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IScience Jun 2024The NAD-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing cancer therapeutics. However, limited...
The NAD-dependent deacetylase SIRT7 is a pivotal regulator of DNA damage response (DDR) and a promising drug target for developing cancer therapeutics. However, limited progress has been made in SIRT7 modulator discovery. Here, we applied peptide-based deacetylase platforms for SIRT7 enzymatic evaluation and successfully identified a potent SIRT7 inhibitor . We initially isolated bioactive from cockroach () extracts and then developed the synthesis of this compound Further investigation revealed that impaired SIRT7 enzymatic activities through occupation of the NAD binding pocket. attenuated DNA damage repair induced by ionizing radiation (IR) in colorectal cancer cells and exhibited a synergistic anticancer effect when used in combination with etoposide. Overall, our study not only identified as a selective SIRT7 inhibitor from insect resources, but also confirmed its potential use in combined chemo-radiotherapy by interfering in the DNA damage repair process.
PubMed: 38947512
DOI: 10.1016/j.isci.2024.110014 -
IScience Jun 2024The impact of endothelial cell-specific molecule 1 (ESM1) on the initiation and progression of diverse cancers has been extensively studied, yet its regulatory...
The impact of endothelial cell-specific molecule 1 (ESM1) on the initiation and progression of diverse cancers has been extensively studied, yet its regulatory mechanisms in relation to cervical cancer remain insufficiently understood. Through bioinformatics analysis, we revealed that ESM1 was highly expressed in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and correlated with dismal clinicopathological features. The activation of ESM1 is facilitated by the presence of oncogenic HPV E6 and E7. HPV E6 and E7 enhance the expression of ESM1 by diminishing the levels of miR-205-5p, which specifically targets the 3' untranslated region of ESM1 mRNA. In addition, we demonstrated that ESM1 facilitates aerobic glycolysis of cervical cancer cells via the Akt/mTOR pathway. Suppression of ESM1 led to a reduction in the expression of HIF-1α and multiple glycolytic enzymes. Taken together, our findings provide insights into the mechanisms by which HPV infections regulate oncogenes, thereby contributing to cervical carcinogenesis.
PubMed: 38947495
DOI: 10.1016/j.isci.2024.110112 -
Heliyon Jun 2024Exserolides are isocoumarin derivatives containing lactone moiety. Recently, some isocoumarins have been demonstrated to ameliorate hyperlipidemia, a major factor for...
Exserolides are isocoumarin derivatives containing lactone moiety. Recently, some isocoumarins have been demonstrated to ameliorate hyperlipidemia, a major factor for inducing cardiovascular diseases. However, the effects and mechanisms of action of exserolides on hyperlipidemia are not known. The aim of this study is to investigate whether the marine fungus sp.-derived exserolides (compounds I, J, E, and F) exert lipid-lowering effects via improving reverse cholesterol transport (RCT) . RAW264.7 macrophages and HepG2 cells were used to establish lipid-laden models, and the levels of intracellular lipids and RCT-related proteins were determined by assay kits and Western blotting, respectively. We observed that exserolides (at a 5 μM concentration) significantly decreased intracellular cholesterol and triglyceride levels in oxidized low-density lipoprotein-laden RAW264.7 cells and markedly improved [H]-cholesterol efflux. Among the four tested compounds, exserolide J increased the protein levels of ATP-binding cassette transporter A1, peroxisome proliferator-activated receptor α (PPARα), and liver X receptor α (LXRα). Furthermore, treatment with exserolides significantly decreased oleic acid-laden lipid accumulation in HepG2 hepatocytes. Mechanistically, exserolides enhance PPARα protein levels; furthermore, compound J increases cholesterol 7 alpha-hydroxylase A1 and LXRα protein levels. Molecular docking revealed that exserolides, particularly compound J, can interact with PPARα and LXRα proteins. These data suggest that the terminal carboxyl group of compound J plays a key role in lowering lipid levels by stimulating LXRα and PPARα proteins. In conclusion, compound J exhibits powerful lipid-lowering effects . However, its hypolipidemic effects should be investigated in the future.
PubMed: 38947487
DOI: 10.1016/j.heliyon.2024.e31861 -
Heliyon Jun 2024Acne inversa (AI) is an inflammatory skin disease associated with nicastrin (NCSTN) mutations. Despite the dysregulated bacterial-host immune interactions being an...
Acne inversa (AI) is an inflammatory skin disease associated with nicastrin (NCSTN) mutations. Despite the dysregulated bacterial-host immune interactions being an essential event in AI, the interaction between bacteria and keratinocytes in AI pathophysiology remains unclear. In this study, the NCSTN gene was suppressed using short hairpin RNA in HaCaT cells. Using RNA sequencing, real-time polymerase chain reaction, and western blotting, the expression of IL-36 cytokines was analyzed. The impact of on AI keratinocyte inflammation and underlying regulatory molecules was investigated by exposing the HaCaT cells to . By stimulating NCSTN knockdown HaCaT cells with IFN-γ, the expression and regulatory mechanism of Cathepsin S (Cat S), an IL-36γ cleavage and activating protease, were investigated. After NCSTN knockdown, the IL-36α expression increased, and the IL-36Ra expression was downregulated. NCSTN/MEK/ERK impairment-induced Krüppel-like factor 4 (KLF4) up-regulation in concert with -induced nuclear factor kappa B elevation acts synergistically to promote IL-36γ production with the subsequent IL-8 activation in HaCaT cells. NCSTN/MEK/ERK impairment was also observed in familial AI lesions. IFN-γ-induced Cat S in keratinocytes was enhanced after NCSTN knockdown. The expression of IFN-II pathway molecules was significantly upregulated in both NCSTN knockdown HaCaT cells and familial AI lesions. The Cat S expression was significantly elevated in the patient's AI lesions. Our findings suggested a synergistic relationship between and NCSTN/MAPK/KLF4 axis in IL-36γ-induced familial AI keratinocytes.
PubMed: 38947455
DOI: 10.1016/j.heliyon.2024.e31509 -
Heliyon Jun 2024L., a plant widely embraced for its therapeutic properties by populations worldwide, including Morocco, has long been recognized for its potential in treating various...
L., a plant widely embraced for its therapeutic properties by populations worldwide, including Morocco, has long been recognized for its potential in treating various ailments. This study aims to comprehensively evaluate the antioxidant, anti-inflammatory, and dermatoprotective properties of essential oil derived from , and thyme honey as well as their combined effects. To unravel the chemical composition, a rigorous GC-MS analysis was conducted. Subsequently, we examined their antioxidant potential through three distinct assays: DPPH●, hydrogen peroxide assay, and xanthine oxidase assay. The anti-inflammatory properties were scrutinized through both in vitro and experiments. Simultaneously, the dermatoprotective efficacy was investigated in vitro by evaluating tyrosinase inhibition. Our findings revealed that pulegone constitutes the predominant compound in essential oil (MPEO), constituting a remarkable 74.82 % of the composition. Significantly, when the essential oil was combined with thym honey, it exhibited superior anti-inflammatory and dermatoprotective effects across all and in vitro tests. Moreover, our in silico molecular docking analysis hinted at the potential role of cyclohexanone, 3-methyl, an element found in the MPEO, in contributing to the observed outcomes. While this study has unveiled promising results regarding the combined in vitro, and in silico biological activities of the essential oil and honey, it is imperative to delve further into the underlying mechanisms through additional experimentation and alternative experimental methods. Understanding these mechanisms in greater detail will not only enhance our comprehension of the therapeutic potential but also pave the way for the development of innovative treatments and applications rooted in the synergy of these natural compounds. Furthermore, it would be advantageous to test different possible combinations using experimental design model. Moreover, it would be better to test the effect of single compounds of MPEO to clearly elucidate their efficiency. MPEO alone or combined with thyme honey may be a useful for the development of novel biopharmaceuticals.
PubMed: 38947443
DOI: 10.1016/j.heliyon.2024.e31922 -
Global Health & Medicine Jun 2024Alzheimer's disease (AD), first diagnosed over a century ago, remains one of the major healthcare crises around the globe. Currently, there is no cure or effective...
Alzheimer's disease (AD), first diagnosed over a century ago, remains one of the major healthcare crises around the globe. Currently, there is no cure or effective treatment. The majority of drug development efforts to date have targeted reduction of amyloid-β peptide (Aβ). Drug development through inhibition of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), resulted in promising early clinical studies. However, nearly all small molecule BACE1 inhibitor drugs failed to live up to expectations in later phase clinical trials, due to toxicity and efficacy issues. This commentary aims to provide a brief review of over two decades of BACE1 inhibitor drug development challenges and efforts for treatment of AD and prospects of future BACE1-based drugs.
PubMed: 38947412
DOI: 10.35772/ghm.2024.01033 -
Journal of Cancer 2024TMEM132A is a transmembrane protein that regulates gastric cancer cell malignancy and overall survival in bladder cancer patients. However, while some studies have...
TMEM132A is a transmembrane protein that regulates gastric cancer cell malignancy and overall survival in bladder cancer patients. However, while some studies have investigated the involvement of TMEM132A in specific cancers, further systematic studies are required to elucidate its specific mechanisms of action in different cancer types. We investigated the pan-cancer role of TMEM132A using several databases. We analyzed TMEM132A expression and its correlation with clinical survival, immune checkpoints, tumor stemness score, prognostic value, immunomodulators, genomic profiles, immunological characteristics, immunotherapy and functional enrichment. First, it was observed that TMEM132A expression levels were higher in the majority of tumors compared to non-tumor tissues. In addition, high TMEM132A expression may have a higher prognostic value in some cancers. Furthermore, TMEM132A was significantly associated with immune checkpoints, immunomodulators, prognosis, immunomodulatory genes, tumor stemness score, cell function status and immune infiltration in most tumors. Further analysis of TMEM132A-related gene enrichment, mutation sites and types, RNA modification and genomic heterogeneity showed that the major mutations of TMEM132A were missense mutations and that TMEM132A plays a very important role in UCEC, LUAD and LIHC. Finally, these results suggest that high TMEM132A expression may be associated with a better response to specific immunotherapies. : This comprehensive study uncovers an important function for TMEM132A in different types of cancer. It also has the potential to identify TMEM132A as a potential biomarker for predicting treatment response. This may help us to better understand how TMEM132A plays a role in cancer and provide valuable insights for developing personalised treatments.
PubMed: 38947398
DOI: 10.7150/jca.96396 -
Journal of Cancer 2024Metabolic reprogramming plays a crucial role in the development of colorectal cancer (CRC), influencing tumor heterogeneity, the tumor microenvironment, and metastasis....
Metabolic reprogramming plays a crucial role in the development of colorectal cancer (CRC), influencing tumor heterogeneity, the tumor microenvironment, and metastasis. While the interaction between metabolism and CRC is critical for developing personalized treatments, gaps remain in understanding how tumor cell metabolism affects prognosis. Our study introduces novel insights by integrating single-cell and bulk transcriptome analyses to explore the metabolic landscape within CRC cells and its mechanisms influencing disease progression. This approach allows us to uncover metabolic heterogeneity and identify specific metabolic genes impacting metastasis, which have not been thoroughly examined in previous studies. We sourced microarray and single-cell RNA sequencing datasets from the Gene Expression Omnibus (GEO) and bulk sequencing data for CRC from The Cancer Genome Atlas (TCGA). We employed Gene Set Variation Analysis (GSVA) to assess metabolic pathway activity, consensus clustering to identify CRC-specific transcriptome subtypes in bulkseq, and rigorous quality controls, including the exclusion of cells with high mitochondrial gene expression in scRNA seq. Advanced analyses such as AUCcell, infercnvCNV, Non-negative Matrix Factorization (NMF), and CytoTRACE were utilized to dissect the cellular landscape and evaluate pathway activities and tumor cell stemness. The hdWGCNA algorithm helped identify prognosis-related hub genes, integrating these findings using a random forest machine learning model. Kaplan-Meier survival curves identified 21 significant metabolic pathways linked to prognosis, with consensus clustering defining three CRC subtypes (C3, C2, C1) based on metabolic activity, which correlated with distinct clinical outcomes. The metabolic activity of the 13 cell subpopulations, particularly the epithelial cell subpopulation with active metabolic levels, was evaluated using AUCcell in scRNA seq. To further analyze tumor cells using infercnv, NMF disaggregated these cells into 10 cellular subpopulations. Among these, the C2 subpopulation exhibited higher stemness and tended to have a poorer prognosis compared to C6 and C0. Conversely, the C8, C3, and C1 subpopulations demonstrated a higher level of the five metabolic pathways, and the C3 and C8 subpopulations tended to have a more favorable prognosis. hdWGCNA identified 20 modules, from which we selected modules primarily expressed in high metabolic tumor subgroups and highly correlated with clinical information, including blue and cyan. By applying variable downscaling of RF to a total of 50 hub genes, seven gene signatures were obtained. Furthermore, molecules that were validated to be protective in GEO were screened alongside related molecules, resulting in the identification of prognostically relevant molecules such as UQCRFS1 and GRSF1. Additionally, the expression of GRSF1 was examined in colon cancer cell lines using qPCR and phenotypically verified by experiments. Our findings emphasize that high activity in specific metabolic pathways, including pyruvate metabolism and the tricarboxylic acid cycle, correlates with improved colon cancer outcomes, presenting new avenues for metabolic-based therapies. The identification of hub genes like GRSF1 and UQCRFS1 and their link to favorable metabolic profiles offers novel insights into tumor neovascularization and metastasis, with significant clinical implications for targeting metabolic pathways in CRC therapy.
PubMed: 38947396
DOI: 10.7150/jca.94630 -
Journal of Cancer 2024In the realm of cancer research, particularly hepatocellular carcinoma (HCC), TAR DNA-binding protein (TARDBP) has transitioned from being associated with...
In the realm of cancer research, particularly hepatocellular carcinoma (HCC), TAR DNA-binding protein (TARDBP) has transitioned from being associated with neurodegenerative diseases to emerging as a significant molecule in oncology due to its aberrant expression in HCC and other malignancies. This shift underlines the versatility of TARDBP and its critical role in tumorigenesis. Our study illuminates TARDBP's universal upregulation across various cancers, indicating its involvement in fundamental oncogenic processes and potential impact on genomic instability. The relationship between TARDBP expression and tumor mutational burden (TMB) across several cancers highlights its influence on a key hallmark of cancer progression. Additionally, TARDBP's interaction with immune and inflammatory factors within the tumor microenvironment, including its association with immune-stimulatory factors and inverse relationship with immune inhibitors, suggests its role in modulating immune evasion. Clinically, TARDBP's aberrant expression correlates with adverse patient outcomes in HCC, making it a promising candidate for therapeutic targeting. The study concludes that TARDBP holds significant potential as a novel therapeutic target in HCC and possibly other malignancies, meriting further exploration to integrate TARDBP-targeted therapies into cancer treatment protocols, thereby advancing the field of precision medicine.
PubMed: 38947395
DOI: 10.7150/jca.96800 -
Journal of Cancer 2024Gastric cancer (GC) is one of the most common malignancies worldwide, with high incidence and mortality rate. Tripartite motif-containing 28 (TRIM28) is an important...
Gastric cancer (GC) is one of the most common malignancies worldwide, with high incidence and mortality rate. Tripartite motif-containing 28 (TRIM28) is an important molecule that affects the occurrence and development of tumors, but its function in GC has not been elucidated clearly. The purpose of this study is to explore the molecular mechanism by which TRIM28 affect the GC. TRIM28 expression was tested in RNA-seq data from TCGA database, tumor tissue samples from patients and GC cell lines. Genes were silenced or overexpressed by siRNA, lentivirus-mediated shRNA, or plasmids. Cell Counting Kit-8 (CCK-8) and colony formation assays were performed to explore the proliferation of GC cells after TRIM28 knockdown. RNA-seq and TCGA database were used to identify target genes. Luciferase report assay was employed to detect the possible mechanism between TRIM28 and Indoleamine 2,3-dioxygenase (IDO1). Tryptophan concentration in cell supernatant was measured using a fluorometric assay kit. MGC-803 and 746T cells were injected into mice to establish xenograft animal models. The expression of TRIM28 was positively correlated with tumor size and poorer prognosis. Upregulation of TRIM28 was observed in GC tissues and cells. , we proved that knockdown of TRIM28 significantly inhibited the proliferation of GC cells. Then TRIM28 was found to be positively correlated with the expression of IDO1 in GC cells. In accordance with this, tryptophan levels in cell supernatants were increased in TRIM28 knockdown GC cells and overexpression of IDO1 could reverse this phenotype. Serum response factor (SRF), a reported regulator of IDO1, was also regulated by TRIM28 in GC cells. And decreased expression of IDO1 induced by TRIM28 knockdown could be partly reversed through overexpression of serum response factor (SRF) in GC cells. Functional research demonstrated that the expression of IDO1 was increased in GC and IDO1 knockdown could also inhibited the proliferation of GC cells. Furthermore, overexpression of IDO1 could partly reverse proliferation inhibited by TRIM28 knockdown in GC cells. , knockdown of TRIM28 significantly inhibited the tumor growth and overexpression of IDO1 and SRF both could reverse proliferation inhibited by TRIM28 knockdown. TRIM28 is crucial in the development of GC, and may regulate IDO1 through SRF. TRIM28 promote GC cell proliferation through SRF/IDO1 axis.
PubMed: 38947391
DOI: 10.7150/jca.95094