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Zhongguo Gu Shang = China Journal of... Jun 2024To explore mechanism of piracetam for the treatment of spinal cord injury in rats through mitogen-activated protein kinase (MAPK) pathway.
OBJECTIVE
To explore mechanism of piracetam for the treatment of spinal cord injury in rats through mitogen-activated protein kinase (MAPK) pathway.
METHODS
Fifty-four healthy 6-week-old SD female rats with body weight of 80 to 100 g were divided into sham operation group, spinal cord injury group and piracetam group by random number table method, with 18 rats in each group. Spinal cord injury model was established in spinal cord injury group and piracetam group using percussion apparatus, while sham operation group did not damage spinal cord. Piracetam group was injected with piracetam injection through tail vein according to 5 ml·kg standard, once a day for 3 days;the other two groups were injected with normal saline at the same dose, the same frequency and the same duration. The rats were sacrificed at 1, 3, and 7 days after surgery, and changes of Basso, Beattie and Bresnahan (BBB) locomotor rating scale was observed and compared. Enzyme-linked immunosorbent assay (ELISA) was used to detect spinal cord inflammatory factors, such as interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-1β (interleukin-1β), necrosis factor-α (IL-1β) and tumor necrosis factor-α (TNF-α);HE staining was used to observe morphological changes of rats with spinal cord injury, and immunohistochemistry was used to observe expression level of aquaporin 4 (AQP4). The activation of MAPK signaling pathway in spinal cord of rats after spinal cord injury was observed by western blotting (WB).
RESULTS
BBB scores of sham operation group on 1, 3 and 7 day were 21 points. In spinal cord injury group, the scores were (1±1), (4±1) and (7±2);piracetam group was (1±1), (5±1), (9±2), respectively;the difference between spinal cord injury group and sham operation group was statistically significant (<0.05). HE staining showed that no abnormality was found in sham operation group. In spinal cord injury group, bleeding and degeneration of spinal cord tissue appeared at 1 day after operation; flaky necrotic areas were appeared in spinal cord at 3 days after surgery, and spinal cord tissue began to slowly repair at 7 days after surgery. In piracetam group, the bleeding area was less than that of spinal cord injury group at 1 day after surgery;at 3 days after operation, the necrotic area was reduced and the range of nuclear disappearance was reduced; and the spinal cord began to recover slowly at 7 days after surgery. AQP4 staining of spinal cord of rats in sham operation group was weak at 1, 3 and 7 days after modeling, AQP4 staining was deepened and area increased in spinal cord injury group, AQP4 staining of piracetam group was lighter than that of spinal cord injury group, and the positive cells were slightly increased and the staining was slightly darker than that of sham operation group. At 1, 3 and 7 days, the level of IL-6, IL-10, IL-1β and TNF-α in spinal cord injury group were higher than those in sham operation group and piracetam group(<0.05). Compared with spinal cord injury group, the area of spinal cord bleeding and necrosis were decreased by HE staining in piracetam group, and AQP4 staining was decreased by immunohistochemistry. WB results showed that P-ERK, P-JNK and P-P38 levels in spinal cord injury group at 3 days were higher than those in sham operation group and piracetam group(<0.05).
CONCLUSION
Piracetam not only showed significant effect in promoting motor function recovery after spinal cord injury, but also showed positive therapeutic potential in reducing lesion area, regulating AQP4 expression to reduce edema, and reducing inflammatory response by regulating MAPK signaling pathway.
Topics: Animals; Spinal Cord Injuries; Rats; Female; Rats, Sprague-Dawley; Piracetam; MAP Kinase Signaling System; Interleukin-6; Tumor Necrosis Factor-alpha
PubMed: 38910382
DOI: 10.12200/j.issn.1003-0034.20230540 -
European Journal of Dermatology : EJD Apr 2024Psoriasis is a common skin disease with a high recurrence rate. Aberrant keratinocyte proliferation is a significant pathogenic characteristic of psoriatic lesions, and...
Psoriasis is a common skin disease with a high recurrence rate. Aberrant keratinocyte proliferation is a significant pathogenic characteristic of psoriatic lesions, and studies have revealed that the development of psoriasis is significantly influenced by pro-inflammatory cytokines, such as IL-17A and TNF-α. Biologics targeting these cytokines have been widely used in psoriasis treatment and achieve remarkable effects, however, the underlying mechanism of how IL-17A and TNF-α specifically regulate keratinocyte proliferation has not been fully elucidated. Dectin-1 is an essential membrane protein that is directly related to the immune microenvironment and the proliferation of multiple cell types. To elucidate how IL-17A and TNF-α may promote keratinocyte proliferation in psoriatic lesions and whether Dectin-1 is involved. The expression of Dectin-1 in keratinocytes from psoriatic lesions was detected by real-time PCR, western blot and immunofluorescence. Correlation analysis and cytological experiments were then performed to determine the relationship between Dectin-1 and IL-17A/TNF-α in psoriatic lesions. Finally, we investigated the signalling pathway through which Dectin-1 may promote keratinocyte proliferation. Dectin-1 was significantly increased in keratinocytes from psoriatic lesions. Moreover, IL-17A and TNF-α effectively induced the expression of Dectin-1 in HaCaT cells, which was shown to activate the Syk/NF-κB signalling pathway and promote the proliferation of keratinocytes. IL-17A and TNF-α may promote the proliferation of keratinocytes in psoriatic lesions through induction of Dectin-1, indicating that Dectin-1 could be a potential therapeutic target for the treatment of psoriasis.
Topics: Humans; Psoriasis; Keratinocytes; Interleukin-17; Lectins, C-Type; Tumor Necrosis Factor-alpha; Cell Proliferation; Signal Transduction; NF-kappa B; Syk Kinase; Male; Female; Cells, Cultured; Adult
PubMed: 38907541
DOI: 10.1684/ejd.2024.4662 -
Communications Biology Jun 2024Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation,...
Tuberous sclerosis complex 2 (TSC2) crucially suppresses Rheb activity to prevent mTORC1 activation. However, mutations in TSC genes lead to mTORC1 overactivation, thereby causing various developmental disorders and cancer. Therefore, the discovery of novel Rheb inhibitors is vital to prevent mTOR overactivation. Here, we reveals that the anti-inflammatory cytokine IL-37d can bind to lysosomal Rheb and suppress its activity independent of TSC2, thereby preventing mTORC1 activation. The binding of IL-37d to Rheb switch-II subregion destabilizes the Rheb-mTOR and mTOR-S6K interactions, further halting mTORC1 signaling. Unlike TSC2, IL-37d is reduced under ethanol stimulation, which results in mitigating the suppression of lysosomal Rheb-mTORC1 activity. Consequently, the recombinant human IL-37d protein (rh-IL-37d) with a TAT peptide greatly improves alcohol-induced liver disorders by hindering Rheb-mTORC1 axis overactivation in a TSC2- independent manner. Together, IL-37d emerges as a novel Rheb suppressor independent of TSC2 to terminate mTORC1 activation and improve abnormal lipid metabolism in the liver.
Topics: Mechanistic Target of Rapamycin Complex 1; Ras Homolog Enriched in Brain Protein; Humans; Animals; Mice; Signal Transduction; Tuberous Sclerosis Complex 2 Protein; Liver Diseases, Alcoholic; Interleukin-1; Mice, Inbred C57BL; Male; HEK293 Cells
PubMed: 38907105
DOI: 10.1038/s42003-024-06427-8 -
Chinese Journal of Natural Medicines Jun 2024Neuroinflammation, mediated by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome, is a significant...
Neuroinflammation, mediated by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome, is a significant contributor to the pathogenesis of neurodegenerative diseases (NDDs). Reynosin, a natural sesquiterpene lactone (SL), exhibits a broad spectrum of pharmacological effects, suggesting its potential therapeutic value. However, the effects and mechanism of reynosin on neuroinflammation remain elusive. The current study explores the effects and mechanisms of reynosin on neuroinflammation using mice and BV-2 microglial cells treated with lipopolysaccharide (LPS). Our findings reveal that reynosin effectively reduces microglial inflammation in vitro, as demonstrated by decreased CD11b expression and lowered interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) mRNA and protein levels. Correspondingly, in vivo, results showed a reduction in the number of Iba-1 positive cells and alleviation of morphological alterations, alongside decreased expressions of IL-1β and IL-18. Further analysis indicates that reynosin inhibits NLRP3 inflammasome activation, evidenced by reduced transcription of NLRP3 and caspase-1, diminished NLRP3 protein expression, inhibited apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization, and decreased caspase-1 self-cleavage. Additionally, reynosin curtailed the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, demonstrated by reduced NADP and NADPH levels, downregulation of gp91 mRNA, protein expression, suppression of p47 expression and translocation to the membrane. Moreover, reynosin exhibited a neuroprotective effect against microglial inflammation in vivo and in vitro. These collective findings underscore reynosin's capacity to mitigate microglial inflammation by inhibiting the NLRP3 inflammasome, thus highlighting its potential as a therapeutic agent for managing neuroinflammation.
Topics: Animals; NLR Family, Pyrin Domain-Containing 3 Protein; Microglia; Mice; Inflammasomes; Sesquiterpenes; NADPH Oxidases; Neurons; Mice, Inbred C57BL; Neuroinflammatory Diseases; Male; Interleukin-1beta; Lipopolysaccharides; Interleukin-18; Cell Line; Inflammation
PubMed: 38906597
DOI: 10.1016/S1875-5364(24)60652-7 -
PloS One 2024At present, the mechanism of fluorosis-induced damage to the hepatic system is unclear. Studies have shown that excess fluoride causes some degree of damage to the...
At present, the mechanism of fluorosis-induced damage to the hepatic system is unclear. Studies have shown that excess fluoride causes some degree of damage to the liver, including inflammation. The SDF-1/CXCR4 signaling axis has been reported to have an impact on the regulation of inflammation in human cells. In this study, we investigated the role of the SDF-1/CXCR4 signaling axis and related inflammatory factors in fluorosis through in vitro experiments on human hepatic astrocytes (LX-2) cultured with sodium fluoride. CCK-8 assays showed that the median lethal dose at 24 h was 2 mmol/l NaF, and these conditions were used for subsequent enzyme-linked immunosorbent assays (ELISAs) and quantitative real-time polymerase chain reaction (qPCR) analysis. The protein expression levels of SDF-1/CXCR4 and the related inflammatory factors nuclear factor-κB (NF-κB), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin 1β (IL-1β) were detected by ELISAs from the experimental and control groups. The mRNA expression levels of these inflammatory indicators were also determined by qPCR in both groups. Moreover, the expression levels of these factors were significantly higher in the experimental group than in the control group at both the protein and mRNA levels (P < 0.05). Excess fluorine may stimulate the SDF-1/CXCR4 signaling axis, activating the inflammatory NF-κB signaling pathway and increasing the expression levels of the related inflammatory factors IL-6, TNF-α and IL-1β. Identification of this mechanism is important for elucidating the pathogenesis of fluorosis-induced liver injury.
Topics: Receptors, CXCR4; Humans; Chemokine CXCL12; Sodium Fluoride; Hepatocytes; Signal Transduction; NF-kappa B; Cell Line; Interleukin-1beta; Tumor Necrosis Factor-alpha; Interleukin-6; Inflammation
PubMed: 38905184
DOI: 10.1371/journal.pone.0302530 -
Noise & HealthPresbycusis can be mediated by the effects of inflammatory processes on the auditory system, and these aging biological mechanisms remain poorly studied.
CONTEXT
Presbycusis can be mediated by the effects of inflammatory processes on the auditory system, and these aging biological mechanisms remain poorly studied.
AIMS
The aim of this study was to determine whether plasma biomarkers are associated with hearing disorders caused by aging in the elderly.
SETTINGS AND DESIGN
Cross-sectional study with 106 participants in the Active Aging Project, 93 (88%) females and 13 (12%) males, with an average age of 70 years.
METHODS AND MATERIAL
Audiological evaluation was performed with pure tone audiometry and collection of peripheral blood for the measurement of plasma levels of interleukins 2, 4, 6, and 10, tumor necrosis factor-α, and interferon-γ by means of flow cytometry.
STATISTICAL ANALYSIS USED
The SPSS (v.0, SPSS Inc., Chicago, USA) was used for the analysis of the data obtained. For all data analyzed, the significance level adopted was P < 0.05 and 95% confidence interval.
RESULTS
There were statistically significant correlations between male and IL-2 (P = 0.031; rs = 0.210), mean II of the right ear (P = 0.004; rs = 0.279), longer in years (P = 0.002; rs = 0.307) and in hours (P = 0.004; rs = 0.281) of noise exposure also in males.
CONCLUSIONS
In the present study, there was an association between the male gender and higher plasma levels of IL-2, an increase in the average hearing in the right ear, and greater time in years and hours of exposure to noise. There was a predominance of mild sensorineural hearing loss and worsening of hearing related to age, characteristics of presbycusis.
Topics: Humans; Male; Female; Aged; Cross-Sectional Studies; Interleukin-2; Audiometry, Pure-Tone; Biomarkers; Presbycusis; Tumor Necrosis Factor-alpha; Interferon-gamma; Middle Aged; Aged, 80 and over; Aging
PubMed: 38904818
DOI: 10.4103/nah.nah_3_23 -
Molecular Biology Reports Jun 2024Olive is an evergreen tree of Oleaceae Olea with numerous bioactive components. While the anti-inflammatory properties of olive oil and the derivatives are...
BACKGROUND
Olive is an evergreen tree of Oleaceae Olea with numerous bioactive components. While the anti-inflammatory properties of olive oil and the derivatives are well-documented, there remains a dearth of in-depth researches on the immunosuppressive effects of olive fruit water extract. This study aimed to elucidate the dose-effect relationship and underlying molecular mechanisms of olive fruit extract in mediating anti-inflammatory responses.
METHODS AND RESULTS
The impacts of olive fruit extract on the release of nitric oxide (NO), tumor necrosis factor (TNF-α), interleukins-6 (IL-6) and reactive oxygen species (ROS) were assessed in RAW264.7 cells induced by lipopolysaccharide (LPS). For deeper understanding, the expression of genes encoding inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α and IL-6 was quantitatively tested. Additionally, the expression patterns of MAPK and NF-κB pathways were further observed to analyze the action mechanisms. Results suggested that olive fruit extract (200, 500, 1000 µg/mL) markedly exhibited a dose-dependent reduction in the generation of NO, TNF-α, IL-6 and ROS, as well as the expression of correlative genes studied. The activation of ERK, JNK, p38, IκB-α and p65 were all suppressed when p65 nuclear translocation was further restricted by olive fruit extract in NF-κB and MAPK signal pathways.
CONCLUSIONS
Olive fruit extract targeted imposing restrictions on the signal transduction of key proteins in NF-κB and MAPK pathways, and thereby lowered the level of inflammatory mediators, which put an enormous hindrance to inflammatory development. Accordingly, it is reasonable to consider olive fruit as a potent ingredient in immunomodulatory products.
Topics: Animals; Olea; Mice; RAW 264.7 Cells; Plant Extracts; Anti-Inflammatory Agents; Lipopolysaccharides; NF-kappa B; Fruit; Reactive Oxygen Species; Signal Transduction; Nitric Oxide; Tumor Necrosis Factor-alpha; MAP Kinase Signaling System; Interleukin-6; Nitric Oxide Synthase Type II; Cyclooxygenase 2; Cell Survival; Mitogen-Activated Protein Kinases; Macrophages
PubMed: 38904794
DOI: 10.1007/s11033-024-09661-9 -
Archives of Dermatological Research Jun 2024Cannabidiol (CBD), which is derived from hemp, is gaining recognition because of its anti-inflammatory and lipid-modulating properties that could be utilized to treat...
Cannabidiol (CBD), which is derived from hemp, is gaining recognition because of its anti-inflammatory and lipid-modulating properties that could be utilized to treat acne. We conducted experiments to quantitatively assess the effects of CBD on acne-related cellular pathways. SEB-1 sebocytes and HaCaT keratinocytes were exposed to various CBD concentrations. CBD exhibited a concentration-dependent impact on cell viability and notably reduced SEB-1 viability; furthermore, it induced apoptosis and a significant increase in the apoptotic area at higher concentrations. Additionally, CBD remarkably reduced pro-inflammatory cytokines, including CXCL8, IL-1α, and IL-1β. Additionally, it inhibited lipid synthesis by modulating the AMPK-SREBP-1 pathway and effectively reduced hyperkeratinization-related protein keratin 16. Simultaneously, CBD stimulated the synthesis of elastin, collagen 1, and collagen 3. These findings emphasize the potential of CBD for the management of acne because of its anti-inflammatory, apoptotic, and lipid-inhibitory effects. Notably, the modulation of the Akt/AMPK-SREBP-1 pathway revealed a novel and promising mechanism that could address the pathogenesis of acne.
Topics: Humans; Acne Vulgaris; Cannabidiol; Apoptosis; Keratinocytes; Cell Survival; Signal Transduction; Cicatrix; Anti-Inflammatory Agents; Sterol Regulatory Element Binding Protein 1; HaCaT Cells; AMP-Activated Protein Kinases; Proto-Oncogene Proteins c-akt; Collagen Type I; Collagen Type III; Elastin; Sebaceous Glands; Interleukin-1alpha; Interleukin-1beta; Interleukin-8; Cell Line
PubMed: 38904694
DOI: 10.1007/s00403-024-03131-9 -
International Journal of Biological... 2024Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a...
Atopic dermatitis (AD) is a common inflammation skin disease that involves dysregulated interplay between immune cells and keratinocytes. Interleukin-38 (IL-38), a poorly characterized IL-1 family cytokine, its role and mechanism in the pathogenesis of AD is elusive. Here, we show that IL-38 is mainly secreted by epidermal keratinocytes and highly expressed in the skin and downregulated in AD lesions. We generated IL-38 keratinocyte-specific knockout mice ( ) and induced AD models by 2,4-dinitrofluorobenzene (DNFB). Unexpectedly, after treatment with DNFB, mice were less susceptible to cutaneous inflammation of AD. Moreover, keratinocyte-specific deletion of IL-38 suppressed the migration of Langerhans cells (LCs) into lymph nodes which results in disturbed differentiation of CD4T cells and decreased the infiltration of immune cells into AD lesions. LCs are a type of dendritic cell that reside specifically in the epidermis and regulate immune responses. We developed LC-like cells from mouse bone marrow (BM) and treated with recombined IL-38. The results show that IL-38 depended on IL-36R, activated the phosphorylated expression of IRAK4 and NF-κB P65 and upregulated the expression of CCR7 to promoting the migration of LCs, nevertheless, the upregulation disappeared with the addition of IL-36 receptor antagonist (IL-36RA), IRAK4 or NF-κB P65 inhibitor. Furthermore, after treatment with IRAK4 inhibitors, the experimental AD phenotypes were alleviated and so IRAK4 is considered a promising target for the treatment of inflammatory diseases. Overall, our findings indicated a potential pathway that IL-38 depends on IL-36R, leading to LCs migration to promote AD by upregulating CCR7 via IRAK4/NF-κB and implied the prevention and treatment of AD, supporting potential clinical utilization of IRAK4 inhibitors in AD treatment.
Topics: Animals; Dermatitis, Atopic; Langerhans Cells; Mice; Cell Movement; Mice, Knockout; Interleukin-1; Keratinocytes; Dinitrofluorobenzene; NF-kappa B; Interleukins
PubMed: 38904012
DOI: 10.7150/ijbs.93843 -
International Journal of Medical... 2024Exploring potential biomarkers for predicting clinical outcomes and developing targeted therapies for acute myeloid leukemia (AML) is of utmost importance. This study...
Exploring potential biomarkers for predicting clinical outcomes and developing targeted therapies for acute myeloid leukemia (AML) is of utmost importance. This study aimed to investigate the expression pattern of the thioredoxin-interacting protein (TXNIP)/nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) pathway and its role in the prognosis of AML patients. In this study, we examined the prognostic value of TXNIP/NLRP3 pathway in AML patients using microarray data from Gene Expression Omnibus (GEO) and transcriptome data from the Cancer Genome Atlas (TCGA) to develop a prognostic model and validated the results by quantitative real-time PCR (qRT-PCR) in a validation cohort of 26 AML patients and 18 healthy individuals from Jinan University (JNU) database. Analysis of the GSE13159 database revealed that , () within the TXNIP/NLRP3 pathway were significantly upregulated and () was downregulated in AML patients (, = 0.031; , = 0.042; , = 0.038). Compared to high expression, AML patients with low expression had a longer overall survival (OS) in the GSE12417 dataset ( = 0.004). Moreover, both the training and validation results indicated that lower , , and expression were associated with favorable prognosis (GSE12417, = 0.009; TCGA, = 0.050; JNU, = 0.026). According to the receiver operating characteristic curve analysis, this model demonstrated a sensitivity of 84% for predicting three-year survival. These data might provide novel predictors for AML outcome and direction for further investigation of the possibility of using // genes in novel targeted therapies for AML.
Topics: Humans; NLR Family, Pyrin Domain-Containing 3 Protein; Leukemia, Myeloid, Acute; Carrier Proteins; Female; Male; Prognosis; Biomarkers, Tumor; Middle Aged; Interleukin-1beta; Inflammasomes; Signal Transduction; Adult; Aged; Gene Expression Regulation, Leukemic; Thioredoxins
PubMed: 38903927
DOI: 10.7150/ijms.96627