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( A ) IL-8 production by CFTR AS ( solid bars )- and S ( open bars )-transfected 16 HBE cells upon stimulation with TNF/IL-1  and ( B ) by IB3 ( solid bars ) and S9 ( open bars ) upon stimulation with TNF. Results are expressed as pg IL-8 secreted/ mg cellular protein. AS cells produced significantly more IL-8 compared with S cells ( P ϭ 0.003 at 6 h, P ϭ 0.0005 at 24 h, and P ϭ 0.0001 at 48 h). IB3 cells produced significantly more IL-8 as compared with S9 cells ( P ϭ 0.01 at 6 h, P ϭ 0.005 at 24 h, and P ϭ 0.001 at 48 h). ( C ) Parthenolide pretreatment, 40 M, 1 h before TNF/IL1  in AS/S cells and ( D ) 15 M, 1 h before TNF in IB3/S9. Results are from two to three com- bined experiments. Values represent the mean Ϯ SEM. ( C ) In AS cells, parthenolide treatment ( shaded bars ) inhibited IL-8 secretion as compared with nontreated cells ( solid bars ) ( P ϭ 0.02 at 3 h), and in S cells parthenolide treatment ( hatched bars ) also inhibited IL-8 as compared with nontreated cells ( open bars ) ( P ϭ 0.03 at 6 h). Similarly, in IB3 cells ( D ) parthenolide treatment ( shaded bars ) inhibited IL-8 secretion as compared with nontreated cells ( solid bars ) ( P ϭ 0.02 at 3 h), and in S9 cells parthenolide treatment ( hatched bars ) also inhibited IL-8 as compared with nontreated cells ( open bars ) ( P ϭ 0.04 at 3 h).
Source publication
Cystic fibrosis (CF) is characterized by prolonged and excessive inflammatory responses in the lung and increased activation of NF-kappaB. Parthenolide is a sesquiterpene lactone derived from the plant feverfew, which has been used in folk medicine for anti-inflammatory activity. Several studies suggest that this compound inhibits the NF-kappaB pat...
Contexts in source publication
Context 1
... first measured the kinetics of IL-8 secretion at 3, 6, 24, and 48 h after incubation with TNF/IL-1 (100 ng/ml each) in AS-and S-transfected 16 HBE cells. Stimulated AS cell lines produced very high concentrations of IL-8 ( Figure 1A, solid bars), while in similarly stimulated S cells ( Figure 1A, open bars) the increase was more modest. Similarly, IB3 cells ( Figure 1B, solid bars) also increased IL-8 production much more than S9 cells ( Figure 1B, open bars) in response to TNF (30 ng/ml) alone. ...
Context 2
... first measured the kinetics of IL-8 secretion at 3, 6, 24, and 48 h after incubation with TNF/IL-1 (100 ng/ml each) in AS-and S-transfected 16 HBE cells. Stimulated AS cell lines produced very high concentrations of IL-8 ( Figure 1A, solid bars), while in similarly stimulated S cells ( Figure 1A, open bars) the increase was more modest. Similarly, IB3 cells ( Figure 1B, solid bars) also increased IL-8 production much more than S9 cells ( Figure 1B, open bars) in response to TNF (30 ng/ml) alone. ...
Context 3
... AS cell lines produced very high concentrations of IL-8 ( Figure 1A, solid bars), while in similarly stimulated S cells ( Figure 1A, open bars) the increase was more modest. Similarly, IB3 cells ( Figure 1B, solid bars) also increased IL-8 production much more than S9 cells ( Figure 1B, open bars) in response to TNF (30 ng/ml) alone. Moreover, in agreement with Kube and coworkers (4), these results showed that the differences between CF cell lines and their controls widened over time, consistent with continued ex- cessive NF-B activation of gene transcription. ...
Context 4
... AS cell lines produced very high concentrations of IL-8 ( Figure 1A, solid bars), while in similarly stimulated S cells ( Figure 1A, open bars) the increase was more modest. Similarly, IB3 cells ( Figure 1B, solid bars) also increased IL-8 production much more than S9 cells ( Figure 1B, open bars) in response to TNF (30 ng/ml) alone. Moreover, in agreement with Kube and coworkers (4), these results showed that the differences between CF cell lines and their controls widened over time, consistent with continued ex- cessive NF-B activation of gene transcription. ...
Context 5
... of the AS and S cells with parthenolide at 40 M caused marked inhibition of the IL-8 production ( Figure 1C, shaded and hatched bars). In both AS and S cells, IL-8 production at 3 h after stimulation was inhibited by 75-85%. ...
Context 6
... both AS and S cells, IL-8 production at 3 h after stimulation was inhibited by 75-85%. Even though the IL-8 production by the AS cells was 10 times greater than that of the S controls at 6 h, this was still inhibited by 48% by parthenolide ( Figure 1C). Similarly, in IB3 and S9 cells, pretreatment with parthenolide (15 M) significantly inhib- ited TNF-mediated IL-8 production by 55% and 44% by 3 h, and 27% and 11% at 6 h, respectively ( Figure 1D). ...
Context 7
... though the IL-8 production by the AS cells was 10 times greater than that of the S controls at 6 h, this was still inhibited by 48% by parthenolide ( Figure 1C). Similarly, in IB3 and S9 cells, pretreatment with parthenolide (15 M) significantly inhib- ited TNF-mediated IL-8 production by 55% and 44% by 3 h, and 27% and 11% at 6 h, respectively ( Figure 1D). Additional application of parthenolide, 1 h after stimulation, had further inhibitory effects, reducing the IL-8 production at 6 h after stimu- lation to less than 25% of that of untreated cells (data not shown). ...
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Citations
... It has been proven that glyburide can inhibit NLRP3 activation and IL-1β secretion induced by lipopolysaccharide in bone marrow-derived macrophages. 38 Some natural product inhibitors such as oridonin and parthenolide can inhibit the NF-κB pathway, 39,40 and thus attenuate lung inflammation induced by SARS-CoV infection and alleviate IBD. 41,42 Furthermore, NLRs play a significant role in vaccine development, especially through their involvement in adjuvant action. ...
Purpose
The rapid global spread of the SARS-CoV-2 Omicron variant introduces a novel complication: the emergence of IBD (inflammatory bowel disease)-like ulcers in certain patients. This research delves into this new challenge by juxtaposing the clinical manifestations and genetic expression patterns of individuals affected by the Omicron variant of COVID-19 with those diagnosed with IBD. It aims to decode the link between these conditions, potentially shedding light on previously unexplored facets of COVID-19 pathophysiology. This investigation emphasizes gene expression analysis as a key tool to identify wider disease correlations and innovative therapeutic avenues.
Patients and Methods
From March to December 2022, patients with SARS-CoV-2 Omicron infection and inflammatory bowel disease and healthy controls were recruited in Shanghai East Hospital, Shanghai, China. The epidemiological and clinical characteristics of the patients were compared. Four RNA sequencing datasets (GSE205244, GSE201530, GSE174159, and GSE186507) were extracted from the Gene Expression Omnibus database to detect mutually differentially expressed genes and common pathways in patients with SARS-CoV-2 infection and inflammatory bowel disease.
Results
Compared to patients with active inflammatory bowel disease, patients with SARS-CoV-2 infection were more likely to have elevated interferon-α levels and an increased lymphocyte count and less likely to have high interleukin-6, tumor necrosis factor-α, and C-reactive protein levels and an elevated neutrophil count. A total of 51 common differentially expressed genes were identified in the four RNA-sequencing datasets. Enrichment analysis suggested that these genes were related to inflammation and the immune response, especially the innate immune response and nucleotide oligomerization domain-like receptor signaling pathway.
Conclusion
The inflammation and immune-response pathways in COVID-19 and inflammatory bowel disease have several similarities and some differences. The study identifies the NLR signaling pathway’s key role in both COVID-19 and IBD, suggesting its potential as a target for therapeutic intervention and vaccine development.
... Results revealed that auranofin exhibited inhibitory efficacy against SARS-CoV-2 replication, demonstrating an EC50 of 1.2 ± 0.2 mM, whereas parthenolide and ML120B did not manifest similar inhibitory effects [166]. Notably, auranofin and parthenolide interfere with NF-kB by inhibiting IKK kinases [167,168]. ...
COVID-19 is a global health threat caused by severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2) and is associated with a significant increase in morbidity and mortality. The present review discusses nuclear factor-kappa B (NF-κB) activation and its potential therapeutical role in treating COVID-19. COVID-19 pathogenesis, the major NF-κB pathways, and the involvement of NF-κB in SARS-CoV-2 have been detailed. Specifically, NF-κB activation and its impact on managing COVID-19 has been discussed. As a central player in the immune and inflammatory responses , modulating NF-κB activation could offer a strategic avenue for managing SARS-CoV-2 infection. Understanding the NF-κB pathway's role could aid in developing treatments against SARS-CoV-2. Further investigations into the intricacies of NF-κB activation are required to reveal effective therapeutic strategies for managing and combating the SARS-CoV-2 infection and COVID-19.
... Parthenolide did not affect CRMP2 or STAT3 activity at the nanomolar concentrations used in this study, both critical for CNS axon regeneration Leibinger et al., 2019), suggesting the reduction of microtubule detyrosination causes the axon growth-promoting effects. Although we cannot exclude the possibility that other known activities of parthenolide/DMAPT, such as oxidative stress or NF-kB inhibition, could have contributed to the observed effects, this is rather unlikely because such effects have only been reported at much higher micromolar concentrations (Bork et al., 1997;Saadane et al., 2007;Carlisi et al., 2016;Gobrecht et al., 2016). Systemic DMAPT treatment significantly promotes axon extension in the optic nerve and regeneration of serotonergic fibers beyond the injury site. ...
Injured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. However, the knockdown of Pten knockout or treatment of neurons with hyper-IL-6 (hIL-6) transforms neurons into a regenerative state, allowing them to regenerate axons in the injured optic nerve and spinal cord. Transneuronal delivery of hIL-6 to the injured brain stem neurons enables functional recovery after severe spinal cord injury. Here we demonstrate that the beneficial hIL-6 and Pten knockout effects on axon growth are limited by the induction of tubulin detyrosination in axonal growth cones. Hence, cotreatment with parthenolide, a compound blocking microtubule detyrosination, synergistically accelerates neurite growth of cultured murine CNS neurons and primary RGCs isolated from adult human eyes. Systemic application of the prodrug dimethylamino-parthenolide (DMAPT) facilitates axon regeneration in the injured optic nerve and spinal cord. Moreover, combinatorial treatment further improves hIL-6-induced axon regeneration and locomotor recovery after severe SCI. Thus, DMAPT facilitates functional CNS regeneration and reduces the limiting effects of pro-regenerative treatments, making it a promising drug candidate for treating CNS injuries.
... The upregulation of pro-inflammatory genes is known to result in brain injury and dysregulation of neurotransmitters, which is attributed to the excessive presence of cytokines and reactive oxygen species (Welcome & Mastorakis, 2021). However, the utilization of parthenolide, a well-known inhibitor, to impede NF-κB activity has demonstrated encouraging outcomes in mitigating COVID-19 infection (Saadane et al., 2007). ...
Coronaviruses are prevalent in mammals and birds, including humans and bats, and they often spread through airborne droplets. In humans, these droplets then interact with angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), which are the main receptors for the SARS-CoV-2 virus. It can infect several organs, including the brain. The blood-brain barrier (BBB) is designed to maintain the homeostatic neural microenvironment of the brain, which is necessary for healthy neuronal activity, function, and stability. It prevents viruses from entering the brain parenchyma and does not easily allow chemicals to pass into the brain while assisting numerous compounds in exiting the brain. The purpose of this review was to examine how COVID-19 influences the BBB along with the mechanisms that indicate the BBB's deterioration. In addition, the cellular mechanism through which SARS-CoV-2 causes BBB destruction by binding to ACE2 was evaluated and addressed. The mechanisms of the immunological reaction that occurs during COVID-19 infection that may contribute to the breakdown of the BBB were also reviewed. It was discovered that the integrity of the tight junction (TJs), basement membrane, and adhesion molecules was damaged during COVID-19 infection, which led to the breakdown of the BBB. Therefore, understanding how the BBB is disrupted by COVID-19 infection will provide an indication of how the SARS-CoV-2 virus is able to reach the central nervous system (CNS). The findings of this research may help in the identification of treatment options for COVID-19 that can control and manage the infection.
... Parthenolide did not affect CRMP2 or STAT3 activity at the nanomolar concentrations used in this study, both critical for CNS axon regeneration Leibinger et al., 2019), suggesting the reduction of microtubule detyrosination causes the axon growth-promoting effects. Although we cannot exclude the possibility that other known activities of parthenolide/DMAPT, such as oxidative stress or NF-kB inhibition, could have contributed to the observed effects, this is rather unlikely because such effects have only been reported at much higher micromolar concentrations (Bork et al., 1997;Saadane et al., 2007;Carlisi et al., 2016;Gobrecht et al., 2016). Systemic DMAPT treatment significantly promotes axon extension in the optic nerve and regeneration of serotonergic fibers beyond the injury site. ...
Injured axons in the central nervous system (CNS) usually fail to regenerate, causing permanent disabilities. However, the knockdown of Pten knockout or treatment of neurons with hyper-IL-6 (hIL-6) transforms neurons into a regenerative state, allowing them to regenerate axons in the injured optic nerve and spinal cord. Transneuronal delivery of hIL-6 to the injured brain stem neurons enables functional recovery after severe spinal cord injury. Here we demonstrate that the beneficial hIL-6 and Pten knockout effects on axon growth are limited by the induction of tubulin detyrosination in axonal growth cones. Hence, cotreatment with parthenolide, a compound blocking microtubule detyrosination, synergistically accelerates neurite growth of cultured murine CNS neurons and primary RGCs isolated from adult human eyes. Systemic application of the prodrug dimethylamino-parthenolide (DMAPT) facilitates axon regeneration in the injured optic nerve and spinal cord. Moreover, combinatorial treatment further improves hIL-6-induced axon regeneration and locomotor recovery after severe SCI. Thus, DMAPT facilitates functional CNS regeneration and reduces the limiting effects of pro-regenerative treatments, making it a promising drug candidate for treating CNS injuries.
... These phenomena evidenced the PTL treatment of periodontitis [64]. Another study revealed that PTL inhibited the activities of NF-κB and IκB kinase in pulmonary cystic fibrosis cells, indicating that PTL may be a promising drug for the treatment of excessive inflammation [65]. Summarily, many papers have reported that PTL plays an antiinflammatory role through the NF-κB pathway. ...
Parthenolide (PTL) is a new compound extracted from traditional Chinese medicine. In recent years, it has been proven to play an undeniable role in tumors, autoimmune diseases, and inflammatory diseases. Similarly, an increasing number of experiments have also confirmed the biological mechanism of PTL in these diseases. In order to better understand the development trend and potential hot spots of PTL in cancer and other diseases, we conducted a detailed bibliometric analysis. The purpose of presenting this bibliometric analysis was to highlight and inform researchers of the important research directions, co-occurrence relationships and research status in this field. Publications related to PTL research from 2002 to 2022 were extracted on the web of science core collection (WoSCC) platform. CiteSpace, VOSviewers and R package “bibliometrix” were applied to build relevant network diagrams. The bibliometric analysis was presented in terms of performance analysis (including publication statistics, top publishing countries, top publishing institutions, publishing journals and co-cited journals, authors and co-cited authors, co-cited references statistics, citation bursts statistics, keyword statistics and trend topic statistics) and science mapping (including citations by country, citations by institution, citations by journal, citations by author, co-citation analysis, and keyword co-occurrence). The detailed discussion of the results explained the focus and latest trends from the bibliometric analysis. Finally, the current status and shortcomings of the research field on PTLwere clearly pointed out for reference by scholars.
... Interestingly, a sharp increase in the levels of NF-κBp65 was observed when transfected MCF-7 cells with anti-mR-204-5p were stimulated with PMA, and this increase of NF-κBp65 was significantly inhibited by AuNPs. To confirm that our experimental setup was suitable for the determination of NF-κB activity, we treated anti-miR-204-5p-transfected MCF-7 cells with parthenolide, a well-known marker for the determination of NF-κB inhibition [46,47]. Treatment of anti-miR-204-5p-transfected MCF-7 cells with parthenolide showed significant inhibition of PMA-induced MMP-9 mRNA, MMP-9 protein secretion and NF-κBp65 activation. ...
Objective:
Breast cancer (BC) is the most common malignancy in females globally. Matrix metalloproteinase-9 (MMP-9) is crucial to the invasion, progression and spread of BC. Gold nanoparticles (AuNPs) have an anti-tumorigenic role, but their therapeutic role in microRNAs (miRNAs) regulation has not been explored. This study determined the potential of AuNPs against MMP-9 overexpression/production and miRNA-204-5p regulation in BC cells.
Methods:
AuNPs were newly engineered, and their stability was analyzed using the zeta potential, polydispersity index, surface-plasmon-resonance peak and transmission electron microscopy. A bioinformatics algorithm was used to predict the pairing of miRNA in the 3'untranslated-region (3'UTR) of MMP-9 mRNA. TaqMan assays were carried out to quantify miRNA and mRNA, whereas MMP-9-specific immunoassays and gelatin zymography were used to determine protein secretion and activity. The binding of miRNA in MMP-9 mRNA 3'UTR was verified by luciferase reporter clone assays and transfection with anti-miRNAs. In addition, NF-κBp65 activity was determined and confirmed with parthenolide treatment.
Results:
Engineered AuNPs were highly stable and spherical in shape, with a mean size of 28.3 nm. Tested in MCF-7 BC cells, microRNA-204-5p directly regulates MMP-9. AuNPs inhibit PMA-induced MMP-9 mRNA and protein via hsa-miR-204-5p upregulation. Anti-miR-204 transfected MCF-7 cells demonstrated enhanced MMP-9 expression (p < 0.001), while AuNPs treatment attenuated MMP-9 expression in a dose-dependent manner (p < 0.05). Moreover, AuNPs also inhibit PMA-induced NF-κBp65 activation in anti-hsa-miR-204 transfected MCF-7 cells.
Conclusion:
Engineered AuNPs were stable and non-toxic to BC cells. AuNPs inhibit PMA-induced MMP-9 expression, production and activation via NF-κBp65 deactivation and hsa-miR-204-5p upregulation. These novel therapeutic potentials of AuNPs on stimulated BC cells provide novel suggestions that AuNPs inhibit carcinogenic activity via inverse regulation of microRNAs.
... SLs has a long history of use around the world for preventing migraine headaches, treating rheumatoid arthritis and anti-infection, actions that are attributable to its anti-inflammatory activity [30,31]. Several studies have demonstrated that SLs was a potent inhibitor of NFκB activation and could inhibit the expression of pro-inflammatory cytokines in vivo and in vitro [32,33]. However, the chemical properties of SLs are instable and can decompose easily in both acidic and basic conditions [34], which severely restrict their clinical application. ...
Background
Microglia-mediated neuroinflammatory response following traumatic brain injury (TBI) is considered as a vital secondary injury factor, which drives trauma-induced neurodegeneration and is lack of efficient treatment. ACT001, a sesquiterpene lactone derivative, is reportedly involved in alleviation of inflammatory response. However, little is known regarding its function in regulating innate immune response of central nervous system (CNS) after TBI. This study aimed to investigate the role and underlying mechanism of ACT001 in TBI.
Methods
Controlled cortical impact (CCI) models were used to establish model of TBI. Cresyl violet staining, evans blue extravasation, neurobehavioral function assessments, immunofluorescence and transmission electron microscopy were used to evaluate therapeutic effects of ACT001 in vivo. Microglial depletion was induced by administering mice with colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622. Cell-cell interaction models were established as co-culture system to simulate TBI conditions in vitro. Cytotoxic effect of ACT001 on cell viability was assessed by cell counting kit-8 and activation of microglia cells were induced by Lipopolysaccharides (LPS). Pro-inflammatory cytokines expression was determined by Real-time PCR and nitric oxide production. Apoptotic cells were detected by TUNEL and flow cytometry assays. Tube formation was performed to evaluate cellular angiogenic ability. ELISA and western blot experiments were used to determine proteins expression. Pull-down assay was used to analyze proteins that bound ACT001.
Results
ACT001 relieved the extent of blood-brain barrier integrity damage and alleviated motor function deficits after TBI via reducing trauma-induced activation of microglia cells. Delayed depletion of microglia with PLX5622 hindered therapeutic effect of ACT001. Furthermore, ACT001 alleviated LPS-induced activation in mouse and rat primary microglia cells. Besides, ACT001 was effective in suppressing LPS-induced pro-inflammatory cytokines production in BV2 cells, resulting in reduction of neuronal apoptosis in HT22 cells and improvement of tube formation in bEnd.3 cells. Mechanism by which ACT001 functioned was related to AKT/NFκB/NLRP3 pathway. ACT001 restrained NFκB nuclear translocation in microglia cells through inhibiting AKT phosphorylation, resulting in decrease of NLRP3 inflammasome activation, and finally down-regulated microglial neuroinflammatory response.
Conclusions
Our study indicated that ACT001 played critical role in microglia-mediated neuroinflammatory response and might be a novel potential chemotherapeutic drug for TBI.
... In order to identify the impact of presumed activation routes in monocyte-derived primary human cells we have used inhibitors directed against three key players of major pathways. For inhibition of NF B the sesquiterpene lactone parthenolide was chosen [34]. For inhibition of the TANK-Binding Kinase 1 (TBK1) the aminopyrimidine compound BX795 that also inhibits IκB kinase ɛ (IKKɛ), was added [35]. ...
Introduction:
Pigs are suitable donor species for xenotransplantation and biological materials from these animals are used for this purpose for many years. A major risk of xenotransplantation is a zoonosis by transspecies transmission of animal viruses. In this regard Porcine Endogenous Retroviruses (PERVs) are of paramount importance because some of them are able to infect human cells and could induce innate immune responses.
Methods:
Using a replication competent polytropic PERV-A/C strain we have analysed induction of innate immune responses by this virus in human monocytes, Monocyte-Derived Macrophages (MDM) and Monocyte-Derived Dendritic Cells (MDDC).
Results:
PERV-A/C elevates expression of the C-X-C motif chemokine 10 (CXCL10) up to 1000-fold in human monocytes and monocyte-derived primary cells. In comparison to CXCL10, the levels of interferon-β (IFN-β) and Interferon-Stimulated Gene 54 (ISG54) were almost unchanged. Heat-inactivated virus did not induce CXCL10 expression. Neither treatment with the reverse transcriptase inhibitors azidothymidine (AZT) and stavudine (d4T) nor treatment with the integrase inhibitor raltegravir (RAL) reduced the activation levels. Furthermore, depletion of SAM domain and HD domain-containing protein 1 (SAMHD1), a restriction factor that blocks PERV-A/C infection at the level of reverse transcription in these myeloid cells, had no significant effect on the CXCL10 induction level. These results imply that innate immune sensing leading to the strong CXCL10 response occurs at an early step of the replication process and does not require products of reverse transcription. Inhibition of Janus Kinases (JAKs) by AT9283 prevented the observed CXCL10 induction by the virus providing evidence that the JAK-STAT signalling pathway is involved in the CXCL10 response in theses myeloid cells.
Conclusion:
Our findings highlight PERVs as inducers of the pro-inflammatory chemokine CXCL10 and other innate immune responses in human monocytes and derived cells with potential implications in the context of xenotransplantation.
... In addition, it exhibits potent anti-inflammatory properties and is widely used worldwide to treat rheumatoid arthritis and prevent migraine headaches [18]. PTL has been demonstrated to be a powerful NF-B activation inhibitor and is able to reduce the expression of pro-inflammatory cytokines in both cultivated cells and experimental animals [19,20]. Furthermore, Monica L. Guzman et al. [21] reported that PTL induces apoptosis in human acute myeloid leukemia stem cells and progenitor cells. ...
Elevated cholesterol significantly increases the risk of developing atherosclerosis and coronary heart disease. The key to treating hypercholesterolemia is lowering plasma cholesterol levels. There have been no studies on the cholesterol-lowering potential of parthenolide (PTL), a naturally occurring small molecule from Tanacetum parthenium. Here, we first put forth PTL’s cholesterol-lowering ability to inhibit cellular uptake of cholesterol in a dose-dependent manner. Its performance was on par with the positive control drug, ezetimibe. Niemann–Pick C1 Like-1 (NPC1L1) has been identified as a potential therapeutic target for hypercholesterolemia. The interaction of PTL with NPC1L1 could be explained by the results of molecular docking and filipin staining further reinforces this hypothesis. Furthermore, PTL reduced the expression of NPC1L1 in HepG2 cells in a concentration-dependent manner, which suggests that PTL functions as a potential NPC1L1 inhibitor with therapeutic potential for hypercholesterolemia.
