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International Journal of Molecular... May 2024Microglia-mediated inflammatory response is one key cause of many central nervous system diseases, like Alzheimer's disease. We hypothesized that a novel C15orf39 (MAPK1...
Microglia-mediated inflammatory response is one key cause of many central nervous system diseases, like Alzheimer's disease. We hypothesized that a novel C15orf39 (MAPK1 substrate) plays a critical role in the microglial inflammatory response. To confirm this hypothesis, we used lipopolysaccharide (LPS)-and interferon-gamma (IFN-γ)-induced human microglia HMC3 cells as a representative indicator of the microglial in vitro inflammatory response. We found that C15orf39 was down-regulated when interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) expression increased in LPS/IFN-γ-stimulated HMC3 cells. Once C15orf39 was overexpressed, IL-6 and TNFα expression were reduced in LPS/IFN-γ-stimulated HMC3 cells. In contrast, C15orf39 knockdown promoted IL-6 and TNFα expression in LPS/IFN-γ-stimulated HMC3 cells. These results suggest that C15orf39 is a suppressive factor in the microglial inflammatory response. Mechanistically, C15orf39 interacts with the cytoplasmic protein arginine methyltransferase 2 (PRMT2). Thus, we termed C15orf39 a PRMT2 interaction protein (PRMT2 IP). Furthermore, the interaction of C15orf39 and PRMT2 suppressed the activation of NF-κB signaling via the PRMT2-IκBα signaling axis, which then led to a reduction in transcription of the inflammatory factors IL6 and TNF-α. Under inflammatory conditions, NF-κBp65 was found to be activated and to suppress C15orf39 promoter activation, after which it canceled the suppressive effect of the C15orf39-PRMT2-IκBα signaling axis on IL-6 and TNFα transcriptional expression. In conclusion, our findings demonstrate that in a steady condition, the interaction of C15orf39 and PRMT2 stabilizes IκBα to inhibit IL-6 and TNFα expression by suppressing NF-κB signaling, which reversely suppresses C15orf39 transcription to enhance IL-6 and TNFα expression in the microglial inflammatory condition. Our study provides a clue as to the role of C15orf39 in microglia-mediated inflammation, suggesting the potential therapeutic efficacy of C15orf39 in some central nervous system diseases.
Topics: Humans; Microglia; Protein-Arginine N-Methyltransferases; Lipopolysaccharides; Inflammation; Cell Line; Interleukin-6; Tumor Necrosis Factor-alpha; Interferon-gamma; Signal Transduction; NF-kappa B
PubMed: 38892217
DOI: 10.3390/ijms25116025 -
International Journal of Molecular... May 2024Osteoarthritis (OA) is increasing worldwide, and previous work found that OA increases systemic cartilage oligomeric matrix protein (COMP), which has also been...
Osteoarthritis (OA) is increasing worldwide, and previous work found that OA increases systemic cartilage oligomeric matrix protein (COMP), which has also been implicated in prostate cancer (PCa). As such, we sought to investigate whether OA augments PCa progression. Cellular proliferation and migration of RM1 murine PCa cells treated with interleukin (IL)-1α, COMP, IL-1α + COMP, or conditioned media from cartilage explants treated with IL-1α (representing OA media) and with inhibitors of COMP were assessed. A validated murine model was used for tumor growth and marker expression analysis. Both proliferation and migration were greater in PCa cells treated with OA media compared to controls ( < 0.001), which was not seen with direct application of the stimulants. Migration and proliferation were not negatively affected when OA media was mixed with downstream and COMP inhibitors compared to controls ( > 0.05 for all). Mice with OA developed tumors 100% of the time, whereas mice without OA only 83.4% ( = 0.478). Tumor weight correlated with OA severity (Pearson correlation = 0.813, = 0.002). Moreover, tumors from mice with OA demonstrated increased Ki-67 expression compared to controls (mean 24.56% vs. 6.91%, = 0.004) but no difference in CD31, PSMA, or COMP expression ( > 0.05). OA appears to promote prostate cancer in vitro and in vivo.
Topics: Male; Animals; Prostatic Neoplasms; Mice; Cell Proliferation; Cartilage Oligomeric Matrix Protein; Cell Line, Tumor; Osteoarthritis; Cell Movement; Humans; Disease Models, Animal; Interleukin-1alpha
PubMed: 38892202
DOI: 10.3390/ijms25116014 -
International Journal of Molecular... May 2024Astronauts on exploratory missions will be exposed to galactic cosmic rays (GCR), which can induce neuroinflammation and oxidative stress (OS) and may increase the risk...
Astronauts on exploratory missions will be exposed to galactic cosmic rays (GCR), which can induce neuroinflammation and oxidative stress (OS) and may increase the risk of neurodegenerative disease. As key regulators of inflammation and OS in the CNS, microglial cells may be involved in GCR-induced deficits, and therefore could be a target for neuroprotection. This study assessed the effects of exposure to helium (He) and iron (Fe) particles on inflammation and OS in microglia in vitro, to establish a model for testing countermeasure efficacy. Rat microglia were exposed to a single dose of 20 cGy (300 MeV/n) He or 2 Gy Fe (600 MeV/n), while the control cells were not exposed (0 cGy). Immediately following irradiation, fresh media was applied to the cells, and biomarkers of inflammation (cyclooxygenase-2 [COX-2], nitric oxide synthase [iNOS], phosphorylated IκB-α [pIκB-α], tumor necrosis factor-α [TNFα], and nitrite [NO]) and OS (NADPH oxidase [NOX2]) were assessed 24 h later using standard immunochemical techniques. Results showed that radiation did not increase levels of NO or protein levels of COX-2, iNOS, pIκB-α, TNFα, or NOX2 compared to non-irradiated control conditions in microglial cells ( > 0.05). Therefore, microglia in isolation may not be the primary cause of neuroinflammation and OS following exposures to helium or iron GCR particles.
Topics: Animals; Microglia; Cosmic Radiation; Oxidative Stress; Rats; Inflammation; Biomarkers; Nitric Oxide Synthase Type II; Iron; Cyclooxygenase 2; Helium; Tumor Necrosis Factor-alpha; NADPH Oxidase 2
PubMed: 38892109
DOI: 10.3390/ijms25115923 -
International Journal of Molecular... May 2024Epidural and subdural hematomas are commonly associated with traumatic brain injury. While surgical removal is the primary intervention for these hematomas, it is also...
Epidural and subdural hematomas are commonly associated with traumatic brain injury. While surgical removal is the primary intervention for these hematomas, it is also critical to prevent and reduce complications such as post-traumatic epilepsy, which may result from inflammatory responses in the injured brain areas. In the present study, we observed that high mobility group box-1 (HMGB1) decreased in the injured brain area beneath the epidural hematoma (EDH) in rats, concurrent with elevated plasma levels of HMGB1. Anti-HMGB1 monoclonal antibody therapy strongly inhibited both HMGB1 release and the subsequent increase in plasma levels. Moreover, this treatment suppressed the up-regulation of inflammatory cytokines and related molecules such as interleukin-1-beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and inducible nitric oxide synthase (iNOS) in the injured areas. Our in vitro experiments using SH-SY5Y demonstrated that hematoma components-thrombin, heme, and ferrous ion- prompted HMGB1 translocation from the nuclei to the cytoplasm, a process inhibited by the addition of the anti-HMGB1 mAb. These findings suggest that anti-HMGB1 mAb treatment not only inhibits HMGB1 translocation but also curtails inflammation in injured areas, thereby protecting the neural tissue. Thus, anti-HMGB1 mAb therapy could serve as a complementary therapy for an EDH before/after surgery.
Topics: HMGB1 Protein; Animals; Rats; Antibodies, Monoclonal; Hematoma, Epidural, Cranial; Male; Humans; Rats, Sprague-Dawley; Interleukin-1beta; Tumor Necrosis Factor-alpha; Cytokines; Nitric Oxide Synthase Type II; Cell Line, Tumor
PubMed: 38892076
DOI: 10.3390/ijms25115889 -
International Journal of Molecular... May 2024Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have...
Doxorubicin is an effective drug for cancer treatment; however, cardiotoxicity limits its use. Cardiotoxicity pathophysiology is multifactorial. GLP-1 analogues have been shown to reduce oxidative stress and inflammation. In this study, we evaluated the effect of pretreatment with liraglutide on doxorubicin-induced acute cardiotoxicity. A total of 60 male Wistar rats were allocated into four groups: Control (C), Doxorubicin (D), Liraglutide (L), and Doxorubicin + Liraglutide (DL). L and DL received subcutaneous injection of liraglutide 0.6 mg/kg daily, while C and D received saline for 2 weeks. Afterwards, D and DL received a single intraperitoneal injection of doxorubicin 20 mg/kg; C and L received an injection of saline. Forty-eight hours after doxorubicin administration, the rats were subjected to echocardiogram, isolated heart functional study, and euthanasia. Liraglutide-treated rats ingested significantly less food and gained less body weight than animals that did not receive the drug. Rats lost weight after doxorubicin injection. At echocardiogram and isolated heart study, doxorubicin-treated rats had systolic and diastolic function impairment. Myocardial catalase activity was statistically higher in doxorubicin-treated rats. Myocardial protein expression of tumor necrosis factor alpha (TNF-α), phosphorylated nuclear factor-κB (p-NFκB), troponin T, and B-cell lymphoma 2 (Bcl-2) was significantly lower, and the total NFκB/p-NFκB ratio and TLR-4 higher in doxorubicin-treated rats. Myocardial expression of OPA-1, MFN-2, DRP-1, and topoisomerase 2β did not differ between groups ( > 0.05). In conclusion, doxorubicin-induced cardiotoxicity is accompanied by decreased Bcl-2 and phosphorylated NFκB and increased catalase activity and TLR-4 expression. Liraglutide failed to improve acute doxorubicin-induced cardiotoxicity in rats.
Topics: Animals; Liraglutide; Doxorubicin; Cardiotoxicity; Male; Rats; Rats, Wistar; Oxidative Stress; Myocardium; NF-kappa B; Tumor Necrosis Factor-alpha; Heart
PubMed: 38892020
DOI: 10.3390/ijms25115833 -
International Journal of Molecular... May 2024Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-β-activated kinase-1 (TAK1) activation, inflammatory...
Chronic inflammation causes muscle wasting. Because most inflammatory cytokine signals are mediated via TGF-β-activated kinase-1 (TAK1) activation, inflammatory cytokine-induced muscle wasting may be ameliorated by the inhibition of TAK1 activity. The present study was undertaken to clarify whether TAK1 inhibition can ameliorate inflammation-induced muscle wasting. SKG/Jcl mice as an autoimmune arthritis animal model were treated with a small amount of mannan as an adjuvant to enhance the production of TNF-α and IL-1β. The increase in these inflammatory cytokines caused a reduction in muscle mass and strength along with an induction of arthritis in SKG/Jcl mice. Those changes in muscle fibers were mediated via the phosphorylation of TAK1, which activated the downstream signaling cascade via NF-κB, p38 MAPK, and ERK pathways, resulting in an increase in myostatin expression. Myostatin then reduced the expression of muscle proteins not only via a reduction in MyoD1 expression but also via an enhancement of Atrogin-1 and Murf1 expression. TAK1 inhibitor, LL-Z1640-2, prevented all the cytokine-induced changes in muscle wasting. Thus, TAK1 inhibition can be a new therapeutic target of not only joint destruction but also muscle wasting induced by inflammatory cytokines.
Topics: Animals; MAP Kinase Kinase Kinases; Muscular Atrophy; Mice; Cytokines; Muscle Weakness; Myostatin; Muscle Proteins; Tumor Necrosis Factor-alpha; NF-kappa B; Inflammation; Signal Transduction; Tripartite Motif Proteins; Disease Models, Animal; Interleukin-1beta; Phosphorylation; Muscle, Skeletal; Zearalenone
PubMed: 38891908
DOI: 10.3390/ijms25115715 -
International Journal of Molecular... May 2024In the cosmetics industry, the extract from L. is fermented using specific starter cultures. These cosmetic ingredients act as preservatives and skin conditioners.... (Comparative Study)
Comparative Study
In the cosmetics industry, the extract from L. is fermented using specific starter cultures. These cosmetic ingredients act as preservatives and skin conditioners. Kombucha is traditionally made by fermenting sweetened tea using symbiotic cultures of bacteria and yeast and is used in cosmetic products. The aim of this study was to evaluate the cosmetic properties of radish leaf and root extract fermented with the SCOBY. Both unfermented water extracts and extracts after 7, 14, and 21 days of fermentation were evaluated. The analysis of secondary plant metabolites by UPLC-MS showed higher values for ferments than for extracts. A similar relationship was noted when examining the antioxidant properties using DPPH and ABTS radicals and the protective effect against HO-induced oxidative stress in fibroblasts and keratinocytes using the fluorogenic dye HDCFDA. The results also showed no cytotoxicity to skin cells using Alamar Blue and Neutral Red tests. The ability of the samples to inhibit IL-1β and COX-2 activity in LPS-treated fibroblasts was also demonstrated using ELISA assays. The influence of extracts and ferments on bacterial strains involved in inflammatory processes of skin diseases was also assessed. Additionally, application tests were carried out, which showed a positive effect of extracts and ferments on TEWL and skin hydration using a TEWAmeter and corneometer probe. The results obtained depended on the concentration used and the fermentation time.
Topics: Plant Extracts; Plant Leaves; Anti-Inflammatory Agents; Raphanus; Fermentation; Anti-Bacterial Agents; Humans; Antioxidants; Plant Roots; Fibroblasts; Kombucha Tea; Cyclooxygenase 2; Interleukin-1beta; Oxidative Stress
PubMed: 38891811
DOI: 10.3390/ijms25115622 -
International Journal of Molecular... May 2024Inflammatory bowel disease (IBD) is a nonspecific chronic inflammatory disease resulting from an immune disorder in the intestine that is prone to relapse and incurable....
Inflammatory bowel disease (IBD) is a nonspecific chronic inflammatory disease resulting from an immune disorder in the intestine that is prone to relapse and incurable. The understanding of the pathogenesis of IBD remains unclear. In this study, we found that (angiotensin-converting enzyme), expressed abundantly in the intestine, plays an important role in IBD. The deletion of in zebrafish caused intestinal inflammation with increased expression of the inflammatory marker genes interleukin 1 beta (), matrix metallopeptidase 9 (), myeloid-specific peroxidase (), leukocyte cell-derived chemotaxin-2-like (), and chemokine (C-X-C motif) ligand 8b (). Moreover, the secretion of mucus in the mutants was significantly higher than that in the wild-type zebrafish, validating the phenotype of intestinal inflammation. This was further confirmed by the IBD model constructed using dextran sodium sulfate (DSS), in which the mutant zebrafish had a higher susceptibility to enteritis. Our study reveals the role of in intestinal homeostasis, providing a new target for potential therapeutic interventions.
Topics: Animals; Zebrafish; Peptidyl-Dipeptidase A; Disease Models, Animal; Dextran Sulfate; Inflammation; Zebrafish Proteins; Intestines; Inflammatory Bowel Diseases; Interleukin-1beta; Intestinal Mucosa
PubMed: 38891786
DOI: 10.3390/ijms25115598 -
Cells Jun 2024Authors have demonstrated that apoptosis activation is a pathway related to cartilage degradation characteristics of the OA process. Autophagy is an adaptive response to...
Authors have demonstrated that apoptosis activation is a pathway related to cartilage degradation characteristics of the OA process. Autophagy is an adaptive response to protect cells from various environmental changes, and defects in autophagy are linked to cell death. In this sense, decreased autophagy of chondrocytes has been observed in OA articular cartilage. The aim of this work was to study the role of OA mitochondria in apoptosis, autophagy, and senescence, using OA and Normal (N) transmitochondrial cybrids. Results: OA cybrids incubated with menadione showed a higher percentage of late apoptosis and necrosis than N cybrids. Stimulation of cybrids with staurosporine and IL-1β showed that OA cybrids were more susceptible to undergoing apoptosis than N cybrids. An analysis of the antioxidant response using menadione on gene expression revealed a lower expression of nuclear factor erythroid 2-like 2 and superoxide dismutase 2 in OA than N cybrids. Activation of microtubule-associated protein 1A/1B-light chain 3 was reduced in OA compared to N cybrids. However, the percentage of senescent cells was higher in OA than N cybrids. Conclusion: This work suggests that mitochondria from OA patients could be involved in the apoptosis, autophagy, and senescence of chondrocytes described in OA cartilage.
Topics: Autophagy; Humans; Osteoarthritis; Apoptosis; Cellular Senescence; Mitochondria; Chondrocytes; Microtubule-Associated Proteins; NF-E2-Related Factor 2; Superoxide Dismutase; Aged; Interleukin-1beta; Male; Middle Aged; Vitamin K 3; Female
PubMed: 38891108
DOI: 10.3390/cells13110976 -
Cells Jun 2024Binge drinking in obese patients positively correlates with accelerated liver damage and liver-related death. However, the underlying mechanism and the effect of alcohol...
Binge drinking in obese patients positively correlates with accelerated liver damage and liver-related death. However, the underlying mechanism and the effect of alcohol use on the progression of metabolic-dysfunction-associated steatotic liver disease (MASLD) remain unexplored. Here, we show that short-term feeding of a metabolic-dysfunction-associated steatohepatitis (MASH) diet plus daily acute alcohol binges for three days induce liver injury and activation of the NLRP3 inflammasome. We identify that a MASH diet plus acute alcohol binges promote liver inflammation via increased infiltration of monocyte-derived macrophages, neutrophil recruitment, and NET release in the liver. Our results suggest that both monocyte-derived macrophages and neutrophils are activated via NLRP3, while the administration of MCC950, an NLRP3 inhibitor, dampens these effects.In this study, we reveal important intercellular communication between hepatocytes and neutrophils. We discover that the MASH diet plus alcohol induces IL-1β via NLRP3 activation and that IL-1β acts on hepatocytes and promotes the production of CXCL1 and LCN2. In turn, the increase in these neutrophils recruits chemokines and causes further infiltration and activation of neutrophils in the liver. In vivo administration of the NLRP3 inhibitor, MCC950, improves the early phase of MetALD by preventing liver damage, steatosis, inflammation, and immune cells recruitment.
Topics: NLR Family, Pyrin Domain-Containing 3 Protein; Animals; Liver; Interleukin-1beta; Neutrophil Infiltration; Male; Neutrophils; Mice, Inbred C57BL; Mice; Inflammasomes; Binge Drinking; Hepatocytes; Cell Communication; Sulfones; Sulfonamides; Macrophages; Furans; Humans; Indenes; Diet; Signal Transduction; Extracellular Traps; Fatty Liver; Sulfoxides
PubMed: 38891092
DOI: 10.3390/cells13110960