CellsPub Date : 2024-10-05DOI: 10.3390/cells13191654
Hongyi Zhou, Vijay Patel, Robert Rice, Richard Lee, Ha Won Kim, Neal L Weintraub, Huabo Su, Weiqin Chen
{"title":"Neddylation and Its Target Cullin 3 Are Essential for Adipocyte Differentiation.","authors":"Hongyi Zhou, Vijay Patel, Robert Rice, Richard Lee, Ha Won Kim, Neal L Weintraub, Huabo Su, Weiqin Chen","doi":"10.3390/cells13191654","DOIUrl":"10.3390/cells13191654","url":null,"abstract":"<p><p>The ongoing obesity epidemic has raised awareness of the complex physiology of adipose tissue. Abnormal adipocyte differentiation results in the development of systemic metabolic disorders such as insulin resistance and diabetes. The conjugation of NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to target protein, termed neddylation, has been shown to mediate adipogenesis. However, much remains unknown about its role in adipogenesis. Here, we demonstrated that neddylation and its targets, the cullin (CUL) family members, are differentially regulated during mouse and human adipogenesis. Inhibition of neddylation by MLN4924 significantly reduced adipogenesis of 3T3-L1 and human stromal vascular cells. Deletion of NAE1, a subunit of the only NEDD8 E1 enzyme, suppressed neddylation and impaired adipogenesis. Neddylation deficiency did not affect mitotic cell expansion. Instead, it disrupted CREB/CEBPβ/PPARγ signaling, essential for adipogenesis. Interestingly, among the neddylation-targeted CUL family members, deletion of CUL3, but not CUL1, CUL2, or CUL4A, largely replicated the adipogenic defects observed with neddylation deficiency. A PPARγ agonist minimally rescued the adipogenic defects caused by the deletion of NAE1 and CUL3. In conclusion, our study demonstrates that neddylation and its targeted CUL3 are crucial for adipogenesis. These findings provide potential targets for therapeutic intervention in obesity and metabolic disorders.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142485688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-10-05DOI: 10.3390/cells13191655
Chinmoy Sarkar, Marta M Lipinski
{"title":"Role and Function of Peroxisomes in Neuroinflammation.","authors":"Chinmoy Sarkar, Marta M Lipinski","doi":"10.3390/cells13191655","DOIUrl":"https://doi.org/10.3390/cells13191655","url":null,"abstract":"<p><p>Peroxisomes are organelles involved in many cellular metabolic functions, including the degradation of very-long-chain fatty acids (VLCFAs; C ≥ 22), the initiation of ether-phospholipid synthesis, and the metabolism of reactive oxygen species. All of these processes are essential for the maintenance of cellular lipid and redox homeostasis, and their perturbation can trigger inflammatory response in immune cells, including in the central nervous system (CNS) resident microglia and astrocytes. Consistently, peroxisomal disorders, a group of congenital diseases caused by a block in peroxisomal biogenesis or the impairment of one of the peroxisomal enzymes, are associated with neuroinflammation. Peroxisomal function is also dysregulated in many neurodegenerative diseases and during brain aging, both of which are associated with neuroinflammation. This suggests that deciphering the role of peroxisomes in neuroinflammation may be important for understanding both congenital and age-related brain dysfunction. In this review, we discuss the current advances in understanding the role and function of peroxisomes in neuroinflammation.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Bile Acids-Based Therapies for Primary Sclerosing Cholangitis: Current Landscape and Future Developments.","authors":"Stefano Fiorucci, Ginevra Urbani, Cristina Di Giorgio, Michele Biagioli, Eleonora Distrutti","doi":"10.3390/cells13191650","DOIUrl":"https://doi.org/10.3390/cells13191650","url":null,"abstract":"<p><p>Primary sclerosing cholangitis (PSC) is a rare, chronic liver disease with no approved therapies. The ursodeoxycholic acid (UDCA) has been widely used, although there is no evidence that the use of UDCA delays the time to liver transplant or increases survival. Several candidate drugs are currently being developed. The largest group of these new agents is represented by FXR agonists, including obeticholic acid, cilofexor, and tropifexor. Other agents that target bile acid metabolism are ASTB/IBAP inhibitors and fibroblasts growth factor (FGF)19 analogues. Cholangiocytes, the epithelial bile duct cells, play a role in PSC development. Recent studies have revealed that these cells undergo a downregulation of GPBAR1 (TGR5), a bile acid receptor involved in bicarbonate secretion and immune regulation. Additional agents under evaluation are PPARs (elafibranor and seladelpar), anti-itching agents such as MAS-related G-protein-coupled receptors antagonists, and anti-fibrotic and immunosuppressive agents. Drugs targeting gut bacteria and bile acid pathways are also under investigation, given the strong link between PSC and gut microbiota.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-10-04DOI: 10.3390/cells13191651
Kavita Prasad, Dipankar Bhattacharya, Shams Gamal Eldin Shams, Kimberly Izarraras, Tia Hart, Brent Mayfield, Maryjka B Blaszczyk, Zhongren Zhou, Utpal B Pajvani, Scott L Friedman, Moshmi Bhattacharya
{"title":"Kisspeptin Alleviates Human Hepatic Fibrogenesis by Inhibiting TGFβ Signaling in Hepatic Stellate Cells.","authors":"Kavita Prasad, Dipankar Bhattacharya, Shams Gamal Eldin Shams, Kimberly Izarraras, Tia Hart, Brent Mayfield, Maryjka B Blaszczyk, Zhongren Zhou, Utpal B Pajvani, Scott L Friedman, Moshmi Bhattacharya","doi":"10.3390/cells13191651","DOIUrl":"https://doi.org/10.3390/cells13191651","url":null,"abstract":"<p><p>The peptide hormone kisspeptin attenuates liver steatosis, metabolic dysfunction-associated steatohepatitis (MASH), and fibrosis in mouse models by signaling via the kisspeptin 1 receptor (KISS1R). However, whether kisspeptin impacts fibrogenesis in the human liver is not known. We investigated the impact of a potent kisspeptin analog (KPA) on fibrogenesis using human precision-cut liver slices (hPCLS) from fibrotic livers from male patients, in human hepatic stellate cells (HSCs), LX-2, and in primary mouse HSCs. In hPCLS, 48 h and 72 h of KPA (3 nM, 100 nM) treatment decreased collagen secretion and lowered the expression of fibrogenic and inflammatory markers. Immunohistochemical studies revealed that KISS1R is expressed and localized to HSCs in MASH/fibrotic livers. In HSCs, KPA treatment reduced transforming growth factor b (TGFβ)-the induced expression of fibrogenic and inflammatory markers, in addition to decreasing TGFβ-induced collagen secretion, cell migration, proliferation, and colony formation. Mechanistically, KISS1R signaling downregulated TGFβ signaling by decreasing SMAD2/3 phosphorylation via the activation of protein phosphatases, PP2A, which dephosphorylates SMAD 2/3. This study revealed for the first time that kisspeptin reverses human hepatic fibrogenesis, thus identifying it as a new therapeutic target to treat hepatic fibrosis.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11476267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-10-04DOI: 10.3390/cells13191652
Chiara Sasia, Vittoria Borgonetti, Caterina Mancini, Giulia Lori, Jack L Arbiser, Maria Letizia Taddei, Nicoletta Galeotti
{"title":"The Neolignan Honokiol and Its Synthetic Derivative Honokiol Hexafluoro Reduce Neuroinflammation and Cellular Senescence in Microglia Cells.","authors":"Chiara Sasia, Vittoria Borgonetti, Caterina Mancini, Giulia Lori, Jack L Arbiser, Maria Letizia Taddei, Nicoletta Galeotti","doi":"10.3390/cells13191652","DOIUrl":"https://doi.org/10.3390/cells13191652","url":null,"abstract":"<p><p>Microglia-mediated neuroinflammation has been linked to neurodegenerative disorders. Inflammation and aging contribute to microglial senescence. Microglial senescence promotes the development of neurodegenerative disorders, including Alzheimer's disease (AD). In this study, we investigated the anti-neuroinflammatory and anti-senescence activity of Honokiol (HNK), a polyphenolic neolignane from <i>Magnolia officinalis</i> Rehder & E.H Wilson, in comparison with its synthetic analogue Honokiol Hexafluoro (CH). HNK reduced the pro-inflammatory cell morphology of LPS-stimulated BV2 microglia cells and increased the expression of the anti-inflammatory cytokine IL-10 with an efficacy comparable to CH. HNK and CH were also able to attenuate the alterations in cell morphology associated with cellular senescence in BV2 cells intermittently stimulated with LPS and significantly reduce the activity and expression of the senescence marker ß-galactosidase and the expression of p21 and pERK1/2. The treatments reduced the expression of senescence-associated secretory phenotype (SASP) factors IL-1ß and NF-kB, decreased ROS production, and abolished H2AX over phosphorylation (γ-H2AX) and acetylated H3 overexpression. Senescent microglia cells showed an increased expression of the Notch ligand Jagged1 that was reduced by HNK and CH with a comparable efficacy to the Notch inhibitor DAPT. Overall, our data illustrate a protective activity of HNK and CH on neuroinflammation and cellular senescence in microglia cells involving a Notch-signaling-mediated mechanism and suggesting a potential therapeutic contribution in aging-related neurodegenerative diseases.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-10-04DOI: 10.3390/cells13191653
Yulian Ding, Connor Denomy, Andrew Freywald, Yi Pan, Franco J Vizeacoumar, Frederick S Vizeacoumar, Fang-Xiang Wu
{"title":"Systematic Comparison of CRISPR and shRNA Screens to Identify Essential Genes Using a Graph-Based Unsupervised Learning Model.","authors":"Yulian Ding, Connor Denomy, Andrew Freywald, Yi Pan, Franco J Vizeacoumar, Frederick S Vizeacoumar, Fang-Xiang Wu","doi":"10.3390/cells13191653","DOIUrl":"https://doi.org/10.3390/cells13191653","url":null,"abstract":"<p><p>Generally, essential genes identified using shRNA and CRISPR are not always the same, raising questions about the choice between these two screening platforms. To address this, we systematically compared the performance of CRISPR and shRNA to identify essential genes across different gene expression levels in 254 cell lines. As both platforms have a notable false positive rate, to correct this confounding factor, we first developed a graph-based unsupervised machine learning model to predict common essential genes. Furthermore, to maintain the unique characteristics of individual cell lines, we intersect essential genes derived from the biological experiment with the predicted common essential genes. Finally, we employed statistical methods to compare the ability of these two screening platforms to identify essential genes that exhibit differential expression across various cell lines. Our analysis yielded several noteworthy findings: (1) shRNA outperforms CRISPR in the identification of lowly expressed essential genes; (2) both screening methodologies demonstrate strong performance in identifying highly expressed essential genes but with limited overlap, so we suggest using a combination of these two platforms for highly expressed essential genes; (3) notably, we did not observe a single gene that becomes universally essential across all cancer cell lines.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-10-03DOI: 10.3390/cells13191646
Zehua Wen, Lei Wang, Shi-Wei Liu, Hua-Jun Shawn Fan, Jong-Won Song, Ho-Jin Lee
{"title":"Exploring DIX-DIX Homo- and Hetero-Oligomers in Wnt Signaling with AlphaFold2.","authors":"Zehua Wen, Lei Wang, Shi-Wei Liu, Hua-Jun Shawn Fan, Jong-Won Song, Ho-Jin Lee","doi":"10.3390/cells13191646","DOIUrl":"https://doi.org/10.3390/cells13191646","url":null,"abstract":"<p><p>Wnt signaling is involved in embryo development and cancer. The binding between the DIX domains of Axin1/2, Dishevelled1/2/3, and Coiled-coil-DIX1 is essential for Wnt/β-catenin signaling. Structural and biological studies have revealed that DIX domains are polymerized through head-to-tail interface interactions, which are indispensable for activating β-catenin Wnt signaling. Although different isoforms of Dvl and Axin proteins display both redundant and specific functions in Wnt signaling, the specificity of DIX-mediated interactions remains unclear due to technical challenges. Using AlphaFold2(AF2), we predict the structures of 6 homodimers and 22 heterodimers of DIX domains without templates and compare them with the reported X-ray complex structures. PRODIGY is used to calculate the binding affinities of these DIX complexes. Our results show that the Axin2 DIX homodimer has a stronger binding affinity than the Axin1 DIX homodimer. Among Dishevelled (Dvl) proteins, the binding affinity of the Dvl1 DIX homodimer is stronger than that of Dvl2 and Dvl3. The Coiled-coil-DIX1(Ccd1) DIX homodimer shows weaker binding than the Axin1 DIX homodimer. Generally, heterodimer interactions tend to be stronger than those of homodimers. Our findings provide insights into the mechanism of the Wnt signaling pathway and highlight the potential of AF2 and PRODIGY for studying protein-protein interactions in signaling pathways.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142485682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-10-03DOI: 10.3390/cells13191648
Ying-Chu Lin, Chia-Chen Ku, Kenly Wuputra, Deng-Chyang Wu, Kazunari K Yokoyama
{"title":"Vulnerability of Antioxidant Drug Therapies on Targeting the Nrf2-Trp53-Jdp2 Axis in Controlling Tumorigenesis.","authors":"Ying-Chu Lin, Chia-Chen Ku, Kenly Wuputra, Deng-Chyang Wu, Kazunari K Yokoyama","doi":"10.3390/cells13191648","DOIUrl":"https://doi.org/10.3390/cells13191648","url":null,"abstract":"<p><p>Control of oxidation/antioxidation homeostasis is important for cellular protective functions, and disruption of the antioxidation balance by exogenous and endogenous ligands can lead to profound pathological consequences of cancerous commitment within cells. Although cancers are sensitive to antioxidation drugs, these drugs are sometimes associated with problems including tumor resistance or dose-limiting toxicity in host animals and patients. These problems are often caused by the imbalance between the levels of oxidative stress-induced reactive oxygen species (ROS) and the redox efficacy of antioxidants. Increased ROS levels, because of abnormal function, including metabolic abnormality and signaling aberrations, can promote tumorigenesis and the progression of malignancy, which are generated by genome mutations and activation of proto-oncogene signaling. This hypothesis is supported by various experiments showing that the balance of oxidative stress and redox control is important for cancer therapy. Although many antioxidant drugs exhibit therapeutic potential, there is a heterogeneity of antioxidation functions, including cell growth, cell survival, invasion abilities, and tumor formation, as well as the expression of marker genes including tumor suppressor proteins, cell cycle regulators, nuclear factor erythroid 2-related factor 2, and Jun dimerization protein 2; their effectiveness in cancer remains unproven. Here, we summarize the rationale for the use of antioxidative drugs in preclinical and clinical antioxidant therapy of cancer, and recent advances in this area using cancer cells and their organoids, including the targeting of ROS homeostasis.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Laherradurin Inhibits Colorectal Cancer Cell Growth by Induction of Mitochondrial Dysfunction and Autophagy Induction.","authors":"Izamary Delgado-Waldo, Svetlana Dokudovskaya, Yahir A Loissell-Baltazar, Eduardo Pérez-Arteaga, Jossimar Coronel-Hernández, Mariano Martínez-Vázquez, Eloy Andrés Pérez-Yépez, Alejandro Lopez-Saavedra, Nadia Jacobo-Herrera, Carlos Pérez Plasencia","doi":"10.3390/cells13191649","DOIUrl":"https://doi.org/10.3390/cells13191649","url":null,"abstract":"<p><p>LAH, an acetogenin from the Annonaceae family, has demonstrated antitumor activity in several cancer cell lines and in vivo models, where it reduced the tumor size and induced programmed cell death. We focused on the effects of LAH on mitochondrial dynamics, mTOR signaling, autophagy, and apoptosis in colorectal cancer (CRC) cells to explore its anticancer potential.</p><p><strong>Methods: </strong>CRC cells were treated with LAH, and its effects on mitochondrial respiration and glycolysis were measured using Seahorse XF technology. The changes in mitochondrial dynamics were observed through fluorescent imaging, while Western blot analysis was used to examine key autophagy and apoptosis markers.</p><p><strong>Results: </strong>LAH significantly inhibited mitochondrial complex I activity, inducing ATP depletion and a compensatory increase in glycolysis. This disruption caused mitochondrial fragmentation, a trigger for autophagy, as shown by increased LC3-II expression and mTOR suppression. Apoptosis was also confirmed through the cleavage of caspase-3, contributing to reduced cancer cell viability.</p><p><strong>Conclusions: </strong>LAH's anticancer effects in CRC cells are driven by its disruption of mitochondrial function, triggering both autophagy and apoptosis. These findings highlight its potential as a therapeutic compound for further exploration in cancer treatment.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142485683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CellsPub Date : 2024-10-03DOI: 10.3390/cells13191647
Rafael Marins Rezende, Roney Santos Coimbra, Markus Kohlhoff, Lukiya Silva Campos Favarato, Hércia Stampini Duarte Martino, Luciano Bernardes Leite, Leoncio Lopes Soares, Samuel Encarnação, Pedro Forte, António Miguel de Barros Monteiro, Maria do Carmo Gouveia Peluzio, Antônio José Natali
{"title":"Effects of Tryptophan and Physical Exercise on the Modulation of Mechanical Hypersensitivity in a Fibromyalgia-like Model in Female Rats.","authors":"Rafael Marins Rezende, Roney Santos Coimbra, Markus Kohlhoff, Lukiya Silva Campos Favarato, Hércia Stampini Duarte Martino, Luciano Bernardes Leite, Leoncio Lopes Soares, Samuel Encarnação, Pedro Forte, António Miguel de Barros Monteiro, Maria do Carmo Gouveia Peluzio, Antônio José Natali","doi":"10.3390/cells13191647","DOIUrl":"https://doi.org/10.3390/cells13191647","url":null,"abstract":"<p><p>Though the mechanisms are not fully understood, tryptophan (Trp) and physical exercise seem to regulate mechanical hypersensitivity in fibromyalgia. Here, we tested the impact of Trp supplementation and continuous low-intensity aerobic exercise on the modulation of mechanical hypersensitivity in a fibromyalgia-like model induced by acid saline in female rats. Twelve-month-old female Wistar rats were randomly divided into groups: [control (n = 6); acid saline (n = 6); acid saline + exercise (n = 6); acid saline + Trp (n = 6); and acid saline + exercise + Trp (n = 6)]. Hypersensitivity was caused using two intramuscular jabs of acid saline (20 μL; pH 4.0; right gastrocnemius), 3 days apart. The tryptophan-supplemented diet contained 7.6 g/hg of Trp. The three-week exercise consisted of progressive (30-45 min) treadmill running at 50 to 60% intensity, five times (Monday to Friday) per week. We found that acid saline induced contralateral mechanical hypersensitivity without changing the levels of Trp, serotonin (5-HT), and kynurenine (KYN) in the brain. Hypersensitivity was reduced by exercise (~150%), Trp (~67%), and its combination (~160%). The Trp supplementation increased the levels of Trp and KYN in the brain, and the activity of indoleamine 2,3-dioxygenase (IDO), and decreased the ratio 5-HT:KYN. Exercise did not impact the assessed metabolites. Combining the treatments reduced neither hypersensitivity nor the levels of serotonin and Trp in the brain. In conclusion, mechanical hypersensitivity induced by acid saline in a fibromyalgia-like model in female rats is modulated by Trp supplementation, which increases IDO activity and leads to improved Trp metabolism via the KYN pathway. In contrast, physical exercise does not affect mechanical hypersensitivity through brain Trp metabolism via either the KYN or serotonin pathways. Because this is a short study, generalizing its findings warrants caution.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11475953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}