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1.
Oncoimmunology ; 13(1): 2363000, 2024.
Article in English | MEDLINE | ID: mdl-38846085

ABSTRACT

NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in most solid cancers, emerging as a promising target for tumor-selective killing. ß-Lapachone (ß-Lap), an NQO1 bioactivatable drug, exhibits significant antitumor effects on NQO1-positive cancer cells by inducing immunogenic cell death (ICD) and enhancing tumor immunogenicity. However, the interaction between ß-Lap-mediated antitumor immune responses and neutrophils, novel antigen-presenting cells (APCs), remains unknown. This study demonstrates that ß-Lap selectively kills NQO1-positive murine tumor cells by significantly increasing intracellular ROS formation and inducing DNA double strand breaks (DSBs), resulting in DNA damage. Treatment with ß-Lap efficiently eradicates immunocompetent murine tumors and significantly increases the infiltration of tumor-associated neutrophils (TANs) into the tumor microenvironment (TME), which plays a crucial role in the drug's therapeutic efficacy. Further, the presence of ß-Lap-induced antigen medium leads bone marrow-derived neutrophils (BMNs) to directly kill murine tumor cells, aiding in dendritic cells (DCs) recruitment and significantly enhancing CD8+ T cell proliferation. ß-Lap treatment also drives the polarization of TANs toward an antitumor N1 phenotype, characterized by elevated IFN-ß expression and reduced TGF-ß cytokine expression, along with increased CD95 and CD54 surface markers. ß-Lap treatment also induces N1 TAN-mediated T cell cross-priming. The HMGB1/TLR4/MyD88 signaling cascade influences neutrophil infiltration into ß-Lap-treated tumors. Blocking this cascade or depleting neutrophil infiltration abolishes the antigen-specific T cell response induced by ß-Lap treatment. Overall, this study provides comprehensive insights into the role of tumor-infiltrating neutrophils in the ß-Lap-induced antitumor activity against NQO1-positive murine tumors.


Subject(s)
NAD(P)H Dehydrogenase (Quinone) , Naphthoquinones , Neutrophils , Tumor Microenvironment , Animals , Naphthoquinones/pharmacology , Naphthoquinones/therapeutic use , NAD(P)H Dehydrogenase (Quinone)/metabolism , NAD(P)H Dehydrogenase (Quinone)/genetics , Neutrophils/drug effects , Neutrophils/metabolism , Neutrophils/immunology , Mice , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Mice, Inbred C57BL , Cell Line, Tumor , Neutrophil Infiltration/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Humans , Female , Phenotype
2.
Plant Cell Rep ; 43(6): 160, 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38825616

ABSTRACT

KEY MESSAGE: LeBAHD56 is preferentially expressed in tissues where shikonin and its derivatives are biosynthesized, and it confers shikonin acylation in vivo. Two WRKY transcriptional factors might regulate LeBAHD56's expression. Shikonin and its derivatives, found in the roots of Lithospermum erythrorhizon, have extensive application in the field of medicine, cosmetics, and other industries. Prior research has demonstrated that LeBAHD1(LeSAT1) is responsible for the biochemical process of shikonin acylation both in vitro and in vivo. However, with the exception of its documented in vitro biochemical function, there is no in vivo genetic evidence supporting the acylation function of the highly homologous gene of LeSAT1, LeBAHD56(LeSAT2), apart from its reported role. Here, we validated the critical acylation function of LeBAHD56 for shikonin using overexpression (OE) and CRISPR/Cas9-based knockout (KO) strategies. The results showed that the OE lines had a significantly higher ratio of acetylshikonin, isobutyrylshikonin or isovalerylshikonin to shikonin than the control. In contrast, the KO lines had a significantly lower ratio of acetylshikonin, isobutyrylshikonin or isovalerylshikonin to shikonin than controls. As for its detailed expression patterns, we found that LeBAHD56 is preferentially expressed in roots and callus cells, which are the biosynthesis sites for shikonin and its derivatives. In addition, we anticipated that a wide range of putative transcription factors might control its transcription and verified the direct binding of two crucial WRKY members to the LeBAHD56 promoter's W-box. Our results not only confirmed the in vivo function of LeBAHD56 in shikonin acylation, but also shed light on its transcriptional regulation.


Subject(s)
Gene Expression Regulation, Plant , Lithospermum , Naphthoquinones , Plant Proteins , Plants, Genetically Modified , Naphthoquinones/metabolism , Lithospermum/genetics , Lithospermum/metabolism , Acylation , Plant Proteins/genetics , Plant Proteins/metabolism , Plant Roots/genetics , Plant Roots/metabolism , Transcription Factors/metabolism , Transcription Factors/genetics , CRISPR-Cas Systems , Anthraquinones
3.
J Exp Clin Cancer Res ; 43(1): 159, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38840237

ABSTRACT

BACKGROUND: Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation. EXPERIMENTAL DESIGN: We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization. RESULTS: EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy. CONCLUSION: Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.


Subject(s)
Carcinoma, Renal Cell , DNA Repair , Kidney Neoplasms , Survivin , TOR Serine-Threonine Kinases , Xenograft Model Antitumor Assays , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/radiotherapy , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/metabolism , Animals , Survivin/metabolism , Humans , Mice , Cell Line, Tumor , Kidney Neoplasms/pathology , Kidney Neoplasms/radiotherapy , Kidney Neoplasms/drug therapy , DNA Repair/drug effects , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Mitosis/drug effects , Mitosis/radiation effects , Imidazoles/pharmacology , DNA Damage , Everolimus/pharmacology , Naphthoquinones/pharmacology , Naphthoquinones/therapeutic use , Radiation-Sensitizing Agents/pharmacology , Radiation-Sensitizing Agents/therapeutic use , Liposomes/pharmacology , MTOR Inhibitors/pharmacology , MTOR Inhibitors/therapeutic use
5.
Int J Immunopathol Pharmacol ; 38: 3946320241260262, 2024.
Article in English | MEDLINE | ID: mdl-38876119

ABSTRACT

INTRODUCTION: TYK2 inhibitors and traditional natural drugs as promising drugs for psoriasis therapy are receiving increasing attention. They both affect different molecules of JAK/STAT pathway, but it is currently unclear whether their combination will enhance the effect on psoriasis. In this study, we used imiquimod (IMQ)-induced psoriasis mouse model to investigate the therapeutic effects of the combined administration of deucravacitinib (TYK2 inhibitor) and shikonin. METHODS: Aldara cream containing 5% IMQ was used to topically treat the dorsal skin of each mouse for a total of six consecutive days to induce psoriasis. The psoriasis area and severity index (PASI) scores were recorded every day. On the 7th day, skin tissues were taken for histopathological examination and the content of cytokines in skin were evaluated. The frequency of immune cells in peripheral blood, spleen and skin were detected through flow cytometry. RESULTS: Compared to the vehicle control group, the psoriasis symptoms and immune disorder improved significantly in the combination therapy group and deucravacitinib treatment group on the 7th day, and the expressions of p-STAT3 and Ki67 in skin were reduced as well. Moreover, the combined treatment of deucravacitinib and shikonin for psoriasis was superior to the monotherapy group, especially in inhibiting abnormal capillaries proliferation, reducing immune cells infiltration and decreasing the concentration of IL-12p70 in skin. CONCLUSION: The combination of deucravacitinib and shikonin is a promising clinical application.


Subject(s)
Drug Therapy, Combination , Imiquimod , Naphthoquinones , Psoriasis , Skin , Animals , Psoriasis/drug therapy , Psoriasis/chemically induced , Naphthoquinones/pharmacology , Naphthoquinones/therapeutic use , Mice , Skin/drug effects , Skin/pathology , Skin/metabolism , Disease Models, Animal , Cytokines/metabolism , Mice, Inbred BALB C , Male , Female , Benzimidazoles , Quinolones
6.
Arch Dermatol Res ; 316(6): 235, 2024 May 25.
Article in English | MEDLINE | ID: mdl-38795154

ABSTRACT

The aim of this study is to delineate the expression patterns of prolyl cis-trans isomerase NIMA-interacting protein 1 (Pin1), Glial cell-derived neurotrophic factor (GDNF), and Angiotensin II (ANG II) during the process of wound repair, and to ascertain the effects of Pin1, GDNF, and ANG II on the healing of wounds in a rat model. A total of 18 rats were allocated into three groups-sham (control), DMSO (vehicle control), and Pin1 inhibitor (treatment with juglone)-with six animals in each group. An animal model of wound healing was established, followed by the intraperitoneal administration of juglone. Tissue samples from the wounds were subsequently collected for histopathological evaluation. Expression levels of Pin1, GDNF, and Ang II were quantified. In addition, an in vitro model of wound healing was created using human umbilical vein endothelial cells (HUVEC), to assess cell proliferation, migration, and tube formation under conditions of juglone pre-treatment. The expression levels of Pin1, GDNF, and ANG II were notably elevated on 7-, and 10- days post-wound compared to those measured on 3-day. Contrastingly, pre-treatment with juglone significantly inhibited the expression of these molecules. Histological analyses, including HE (Hematoxylin and Eosin), Masson's trichrome, and EVG (Elastic van Gieson) staining, demonstrated that vascular angiogenesis, as well as collagen and elastin deposition, were substantially reduced in the juglone pre-treated group when compared to the normal group. Further, immunohistochemical analysis revealed a considerable decrease in CD31 expression in the juglone pre-treatment group relative to the normal control group. Pin1 serves as a pivotal facilitator of wound repair. The findings indicate that the modulation of Pin1, GDNF, and ANG II expression impacts the wound healing process in rats, suggesting potential targets for therapeutic intervention in human wound repair.


Subject(s)
Angiotensin II , Cell Proliferation , Glial Cell Line-Derived Neurotrophic Factor , Human Umbilical Vein Endothelial Cells , NIMA-Interacting Peptidylprolyl Isomerase , Naphthoquinones , Wound Healing , Animals , Wound Healing/drug effects , NIMA-Interacting Peptidylprolyl Isomerase/metabolism , NIMA-Interacting Peptidylprolyl Isomerase/genetics , Humans , Rats , Naphthoquinones/pharmacology , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Glial Cell Line-Derived Neurotrophic Factor/genetics , Male , Cell Proliferation/drug effects , Angiotensin II/metabolism , Cell Movement/drug effects , Disease Models, Animal , Rats, Sprague-Dawley , Skin/pathology , Skin/metabolism , Skin/injuries , Skin/drug effects , Adaptor Proteins, Signal Transducing
7.
PLoS One ; 19(5): e0299921, 2024.
Article in English | MEDLINE | ID: mdl-38814975

ABSTRACT

Non-small cell lung cancer (NSCLC) is one of the most common malignancies worldwide, and oxidative stress plays a crucial role in its development. Juglone, a naturally occurring naphthoquinone in J. mandshurica, exhibits significant cytotoxic activity against various cancer cell lines. However, whether the anticancer activity of juglone is associated with oxidative stress remains unexplored. In this study, mouse Lewis lung cancer (LLC) and human non-small cell lung cancer A549 cells were used to explore the anticancer mechanisms of juglone. Juglone inhibited LLC and A549 cells viability, with IC50 values of 10.78 µM and 9.47 µM, respectively, for 24 h, and substantially suppressed the migration and invasion of these two lung cancer cells. Additionally, juglone arrested the cell cycle, induced apoptosis, increased the cleavage of caspase 3 and the protein expression of Bax and Cyt c, and decreased the protein expression of Bcl-2 and caspase-3. Furthermore, juglone treatment considerably increased intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, but suppressed glutathione peroxidase 4 (GPX4) and superoxide dismutase (SOD) activities. It also inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which was attenuated by 1,3-diCQA (an activator of PI3K/Akt). Moreover, N-acetylcysteine (a ROS scavenger) partially reversed the positive effects of juglone in terms of migration, invasion, ROS production, apoptosis, and PI3K/Akt pathway-associated protein expression. Finally, in tumor-bearing nude mouse models, juglone inhibited tumor growth without any apparent toxicity and significantly induced apoptosis in NSCLC cells. Collectively, our findings suggest that juglone triggers apoptosis via the ROS-mediated PI3K/Akt pathway. Therefore, juglone may serve as a potential therapeutic agent for the treatment of NSCLC.


Subject(s)
Apoptosis , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Naphthoquinones , Phosphatidylinositol 3-Kinases , Proto-Oncogene Proteins c-akt , Reactive Oxygen Species , Signal Transduction , Naphthoquinones/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Reactive Oxygen Species/metabolism , Humans , Animals , Apoptosis/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mice , Signal Transduction/drug effects , A549 Cells , Cell Movement/drug effects , Carcinoma, Lewis Lung/drug therapy , Carcinoma, Lewis Lung/pathology , Carcinoma, Lewis Lung/metabolism , Cell Line, Tumor
8.
Cancer Lett ; 593: 216949, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38729558

ABSTRACT

Hypomethylating agents (HMAs) are widely employed in the treatment of myeloid malignancies. However, unresponsive or resistant to HMAs occurs in approximately 50 % of patients. ASXL1, one of the most commonly mutated genes across the full spectrum of myeloid malignancies, has been reported to predict a lower overall response rate to HMAs, suggesting an essential need to develop effective therapeutic strategies for the patients with HMA failure. Here, we investigated the impact of ASXL1 on cellular responsiveness to decitabine treatment. ASXL1 deficiency increased resistance to decitabine treatment in AML cell lines and mouse bone marrow cells. Transcriptome sequencing revealed significant alterations in genes regulating cell cycle, apoptosis, and histone modification in ASXL1 deficient cells that resistant to decitabine. BIRC5 was identified as a potential target for overcoming decitabine resistance in ASXL1 deficient cells. Furthermore, our experimental evidence demonstrated that the small-molecule inhibitor of BIRC5 (YM-155) synergistically sensitized ASXL1 deficient cells to decitabine treatment. This study sheds light on the molecular mechanisms underlying the ASXL1-associated HMA resistance and proposes a promising therapeutic strategy for improving treatment outcomes in affected individuals.


Subject(s)
Decitabine , Drug Resistance, Neoplasm , Leukemia, Myeloid, Acute , Repressor Proteins , Survivin , Animals , Decitabine/pharmacology , Humans , Drug Resistance, Neoplasm/genetics , Drug Resistance, Neoplasm/drug effects , Survivin/genetics , Survivin/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Mice , Cell Line, Tumor , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Antimetabolites, Antineoplastic/pharmacology , Apoptosis/drug effects , Imidazoles , Naphthoquinones
9.
Cancer Lett ; 593: 216964, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38762193

ABSTRACT

Tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME) and strongly associated with poor prognosis and drug resistance, including checkpoint blockade immunotherapy in solid tumor patients. However, the mechanism by which TAM affects immune metabolism reprogramming and immune checkpoint signalling pathway in the TME remains elusive. In this study we found that transforming growth factor-beta (TGF-ß) secreted by M2-TAMs increased the level of glycolysis in bladder cancer (BLCA) and played important role in PD-L1-mediated immune evasion through pyruvate kinase isoenzymes M2 (PKM2). Mechanistically, TGF-ß promoted high expression of PKM2 by promoting the nuclear translocation of PKM2 dimer in conjunction with phosphorylated signal transducer and activator of transcription (p-STAT3), which then exerted its kinase activity to promote PD-L1 expression in BLCA. Moreover, SB-431542 (TGF-ß blocker) and shikonin (PKM2 inhibitor) significantly reduced PD-L1 expression and inhibited BLCA growth and organoids by enhancing anti-tumor immune responses. In conclusion, M2-TAM-derived TGF-ß promotes PD-L1-mediated immune evasion in BLCA by increasing the PKM2 dimer-STAT3 complex nuclear translocation. Combined blockade of the TGF-ß receptor and inhibition of PKM2 effectively prevent BLCA progression and immunosuppression, providing a potential targeted therapeutic strategy for BLCA.


Subject(s)
B7-H1 Antigen , Membrane Proteins , STAT3 Transcription Factor , Thyroid Hormone-Binding Proteins , Thyroid Hormones , Transforming Growth Factor beta , Tumor Escape , Tumor Microenvironment , Tumor-Associated Macrophages , Urinary Bladder Neoplasms , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/genetics , STAT3 Transcription Factor/metabolism , B7-H1 Antigen/metabolism , B7-H1 Antigen/genetics , Humans , Thyroid Hormones/metabolism , Tumor-Associated Macrophages/immunology , Tumor-Associated Macrophages/metabolism , Membrane Proteins/metabolism , Membrane Proteins/genetics , Tumor Microenvironment/immunology , Animals , Transforming Growth Factor beta/metabolism , Mice , Cell Line, Tumor , Carrier Proteins/metabolism , Carrier Proteins/genetics , Signal Transduction , Glycolysis , Cell Nucleus/metabolism , Naphthoquinones
10.
Biomaterials ; 309: 122608, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38744189

ABSTRACT

Necroptotic immunogenic cell death (ICD) can activate the human immune system to treat the metastasis and recurrence of triple-negative breast cancer (TNBC). However, developing the necroptotic inducer and precisely delivering it to the tumor site is the key issue. Herein, we reported that the combination of shikonin (SHK) and chitosan silver nanoparticles (Chi-Ag NPs) effectively induced ICD by triggering necroptosis in 4T1 cells. Moreover, to address the lack of selectivity of drugs for in vivo application, we developed an MUC1 aptamer-targeted nanocomplex (MUC1@Chi-Ag@CPB@SHK, abbreviated as MUC1@ACS) for co-delivering SHK and Chi-Ag NPs. The accumulation of MUC1@ACS NPs at the tumor site showed a 6.02-fold increase compared to the free drug. Subsequently, upon reaching the tumor site, the acid-responsive release of SHK and Chi-Ag NPs from MUC1@ACS NPs cooperatively induced necroptosis in tumor cells by upregulating the expression of RIPK3, p-RIPK3, and tetrameric MLKL, thereby effectively triggering ICD. The sequential maturation of dendritic cells (DCs) subsequently enhanced the infiltration of CD8+ and CD4+ T cells in tumors, while inhibiting regulatory T cells (Treg cells), resulting in the effective treatment of primary and distal tumor growth and the inhibition of TNBC metastasis. This work highlights the importance of nanoparticles in mediating drug interactions during necroptotic ICD.


Subject(s)
Chitosan , Metal Nanoparticles , Naphthoquinones , Necroptosis , Receptor-Interacting Protein Serine-Threonine Kinases , Silver , Triple Negative Breast Neoplasms , Naphthoquinones/pharmacology , Naphthoquinones/chemistry , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/drug therapy , Chitosan/chemistry , Silver/chemistry , Silver/pharmacology , Animals , Metal Nanoparticles/chemistry , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Cell Line, Tumor , Female , Necroptosis/drug effects , Humans , Mice , Immunogenic Cell Death/drug effects , Mice, Inbred BALB C , Mucin-1/metabolism , Drug Synergism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemistry
11.
Cell Mol Biol Lett ; 29(1): 63, 2024 May 02.
Article in English | MEDLINE | ID: mdl-38698330

ABSTRACT

BACKGROUND: Endometrial cancer (EC) is one of the most common gynecological cancers. Herein, we aimed to define the role of specific myosin family members in EC because this protein family is involved in the progression of various cancers. METHODS: Bioinformatics analyses were performed to reveal EC patients' prognosis-associated genes in patients with EC. Furthermore, colony formation, immunofluorescence, cell counting kit 8, wound healing, and transwell assays as well as coimmunoprecipitation, cycloheximide chase, luciferase reporter, and cellular thermal shift assays were performed to functionally and mechanistically analyze human EC samples, cell lines, and a mouse model, respectively. RESULTS: Machine learning techniques identified MYH14, a member of the myosin family, as the prognosis-associated gene in patients with EC. Furthermore, bioinformatics analyses based on public databases showed that MYH14 was associated with EC chemoresistance. Moreover, immunohistochemistry validated MYH14 upregulation in EC cases compared with that in normal controls and confirmed that MYH14 was an independent and unfavorable prognostic indicator of EC. MYH14 impaired cell sensitivity to carboplatin, paclitaxel, and progesterone, and increased cell proliferation and metastasis in EC. The mechanistic study showed that MYH14 interacted with MYH9 and impaired GSK3ß-mediated ß-catenin ubiquitination and degradation, thus facilitating the Wnt/ß-catenin signaling pathway and epithelial-mesenchymal transition. Sesamolin, a natural compound extracted from Sesamum indicum (L.), directly targeted MYH14 and attenuated EC progression. Additionally, the compound disrupted the interplay between MYH14 and MYH9 and repressed MYH9-regulated Wnt/ß-catenin signaling. The in vivo study further verified sesamolin as a therapeutic drug without side effects. CONCLUSIONS: Herein, we identified that EC prognosis-associated MYH14 was independently responsible for poor overall survival time of patients, and it augmented EC progression by activating Wnt/ß-catenin signaling. Targeting MYH14 by sesamolin, a cytotoxicity-based approach, can be applied synergistically with chemotherapy and endocrine therapy to eventually mitigate EC development. This study emphasizes MYH14 as a potential target and sesamolin as a valuable natural drug for EC therapy.


Subject(s)
Endometrial Neoplasms , Glycogen Synthase Kinase 3 beta , Myosin Heavy Chains , beta Catenin , Humans , Female , Endometrial Neoplasms/drug therapy , Endometrial Neoplasms/genetics , Endometrial Neoplasms/metabolism , Endometrial Neoplasms/pathology , Myosin Heavy Chains/metabolism , Myosin Heavy Chains/genetics , Animals , Glycogen Synthase Kinase 3 beta/metabolism , Glycogen Synthase Kinase 3 beta/genetics , Cell Line, Tumor , beta Catenin/metabolism , beta Catenin/genetics , Mice , Cell Proliferation/drug effects , Mice, Nude , Gene Expression Regulation, Neoplastic/drug effects , Signal Transduction/drug effects , Prognosis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Middle Aged , Naphthoquinones/pharmacology
12.
Zhongguo Zhong Yao Za Zhi ; 49(9): 2345-2354, 2024 May.
Article in Chinese | MEDLINE | ID: mdl-38812135

ABSTRACT

To investigate the effects of plumbagin on the proliferation and apoptosis of human hepatoma Huh-7 cells and its mechanism based on the creatine kinase B(CKB)/p53 signaling pathway. Huh-7 cells were treated with plumbagin from 1 to 12 µmol·L~(-1) for cell counting kit-8(CCK-8) assay, and 1, 3, and 6 µmol·L~(-1) were determined as low, medium, and high concentrations of plumbagin for subsequent experiments. CKB gene was knocked out in Huh-7 cells by clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated proteins(Cas)-9 gene editing technology. CKB overexpression lentivirus was transfected into Huh-7 cells to up-regulate the expression of CKB. Cell proliferation and apoptosis were detected by plate cloning assay and flow cytometry. The mRNA expression of CKB was detected by quantitative real-time PCR(qRT-PCR). CKB, p53, mouse double minute 2 homolog(MDM2), B-cell lymphoma 2(Bcl-2), Bcl-2 associated X protein(Bax), and caspase-3 protein were detected by Western blot(WB). The results showed that plumbagin significantly inhibited the proliferation of Huh-7 cells and induced cell apoptosis. Compared with the control group, the apoptosis level was significantly increased in the plumbagin group, while the apoptosis level was significantly decreased in the plumbagin combined with the apoptosis inhibitor group. Plumbagin significantly down-regulated the protein expression levels of CKB, Bcl-2, and MDM2 and up-regulated the protein expression levels of p53, Bax, and caspase-3. Knockdown of the CKB gene decreased the proliferative ability of Huh-7 cells, increased the apoptotic rate, decreased the expression levels of Bcl-2 and MDM2 proteins, and increased the expression levels of p53, Bax, and caspase-3 proteins. After up-regulation of CKB expression, the proliferation ability of Huh-7 cells was enhanced, and the protein expression levels of Bcl-2 and MDM2 were elevated. The protein expression levels of p53, Bax, and caspase-3 were decreased. In addition, plumbagin reversed the effect of overexpression of CKB on the proliferation and apoptosis of Huh-7 cells. In conclusion, plumbagin significantly inhibited the proliferative ability of Huh-7 cells, and the mechanism may be related to the inhibition of CKB expression, activation of the p53 signaling pathway, and regulation of the expression of mitochondrial-associated apoptotic proteins, ultimately inducing cell apoptosis.


Subject(s)
Apoptosis , Carcinoma, Hepatocellular , Cell Proliferation , Liver Neoplasms , Naphthoquinones , Signal Transduction , Tumor Suppressor Protein p53 , Humans , Naphthoquinones/pharmacology , Apoptosis/drug effects , Cell Proliferation/drug effects , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Signal Transduction/drug effects , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/drug therapy , Cell Line, Tumor , Proto-Oncogene Proteins c-mdm2/genetics , Proto-Oncogene Proteins c-mdm2/metabolism
13.
Int J Biol Macromol ; 270(Pt 2): 132413, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38761911

ABSTRACT

Herein, 5-fluorouracil and shikonin (extracted from Fusarium tricinctum) were loaded in chitosan/pectin nanoparticle (CS/PEC-NPs), prepared by blending (B-CS/PEC-NPs) and coating (C-CS/PEC-NPs) methods. The nanoparticles characterized by Fourier Transform Infrared (FTIR), X-ray diffraction (XRD), Energy-dispersive X-ray (EDX), Scanning Electron Microscope (SEM) and Differential Light Scattering (DLS). Then, some properties of the nanoparticles such as drug release rate and the nanoparticles cytotoxicity were studied. The FTIR, XRD, EDX, SEM and DLS results showed that the nanoparticles synthesized properly with an almost spherical morphology, an average size of 82-93 nm for B-CS/PEC-NPs, an average diameter of below 100 nm (mostly 66-89 nm) for C-CS/PEC-NPs, and hydrodynamic diameter of 310-817 nm. The drug release results indicated the lower release rate of drugs for B-CS/PEC-NPs relative to C-CS/PEC-NPs at different pHs, high release rate of drugs for the nanoparticles in the simulated large intestinal fluids containing pectinase, and Korsmeyer-Peppas model for release of the drugs. The results showed more cytotoxicity of B-CS/PEC-NPs containing drugs, especially B-CS/PEC-NPs containing both drugs (B-CS/PEC/5-FU/SHK-NPs) after treating with pectinase (IC50 of 18.6 µg/mL). In conclusion, despite the limitation of C-CS/PEC-NPs for simultaneous loading of hydrophilic and hydrophobic drugs, B-CS/PEC-NPs showed suitable potency for loading and targeted delivery of the drugs.


Subject(s)
Chitosan , Colonic Neoplasms , Drug Carriers , Drug Liberation , Fluorouracil , Nanoparticles , Naphthoquinones , Pectins , Fluorouracil/chemistry , Fluorouracil/pharmacology , Fluorouracil/administration & dosage , Chitosan/chemistry , Pectins/chemistry , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Naphthoquinones/administration & dosage , Nanoparticles/chemistry , Drug Carriers/chemistry , Humans , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Drug Delivery Systems , Cell Line, Tumor , Particle Size
14.
J Enzyme Inhib Med Chem ; 39(1): 2357174, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38814149

ABSTRACT

Tyrosinase, a pivotal enzyme in melanin synthesis, is a primary target for the development of depigmenting agents. In this work, in vitro and in silico techniques were employed to identify novel tyrosinase inhibitors from a set of 12 anilino-1,4-naphthoquinone derivatives. Results from the mushroom tyrosinase activity assay indicated that, among the 12 derivatives, three compounds (1, 5, and 10) demonstrated the most significant inhibitory activity against mushroom tyrosinase, surpassing the effectiveness of the kojic acid. Molecular docking revealed that all studied derivatives interacted with copper ions and amino acid residues at the enzyme active site. Molecular dynamics simulations provided insights into the stability of enzyme-inhibitor complexes, in which compounds 1, 5, and particularly 10 displayed greater stability, atomic contacts, and structural compactness than kojic acid. Drug likeness prediction further strengthens the potential of anilino-1,4-naphthoquinones as promising candidates for the development of novel tyrosinase inhibitors for the treatment of hyperpigmentation disorders.


Subject(s)
Agaricales , Dose-Response Relationship, Drug , Enzyme Inhibitors , Monophenol Monooxygenase , Naphthoquinones , Monophenol Monooxygenase/antagonists & inhibitors , Monophenol Monooxygenase/metabolism , Naphthoquinones/pharmacology , Naphthoquinones/chemistry , Naphthoquinones/chemical synthesis , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/chemical synthesis , Agaricales/enzymology , Structure-Activity Relationship , Molecular Structure , Molecular Docking Simulation , Molecular Dynamics Simulation
15.
Int J Mol Sci ; 25(9)2024 May 03.
Article in English | MEDLINE | ID: mdl-38732208

ABSTRACT

The current study investigated the impact of cold stress on the morphological, physiological, and phytochemical properties of Juglans regia L. (J. regia) using in vitro microclone cultures. The study revealed significant stress-induced changes in the production of secondary antioxidant metabolites. According to gas chromatography-mass spectrometry (GC-MS) analyses, the stress conditions profoundly altered the metabolism of J. regia microclones. Although the overall spectrum of metabolites was reduced, the production of key secondary antioxidant metabolites significantly increased. Notably, there was a sevenfold (7×) increase in juglone concentration. These findings are crucial for advancing walnut metabolomics and enhancing our understanding of plant responses to abiotic stress factors. Additionally, study results aid in identifying the role of individual metabolites in these processes, which is essential for developing strategies to improve plant resilience and tolerance to adverse conditions.


Subject(s)
Antioxidants , Cold-Shock Response , Juglans , Phytochemicals , Juglans/metabolism , Juglans/chemistry , Phytochemicals/metabolism , Antioxidants/metabolism , Secondary Metabolism , Metabolomics/methods , Gas Chromatography-Mass Spectrometry , Metabolome , Naphthoquinones
16.
An Acad Bras Cienc ; 96(2): e20230375, 2024.
Article in English | MEDLINE | ID: mdl-38747836

ABSTRACT

In pursuit of potential agents to treat Chagas disease and leishmaniasis, we report the design, synthesis, and identification novel naphthoquinone hydrazide-based molecular hybrids. The compounds were subjected to in vitro trypanocide and leishmanicidal activities. N'-(1,4-Dioxo-1,4-dihydronaphthalen-2-yl)-3,5-dimethoxybenzohydrazide (13) showed the best performance against Trypanosoma cruzi (IC50 1.83 µM) and Leishmania amazonensis (IC50 9.65 µM). 4-Bromo-N'-(1,4-dioxo-1,4-dihydronaphthalen-2-yl)benzohydrazide (16) exhibited leishmanicidal activity (IC50 12.16 µM). Regarding trypanocide activity, compound 13 was low cytotoxic to LLC-MK2 cells (SI = 95.28). Furthermore, through molecular modeling studies, the cysteine proteases cruzain, rhodesain and CPB2.8 were identified as the potential biological targets.


Subject(s)
Drug Design , Hydrazines , Leishmania , Naphthoquinones , Trypanocidal Agents , Trypanosoma cruzi , Naphthoquinones/pharmacology , Naphthoquinones/chemistry , Naphthoquinones/chemical synthesis , Trypanosoma cruzi/drug effects , Trypanocidal Agents/pharmacology , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistry , Leishmania/drug effects , Hydrazines/chemistry , Hydrazines/pharmacology , Animals , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Parasitic Sensitivity Tests , Inhibitory Concentration 50 , Structure-Activity Relationship , Cysteine Endopeptidases
17.
J Ovarian Res ; 17(1): 101, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38745186

ABSTRACT

BACKGROUND: Shikonin (SK), a naphthoquinone with anti-tumor effects, has been found to decrease production of tumor-associated exosomes (exo). This study aims to verify the treatment effect of SK on ovarian cancer (OC) cells, especially on the production of exo and their subsequent effect on macrophage polarization. METHODS: OC cells SKOV3 and A2780 were treated with SK. The exo were isolated from OC cells with or without SK treatment, termed OC exo and SK OC exo, respectively. These exo were used to treat PMA-induced THP-1 cells (M0 macrophages). M2 polarization of macrophages was determined by measuring the M2 specific cell surface markers CD163 and CD206 as well as the secretion of M2 cytokine IL-10. The functions of galectin 3 (LGALS3/GAL3) and ß-catenin in macrophage polarization were determined by gain- or loss-of-function assays. CB-17 SCID mice were subcutaneously injected with SKOV3 cells to generate xenograft tumors, followed by OC exo or SK OC exo treatment for in vivo experiments. RESULTS: SK suppressed viability, migration and invasion, and apoptosis resistance of OC cells in vitro. Compared to OC exo, SK OC exo reduced the M2 polarization of macrophages. Regarding the mechanism, SK reduced exo production in cancer cells, and it decreased the protein level of GAL3 in exo and recipient macrophages, leading to decreased ß-catenin activation. M2 polarization of macrophages was restored by LGALS3 overexpression but decreased again by the ß-catenin inhibitor FH535. Compared to OC exo, the SK OC exo treatment reduced the xenograft tumor growth in mice, and it decreased the M2 macrophage infiltration within tumor tissues. CONCLUSION: This study suggests that SK reduces M2 macrophage population in OC by repressing exo production and blocking exosomal GAL3-mediated ß-catenin activation.


Subject(s)
Exosomes , Galectin 3 , Macrophages , Naphthoquinones , Ovarian Neoplasms , beta Catenin , Naphthoquinones/pharmacology , Naphthoquinones/therapeutic use , Female , Ovarian Neoplasms/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Humans , Exosomes/metabolism , Animals , Macrophages/metabolism , Macrophages/drug effects , beta Catenin/metabolism , Galectin 3/metabolism , Mice , Cell Line, Tumor , Xenograft Model Antitumor Assays , Cell Movement/drug effects , Apoptosis/drug effects , Mice, SCID
18.
Luminescence ; 39(5): e4761, 2024 May.
Article in English | MEDLINE | ID: mdl-38807512

ABSTRACT

The fear of an increase in blood sugar can be very traumatic. Being diabetic either type I or type II leads to a disorder called diabetes distress having traits of stress, depression, and anxiety. Among risk factors of diabetes mellitus heavy and trace metal toxicity emerges as new risk factors reported in many studies. In this study we target toxic metals, viz., Ni2+, Zn2+, and Cu2+, involved in the pathogenesis of diabetes and diabetic stress with naphthazarin esters. The compounds C1-C3 isolated from the leaves and roots of Arnebia guttata were tested for their metal-binding ability in an aqueous medium in UV-Visible and nuclear magnetic resonance (NMR) studies. These probes are well-known naphthoquinones present in the Arnebia species. In the UV-Visible titrations of compounds C1-C3 with Na2+, K2+, Zn2+, Ca2+, Cu2+, Mg2+, Co2+, and Ni2+ ions, significant binding was observed with Ni2+, Cu2+, and Zn2+ ions in MeOH/H2O. There occurs a beautiful formation of red-shifted bands between the 520 to 620 nm range with a synergistic increase in absorbance. Also, the disappearance of proton peaks in the 1H NMR spectrum on addition of metal ions confirmed binding. Compounds C1-C3 isolated from A. guttata came out as potent Ni2+, Zn2+, and Cu2+ sensors that are reportedly involved in islet function and induction of diabetes.


Subject(s)
Esters , Naphthoquinones , Esters/chemistry , Naphthoquinones/chemistry , Diabetes Mellitus/metabolism , Neurotoxins/chemistry , Neurotoxins/metabolism , Water/chemistry , Molecular Structure , Plant Leaves/chemistry
19.
Vet Parasitol ; 328: 110183, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38608378

ABSTRACT

Tropical theileriosis is a tick-borne disease that caused by Theileria annulata, and leads to substantial economic impact in endemic area. Distinguishes to other piroplasms, Theileria is the only eukaryotic parasite could transform mammalian leukocytes. At present, buparvaquone is the most effective drug used for treatment of Theileria infection. However, frequently reported of failure treatment with buparvaquone for some T. annulata isolates. Mutation of TaPIN1 was reported to be the direct reason for failure of buparvaquone treatment. Through in vitro culture, a T. annulata isolate with a TaPIN1 mutation that is similar to the reported strain was recently identified in China. In order to understand the distribution of Theileria with mutation of TaPIN1 in China, here we developed a TaqMan probe-based real-time PCR technology to detect the mutated TaPIN1 gene. The specificity, sensitivity and reproducibility of the established TaqMan Real-time PCR method were evaluated, and field cattle blood samples collected from Xinjiang Uyghur Autonomous Region were used to test its application. Among 1683 samples, 335 samples were confirmed positive for T. annulata by traditional PCR method and 34 samples were positive for buparvaquone-resistant. The TaPIN1 gene of those 34 samples was sequenced and analyzed with the published gene sequences from NCBI database. The results showed that the sequence obtained from the present study has good consistency with those published sequences. In conclusion, the TaqMan probe-based real-time PCR targeting T. annulata mutated TaPIN1 gene was successfully established and can be used to detect clinical samples to investigation of buparvaquone-resistant parasites in Xinjiang region quickly and accurately, which will be useful for guiding clinical medicine application.


Subject(s)
Drug Resistance , Naphthoquinones , Protozoan Proteins , Real-Time Polymerase Chain Reaction , Sensitivity and Specificity , Theileria annulata , Theileriasis , Theileria annulata/genetics , Theileria annulata/drug effects , Theileria annulata/isolation & purification , Animals , Naphthoquinones/pharmacology , Theileriasis/parasitology , Theileriasis/diagnosis , Theileriasis/drug therapy , Cattle , Real-Time Polymerase Chain Reaction/veterinary , Real-Time Polymerase Chain Reaction/methods , Drug Resistance/genetics , Protozoan Proteins/genetics , China/epidemiology , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Reproducibility of Results , Mutation
20.
Biochem Pharmacol ; 224: 116242, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38679209

ABSTRACT

Although the anticancer activity of ONC212 has been reported, the precise mechanism underlying its apoptotic effects remains unclear. In this study, we investigated the apoptotic mechanism of ONC212 in acute myeloid leukemia (AML) cells. ONC212 induces apoptosis, MCL1 downregulation, and mitochondrial depolarization in AML U937 cells. Ectopic MCL1 expression alleviates mitochondria-mediated apoptosis in ONC212-treated U937 cells. ONC212 triggers AKT phosphorylation, inducing NOX4-dependent ROS production and promoting HuR transcription. HuR-mediated ATF4 mRNA stabilization stimulates NOXA and SLC35F2 expression; ONC212-induced upregulation of NOXA leads to MCL1 degradation. The synergistic effect of ONC212 on YM155 cytotoxicity was dependent on increased SLC35F2 expression. In addition, YM155 feedback facilitated the activation of the ONC212-induced signaling pathway. A similar mechanism explains ONC212- and ONC212/YM155-induced AML HL-60 cell death. The continuous treatment of U937 cells with the benzene metabolite hydroquinone (HQ) generated U937/HQ cells, exhibiting enhanced responsiveness to the cytotoxic effects of ONC212. In U937/HQ cells, ONC212 triggered apoptosis through NOXA-mediated MCL1 downregulation, enhancing YM155 cytotoxicity. Collectively, our data suggested that ONC212 upregulated SLC35F2 expression and triggered NOXA-mediated MCL1 degradation in U937, U937/HQ, and HL-60 cells by activating the AKT/NOX4/HuR/ATF4 pathway. The ONC212-induced signaling pathway showed anti-AML activity and enhanced YM155 cytotoxicity.


Subject(s)
Imidazoles , Leukemia, Myeloid, Acute , Myeloid Cell Leukemia Sequence 1 Protein , Naphthoquinones , Proto-Oncogene Proteins c-bcl-2 , Humans , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Myeloid Cell Leukemia Sequence 1 Protein/genetics , Myeloid Cell Leukemia Sequence 1 Protein/biosynthesis , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-bcl-2/genetics , U937 Cells , Imidazoles/pharmacology , Naphthoquinones/pharmacology , HL-60 Cells , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Drug Synergism , Benzyl Compounds , Heterocyclic Compounds, 3-Ring , Sulfonamides , Bridged Bicyclo Compounds, Heterocyclic
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