA4 that are similar to those of the endogenous ligand $\alpha$-linolenic acid. Specifically, TUG-891 in vitro data demonstrates that the compound stimulates $\text{Ca}^{2+}$ mobilization and promotes the recruitment of both $\beta$-arrestin-1 and $\beta$-arrestin-2. Furthermore, activation of the receptor by TUG-891 leads to the phosphorylation of extracellular signal-regulated kinase (ERK). Research into TUG-891 biological activity also indicates that the activation of human FFA4 results in the rapid phosphorylation and subsequent internalization of the receptor. These findings highlight the compound’s ability to effectively trigger multiple downstream signaling pathways associated with FFA4. In conclusion, TUG-891 is a potent and selective agonist of FFA4/GPR120 that serves as a valuable tool for studying the pharmacology of LCFA receptors.
Keywords
TUG-891, 1374516-07-0, TUG891, TUG 891, Free Fatty Acid Receptor, FFAR, Inhibitor, inhibitor, inhibit
References