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Parthenolide (PTL) is a sesquiterpene lactone that occurs naturally. It demonstrates a variety of beneficial effects, such as antioxidant, anti-inflammatory, and antiapoptotic properties. The study investigated the potential protective impact of PTL on indomethacin (INDO) induced stomach ulcers in rats. The rats were classified into 5 distinct categories. Group 1 served as the "control" group. Rats in the second group received a single oral dosage of INDO (50 mg kg−1). Rats in Groups three and four received 20 and 40 mg kg−1 oral PTL 1 h before INDO. Omeprazole (30 mg kg−1) was given orally to Group 5 rats 1 h before INDO. Pretreatment with PTL increased stomach pH and decreased gastric volume as well as reduced the morphological and histological changes induced by INDO. Analysis of probable pathways showed that pre-treatment with PTL successfully reduced oxidative, inflammatory, and apoptotic consequences caused by INDO. The ingestion of PTL leads to a notable increase in the levels of glutathione reduced (GSH) and the activities of superoxide dismutase (SOD) and catalase (CAT). Furthermore, PTL decreased the concentration of malondialdehyde (MDA). In contrast, it was shown that PTL increased both cyclooxygenase-1 (COX-1) and prostaglandin E2 (PGE2). PTL shows a significant decrease in the expression of interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS), and nuclear factor kappa B (NF-κB). PTL therapy resulted in a decrease in Bcl-2-associated X protein (Bax) levels and an increase in B-cell lymphoma 2 (Bcl2) levels. In conclusion, PTL offers gastroprotection by its antioxidant, anti-inflammatory, and anti-apoptotic qualities. [ABSTRACT FROM AUTHOR]

Background: Huntington's disease (HD) is a progressive neurodegenerative disease that causes motor, cognitive, and psychiatric abnormalities, with no satisfying disease-modifying therapy so far. 3-nitropropionic acid (3NP) induces behavioural deficits, together with biochemical and histological alterations in animals' striata that mimic HD. The role of nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome in HD pathogenesis remains largely uncharacterized. Parthenolide (PTL), a naturally occurring nuclear factor kappa B (NF-κB) inhibitor, is also known to inhibit NLRP3 inflammasome. Whether PTL is beneficial in HD has not been established yet. Aim: This study evaluated the possible neuroprotective effects of PTL against 3NP-induced behavioural abnormalities, striatal biochemical derangements, and histological aberrations. Methods: Male Wistar rats received PTL (0.5 mg/kg/day, i.p) for 3 weeks and 3NP (10 mg/kg/day, i.p) was administered alongside for the latter 2 weeks to induce HD. Finally, animals were subjected to open-field, Morris water maze and rotarod tests. Rat striata were examined histologically, striatal protein expression levels of glial fibrillary acidic protein (GFAP), cluster of differentiation 45 (CD45) and neuron-specific enolase (NSE) were evaluated immunohistochemically, while those of interleukin (IL)-1β, IL-18, ionized calcium-binding adapter molecule-1 (Iba1) and glutamate were determined by ELISA. Striatal nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein (Keap1), NF-κB, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, S100 calcium-binding protein A10 (S100A10) and complement-3 (C3) were assessed by gene expression analysis. Results: PTL improved motor, locomotor, cognitive and anxiety-like behaviours, restored neuronal integrity, upregulated Nrf2, and inhibited NLRP3 inflammasome, NF-κB and microglial activation. Additionally, PTL induced astrocyte shifting towards the neuroprotective A2 phenotype. Conclusion: PTL exhibits neuroprotection against 3NP-induced HD, that might be ascribed, at least in part, to its modulatory effects on Keap1/Nrf2 and NF-κB/NLRP3 inflammasome signaling. [ABSTRACT FROM AUTHOR]

The freshwater planarian is an emerging animal model in neuroscience due to its centralized nervous system that closely parallels closely parallels the nervous system of vertebrates. Cocaine, an abused drug, is the 'founding member' of the local anesthetic family. Parthenolide, a sesquiterpene lactone, acts as a behavioral and physiological antagonist of cocaine in planarians and rats, respectively. Previous work from our laboratory showed that both parthenolide and cocaine reduced planarian motility and that parthenolide reversed the cocaine-induced motility decrease at concentrations where parthenolide does not affect the movement of the worms. However, the exact mechanism of the cocaine/parthenolide antagonism is unknown. Here, we report the results of a Schild analysis to explore the parthenolide/cocaine relationship in the planarian Girardia tigrina. The Schild slopes of a family of concentration–response curves of parthenolide ± a single concentration of cocaine and vice versa were −0.55 and −0.36, respectively. These slopes were not statistically different from each other. Interestingly, the slope corresponding to the parthenolide ± cocaine (but not the cocaine ± parthenolide) data set was statistically different from −1. Our data suggest an allosteric relationship between cocaine and parthenolide for their effect on planarian motility. To the best of our knowledge, this is the first study about the mechanism of action of the antagonism between cocaine and parthenolide. Further studies are needed to determine the specific nature of the parthenolide/cocaine target(s) in this organism. [ABSTRACT FROM AUTHOR]

Abstract Background Huntington’s disease (HD) is a progressive neurodegenerative disease that causes motor, cognitive, and psychiatric abnormalities, with no satisfying disease-modifying therapy so far. 3-nitropropionic acid (3NP) induces behavioural deficits, together with biochemical and histological alterations in animals’ striata that mimic HD. The role of nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3) inflammasome in HD pathogenesis remains largely uncharacterized. Parthenolide (PTL), a naturally occurring nuclear factor kappa B (NF-κB) inhibitor, is also known to inhibit NLRP3 inflammasome. Whether PTL is beneficial in HD has not been established yet. Aim This study evaluated the possible neuroprotective effects of PTL against 3NP-induced behavioural abnormalities, striatal biochemical derangements, and histological aberrations. Methods Male Wistar rats received PTL (0.5 mg/kg/day, i.p) for 3 weeks and 3NP (10 mg/kg/day, i.p) was administered alongside for the latter 2 weeks to induce HD. Finally, animals were subjected to open-field, Morris water maze and rotarod tests. Rat striata were examined histologically, striatal protein expression levels of glial fibrillary acidic protein (GFAP), cluster of differentiation 45 (CD45) and neuron-specific enolase (NSE) were evaluated immunohistochemically, while those of interleukin (IL)-1β, IL-18, ionized calcium-binding adapter molecule-1 (Iba1) and glutamate were determined by ELISA. Striatal nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein (Keap1), NF-κB, NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, S100 calcium-binding protein A10 (S100A10) and complement-3 (C3) were assessed by gene expression analysis. Results PTL improved motor, locomotor, cognitive and anxiety-like behaviours, restored neuronal integrity, upregulated Nrf2, and inhibited NLRP3 inflammasome, NF-κB and microglial activation. Additionally, PTL induced astrocyte shifting towards the neuroprotective A2 phenotype. Conclusion PTL exhibits neuroprotection against 3NP-induced HD, that might be ascribed, at least in part, to its modulatory effects on Keap1/Nrf2 and NF-κB/NLRP3 inflammasome signaling.

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, and is due to the degeneration of dopaminergic neurons. It is multifactorial, caused by genetic and environmental factors and currently has no definitive cure. We have investigated the protective effects of parthenolide (PTN), a compound with known anti-inflammatory and antioxidant properties, in an in vitro model of PD, that is induced by 6-OHDA, and that causes neurotoxicity in SH-SY5Y human neuroblastoma cells. Methods and results: SH-SY5Y cells were pretreated with PTN to assess its protective effects in 6-OHDA-induced cellular damage. Cell viability was measured using Alamar blue. Apoptosis was evaluated using an Annexin V-FITC/PI kit. Reactive oxygen species (ROS) levels were quantified, and expression levels of apoptotic markers (Bax, Bcl-2, p53) and NF-κB were analyzed via Western blotting and Quantitative real-time- (qRT-) PCR. We found that 6-OHDA reduced cell viability, that was inhibited significantly by pre-treatment with PTN (p < 0.05). Flow cytometry revealed that PTN reduced apoptosis induced by 6-OHDA. PTN also reduced the ROS levels raised by 6-OHDA (p < 0.05). Moreover, PTN decreased the expression of Bax, p53, NF-κB, and p-NF-κB that were increased by treatment with 6-OHDA. Conclusion: These findings indicate the potential beneficial effects of PTN in an in vitro model of PD via mitigating oxidative stress and inflammation, suggested PTN as a promising agent to be used for PD therapy, warranting further investigation in preclinical and clinical studies. [ABSTRACT FROM AUTHOR]

Aggressive triple-negative breast cancer (TNBC) is a current threat worldwide. The ineffectiveness of current TNBC therapy options highlights the need for innovative therapeutics. Due to bioavailability issues and probable side effects, parthenolide (PTL), the potent anticancer bioactive component of Tanacetum parthenium , has restricted therapeutic applicability. To address these challenges, a pH-responsive nanodelivery system containing PTL (cross-linked nanocarrier endowed with poly-β-thioester activity carrying PTL (CBAPTL)) was developed. In order to facilitate sustained release of PTL at endosomal-like pH (5.0–5.3) in cancer cells, the pH-responsive CBAPTL was synthesized. The effectiveness of CBAPTL was examined in vitro using human TNBC cells (MDA-MB-231) through Western blotting, flow cytometry, invasion assay, and mammosphere inhibition study and compared its effect on WRL-68 normal cells. In MDA-MB-231 cells, CBAPTL exhibited selective cytotoxicity and arrested the cell cycle at the G2-M phase more effectively than PTL. CBAPTL induced apoptosis via downregulating Bcl-2 and upregulating p53, BAD, and p21. It showed antimetastatic efficacy by inhibiting AKT-phosphorylation, p38, and MMP1 expression. CBAPTL caused Δψm disruption and hindered cell migration, invasion, and EMT by suppressing vimentin, Snail, CD44, and mammosphere development, demonstrating its effect against metastasis and cancer stem cells (CSCs). Contrarily, CBAPTL showed no effect on WRL-68 normal cells. CBAPTL selectively delivered PTL at the TME, facilitating enhanced internalization through endocytosis in MDA-MB-231 cells. The findings highlight the superior and selective efficacy of CBAPTL compared to PTL against TNBC cells, indicating a potential therapeutic strategy for managing cancer aggressiveness without impacting normal cells. [ABSTRACT FROM AUTHOR]

An anticancer agent derived from a natural product, parthenolide (PN), was studied to formulate PN into poly(lactic-co-glycolic acid) (PLGA). Polydopamine (PDA) was employed to modify the surface of PN-PLGA. Following characterization, the PN-PLGA-PDA was evaluated for its in vitro release, cytotoxicity, and ability to induce apoptosis using flow cytometry and real-time quantitative PCR. According to the present study, PN-PLGA-PDA had a size of 195.5 nm which is acceptable for efficient enhanced permeation and retention (EPR) performance. The SEM results confirmed the size and spherical shape of the nanoparticles. The percentage of encapsulation efficiency was 96.9%. The zeta potential of PN-PLGA-PDA was − 31.8 mV which was suitable for its stability. FTIR spectra of the PN-PLGA-PDA indicated the chemical stability of the PN due to intermolecular hydrogen bonds between polymer and drug. The release of PN from PN-PLGA-PDA in PBS (pH 7.4) was only 20% during the first 48 h and less than 40% during 144 h. PN-PLGA-PDA exhibited anticancer properties in a dose-dependent manner that was more cytotoxic against cancer cells than normal cells. Moreover, real-time qPCR results indicated that the formulation activated apoptosis genes to exert its cytotoxic effect and activate the NF-kB pathway. Based on our findings, PN-PLGA-PDA could serve as a potential treatment for cancer. [ABSTRACT FROM AUTHOR]

Sesquiterpene lactones are naturally occurring, highly active -specialised metabolites, which are biosynthesized by important medicinal plants, fulfilling many functions. The in vitro metabolism of parthenolide (1), grosheimin (2), carbetolide C (3), 8α-O-(3,4-dihydroxy--methylenebutanoyloxy)-dehydromelitensin (4) and arteludovicinolide A (5) was examined using human liver microsomes. Phase I, phase II (glucuronidation), as well as combined phase I + II metabolism were studied. Metabolites were identified via liquid chromatography-high resolution quadrupole time-of-flight mass spectrometry. Monohydroxylated, hydrated, carboxylated, methylated derivatives, together with corresponding monoglucuronides were detected, suggesting that the metabolism of sesquiterpene lactones is changeable due to structural features and scaffold diversity, though the lactone ring is the main site of metabolism. [ABSTRACT FROM AUTHOR]

BACKGROUND: Bacterial leaf blight caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of the most serious diseases of rice, and there is a lack of bactericides for controlling this disease. We previously found parthenolide (PTL) is a potential lead for developing bactericides against Xoo, and subunit F of respiratory chain complex I (NuoF) is an important target protein of PTL. However, the binding modes of PTL with NuoF need further elucidation. RESULTS: In this study, we obtained the crystal structure of Xoo NuoEF (complex of subunit E and F of respiratory chain complex I) with a resolution of 2.36 Å, which is the first report on the protein structure of NuoEF in plant‐pathogenic bacteria. The possible binding sites of PTL with NuoF (Cys105 and Cys187) were predicted with molecular docking and mutated into alanine using a base mismatch method. The mutated proteins were expressed in Escherichia coli and purified with affinity chromatography. The binding abilities of PTL with mutated proteins were investigated via pull‐down assay and BIAcore analysis, which revealed that double mutation of Cys105 and Cys187 in NuoF severely affected the binding ability of PTL with NuoF. In addition, the binding modes were further simulated with combined quantum mechanical/molecular mechanical calculations, and the results indicated that PTL may have a stronger binding with Cys105 than Cys187. CONCLUSION: NuoEF protein structure of Xoo was resolved, and Cys105 and Cys187 in NuoF are important binding sites of PTL. This study further clarified the action mechanism of PTL against Xoo, and will promote the innovation of bactericides targeting Xoo complex I. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Objective To explore the impact of the sialic acid binding lectin-E (Siglec-E) on the inhibitory properties of parthenolide(PTL) against lipopolysaccharide (LPS)-induced M1 polarization of microglia(BV2). Methods ① Single cell sequencing data of Siglece related mouse brain tissue was obtained from Gene Expression Omnibus (GEO) database and divided into the WT group (n=3) and the Siglece-/- group (n=4). The microglia cells were screened, and the enrichment analysis was performed to analyze related differential genes and pathways. BV2 cells were constructed by the shRNA interference technique and were divided into NC-shRNA and Siglece-shRNA to detect the expression level of Siglec-E (Siglece). ② NC-shRNA and Siglece-shRNA cells were respectively divided into the Control group, LPS group, PTL group and PTL+LPS group (n=3). The mRNA levels of markers of M1 polarization in microglia, iNOS, IL-1β and IL-6, were detected by RT-qPCR. Siglecefl/fl and Cx3cr1cre mice were mated to obtain microglia-specific Siglece deletion (Siglecefl/fl×Cx3cr1cre) mice, and LPS-induced neuroinflammation model was established. ③ Nine WT and Siglecefl/fl×Cx3cr1cre male mice were assigned to the Control group, LPS group and PTL+LPS group (n=3). RT-qPCR, immunofluorescence assay and Western blotting were used to verify the knock-out effect and polarization-related pathways, and to investigate the mechanism of Siglec-E affecting PTL inhibition of M1 polarization of microglia. Results Compared with the NC-shRNA group, the expression of Siglec-E in the Siglece-shRNA group was significantly decreased (P < 0.01), indicating that the Siglec-E knock-down cell model was successfully established. With the stimulation of LPS, mRNA levels of iNOS, IL-1β and IL-6 were significantly up-regulated compared with the Control group both in shRNA cells and Siglece -shRNA cells (P < 0.01). With the influence of PTL and LPS, the markers of M1 polarization in NC-shRNA cells mentioned before were significantly decreased (P < 0.05), while for Siglice-shRNA cells, there were no significant changes in the markers of M1 polarization. PTL inhibited the phosphorylation of JNK and IκB protein (P < 0.01) and the nuclear translocation of NF-κB in BV2 cells, down-regulated Siglec-E, and weakened the inhibitory effect. Compared with mice in the WT group, the expression of Siglec-E in microglia of Siglecefl/fl×Cx3cr1cre mice was decreased significantly (P < 0.01), and the inhibitory effect of PTL on the phosphorylation of NF-κB in microglia of Siglecefl/fl×Cx3cr1cre mice was also decreased. Conclusion The absence of Siglec-E in microglia attenuates the inhibition of M1 polarization by the MAPK/NF-κB pathway targeted by PTL.

Treatments accelerating axon regeneration in the nervous system are still clinically unavailable. However, parthenolide promotes adult sensory neurons' axon growth in culture by inhibiting microtubule detyrosination. Here, we show that overexpression of vasohibins increases microtubule detyrosination in growth cones and compromises growth in culture and in vivo. Moreover, overexpression of these proteins increases the required parthenolide concentrations to promote axon regeneration. At the same time, the partial knockdown of endogenous vasohibins or their enhancer SVBP in neurons facilitates axon growth, verifying them as pharmacological targets for promoting axon growth. In vivo, repeated intravenous application of parthenolide or its prodrug di-methyl-aminoparthenolide (DMAPT) markedly facilitates the regeneration of sensory, motor, and sympathetic axons in injured murine and rat nerves, leading to acceleration of functional recovery. Moreover, orally applied DMAPT was similarly effective in promoting nerve regeneration. Thus, pharmacological inhibition of vasohibins facilitates axon regeneration in different species and nerves, making parthenolide and DMAPT the first promising drugs for curing nerve injury. [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is a respiratory failure disease associated with high mortality rates in patients. The primary pathological damage is attributed to the excessive release of pro-inflammatory mediators in pulmonary tissue. However, specific therapy for ALI has not been developed. In this study, a series of novel ferulic acid-parthenolide (FA-PTL) and ferulic acid-micheliolide (FA-MCL) hybrid derivatives were designed, synthesized, and evaluated for their anti-inflammatory activities in vitro. Compounds 2, 4, and 6 showed pronounced anti-inflammatory activity against LPS-induced expression of pro-inflammatory cytokines in vitro. Importantly, compound 6 displayed good water solubility, and treatment of mice with compound 6 (10 mg/kg) significantly prevented weight loss and ameliorated inflammatory cell infiltration and edema in lung tissue, as well as improving the alveolar structure. These results suggest that compound 6 (((1aR,7aS,8R,10aS,10bS,E)-8-((dimethylamino)methyl)-1a-methyl-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-5-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate 2-hydroxypropane-1,2,3-tricarboxylate) might be considered as a lead compound for further evaluation as a potential anti-ALI agent. [ABSTRACT FROM AUTHOR]

Purpose: Cervical cancer (CC) ranks as the fourth most prevalent malignancy among women worldwide, necessitating effective therapeutic interventions to mitigate its detrimental impact on both physical and mental health. Parthenolide (PTL), a natural product of the sesquiterpene lactone derived from Feverfew leaves, has exhibited promising anti-tumor properties in previous studies; however, its precise effects and underlying molecular mechanisms in CC remain elusive. Methods: In this work, we investigated the effect of PTL on the proliferation and migration of CC cells. Western blot analysis and Reverse transcription‑quantitative PCR were used for mechanistic elucidation. Results: Our findings indicated that PTL substantially inhibited the proliferation of HeLa and SiHa CC cell lines in a dose- and time-dependent manner. Moreover, PTL significantly suppressed the migration of CC cells by down-regulating the expression of vascular endothelial growth factor (VEGF), metastasis-associated protein 1 (MTA1), and transforming growth factor-β1 (TGF-β1). Mechanistically, PTL blocked the phosphorylation of focal adhesion kinase (FAK) and glycogen synthase kinase-3β (GSK3β) induced by epidermal growth factor (EGF). Further investigations revealed that PTL suppressed the proliferation of CC cells by inhibiting the EGF-mediated phosphorylation of the FAK/GSK3β signaling pathway. Conclusion: Taken together, the present in vitro results suggest that PTL may inhibit the proliferation and migration of CC cells through down-regulating the FAK/GSK3β signaling pathway, providing new insights for the application of PTL in the treatment of CC. [ABSTRACT FROM AUTHOR]

We previously established pancreatic cancer (PaCa) cell lines resistant to gemcitabine and found that the activity of nuclear factor κB (NF-κB) was enhanced upon the acquisition of gemcitabine resistance. Parthenolide, the main active ingredient in feverfew, has been reported to exhibit antitumor activity by suppressing the NF-κB signaling pathway in several types of cancers. However, the antitumor effect of parthenolide on gemcitabine-resistant PaCa has not been elucidated. Here, we confirmed that parthenolide significantly inhibits the proliferation of both gemcitabine-resistant and normal PaCa cells at concentrations of 10 µM and higher, and that the NF-κB activity is significantly inhibited, even by 1 µM parthenolide. In Matrigel invasion assays and angiogenesis assays, the invasive and angiogenic potentials were higher in gemcitabine-resistant than normal PaCa cells and were inhibited by a low concentration of parthenolide. Furthermore, Western blotting showed suppressed MRP1 expression in gemcitabine-resistant PaCa treated with a low parthenolide concentration. In a colony formation assay, the addition of 1 µM parthenolide improved the sensitivity of gemcitabine-resistant PaCa cell lines to gemcitabine. These results suggest that parthenolide may be used as a novel therapeutic agent for the treatment of gemcitabine-resistant PaCa. [ABSTRACT FROM AUTHOR]

Objective: Acute lymphoblastic leukemia (ALL) is a highly heterogeneous leukemia. Despite the current improvement inconventional chemotherapy and high survival rates, the outcomes remain challenging. Sesquiterpen extracted from theTanacetum parthenium, parthenolide, is a potential anticancer agent that can modulate the expression of miRNAs and induceapoptosis. The objective of this study was to investigate the effect of parthenolide in combination with vincristine and alone onthe apoptosis rate and expression of miR-125b-5p, miR-181b-5p, and miR-17-5p in the NALM6 cell line.Materials and Methods: In this experimental study, cell viability and metabolic activity were determined through MTTassay and PI staining. Flow cytometry was applied to evaluate the rate of apoptosis. The expression of miRNAs wasassessed using real-time polymerase chain reaction. Bioinformatic analyses, including Cytoscape, RNAhybrid, andsignaling pathway analysis were employed to investigate the association of miR-17-5p, miR-181b-5p and miR-125b-5p with apoptosis. Further, molecular docking served to validate the modulation of these miRNAs by parthenolide andvincristine treatment.Results: The MTT assay indicated that 7.7 μM of parthenolide decreased the metabolic activity to 50% after 48 hours. PIstaining analysis indicated that at concentrations below the half maximal inhibitory concentration, parthenolide caused50% cell death. Flow cytometric analysis indicated that parthenolide (1.925 μM) in combination with vincristine (1.2 nM)induced apoptosis in 83.2% of the cells. Real-time quantitative reverse transcription polymerase chain reaction (qRTPCR)analysis showed significant changes in the expression levels of miR-17-5p, miR-125b-5p, and miR-181b-5p.Moreover, the combination therapy downregulated the expression of miRNAs significantly. This was consistent with ourbioinformatic analysis demonstrating that the studied miRNAs are regulators of apoptosis. Finally, molecular dockingvalidated the modulation of the miRNAs by parthenolide and vincristine.Conclusion: Parthenolide in combination with vincristine triggers apoptosis at a high rate in the NALM6 cell line.Moreover, this combination therapy can decrease the expression of miR-17-5p, miR-181b-5p, and miR-125b-5p.

Most patients with muscle‐invasive bladder cancer (MIBC) are not cured with platinum chemotherapy. Up‐regulation of nuclear factor kappa light‐chain enhancer of activated B cells (NF‐κB) is a major mechanism underlying chemoresistance, suggesting that its pharmacological inhibition may increase platinum efficacy. NF‐κB signaling was investigated in two patient cohorts. The Cancer Genome Atlas (TCGA) was used to correlate NF‐κB signaling and patient survival. The efficacy of cisplatin plus the NF‐κB inhibitor dimethylaminoparthenolide (DMAPT) versus cisplatin or DMAPT alone was tested in vitro. Xenografted and immunocompetent MIBC mouse models were studied in vivo. Platinum‐naive claudin‐low MIBC showed constitutive NF‐κB signaling and this was associated with reduced disease‐specific survival in TCGA patients. Chemotherapy up‐regulated NF‐κB signaling and chemoresistance‐associated genes, including SPHK1, PLAUR, and SERPINE1. In mice, DMAPT significantly improved the efficacy of cisplatin in both models. The combination preserved body weight, renal function, and morphology, reduced muscle fatigue and IL‐6 serum levels, and did not aggravate immuno‐hematological toxicity compared with cisplatin alone. These data provide a rationale for combining NF‐κB inhibition with platinum‐based chemotherapy and conducting a clinical trial in MIBC patients.

The freshwater planarian is an emerging animal model in neuroscience due to its centralized nervous system that closely parallels closely parallels the nervous system of vertebrates. Cocaine, an abused drug, is the ‘founding member’ of the local anesthetic family. Parthenolide, a sesquiterpene lactone, acts as a behavioral and physiological antagonist of cocaine in planarians and rats, respectively. Previous work from our laboratory showed that both parthenolide and cocaine reduced planarian motility and that parthenolide reversed the cocaine-induced motility decrease at concentrations where parthenolide does not affect the movement of the worms. However, the exact mechanism of the cocaine/parthenolide antagonism is unknown. Here, we report the results of a Schild analysis to explore the parthenolide/cocaine relationship in the planarian Girardia tigrina. The Schild slopes of a family of concentration–response curves of parthenolide ± a single concentration of cocaine and vice versa were −0.55 and −0.36, respectively. These slopes were not statistically different from each other. Interestingly, the slope corresponding to the parthenolide ± cocaine (but not the cocaine ± parthenolide) data set was statistically different from −1. Our data suggest an allosteric relationship between cocaine and parthenolide for their effect on planarian motility. To the best of our knowledge, this is the first study about the mechanism of action of the antagonism between cocaine and parthenolide. Further studies are needed to determine the specific nature of the parthenolide/cocaine target(s) in this organism.

Background: In this study the formulation of parthenolide (PN), an anticancer agent extracted from a natural product, into a liposome (PN-liposome), was examined. The surface of the PN-liposome was modified using chitosan (PN-chitosome). By using real-time quantitative PCR and flow cytometry, we examined the release of PN-chitosomes, cytotoxicity, and ability to induce apoptosis in vitro. Methods and results: According to the present study, PN-chitosomes had a size of 251 nm which is acceptable for efficient enhanced permeation and retention (EPR) performance. PN-chitosomes were confirmed to be spherical in shape and size through FESEM analysis. In terms of encapsulation efficiency, 94.5% was achieved. PN-chitosome possessed a zeta potential of 34.72 mV, which was suitable for its stability. According to the FTIR spectra of PN and PN-chitosome, PN was chemically stable due to the intermolecular interaction between the liposome and the drug. After 48 h, only 10% of the PN was released from the PN-chitosome in PBS (pH 7.4), and less than 20% was released after 144 h. Conclusion: In a dose-dependent manner, PN-chitosome exhibited anticancer properties that were more cytotoxic against cancer cells than normal cells. Moreover, the formulation activated both the apoptosis pathway and cytotoxic genes in real-time qPCR experiments. According to the cytotoxicity and activating apoptosis of the prepared modified particle, PN-chitosome may be helpful in the treatment of cancer. [ABSTRACT FROM AUTHOR]

Objective: Acute lymphoblastic leukemia (ALL) is a highly heterogeneous leukemia. Despite the current improvement in conventional chemotherapy and high survival rates, the outcomes remain challenging. Sesquiterpen extracted from the Tanacetum parthenium, parthenolide, is a potential anticancer agent that can modulate the expression of miRNAs and induce apoptosis. The objective of this study was to investigate the effect of parthenolide in combination with vincristine and alone on the apoptosis rate and expression of miR-125b-5p, miR-181b-5p, and miR-17-5p in the NALM6 cell line. Materials and Methods: In this experimental study, cell viability and metabolic activity were determined through MTT assay and PI staining. Flow cytometry was applied to evaluate the rate of apoptosis. The expression of miRNAs was assessed using real-time polymerase chain reaction. Bioinformatic analyses, including Cytoscape, RNAhybrid, and signaling pathway analysis were employed to investigate the association of miR-17-5p, miR-181b-5p and miR-125b5p with apoptosis. Further, molecular docking served to validate the modulation of these miRNAs by parthenolide and vincristine treatment. Results: The MTT assay indicated that 7.7 µM of parthenolide decreased the metabolic activity to 50% after 48 hours. PI staining analysis indicated that at concentrations below the half maximal inhibitory concentration, parthenolide caused 50% cell death. Flow cytometric analysis indicated that parthenolide (1.925 µM) in combination with vincristine (1.2 nM) induced apoptosis in 83.2% of the cells. Real-time quantitative reverse transcription polymerase chain reaction (qRTPCR) analysis showed significant changes in the expression levels of miR-17-5p, miR-125b-5p, and miR-181b-5p. Moreover, the combination therapy downregulated the expression of miRNAs significantly. This was consistent with our bioinformatic analysis demonstrating that the studied miRNAs are regulators of apoptosis. Finally, molecular docking validated the modulation of the miRNAs by parthenolide and vincristine. Conclusion: Parthenolide in combination with vincristine triggers apoptosis at a high rate in the NALM6 cell line. Moreover, this combination therapy can decrease the expression of miR-17-5p, miR-181b-5p, and miR-125b-5p. [ABSTRACT FROM AUTHOR]

Parthenolide, a sesquiterpene lactone derived from Feverfew (Tanacetum parthenium) buds, has attracted significant attention due to its versatile pharmacological potential. It and its derivatives exhibit a range of bioactivities, including antibacterial, anti-leukemia, anticancer, and anti-inflammatory effects. Current research focuses on the structural modifications of parthenolide, exploring how alterations impact its bioactivity. This review aims to provide an overview of recent studies involving parthenolide's structural modifications and their corresponding impact on its biological functionality. By examining these modifications, the intricate relationship between structural changes and enhanced bioactivity is unveiled. The potential implications for drug development and therapeutic strategies are discussed. References have been downloaded via Web of Science, PubMed, Science Direct, and SciFinder Scholar. Publications that report only on the chemical properties of Parthenolide derivatives are beyond the scope of this review and are not included. [ABSTRACT FROM AUTHOR]

Most patients with muscle‐invasive bladder cancer (MIBC) are not cured with platinum chemotherapy. Up‐regulation of nuclear factor kappa light‐chain enhancer of activated B cells (NF‐κB) is a major mechanism underlying chemoresistance, suggesting that its pharmacological inhibition may increase platinum efficacy. NF‐κB signaling was investigated in two patient cohorts. The Cancer Genome Atlas (TCGA) was used to correlate NF‐κB signaling and patient survival. The efficacy of cisplatin plus the NF‐κB inhibitor dimethylaminoparthenolide (DMAPT) versus cisplatin or DMAPT alone was tested in vitro. Xenografted and immunocompetent MIBC mouse models were studied in vivo. Platinum‐naive claudin‐low MIBC showed constitutive NF‐κB signaling and this was associated with reduced disease‐specific survival in TCGA patients. Chemotherapy up‐regulated NF‐κB signaling and chemoresistance‐associated genes, including SPHK1, PLAUR, and SERPINE1. In mice, DMAPT significantly improved the efficacy of cisplatin in both models. The combination preserved body weight, renal function, and morphology, reduced muscle fatigue and IL‐6 serum levels, and did not aggravate immuno‐hematological toxicity compared with cisplatin alone. These data provide a rationale for combining NF‐κB inhibition with platinum‐based chemotherapy and conducting a clinical trial in MIBC patients. [ABSTRACT FROM AUTHOR]

In this study, we determined the therapeutic effect of parthenolide (PTL), the active component of Tanacetum parthenium, on neuropathic pain caused by paclitaxel (PTX), a chemotherapeutic drug frequently used in cancer treatment, at the gene and protein levels. To this end, 6 groups were formed: control, PTX, sham, 1 mg/PTL, 2 mg/kg PTL, and 4 mg/kg PTL. Pain formation was tested by Randall-Selitto analgesiometry and locomotor activity behavioral analysis. Then, PTL treatment was performed for 14 days. After the last dose of PTL was taken, Hcn2, Trpa1, Scn9a, and Kcns1 gene expressions were measured in rat brain (cerebral cortex/CTX) tissues. In addition, changes in the levels of SCN9A and KCNS1 proteins were determined by immunohistochemical analysis. Histopathological hematoxylin-eosin staining was also performed to investigate the effect of PTL in treating tissue damage on neuropathic pain caused by PTX treatment. When the obtained data were analyzed, pain threshold and locomotor activity decreased in PTX and sham groups and increased with PTL treatment. In addition, it was observed that the expression of the Hcn2, Trpa1, and Scn9a genes decreased while the Kcns1 gene expression increased. When protein levels were examined, it was determined that SCN9A protein expression decreased and the KCNS1 protein level increased. It was determined that PTL treatment also improved PTX-induced tissue damage. The results of this study demonstrate that non-opioid PTL is an effective therapeutic agent in the treatment of chemotherapy-induced neuropathic pain, especially when used at a dose of 4 mg/kg acting on sodium and potassium channels. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is among the prevalent gastrointestinal malignancies and is the leading reason for cancer-related mortality. There is an urgent need for novel anti-cancer drugs that are highly active against GC. Parthenolide extracted from the traditional medicines houpo and xinyi is a potential small molecular agent against GC. Methods: GC cell proliferation was assessed in vitro and in vivo using Cell Counting Kit-8 (CCK-8), the colony formation assay, and a xenograft tumor model. Cell death, the cytoskeleton, and mitochondrial membrane potential were examined using TUNEL, phalloidin, and JC-1 staining, respectively. Reactive oxygen and nitrogen species (ROS and RNS, respectively) were investigated using DCFH-DA and DAF-FM DA probes. Cell metabolites were discovered using metabonomics. The degree of DNA damage in GC cells was described using the comet assay and γ-H2AX immunofluorescence staining. Subsequently, protein levels were determined using western blotting. Furthermore, DNA agarose gel electrophoresis was performed to clarify whether parthenolide bound directly to DNA. Results: The potent anti-cancer mechanisms of parthenolide were attributed to its ability to interfere with microtubule assembly, trigger an oxidative stress response, damage DNA by directly binding to DNA or generating excessive free radicals, and ultimately activate the mitochondrial pathway, leading to GC cell death. This investigation determined that parthenolide exhibited a suppressive effect on GC cells in vitro and in vivo. Conclusion: Parthenolide is a potential GC therapeutic agent.

Alzheimer's disease (AD) stands as the predominant age-related neurodegenerative disorder, for which efficacious treatment remains elusive. An auspicious avenue for this disease lies in natural compounds sourced from tranditional medicine and plant origins. Parthenolide (PTN) is a natural product with multiple biological functionsand. Recent investigations have illuminated PTN's protective properties against neurological maladies; however, its potential therapeutic role against AD remains uncharted. This study aims to explore the role of PTN in treating AD. Our in vitro findings underscore PTN's bioactivity, as evidenced by its capacity to curtail apoptosis, reduce reactive oxygen species (ROS) production, and restore mitochondrial membrane potential in PC12 cells. Moreover, PTN treatment demonstrates a capacity to ameliorate deficits in spatial learning and memory in the 3 ×Tg-AD murine model. Notably, PTN's therapeutic efficacy surpasses that of a clinical agent, donepezil. Mechanistically, PTN's neuroprotective effects stem from its adept regulation of the AMPK/GSK3β(ser9)/Nrf2 signaling pathway and protection on neuronal cells from ROS-related apoptosis. Although the molecular target and the pre-clinical evaluations of PTN need to be further explored, this study indicates PTN as a potential agent or lead compound for the drug development against AD.

Background: This study aimed to explore the mechanism of parthenolide in inhibiting melanoma metastasis through network pharmacology and cell experiment. Materials and Methods: This research obtained the targets of the drug from the HERB database and PubChem database, the differential expression gene of metastatic cutaneous melanoma was obtained by differentially expression gene analysis of four Gene Expression Omnibus (GEO) datasets. The intersection of drug targets and differentially expression genes were considered to be related to drugs that inhibit metastasis of cutaneous melanoma. The STRING database was used to construct the protein–protein interaction (PPI) network, and cytohubba package in Cytoscape software was used to rank the PPI network targets. The enrichment analysis was used to screen out the relevance Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology to explain the underlying mechanism of drug inhibiting the cutaneous melanoma metastatic; cell viability, apoptosis, cell migration and protein levels were assessed using cell counting kit‐8 (CCK‐8) assay, Annexin V‐FITC/PI assay, wound healing assay, respectively. Finally, combining pathway maps and literature, we detected ATF4 and proteins upstream and downstream of ATF4 through Western blot. Results: A total of 87 targets were screened out from the drug databases, and a total of 1635 differentially expression genes was obtained from the differentially expression genes analysis of GEO datasets, a total of nine targets (VEGFA, ANXA5, ICAM1, SELE, NFKBIA, ATF4, CTNNB1, SELP and HPGDS) were considered to be related to drugs that inhibit metastasis of cutaneous melanoma. The result of enrichment analysis showed that the drug inhibits the metastatic of cutaneous melanoma through multiple pathways such as TNF signalling pathway, lipid and atherosclerosis and fluid shear stress and atherosclerosis, relevance multiple biological processes, cellular components and molecular function; cell experiments showed that parthenolide could inhibit tumour cell migration and induce a decrease of cell viability. Flow cytometry results showed that parthenolide induced tumour cell apoptosis. Western blot results suggested that parthenolide exerted therapeutic effects by regulating ATF4 protein and its upstream and downstream proteins, namely endoplasmic reticulum (ER) stress signalling pathway. Conclusion: Parthenolide induces ER stress‐dependent apoptosis in melanoma cells. We have previously explored the many mechanisms by which pathenolide inhibits melanoma metastasis through network pharmacology and found that ERS can interfere with melanoma metastasis, and our cellular assay selected one of the classical ERS pathways (PERK) to validate the network pharmacology results. [ABSTRACT FROM AUTHOR]

Traumatic axonal damage disrupts connections between neurons, leading to the loss of motor and sensory functions. Although damaged peripheral nerves can regenerate, recovery depends on the variety and severity of nerve damage. Thus, many phytochemicals have been studied for their ability to reduce peripheral nerve degeneration, and among them, Parthenolide (PTL), which is extracted from Feverfew has effects against production of free radicals, inflammation, and apoptosis. Thus, we conducted a study to investigate whether PTL has an inhibitory effect on peripheral nerve degeneration during peripheral nerve damage. To verify the effect of PTL on peripheral nerve degeneration process, a morphological comparison of peripheral nerves with and without PTL was performed. PTL significantly reduced the quantity of fragmented ovoid formations at 3DIV (days in vitro). Immunostaining for MBP revealed that the ratio of intact myelin sheaths increased significantly in sciatic nerve with PTL compared with absence of PTL at 3DIV. Furthermore, nerve fibers in the presence of PTL maintained the continuity of Neurofilament (NF) compared to those without at 3DIV. Immunostaining for LAMP1 and p75 NTR showed that the expression of LAMP1 and p75 NTR decreased in the nerve after PTL addition at 3DIV. Lastly, immunostaining for anti-Ki67 revealed that PTL inhibited Ki67 expression at 3DIV compared to without PTL. These results confirm that PTL inhibits peripheral nerve degenerative processes. PTL may be a good applicant to inhibit peripheral nerve degeneration. Our study examined the effect of Parthenolide in preventing degeneration of peripheral nerves by inhibiting the breakdown of peripheral axons and myelin, also inhibiting Schwann cell trans-dedifferentiation and proliferation. [ABSTRACT FROM AUTHOR]

The activation of the nuclear factor‐κB (NF‐κB) pathway has been associated with the development and progression of colorectal cancer (CRC). Parthenolide (PTL), a well‐known inhibitor of the NF‐κB pathway, has emerged as an alternative treatment. However, whether PTL activity is tumor cell‐specific and dependent on the mutational background has not been defined. This study investigated the antitumor role of PTL after tumor necrosis factor‐α (TNF‐α) stimulation in various CRC cell lines with different mutational statuses of TP53. We observed that CRC cells displayed different patterns of basal p‐IκBα levels; PTL reduced cell viability according to p‐IκBα levels and p‐IκBα levels varied among the cell lines according to the time of TNF‐α stimulation. High concentrations of PTL reduced more effectively p‐IκBα levels than low doses of PTL. However, PTL increased total IκBα levels in Caco‐2 and HT‐29 cells. In addition, PTL treatment downregulated p‐p65 levels in HT‐29 and HCT‐116 cells stimulated by TNF‐α in a dose‐dependent manner. Moreover, PTL induced cell death via apoptosis and reduced the proliferation rate of TNF‐α‐treated HT‐29 cells. Finally, PTL downregulated the messenger RNA levels of interleukin‐1β, a downstream cytokine of NF‐κB, reverted the E‐cadherin‐mediated disorganization of cell–cell contacts, and decreased the invasion of HT‐29 cells. Together, these results suggest a differential antitumoral activity of PTL on CRC cells with different mutational statuses of TP53, modulating cell death, survival, and proliferation underlying the NF‐κB pathway TNF‐α‐induced. Therefore, PTL has emerged as a potential treatment for CRC in an inflammatory NF‐κB‐dependent manner. [ABSTRACT FROM AUTHOR]

Objective To investigate the effects of parthenolide (PTL) on the differentiation of osteoblasts (MC3T3-E1) induced by dexamethasone (Dex) and the Wnt/β-catenin signal pathway. Methods MC3T3-E1 cells were treated with 2.5-80 μmol/L pyrethrone and dexamethasone. The cell proliferation activity was detected with CCK-8 method. MC3T3-E1 cells were divided into Control group, dexamethasone group (Dex group), low-, medium-, and high-concentration parthenolide groups (PTL-L group, PTL-M group, and PTL-H group), and high concentration parthenolide+Wnt inhibitor group (PTL-H+DKK1 group). ALP activity was detected with alkaline phosphatase (ALP) staining. The formation of mineralized nodules was observed with Alizarin red S staining. Western blotting was applied to detect the expression levels of Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), bone morphogenetic protein 2 (BMP2), cyclin D1, and Wnt/β-catenin pathway related proteins. Results Chrysanthemone with a concentration of 2.5-80 μmol/L promoted the proliferation of MC3T3-E1 cells induced by dexamethasone, so the Chrysanthemone with a concentration of 5.0, 10.0, and 20.0 μmol/L was selected for subsequent experiments. Compared with those in the control group, ALP activity and mineralized nodules in Dex group decreased obviously, and the expression levels of RUNX2, OCN, BMP2, Cyclin D1, Wnt3a, and β-catenin proteins decreased obviously (P<0.05). Compared with those in Dex group, ALP activity and the number of mineralized nodules in PTL-L group, PTL-M group, and PTL-H group increased in turn, and the protein expression levels of RUNX2, OCN, BMP2, Cyclin D1, Wnt3a, and β-catenin increased in turn (P<0.05). Compared with those in PTL-H group, ALP activity and mineralized nodules in PTL-H+DKK1 group decreased obviously, and the protein expression levels of UNX2, OCN, BMP2, Cyclin D1, Wnt3a, and β-catenin decreased obviously (P<0.05). Conclusion Parthenolide alleviates the inhibitory effects of dexamethasone on the proliferation and differentiation of osteoblasts by activating Wnt/β-catenin signal pathway. [ABSTRACT FROM AUTHOR]

Abstract Background With fast rising incidence, papillary thyroid carcinoma (PTC) is the most common head and neck cancer. Parthenolide, isolated from traditional Chinese medicine, inhibits various cancer cells, including PTC cells. The aim was to investigate the lipid profile and lipid changes of PTC cells when treated with parthenolide. Methods Comprehensive lipidomic analysis of parthenolide treated PTC cells was conducted using a UHPLC/Q-TOF–MS platform, and the changed lipid profile and specific altered lipid species were explored. Network pharmacology and molecular docking were performed to show the associations among parthenolide, changed lipid species, and potential target genes. Results With high stability and reproducibility, a total of 34 lipid classes and 1736 lipid species were identified. Lipid class analysis indicated that parthenolide treated PTC cells contained higher levels of fatty acid (FA), cholesterol ester (ChE), simple glc series 3 (CerG3) and lysophosphatidylglycerol (LPG), lower levels of zymosterol (ZyE) and Monogalactosyldiacylglycerol (MGDG) than controlled ones, but with no significant differences. Several specific lipid species were changed significantly in PTC cells treated by parthenolide, including the increasing of phosphatidylcholine (PC) (12:0e/16:0), PC (18:0/20:4), CerG3 (d18:1/24:1), lysophosphatidylethanolamine (LPE) (18:0), phosphatidylinositol (PI) (19:0/20:4), lysophosphatidylcholine (LPC) (28:0), ChE (22:6), and the decreasing of phosphatidylethanolamine (PE) (16:1/17:0), PC (34:1) and PC (16:0p/18:0). Four key targets (PLA2G4A, LCAT, LRAT, and PLA2G2A) were discovered when combining network pharmacology and lipidomics. Among them, PLA2G2A and PLA2G4A were able to bind with parthenolide confirmed by molecular docking. Conclusions The changed lipid profile and several significantly altered lipid species of parthenolide treated PTC cells were observed. These altered lipid species, such as PC (34:1), and PC (16:0p/18:0), may be involved in the antitumor mechanisms of parthenolide. PLA2G2A and PLA2G4A may play key roles when parthenolide treated PTC cells.

Sesquiterpene lactones - such as those found in chicory - are considered promising bioactive compounds. These small molecules have shown several health benefits for various diseases, including brain disorders. However, it is unknown whether these compounds can cross the blood-brain barrier (BBB), and which could be the effects on brain microvascular endothelial cells. We show that six sesquiterpene lactones evaluated in an in vitro model of the BBB have different capacities to be transported through the barrier. Costunolide presented more than 20 % of transport while lactucin, 11β-13-dihydrolactucin, 11β-13-dihydrolactucopicrin, and parthenolide presented between 10 % and 20 %, whilst almost no transport was detected for lactucopicrin. Furthermore, costunolide and parthenolide reduced P-gp ABC transporter expression alongside an increase in caveolin-1, the main protein of caveolae. Remarkably, these two compounds improved barrier tightness by increasing the expression of both tight and adherens junctions. These findings open a new avenue to explore costunolide and parthenolide as promising compounds for brain therapies.

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.

Parthenolide (PA) shows promising therapeutic effect on ulcerative colitis and colorectal cancer, and can ameliorate colon inflammation in a gut microbiota-dependent manner. In the present study, an effective UHPLC-QTOF-MS method aided by rat intestinal microbiota biotransformation was applied to characterize 34 metabolites (including a series of characteristic R-Sn-R type organosulfur compounds) of PA for the first time. Noteworthy, organosulfur metabolites PA-S2-PA and PA-S3-PA could react with cysteine to generate H2S via persulfide/polysulfide intermediates and significantly inhibit colonic cancer HT-29 and HCT116 cells viability and pro-inflammatory cytokine IL-6 release. These results indicated that PA and its organosulfur metabolites involved in H2S regulation in intestinal tract, which should be beneficial for a more in-depth understanding of the action mechanism of PA.

Simple Summary: Breast cancer has a high prevalence in females worldwide, with persistent challenges in its treatment. Gold nanoparticles (AuNPs) have gained popularity for their anti-tumorigenic role, but their therapeutic function in microRNA (miRNA) regulation has never been explored. This study determines the potential of chemically engineered AuNPs against tumorigenic protein matrix metallopeptidase 9 (MMP-9). The data shows that in breast cancer cells, microRNA-204-5p is a direct regulator of MMP-9. AuNPs inhibit MMP-9 expression through the upregulation of microRNA-204-5p in a dose-dependent manner. Moreover, AuNPs also inhibit nuclear transcription factor, NF-κB activation in breast cancer cells transfected with anti-hsa-miR-204. In short, AuNPs are stable and non-toxic to breast cancer cells. AuNPs inhibit MMP-9 expression and NF-κBp65 induction and upregulate microRNA-204. These novel therapeutic potentials of AuNPs on breast cancer cells provide insight that AuNPs inhibit carcinogenic activity via microRNAs. 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. [ABSTRACT FROM AUTHOR]

Objective To investigate the protective effects of parthenolide (PTL) on intestinal barrier function in septic rats. Methods The septic model of rats was established by cecal ligation and puncture (CLP), and SD rats (200±20 g, male/female) were randomly divided into 6 groups: normal control (NC) group, sepsis (Sep) group, conventional treatment (LR) group (lactated Ringer's solution resuscitation+dopamine+cefuroxime sodium), and parthenolide (PTL) groups (1, 5 and 10 mg/kg parthenolide respectively on the basis of LR group). The changes of arterial blood pressure, survival rate and survival time of rats in each group were observed, and the optimal concentration of parthenolide in the treatment was determined. Moreover, the effects of parthenolide (at the optimal concentration) on the intestinal permeability, intestinal pathology, inflammatory cytokine levels, as well as liver and kidney functions in septic rats were further investigated. Results As compared with the NC group, the survival rate and survival time of septic rats were significantly decreased, so was the mean arterial pressure (MAP), while the levels of blood inflammatory cytokines were increased, and the liver and kidney functions were damaged. Conventional treatment improved the survival rate and survival time of septic rats to a certain extent, reduced the levels of inflammation cytokines and alleviated the liver and kidney damages. When compared with the LR group, the survival rates of 1, 5, and 10 mg/kg PTL groups were increased by 6.3%, 43.8%, and 18.8%, respectively, and the MAP in the PTL groups was elevated by 1.4%, 12.8%, and 7.1%, respectively, with those of 5 mg/kg PTL more significant. Further research found that PTL remarkably ameliorated the intestinal barrier function in septic rats, shown as a 55.1% reduction in the content of intestinal Evans blue (EB), a 69.5% decline in blood D-lactic acid concentration as compared with the LR group (P < 0.05), along with an improvement in intestinal epithelial structure, and a decrease in epithelial cell necrosis. In addition, PTL reduced the inflammatory cytokine levels greatly and improved the liver and kidney functions in septic rats. Conclusion PTL shows obvious protective effects on the intestinal barrier function of septic rats, and its mechanism may be related to the inhibition of septic inflammatory response.

Background: With fast rising incidence, papillary thyroid carcinoma (PTC) is the most common head and neck cancer. Parthenolide, isolated from traditional Chinese medicine, inhibits various cancer cells, including PTC cells. The aim was to investigate the lipid profile and lipid changes of PTC cells when treated with parthenolide. Methods: Comprehensive lipidomic analysis of parthenolide treated PTC cells was conducted using a UHPLC/Q-TOF–MS platform, and the changed lipid profile and specific altered lipid species were explored. Network pharmacology and molecular docking were performed to show the associations among parthenolide, changed lipid species, and potential target genes. Results: With high stability and reproducibility, a total of 34 lipid classes and 1736 lipid species were identified. Lipid class analysis indicated that parthenolide treated PTC cells contained higher levels of fatty acid (FA), cholesterol ester (ChE), simple glc series 3 (CerG3) and lysophosphatidylglycerol (LPG), lower levels of zymosterol (ZyE) and Monogalactosyldiacylglycerol (MGDG) than controlled ones, but with no significant differences. Several specific lipid species were changed significantly in PTC cells treated by parthenolide, including the increasing of phosphatidylcholine (PC) (12:0e/16:0), PC (18:0/20:4), CerG3 (d18:1/24:1), lysophosphatidylethanolamine (LPE) (18:0), phosphatidylinositol (PI) (19:0/20:4), lysophosphatidylcholine (LPC) (28:0), ChE (22:6), and the decreasing of phosphatidylethanolamine (PE) (16:1/17:0), PC (34:1) and PC (16:0p/18:0). Four key targets (PLA2G4A, LCAT, LRAT, and PLA2G2A) were discovered when combining network pharmacology and lipidomics. Among them, PLA2G2A and PLA2G4A were able to bind with parthenolide confirmed by molecular docking. Conclusions: The changed lipid profile and several significantly altered lipid species of parthenolide treated PTC cells were observed. These altered lipid species, such as PC (34:1), and PC (16:0p/18:0), may be involved in the antitumor mechanisms of parthenolide. PLA2G2A and PLA2G4A may play key roles when parthenolide treated PTC cells. [ABSTRACT FROM AUTHOR]

Parthenolide (PTL or PAR) was first isolated from Magnolia grandiflora and identified as a small molecule cancer inhibitor. PTL has the chemical structure of C15H20O3 with characteristics of sesquiterpene lactones and exhibits the biological property of inhibiting DNA biosynthesis of cancer cells. In this review, we summarise the recent research progress of medicinal PTL, including the therapeutic effects on skeletal diseases, cancers, and inflammation-induced cytokine storm. Mechanistic investigations reveal that PTL predominantly inhibits NF-κB activation and other signalling pathways, such as reactive oxygen species. As an inhibitor of NF-κB, PTL appears to inhibit several cytokines, including RANKL, TNF-α, IL-1β, together with LPS induced activation of NF-κB and NF-κB -mediated specific gene expression such as IL-1β, TNF-α, COX-2, iNOS, IL-8, MCP-1, RANTES, ICAM-1, VCAM-1. It is also proposed that PTL could inhibit cytokine storms or hypercytokinemia triggered by COVID-19 via blocking the activation of NF-κB signalling. Understanding the pharmacologic properties of PTL will assist us in developing its therapeutic application for medical conditions, including arthritis, osteolysis, periodontal disease, cancers, and COVID-19-related disease. [ABSTRACT FROM AUTHOR]

Nephrotoxicity is a serious complication that limits the clinical use of gentamicin (GEN). Parthenolide (PTL) is a sesquiterpene lactone derived from feverfew with various therapeutic benefits. However, PTL possesses low oral bioavailability. This study aimed to evaluate the therapeutic protective effects of PTL-phytosomes against GEN-induced nephrotoxicity in rats. The PTL was prepared as phytosomes to improve the pharmacological properties with a particle size of 407.4 nm, and surface morphology showed oval particles with multiple edges. Rats were divided into six groups: control, nano-formulation plain vehicle, PTL-phytosomes (10 mg/kg), GEN (100 mg/kg), GEN + PTL-phytosomes (5 mg/kg), and GEN + PTL-phytosomes (10 mg/kg). The administration of PTL-phytosomes alleviated GEN-induced impairment in kidney functions and histopathological damage, and decreased kidney injury molecule-1 (KIM-1). The anti-oxidative effect of PTL-phytosomes was demonstrated by the reduced malondialdehyde (MDA) concentration and increased superoxide dismutase (SOD) and catalase (CAT) activities. Furthermore, PTL-phytosomes treatment significantly enhanced sirtuin 1 (Sirt-1), nuclear factor erythroid-2-related factor-2 (Nrf2), NAD(P)H quinone dehydrogenase 1 (NQO1), and heme oxygenase-1 (HO-1). Additionally, PTL-phytosomes treatment exhibited anti-inflammatory and anti-apoptotic properties in the kidney tissue. These findings suggest that PTL-phytosomes attenuate renal dysfunction and structural damage by reducing oxidative stress, inflammation, and apoptosis in the kidney. [ABSTRACT FROM AUTHOR]

Objectives: Apigenin and parthenolide as natural products have potent antioxidant and anti-inflammatory outcomes that could make them a perfect option for endometriosis therapy. This study aimed to determine the effects of apigenin and parthenolide on created endometrial implants in a rat model of endometriosis. Methods: Thirty-nine mature, female Sprague-Dawley rats were assigned randomly to six experimental groups four weeks after endometriosis induction. Group 1 (n = 5): Control (CTRL) that opened and closed the abdomen; Group 2 (n = 6): Peritoneal and ovarian endometriosis (POE) + drug-free; Group 3 (n = 7): POE+ Apigenin (APG) (50 mg/kg); Group 4 (n = 7): POE+ Parthenolide (PTL) (10 mg/kg); Group 5 (n = 7): POE+ Apigenin (APG) (50 mg/kg) + Parthenolide (PTL) (10 mg/kg); Group 6 (n = 7): POE+ DMSO. An endometriosis model was created, and histopathological analysis and biochemical evaluation were performed. Serum and peritoneal levels of pro-and-anti-inflammatory cytokine, and oxidative stress of implant tissue were measured. Results: Serum IL-37 levels decreased significantly in the APG-treated group compared to the drug-free group (p = 0.016). The peritoneum and ovary endometriosis histopathologic scores were significantly lower in APG-treated (p = 0.001) and PTL-treated (p = 0.001) groups in comparison to the drug-free group. The oxidative stress index (OSI) values were increased statistically significantly in ovary endometriosis tissue in the drug-free group, (p = 0.001). However, compared to the drug-free group, OSI values decreased statistically significantly in the APG-treated group (p = 0.003) Conclusions: The application of apigenin caused a decrease in oxidative stress and an improvement in histopathological grade. Apigenin may be a novel therapeutic agent for the treatment of endometriosis. [ABSTRACT FROM AUTHOR]

Feverfew (Tanacetum parthenium (L.) Schults-bip.) is a perennial medicinal plant from Asteraceae family and a rich source of sesquiterpene lactone parthenolide with anti-cancer, anti-inflammatory, anti-spasm, and especially anti-migraine properties. In this study, the aerial parts of five wild populations of this plant were harvested from Mazandaran (Marzanabad, Siah Bisheh, and Valiabad) and Tehran (Ahar and Gachsar) provinces at full flowering stage in 2020 to evaluate their morphological traits and parthenolide content. The results showed a significant difference at 1% probability level among the studied populations for all the traits. The highest plant height (130 cm), flower dry weight (8.60 g.plant-1), and parthenolide content (0.33 mg.g-1 dry weight) were observed in Gachsar, Siah Bisheh, and Marzanabad populations, respectively. Parthenolide content correlated with leaf length, number of lateral branches, and crown diameter negatively and with number of capitols positively and significantly at 5% probability level. Cluster analysis put the feverfew populations in two main groups. Principal coordinate analysis showed that the first three factors could explain 93.06% of the total variance. Overall, the results indicated the existence of high diversity in feverfew populations for use in breeding programs and cultivation and domestication of this species. [ABSTRACT FROM AUTHOR]

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.

Acute lung injury (ALI) is a respiratory failure disease associated with high mortality rates in patients. The primary pathological damage is attributed to the excessive release of pro-inflammatory mediators in pulmonary tissue. However, specific therapy for ALI has not been developed. In this study, a series of novel ferulic acid-parthenolide (FA-PTL) and ferulic acid-micheliolide (FA-MCL) hybrid derivatives were designed, synthesized, and evaluated for their anti-inflammatory activities in vitro. Compounds 2, 4, and 6 showed pronounced anti-inflammatory activity against LPS-induced expression of pro-inflammatory cytokines in vitro. Importantly, compound 6 displayed good water solubility, and treatment of mice with compound 6 (10 mg/kg) significantly prevented weight loss and ameliorated inflammatory cell infiltration and edema in lung tissue, as well as improving the alveolar structure. These results suggest that compound 6 (((1aR,7aS,8R,10aS,10bS,E)-8-((dimethylamino)methyl)-1a-methyl-9-oxo-1a,2,3,6,7,7a,8,9,10a,10b-decahydrooxireno[2′,3′:9,10]cyclodeca[1,2-b]furan-5-yl)methyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate 2-hydroxypropane-1,2,3-tricarboxylate) might be considered as a lead compound for further evaluation as a potential anti-ALI agent.

We previously established pancreatic cancer (PaCa) cell lines resistant to gemcitabine and found that the activity of nuclear factor κB (NF-κB) was enhanced upon the acquisition of gemcitabine resistance. Parthenolide, the main active ingredient in feverfew, has been reported to exhibit antitumor activity by suppressing the NF-κB signaling pathway in several types of cancers. However, the antitumor effect of parthenolide on gemcitabine-resistant PaCa has not been elucidated. Here, we confirmed that parthenolide significantly inhibits the proliferation of both gemcitabine-resistant and normal PaCa cells at concentrations of 10 µM and higher, and that the NF-κB activity is significantly inhibited, even by 1 µM parthenolide. In Matrigel invasion assays and angiogenesis assays, the invasive and angiogenic potentials were higher in gemcitabine-resistant than normal PaCa cells and were inhibited by a low concentration of parthenolide. Furthermore, Western blotting showed suppressed MRP1 expression in gemcitabine-resistant PaCa treated with a low parthenolide concentration. In a colony formation assay, the addition of 1 µM parthenolide improved the sensitivity of gemcitabine-resistant PaCa cell lines to gemcitabine. These results suggest that parthenolide may be used as a novel therapeutic agent for the treatment of gemcitabine-resistant PaCa.

Parthenolide, a natural product from the feverfew plant and member of the large family of sesquiterpene lactones, exerts multiple biological and therapeutic activities including anti-inflammatory and anti-cancer effects. Here, we further study the parthenolide mechanism of action using activity-based protein profiling-based chemoproteomic platforms to map additional covalent targets engaged by parthenolide in human breast cancer cells. We find that parthenolide, as well as other related exocyclic methylene lactone-containing sesquiterpenes, covalently modify cysteine 427 of focal adhesion kinase 1 (FAK1), leading to impairment of FAK1-dependent signaling pathways and breast cancer cell proliferation, survival, and motility. These studies reveal a functional target exploited by members of a large family of anti-cancer natural products.

The coronavirus papain-like protease (PLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for viral polypeptide cleavage and the deISGylation of interferon-stimulated gene 15 (ISG15), which enable it to participate in virus replication and host innate immune pathways. Therefore, PLpro is considered an attractive antiviral drug target. Here, we show that parthenolide, a germacrane sesquiterpene lactone, has SARS-CoV-2 PLpro inhibitory activity. Parthenolide covalently binds to Cys-191 or Cys-194 of the PLpro protein, but not the Cys-111 at the PLpro catalytic site. Mutation of Cys-191 or Cys-194 reduces the activity of PLpro. Molecular docking studies show that parthenolide may also form hydrogen bonds with Lys-192, Thr-193, and Gln-231. Furthermore, parthenolide inhibits the deISGylation but not the deubiquitinating activity of PLpro in vitro. These results reveal that parthenolide inhibits PLpro activity by allosteric regulation.

Nanomaterials can be used as elicitors for improving the biosynthesis of secondary metabolites in medicinal plants. The present study was conducted to assay the titanium dioxide-nanoparticles (TiO 2 -NPs) effects on feverfew (Tanacetum parthenium) as an anti-cancer plant. The study showed that TiO 2 -NPs application increased the amounts of the main compounds and oxygenated monoterpene in essential oils, thereby causing an improvement in the quantity and quality of the essential oils compared to control. The highest effect was related to 1500 ppm TiO 2 -NPs concentration. Regarding parthenolide, TiO 2 -NPs had no positive effect on parthenolide content and the highest content was observed in control. Increasing the concentrations over 1500 ppm resulted in a decrease in chlorophyll content, capitule diameter, flower yield, and harvest index compared to other concentrations and control. Additionally, the results indicated that TiO 2 -NPs foliar spray reduced flower number, biological yield, fresh weight, and dry weights compared with untreated plants. The increase in quality and content of essential oil and lack of increase in parthenolide content, and reproductive and vegetative characteristics showed that TiO 2 -NPs mainly affected the content and composition of essential oil. Totally, the application of TiO2-NPs in terms of positive effect on the yield and metabolites (without damaging biological effects) can be recommended and followed up to the concentration of 1000 ppm. Overall, the results indicated that improving the synthesis of valuable medicinal metabolites using TiO 2 -NPs has promising results depending on the type of species, concentration used and target metabolites. [Display omitted] • TiO 2 nanoparticles improved quantity and quality of essential oil. • The main compounds amounts significantly enhanced with TiO 2 nanoparticles. • High TiO 2 nanoparticles rate was associated with low reproductive and vegetative growth. • TiO 2 nanoparticles had no positive effect on the parthenolide content. [ABSTRACT FROM AUTHOR]

Feverfew is an herb used to treat different diseases such as migraine headaches. Due to the economic aspect of its metabolites in the pharmaceutical industry, establishing new approaches to produce the compounds on a large scale is essential. To investigate the effects of stimulators on parthenolide synthesis, feverfew plants were treated with different elicitors, including methyl jasmonate, salicylic acid, NaCl, aluminum oxide, and magnesium aluminate spinel nanoparticles. The expression of genes, E-beta-caryophyllene synthase, Germacrene A synthase, and Costunolide Synthase in the metabolite biosynthesis pathway was examined using qRT-PCR. In addition, parthenolide content, total flavonoids, and polyphenols antioxidant activity were evaluated by HPLC and spectrophotometry. Our results indicated that methyl jasmonate and salicylic acid were more effective on the final concentration of parthenolide, but magnesium aluminate spinel affected the genes' expression, positively. The results show that the elicitors can be used to increase the metabolite in the plant, commercially. [ABSTRACT FROM AUTHOR]

Tao An,1 Huanhuan Yin,1 Yanting Lu,2 Feng Liu1,3 1School of Pharmaceutical Sciences, Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong Province, People’s Republic of China; 2College of TCM, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China; 3Key Laboratory for Applied Technology of Sophisticated Analytical Instruments of Shandong Province, Shandong Analysis and Test Center (SDATC), Qilu University of Technology (Shandong Academy of Sciences), Jinan, Shandong Province, People’s Republic of ChinaCorrespondence: Feng Liu, Key Laboratory for Applied Technology of Sophisticated Analytical Instruments of Shandong Province, Shandong Analysis and Test Center (SDATC), Qilu University of Technology (Shandong Academy of Sciences), 19th Keyuan Road, Jinan, 250014, Shandong Province, People’s Republic of China, Tel +86 531-82605319, Fax +86 531-82964889, Email liufeng8109@163.comAbstract: Plant-derived sesquiterpene lactones are promising natural sources for the discovery of anti-cancer drugs. As an extensively studied sesquiterpene lactone, the tumor suppression effect of parthenolide (PTL) has been clarified by targeting a number of prominent signaling pathways and key protein regulators in carcinogenesis. Notably, PTL was also the first small molecule reported to eradicate cancer stem cells. Nevertheless, the clinical application of PTL as an antitumor agent remains limited, owing to some disadvantages such as low water solubility and poor bioavailability. Thus, nanomedicine has attracted much interest because of its great potential for transporting poorly soluble drugs to desired body sites. In view of the significant advantages over their free small-molecule counterparts, nanoparticle delivery systems appear to be a potential solution for addressing the delivery of hydrophobic drugs, including PTL. In this review, we summarized the key anticancer mechanisms underlined by PTL as well as engineered PTL nanoparticles synthesized to date. Therefore, PTL nanoformulations could be an alternative strategy to maximize the therapeutic value of PTL.Graphical Abstract: Keywords: parthenolide, signaling pathways, cellular processes, nanomedicine, cancer therapy

Abstract Background Parthenolide has anti-inflammatory, immunomodulatory and anti-cancer activities. But its effect on thyroid cancer cells is still largely unknown. Methods Label-free quantitative proteomics and bioinformatics analysis were used to investigate the differentially expressed proteins and their functions in thyroid cancer treated with parthenolide and control pair. Hoechst 33258 fluorescent staining and Annexin V-FITC/PI double staining flow cytometry were used to detected BCPAP cells apoptosis. Parallel reaction monitoring (PRM) and quantitative real-time PCR were used to verify the expression of apoptosis-related differential proteins and their mRNA. Results Sixty up-regulated and 96 down-regulated differentially expressed proteins were identified in parthenolide treated thyroid cancer cells BCPAP compared with control thyroid cancer cells. The proteins were mainly relevant to various biological processes that included metabolic processes, response to extracellular stimulus and interaction with host. The molecular functions of most differentially expressed proteins were associated with binding functions and nucleotidyltransferase activity. According to the Kyoto Encyclopedia of Genes and Genomes, the differentially expressed proteins identified are primarily related to various types of metabolic pathways and DNA replication. In cell experiments in vitro, with the increase of the dose of parthenolide, the number of cells gradually decreased, the apoptosis rate gradually increased. PRM verified that the apoptosis-related proteins HMOX1 and GCLM were up-regulated and IL1B was down-regulated in BCPAP cells treated with parthenolide. The mRNA expressions of HMOX1, GCLM, ITGA6 and CASP8 were up-regulated and HSPA1A was down-regulated by PCR. Conclusions Parthenolide may influence the biological behavior of human thyroid cancer cells by affecting the expression of proteins related to cell metabolism and DNA replication. Parthenolide induced significant cellular morphological changes and apoptosis in human thyroid cancer cells, leading to an anti-proliferative effect.

This study aimed to evaluate the efficacy and therapeutic mechanism of parthenolide (PTL) in breast cancer (BC) through a comprehensive strategy integrating network pharmacology, single-cell RNA sequencing (scRNA-seq) and metabolomics. In network pharmacology, 70 therapeutic targets were identified, of which 16 core targets were filtered out through seven classical algorithms of Cytohubba plugin. Additionally, the hub module of PPI network was extracted using MCODE plugin. Molecular docking and molecular dynamics simulation showed a potent binding affinity between PTL and JNK, subsequently validated by MST and SPR assays. Further, Mendelian randomization analysis indicated that JNK was causally associated with BC. GO and KEGG enrichment analyses revealed that PTL counteracted BC via promoting ROS generation, inducing apoptosis and suppressing proliferation, which potentially involved the coordinated regulation of MAPK and FoxO1 pathways. Moreover, ssGSEA and scRNA-seq analysis suggested that PTL may act on T cell immune microenvironment of BC. Subsequently, these bioinformatics-based predictions were experimentally validated using in-vitro and in-vivo models. Finally, metabolome profiling unveiled that PTL remodeled the glycine, serine and threonine metabolism as well as biosynthesis of unsaturated fatty acids, and thereby contributed to BC inhibition. From molecular, immune and metabolic perspectives, this study not only provided a unique insight into the mechanistic details of PTL against BC, but also proposed a novel promising therapeutic strategy for BC. • A comprehensive interpretation integrating network pharmacology, single-cell RNA sequencing, and metabolomics. • The combination of molecular docking, MD simulation, MST assay, and SPR assay. • The combined application of DEG analysis, LASSO regression analysis and WGCNA algorithm. • In-vitro and in-vivo experimental verification. • Provide a reliable direction on the molecular design of the novel anti-BC agents. [ABSTRACT FROM AUTHOR]

• Parthenolide significantly alleviated the symptoms of PH rats via attenuating pulmonary arterial remodeling. • Parthenolide could prevent the proliferation and migration of PASMCs and induces the apoptosis of PASMCs. • Parthenolide inhibited signal transducer and activator of transcription-3 (STAT3) signaling. • Parthenolide markedly inhibited STAT3 phosphorylation and nuclear translocation in PASMCs. • Parthenolide could directly bind to STAT3. Pulmonary hypertension (PH) is a chronic lung disease characterized by the progressive pulmonary vascular remodeling with increased pulmonary arterial pressure and right ventricular failure. Pulmonary vascular remodeling involves the proliferation, migration, and resistance to apoptosis of pulmonary artery smooth cells (PASMCs). Parthenolide (PTN) is a bioactive compound derived from a traditional medical plant feverfew (Tanacetum parthenium), and it has been studied for treatment of pulmonary fibrosis, lung cancer, and other related ailments. However, the function of PTN in the treatment of PH has not been studied. This study aimed to evaluate the anti-proliferation and pro-apoptosis effects of PTN on PH and investigate its potential mechanisms. An in vivo hypoxia-induced pulmonary hypertension (HPH) model was established by maintaining male rats in a hypoxia chamber (10% O 2) for 3 weeks, and PTN was intraperitoneally administered at the dose of 10 or 30 mg/kg. We assessed the impact of PTN on mean pulmonary arterial pressure (mPAP), pulmonary vascular remodeling, and right ventricular hypertrophy. In vitro , we evaluated hypoxia-induced cellular proliferation, migration, and apoptosis of rat PASMCs. Proteins related to the STAT3 signaling axis were analyzed by western blotting and immunofluorescence assays. Recovery experiments were performed using the STAT3 activator, colivelin TFA. PTN significantly alleviated the symptoms of HPH rats by attenuating pulmonary arterial remodeling. It also prevented the proliferation and migration of PASMCs. PTN also induced the apoptosis of PASMCs. PTN could directly interact with STAT3 and markedly inhibited STAT3 phosphorylation and nuclear translocation. In vitro , and in vivo experiments demonstrated that overexpression of STAT3 partially suppressed the effect of PTN. Our study indicated that PTN alleviated hypoxia-induced pulmonary hypertension in rats by suppressing STAT3 activity. [ABSTRACT FROM AUTHOR]