LXR Agonist T0901317's Hepatic Impact Overrules Its Atheroprotective Action in Macrophages, Driving Early Atherogenesis in Chow-Diet-Fed Male Apolipoprotein E Knockout Mice.

Preclinical studies regarding the potential of liver X receptor (LXR) agonists to inhibit macrophage foam cell formation and the development of atherosclerotic lesions are generally executed in mice fed with Western-type diets enriched in cholesterol and fat. Here, we investigated whether LXR agonism remains anti-atherogenic under dietary conditions with a low basal hepatic lipogenesis rate. Hereto, atherosclerosis-susceptible male apolipoprotein E knockout mice were fed a low-fat diet with or without 10 mg/kg/day LXR agonist T0901317 supplementation for 8 weeks. Importantly, T0901317 significantly stimulated atherosclerosis susceptibility, despite an associated increase in the macrophage gene expression levels of cholesterol efflux transporters ABCA1 and ABCG1. The pro-atherogenic effect of T0901317 coincided with exacerbated hypercholesterolemia, hypertriglyceridemia, and a significant rise in hepatic triglyceride stores and macrophage numbers. Furthermore, T0901317-treated mice exhibited elevated plasma MCP-1 levels and monocytosis. In conclusion, these findings highlight that the pro-atherogenic hepatic effects of LXR agonism are dominant over the anti-atherogenic effects in macrophages in determining the overall atherosclerosis outcome under low-fat diet feeding conditions. A low-fat diet experimental setting, as compared to the commonly used high-fat-diet-based preclinical setup, thus appears more sensitive in uncovering the potential relevance of the off-target liver effects of novel anti-atherogenic therapeutic approaches that target macrophage LXR.

TBAF-Mediated [3+1] Cycloaddition of Difluorocarbene to Access gem-Difluorinated 1,2-Diazetidine Analogues as Potent Anticancer Agents.

The facile synthesis of gem-difluorinated 1,2-diazetidines was achieved by metal-free [3+1] annulation between C,N-cyclic azomethine imines with difluorocarbene. A library of 30 compounds benefiting from the TBAF-mediated cyclization process could be directly assembled in moderate to good yield under mild conditions. A plausible mechanism involving the difluorocarbene pathway was proposed based on carbene trapping and control experiments. Many compounds exhibited dramatic antiproliferative activity in 4T1, A549, and HeLa tumor cell lines.

Activity of the new OSBP inhibitor Y18501 against Pseudoperonospora cubensis and its application for the control of cucumber downy mildew.

Y18501 is a new oxysterol-binding protein inhibitor (OSBPI) with a similar structure to oxathiapiprolin. Y18501 showed strong inhibitory activities against Phytophthora spp. and Pseudoperonospora cubensis, with EC50 ranging from 0.0005 to 0.0046 µg/mL. It also had good control efficacy on cucumber downy mildew (CDM) in the green house and in the field, and could effectively inhibit different development stages of P. cubensis, especially for sporangiophore production, sporangial production, mycelium extension, and elongation of germ tube. In addition, Y18501 showed excellent protective and curative activities against P. cubensis. It also had acropetal systemic mobility in the cucumber leaves, and could be taken up and translocated to the upper leaves more effectively from the lower leaves than from the roots. Y18501 had poorer permeability in cucumber leaves compared to oxathiapiprolin. The simultaneous application of Y18501 and chlorothalonil could significantly promote the inhibition of P. cubensis.

Development of Light-Activated LXR Agonists.

Activation of the oxysterol-sensing transcription factor liver X receptor (LXR) has been studied as a therapeutic strategy in metabolic diseases and cancer but is compromised by the side effects of LXR agonists. Local LXR activation in cancer treatment may offer an opportunity to overcome this issue suggesting potential uses of photopharmacology. We report the computer-aided development of photoswitchable LXR agonists based on the T0901317 scaffold, which is a known LXR agonist. Azologization and structure-guided structure-activity relationship evaluation enabled the design of an LXR agonist, which activated LXR with low micromolar potency in its light-induced (Z)-state and was inactive as (E)-isomer. This tool sensitized human lung cancer cells to chemotherapeutic treatment in a light-dependent manner supporting potential of locally activated LXR agonists as adjuvant cancer treatment.

T0901317, a liver X receptor agonist, ameliorates perinatal white matter injury induced by ischemia and hypoxia in neonatal rats.

Perinatal white matter injury (PWMI) can lead to permanent neurological damage in preterm infants and bring a huge economic burden to their families and society. Liver X receptors (LXRs) are transcription factors that have been confirmed to mediate the myelination process under physiological conditions and are involved in regulating neurogenesis in adult animal models of acute and chronic cerebral ischemia. However, the role of LXRs in PWMI induced by both ischemic and hypoxic stimulation in the immature brain has not been reported. Herein, we investigated the role of LXRs in a neonatal rat model of white matter loss after hypoxia-ischemia (HI) injury through intraperitoneal injection of the LXR agonist T0901317 (T09) 1 day before and 15 min postinjury. The in vivo data showed that T09 treatment significantly facilitated myelination and ameliorated neurological behavior after PWMI. Moreover, T09 enhanced the proliferation of oligodendrocyte lineage cells and reduced microgliosis and astrogliosis in the microenvironment for oligodendrocytes (OLs), maintaining a healthy microenvironment for myelinating OLs. In vitro data suggested that the expression of the myelin-related genes Plp and Cnpase was increased in OLN-93 cells after T09 intervention compared with OLN-93 cells injured by oxygen and glucose deprivation (OGD). In primary mixed astrocytes/microglia cells, T09 also reduced the expression of Il6, Cox2, Tnfa and Il10 that was induced by OGD. Mechanistically, the mRNA expression level and the protein level of ATP binding cassette subfamily A member 1 (Abca1) decreased after HI injury, and the protective effect of T09 might be related to the activation of the LXRß-ABCA1 signaling pathway. Our study revealed the protective role of LXRs in myelination and white matter homeostasis, providing a potential therapeutic option for PWMI.

Effect of liver X receptor agonist TO901317 on cognitive function in APP/PS1 double transgenic mice with Alzheimer's disease and the underlying mechanism. / 肝脏X受体激动剂TO901317对APP/PS1åŒè½¬åŸºå› é˜¿å°”èŒ¨æµ·é»˜ç— å°é¼ è®¤çŸ¥åŠŸèƒ½çš„å½±å“åŠå ¶æœºåˆ¶.

OBJECTIVES: The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily, and LXR-ß is an important receptor for cholesterol content in brain cells. LXR-ß/retinoic X receptor (RXR-α)/ATP binding cassette transporter A1 (ABCA1) cholesterol transmembrane transport system is closely related to the occurrence and development of Alzheimer's disease (AD). LXR agonist TO901317 can affect the accumulation of ß- amyloid protein in the brain tissue of APP/PS1 double transgenic AD mice. However, the molecular mechanism is not clarified in detail. This study aims to evaluate the effects of LXR agonist TO901317 on the cognitive function of AD mice fed with high cholesterol diet, and to explore its possible mechanism from the perspective of cholesterol metabolism. METHODS: Twenty four male 6-month-old APP/PS1 double transgenic AD mice were randomly divided into 4 groups, 6 mice in each group: a control group (fed with normal diet), a cholesterol rich diet (CRD) group, a TO901317 group (fed with CRD combined with TO901317), and a GSK2033 group (fed with CRD combined with TO901317 and LXR antagonist GSK2033). The mice were fed with pellet feed made of high cholesterol feed, mixed with lard, egg yolk powder, and cod liver oil twice a day. TO901317 and GSK2033 were dissolved and diluted to a final concentration at 0.03%. The drugs were given to the mice daily through gastric tube according to their body weight. Meanwhile, the mice in the drug group were fed with high cholesterol diet . After feeding for 3 months, Morris water maze was used to observe the changes of spatial exploration and memory ability of AD mice in each group. The contents of TC, LDL, and HDL in serum of mice in each group were detected by cholesterol enzyme colorimetry, and the differences among the groups were compared. The expression of Aß42 in the brain of AD mice was detected by ELISA. Western blotting was used to detect the protein levels of LXR-ß, RXR-α, ABCA1, and Caveolin-1 in the brain of each group. RESULTS: Morris water maze results showed that the times, distance and the duration of mice crossing the platform in the CRD group were significantly decreased compared with the control group (all P<0.05), while these three figures in TO901317 group were significantly increased compared with the CRD group (all P<0.05). Compared with the TO901317 group, there was a decrease of these figures in the GSK2033 group (all P<0.05). The serum TC and LDL levels in the CRD group were significantly higher than those in the control group, while HDL levels were significantly lower (all P<0.001). The figures of the TC and LDL contents level in the TO901317 group were lower than those in the CRD group, while HDL levels were higher (all P<0.001). Compared with TO901317 group, the contents of the TC and LDL in GSK2033 group were significantly increased, while HDL content was significantly decreased (all P<0.001). ELISA results showed that the production of Aß42 peptides in the brain of CRD group was the highest while the content in the TO901317 group was significantly decreased (P<0.001), which was the lowest among the groups. The figure in the control group was close to the GSK2033 group. Western blotting results showed that the protein levels of LXR-ß, RXR-α, and ABCA1 in the CRD group were significantly decreased compared with the control group, but the protein level of Caveolin-1 was increased (all P<0.01). After TO901317 treatment, the protein levels of LXR-ß, RXR-α and ABCA1 were significantly increased, while the protein level of Caveolin-1 was decreased partially (all P<0.001). In the GSK2033 group, the effect of TO901317 on AD mice was partially reversed by GSK2033. Compared to TO901317 group, the protein levels of LXR-ß, RXR-α, and ABCA1 showed a decrease trend, while the protein level of Caveolin-1 showed an increase state (all P<0.05). CONCLUSIONS: High cholesterol diet leads to severer spatial exploration, learning and memory impairment in transgenic AD mice, while the LXR agonist TO901317 attenuates this effect. The mechanism may be that TO901317 promotes cholesterol efflux by activating LXR-ß/RXR-α/ABCA1 transmembrane transport system, reduces the expression of Caveolin-1, improves the composition of lipid raft, and ultimately reduces the production of Aß42 in the brain.

Activity and Point Mutation G699V in PcoORP1 Confer Resistance to Oxathiapiprolin in Phytophthora colocasiae Field Isolates.

The oxysterol-binding protein inhibitor oxathiapiprolin is a new fungicide for controlling oomycetes diseases. Besides, laboratory mutagenesis oxathiapiprolin-resistance among phytopathogenic oomycetes in the field remains unknown. Here, the sensitivity of 97 P. colocasiae isolates to oxathiapiprolin was examined that were collected between 2011 and 2016. We obtained a baseline sensitivity with a mean EC50 value of 5.2639 × 10-4 µg mL-1. We showed that 6/32 isolates collected in Fujian Province from 2019 to 2020 were resistant to oxathiapiprolin without a significant fitness penalty on sporulation, vegetative growth, and virulence of the field isolates. The oxathiapiprolin resistance field isolates contained the point mutation glycine to valine at 699 in PcoORP1. The point mutation G699V was verified to confer resistance of P. colocasiae to oxathiapiprolin using the CRISPR/Cas9 system. The mutation G699V decreased the binding affinity between oxathiapiprolin and PcoORP1. These results will improve our understanding of the mechanism of P. colocasiae resistance to oxathiapiprolin under field conditions.

Treatment with the soluble guanylate cyclase activator BAY 60-2770 normalizes bladder function in an in vivo rat model of chronic prostatitis.

BACKGROUND AND PURPOSE: Chronic pelvic pain syndrome (CPPS) is a common and bothersome condition for which no pharmacological treatment options with acceptable efficacy exist. The aim of this study was to investigate the effects of the soluble guanylate cyclase (sGC) activator BAY 60-2770 and the COX-2 inhibitor celecoxib on bladder function in a rat model of CPPS. EXPERIMENTAL APPROACH: Forty-eight male Sprague-Dawley rats were intraprostatically injected with either saline, serving as control, or zymosan, to induce prostatitis. On days 8-20, the rats were treated with either dimethylsulphoxide (DMSO; vehicle), celecoxib, BAY 60-2770 or a combination of celecoxib and BAY 60-2770. Thereafter, micturition parameters were assessed in a metabolic cage and urine samples were collected. The following day, cystometry was performed. Subsequently, the urinary bladder and prostate were removed and examined histopathologically. KEY RESULTS: Induction of prostatitis led to a significant increase of micturition frequency and corresponding decrease of volume per micturition. These alterations were ameliorated by celecoxib, and completely normalized by BAY 60-2770. Induction of prostatitis led to a significantly increased number of non-voiding contractions, decreased bladder compliance and increased voiding time. These parameters were normalized by treatment with BAY 60-2770, either alone or in combination with celecoxib. The immunohistochemical analysis showed signs of prostate inflammation, but not bladder inflammation. CONCLUSION AND IMPLICATIONS: Induction of prostatitis led to significant impairment in bladder function. These alterations could be prevented by BAY 60-2770, alone or in combination with celecoxib. This is the first study to show that sGC activators could be a promising option for the treatment of CPPS.

LXRß Activation Inhibits the Proliferation of Small-cell Lung Cancer Cells by Depleting Cellular Cholesterol.

BACKGROUND/AIM: Liver X receptors (LXRs) are nuclear receptors with various functions, including the regulation of cholesterol metabolism, glucose homeostasis, and inflammation. We previously reported that LXR activation inhibits the growth of oral cancer cells by inducing cellular cholesterol efflux and that LXRß is expressed mainly in small-cell lung cancer (SCLC) tissues. SCLC is one of the most aggressive cancers, and identifying an effective therapeutic target molecule is desirable. Therefore, we investigated whether LXRß could be an effective target molecule for SCLC treatment through in vitro experiments. MATERIALS AND METHODS: We evaluated the influence of treatment with the LXR agonist T0901317 on cell proliferation and apoptosis in SCLC cell lines using cell viability, BrdU-ELISA, FACS, and western blot analyses. Moreover, the mechanism by which T0901317 inhibits SCLC cell proliferation was elucidated using qRT-PCR, western blot, a cholesterol quantification assay, and a genome editing technique. RESULTS: We showed that cultivated SCLC cells expressed LXRß and that an LXR agonist inhibited the proliferation of SCLC cells without toxicity to normal cells. Furthermore, the antitumoral effect of an LXR agonist on SCLC cells was attributed to the induction of ABCA1 by LXRß activation, resulting in an increase in cellular cholesterol efflux via ABCA1. CONCLUSION: The activation of LXRß up-regulates ABCA1 expression, causing cholesterol depletion in cancer cells. This mechanism could be a novel target strategy for SCLC.

Design, synthesis and structure-activity relationship of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxyisoprop-2-yl)phenylsilane derivatives as liver X receptor agonists.

Liver X receptor (LXR) α and LXRß are nuclear receptors playing key roles in lipid metabolism, and LXR ligands are attractive drug candidates for metabolic disorders. Here we report the structural development of 4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenylsilane derivatives as LXR agonists bearing silyl functionalities as the hydrophobic pharmacophore, based on the structure of the known sulfonamide LXR agonist T0901317. Most of the synthesized compounds exhibit agonistic activity toward LXRs, but the LXR subtype-selectivity differs depending upon the substituents on the silicon atom. Among them, tri(n-propyl) derivative 12 shows potent LXR-agonistic activity with moderate α subtype-selectivity, while dimethylphenylsilyl derivative 19 shows modest ß-selectivity. These results indicate that silanes can serve as an alternative to the sulfonamide moiety of LXR agonists, and are promising structural options for the development of novel subtype-selective LXR agonists.

Effects of elagolix on the pharmacokinetics of omeprazole and its metabolites in healthy premenopausal women.

This study evaluated the effect of repeated doses of elagolix on the pharmacokinetics (PK) of omeprazole and its metabolites in healthy premenopausal female subjects. Adult premenopausal female subjects (N = 20) received a single oral dose of omeprazole (40 mg) on day 1 and day 11 and oral doses of elagolix (300 mg) twice-daily on days 3-11. Serial blood samples for assay of omeprazole and its metabolites were collected for 24 h after dosing on days 1 and 11. PK parameters were calculated for omeprazole, 5-hydroxyomeprazole and omeprazole sulfone; and were compared between day 1 and day 11. Pharmacogenetic testing was performed for CYP2C19 variant alleles and the results were used to compare the magnitude of elagolix-omeprazole drug-drug interaction (DDI) between the different genotype subgroups. Administration of elagolix 300 mg twice-daily for 9 days increased omeprazole exposure by 1.8-fold and decreased the metabolite-to-parent ratio for 5-hydroxyomeprazole by ~60%. Conversely, there was an increase in the metabolite-to-parent ratio for omeprazole sulfone by 25%. Elagolix increased omeprazole exposures by 2- to 2.5-fold in CYP2C19 extensive (EM) and intermediate (IM) metabolizer subjects, but decreased omeprazole exposures by 40% in poor metabolizer subjects. Exposures of 5-hydroxyomeprazole decreased by 20%-30% in all genotype subgroups, and omeprazole sulfone exposures increased by ~3-fold in EM and IM subjects. Elagolix is a weak inhibitor of CYP2C19 and exposure of CYP2C19 substrates may be increased upon coadministration with elagolix. Omeprazole may exhibit drug interactions due to multiple mechanisms other than CYP2C19-mediated metabolism; complicating the interpretation of results from omeprazole DDI studies.

Capillary hemodynamics and contracting skeletal muscle oxygen pressures in male rats with heart failure: Impact of soluble guanylyl cyclase activator.

In heart failure with reduced ejection fraction (HFrEF), nitric oxide-soluble guanylyl cyclase (sGC) pathway dysfunction impairs skeletal muscle arteriolar vasodilation and thus capillary hemodynamics, contributing to impaired oxygen uptake (V̇O2) kinetics. Targeting this pathway with sGC activators offers a new treatment approach to HFrEF. We tested the hypotheses that sGC activator administration would increase the O2 delivery (Q̇O2)-to-V̇O2 ratio in the skeletal muscle interstitial space (PO2is) of HFrEF rats during twitch contractions due, in part, to increases in red blood cell (RBC) flux (fRBC), velocity (VRBC), and capillary hematocrit (Hctcap). HFrEF was induced in male Sprague-Dawley rats via myocardial infarction. After 3 weeks, rats were treated with 0.3 mg/kg of the sGC activator BAY 60-2770 (HFrEF + BAY; n = 11) or solvent (HFrEF; n = 9) via gavage b.i.d for 5 days prior to phosphorescence quenching (PO2is, in contracting muscle) and intravital microscopy (resting) measurements in the spinotrapezius muscle. Intravital microscopy revealed higher fRBC (70 ± 9 vs 25 ± 8 RBC/s), VRBC (490 ± 43 vs 226 ± 35 µm/s), Hctcap (16 ± 1 vs 10 ± 1%) and a greater number of capillaries supporting flow (91 ± 3 vs 82 ± 3%) in HFrEF + BAY vs HFrEF (all P < 0.05). Additionally, PO2is was especially higher during 12-34s of contractions in HFrEF + BAY vs HFrEF (P < 0.05). Our findings suggest that sGC activators improved resting Q̇O2 via increased fRBC, VRBC, and Hctcap allowing for better Q̇O2-to-V̇O2 matching during the rest-contraction transient, supporting sGC activators as a potential therapeutic to target skeletal muscle vasomotor dysfunction in HFrEF.

Characterization of an aromatic trifluoromethyl ketone as a new warhead for covalently reversible kinase inhibitor design.

An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for covalently reversible kinase inhibitor design to target the non-catalytic cysteine residue. Potent and selective covalently reversible inhibitors of FGFR4 kinase were successfully designed and synthesized by utilizing this new warhead. The binding mode of a representative inhibitor was fully characterized by using multiple technologies including MALDI-TOF mass spectrometry, dialysis assay and X-ray crystallographic studies etc. This functional group was also successfully applied to discovery of a new JAK3 inhibitor, suggesting its potential application in designing other kinase inhibitors.

Structural Biology-Based Exploration of Subtype-Selective Agonists for Peroxisome Proliferator-Activated Receptors.

Progress in understanding peroxisome proliferator-activated receptor (PPAR) subtypes as nuclear receptors that have pleiotropic effects on biological responses has enabled the exploration of new subtype-selective PPAR ligands. Such ligands are useful chemical biology/pharmacological tools to investigate the functions of PPARs and are also candidate drugs for the treatment of PPAR-mediated diseases, such as metabolic syndrome, inflammation and cancer. This review summarizes our medicinal chemistry research of more than 20 years on the design, synthesis, and pharmacological evaluation of subtype-selective PPAR agonists, which has been based on two working hypotheses, the ligand superfamily concept and the helix 12 (H12) holding induction concept. X-ray crystallographic analyses of our agonists complexed with each PPAR subtype validate our working hypotheses.

T0901317, an Agonist of Liver X Receptors, Attenuates Neuronal Apoptosis in Early Brain Injury after Subarachnoid Hemorrhage in Rats via Liver X Receptors/Interferon Regulatory Factor/P53 Upregulated Modulator of Apoptosis/Dynamin-1-Like Protein Pathway.

METHODS: Subarachnoid hemorrhage (SAH) models of Sprague-Dawley rats were established with perforation method. T0901317 was injected intraperitoneally 1-hour post-SAH. GSK2033, an inhibitor of LXRs, and interferon regulatory factor (IRF-1) CRISPR activation were injected intracerebroventricularly to evaluate potential signaling pathway. The severity of SAH, neurobehavior test in both short- and long-term and apoptosis was measured with Western blot and immunofluorescence staining. RESULTS: Expression of LXR-α and IRF-1 increased and peaked at 24 h post-SAH, while LXR-ß remained unaffected in SAH+vehicle group compared with Sham group. Post-SAH T0901317 treatment attenuated neuronal impairments in both short- and long-term and decreased neuronal apoptosis, the expression of IRF-1, P53 upregulated modulator of apoptosis (PUMA), dynamin-1-like protein (Drp1), Bcl-2-associated X protein (Bax) and cleaved caspase-3, and increasing B-cell lymphoma 2 (Bcl-2) at 24 h from modeling. GSK2033 inhibited LXRs and reversed T0901317's neuroprotective effects. IRF-1 CRISPR activation upregulated the expression of IRF-1 and abolished the treatment effects of T0901317. CONCLUSION: T0901317 attenuated neuronal apoptosis via LXRs/IRF-1/PUMA/Drp1 pathway in SAH rats.

Synthesis and Biological Evaluation of CF3 Se-Substituted α-Amino Acid Derivatives.

Several CF3 Se-substituted α-amino acid derivatives, such as (R)-2-amino-3-((trifluoromethyl)selanyl)propanoates (5 a/6 a), (S)-2-amino-4-((trifluoromethyl)selanyl)butanoates (5 b/6 b), (2R,3R)-2-amino-3-((trifluoromethyl)selanyl)butanoates (5 c/6 c), (R)-2-((S)-2-amino-3-phenylpropanamido)-3-((trifluoromethyl)selanyl)propanoates (11 a/12 a), and (R)-2-(2-aminoacetamido)-3-((trifluoromethyl)selanyl)propanoates (11 b/12 b), were readily synthesized from natural amino acids and [Me4 N][SeCF3 ]. The primary in vitro cytotoxicity assays revealed that compounds 6 a, 11 a and 12 a were more effective cell growth inhibitors than the other tested CF3 Se-substituted derivatives towards MCF-7, HCT116, and SK-OV-3 cells, with their IC50 values being less than 10 µM for MCF-7 and HCT116 cells. This study indicated the potentials of CF3 Se moiety as a pharmaceutically relevant group in the design and synthesis of novel biologically active molecules.

Validation of a quantitative systems pharmacology model of calcium homeostasis using elagolix Phase 3 clinical trial data in women with endometriosis.

Elagolix is a novel, oral gonadotropin-releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Consistent with its mechanism of action, elagolix exhibited dose-dependent suppression of estradiol (E2) in clinical studies. A dose-response model that describes the relationship between elagolix dosages and average E2 levels was combined with a previously published quantitative systems pharmacology (QSP) model of calcium homeostasis to predict bone mineral density (BMD) changes during and following elagolix treatment. In the QSP model, changes in E2 levels were linked to downstream changes in markers of bone resorption (carboxyterminal cross-linked telopeptide of type 1 collagen [CTX]), formation (N-terminal propeptide of type 1 procollagen [P1NP]) and BMD. The BMD, CTX, and P1NP predictions by the QSP model were validated against observed data from four phase III clinical trials of elagolix in premenopausal women with endometriosis. BMD, CTX, and P1NP were successfully described by the QSP model, without any model fitting, suggesting that the model was validated for further predictions of elagolix effects on BMD. Simulations using the validated QSP model demonstrated that elagolix 150 mg once daily dosing for 24 months is predicted to result in -0.91% change from baseline in lumbar spine BMD. The QSP model simulation results were part of the totality of evidence to support the approved duration of therapy for elagolix 150 mg once daily in patients with endometriosis.

Histone Deacetylase 1 Reduces Lipogenesis by Suppressing SREBP1 Transcription in Human Sebocyte Cell Line SZ95.

Proper regulation of sebum production is important for maintaining skin homeostasis in humans. However, little is known about the role of epigenetic regulation in sebocyte lipogenesis. We investigated histone acetylation changes and their role in key lipogenic gene regulation during sebocyte lipogenesis using the human sebaceous gland cell line SZ95. Sebocyte lipogenesis is associated with a significant increase in histone acetylation. Treatment with anacardic acid (AA), a p300 histone acetyltransferase inhibitor, significantly decreased the lipid droplet number and the expression of key lipogenic genes, including sterol regulatory-binding protein 1 (SREBP1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). In contrast, treatment with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, increased the expression of these genes. Global HDAC enzyme activity was decreased, and HDAC1 and HDAC2 expression was downregulated during sebaceous lipogenesis. Interestingly, HDAC1 knockdown increased lipogenesis through SREBP1 induction, whereas HDAC1 overexpression decreased lipogenesis and significantly suppressed SREBP1 promoter activity. HDAC1 and SREBP1 levels were inversely correlated in human skin sebaceous glands as demonstrated in immunofluorescence images. In conclusion, HDAC1 plays a critical role in reducing SREBP1 transcription, leading to decreased sebaceous lipogenesis. Therefore, HDAC1 activation could be an effective therapeutic strategy for skin diseases related to excessive sebum production.

Elagolix in the treatment of heavy menstrual bleeding associated with uterine fibroids in premenopausal women.

INTRODUCTION: Uterine fibroids (UFs) are the most common benign tumor arising from myometrium of reproductive age women, with significant financial burden estimated in hundreds of billions of dollars. Unfortunately, there are limitations in available long-term treatment options. Thus, there is a large unmet need in the UF space for noninvasive therapeutics. AREAS COVERED: Authors reviewed the literature available for elagolix; an orally bioavailable, second-generation, non-peptide gonadotropin-releasing hormone (GnRH) antagonist recently approved by the US Food and Drug Administration (FDA) in combination with estradiol/norethindrone acetate for the management of heavy menstrual bleeding associated with UFs in premenopausal women. EXPERT OPINION: The utility of new-generation oral GnRH-antagonists, such as elagolix, relugolix and linzagolix, is offering a new potential opportunity for the future therapy of UFs: elagolix has been the most studied drug of this class for treating benign gynecological diseases, including endometriosis and UFs, for which it has been US FDA-approved in 2018 and 2020, respectively.

Encapsulation of LXR ligand by D-Nap-GFFY hydrogel enhances anti-tumorigenic actions of LXR and removes LXR-induced lipogenesis.

Background and purpose: Activation of liver X receptor (LXR) by its ligand T0901317 (T317) enhances interferon-γ (IFNγ) production to inhibit tumor growth. However, induction of severe hypertriglyceridemia and fatty liver by T317 limits its application. The naphthylacetic acid modified D-enantiomeric-glycine-phenylalanine-phenylalanine-tyrosine (D-Nap-GFFY) can form a nanofiber hydrogel which is selectively taken up by antigen-presenting cells (APCs). In this study, we determined if D-Nap-GFFY-encapsulated T317 (D-Nap-GFFY-T317) can potently inhibit tumor growth while having no adverse lipogenic effects on the liver. Methods: We prepared D-Nap-GFFY-T317 nanofiber hydrogel and subcutaneously injected it into IFNγ deficient (IFNγ-/-) and wild-type (WT) mice with lung carcinoma, either inoculated LLC1 cells or urethane-induced carcinoma. Mice received oral T317 administration were used for comparison. Effects of treatment on tumor growth, lipogenesis and involved mechanisms were investigated. Results: Compared with T317 oral administration, injection of D-Nap-GFFY-T317 more potently inhibited LLC1 tumor growth in mice. The inhibition was dependent on LXR-activated IFNγ expression in APCs. D-Nap-GFFY-T317 increased M1 while reducing M2 type macrophages in tumors. Associated with activation of IFNγ expression, D-Nap-GFFY-T317 enhanced dendritic cell maturation and infiltration into tumors, increased CD3+/CD8+ cells in tumors, and inhibited tumor angiogenesis. Similarly, D-Nap-GFFY-T317 more potently inhibited growth of urethane-induced lung carcinomas than T317 oral administration. In these two tumor models, T317 oral administration, but not D-Nap-GFFY-T317 injection, activated hepatic lipogenesis and induced fatty liver. Conclusion: Our study demonstrates that D-Nap-GFFY-T317 inhibits lung tumor growth without adverse effects on the liver, indicating the hydrogel-encapsulated LXR ligand might be a novel therapy for tumor treatment.