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ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn (Hippophae rhamnoides), a traditional Tibetan medicinal herb, exhibits protective effects against cardiovascular and respiratory diseases. Although Sea buckthorn extract (SBE) has been confirmed to alleviate airway inflammation in mice, its therapeutic effect and underlying mechanism on chronic obstructive pulmonary disease (COPD) requires further clarification. AIM OF THE STUDY: To elucidate the alleviative effect and molecular mechanism of SBE on lipopolysaccharides (LPS)/porcine pancreatic elastase (PPE)-induced COPD by blocking ferroptosis. METHODS: The anti-ferroptotic effects of SBE were evaluated in human BEAS-2B bronchial epithelial cells using CCK8, RT-qPCR, western blotting, and transmission electron microscopy. Transwell was employed to detect chemotaxis of neutrophils. COPD model was induced by intranasally administration of LPS/PPE in mice and measured by alterations of histopathology, inflammation, and ferroptosis. RNA-sequencing, western blotting, antioxidant examination, flow cytometry, DARTS, CETSA, and molecular docking were then used to investigate its anti-ferroptotic mechanisms. RESULTS: In vitro, SBE not only suppressed erastin- or RSL3-induced ferroptosis by suppressing lipid peroxides (LPOs) production and glutathione (GSH) depletion, but also suppressed ferroptosis-induced chemotactic migration of neutrophils via reducing mRNA expression of chemokines. In vivo, SBE ameliorated LPS/PPE-induced COPD phenotypes, and inhibited the generation of LPOs, cytokines, and chemokines. RNA-sequencing showed that p53 pathway and mitogen-activated protein kinases (MAPK) pathway were implicated in SBE-mediated anti-ferroptotic action. SBE repressed erastin- or LPS/PPE-induced overactivation of p53 and MAPK pathway, thereby decreasing expression of diamine acetyltransferase 1 (SAT1) and arachidonate 15-lipoxygenase (ALOX15), and increasing expression of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Mechanistically, erastin-induced elevation of reactive oxygen species (ROS) was reduced by SBE through directly scavenging free radicals, thereby contributing to its inhibition of p53 and MAPK pathways. CETSA, DARTS, and molecular docking further showed that ROS-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4) may be the target of SBE. Overexpression of NOX4 partially impaired the anti-ferroptotic activity of SBE. CONCLUSION: Our results demonstrated that SBE mitigated COPD by suppressing p53 and MAPK pro-ferroptosis pathways via directly scavenging ROS and blocking NOX4. These findings also supported the clinical application of Sea buckthorn in COPD therapy.

Asunto(s)

Ferroptosis , Hippophae , Extractos Vegetales , Enfermedad Pulmonar Obstructiva Crónica , Especies Reactivas de Oxígeno , Proteína p53 Supresora de Tumor , Ferroptosis/efectos de los fármacos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Animales , Humanos , Especies Reactivas de Oxígeno/metabolismo , Hippophae/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Proteína p53 Supresora de Tumor/metabolismo , Ratones , Masculino , Ratones Endogámicos C57BL , Línea Celular , Lipopolisacáridos/toxicidad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Modelos Animales de Enfermedad , Simulación del Acoplamiento Molecular

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is a serious health-threatening syndrome of intense inflammatory response in the lungs, with progression leading to acute respiratory distress syndrome (ARDS). Dachengqi decoction dispensing granule (DDG) has a pulmonary protective role, but its potential modulatory mechanism to alleviate ALI needs further excavation. AIM OF THE STUDY: This study aims to investigate the effect and potential mechanism of DDG on lipopolysaccharide (LPS)-induced ALI models in vivo and in vitro. MATERIALS AND METHODS: LPS-treated Balb/c mice and BEAS-2B cells were used to construct in vivo and in vitro ALI models, respectively. Hematoxylin-eosin (HE), Wet weight/Dry weight (W/D) calculation of lung tissue, and total protein and Lactic dehydrogenase (LDH) assays in BALF were performed to assess the extent of lung tissue injury and pulmonary edema. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-18 (IL-18) in BALF, serum, and cell supernatant. The qRT-PCR was used to detect inflammatory factors, Z-DNA binding protein 1 (ZBP1), and receptor-interacting protein kinase 1 (RIPK1) expression in lung tissues and BEAS-2B cells. Double immunofluorescence staining and co-immunoprecipitation were used to detect the relative expression and co-localization of ZBP1 and RIPK1. The effects of LPS and DDG on BEAS-2B cell activity were detected by Cell Counting Kit-8 (CCK-8). Western blot (WB) was performed to analyze the expression of PANoptosis-related proteins in lung tissues and BEAS-2B cells. RESULTS: In vivo, DDG pretreatment could dose-dependently improve the pathological changes of lung tissue in ALI mice, and reduce the W/D ratio of lung, total protein concentration, and LDH content in BALF. In vitro, DDG reversed the inhibitory effect of LPS on BEAS-2B cell viability. Meanwhile, DDG significantly reduced the levels of inflammatory factors in vitro and in vivo. In addition, DDG could inhibit the expression levels of PANoptosis-related proteins, especially the upstream key regulatory molecules ZBP1 and RIPK1. CONCLUSION: DDG could inhibit excessive inflammation and PANoptosis to alleviate LPS-induced ALI, thus possessing good anti-inflammatory and lung-protective effects. This study establishes a theoretical basis for the further development of DDG and provides a new prospect for ALI treatment by targeting PANoptosis.

Asunto(s)

Lesión Pulmonar Aguda , Lipopolisacáridos , Ratones Endogámicos BALB C , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Lipopolisacáridos/toxicidad , Humanos , Masculino , Ratones , Línea Celular , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Líquido del Lavado Bronquioalveolar/química , Extractos Vegetales/farmacología , Citocinas/metabolismo , Antiinflamatorios/farmacología , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: In accordance with the tenets of traditional Chinese medicine, sepsis is categorized into three distinct syndromes: heat syndrome, blood stasis syndrome, and deficiency syndrome. Xiaochaihu decoction (XCHD) has many functions, including the capacity to protect the liver, cholagogue, antipyretic, anti-inflammatory, and anti-pathogenic microorganisms. XCHD exerts the effect of clearing heat and reconciling Shaoyang. The XCHD contains many efficacious active ingredients, yet the mechanism of sepsis-induced cardiomyopathy (SIC) remains elusive. AIM OF THE STUDY: To investigate the molecular mechanisms underlying the protective effects of XCHD against SIC using an integrated approach combining network pharmacology and molecular biology techniques. MATERIALS AND METHODS: Network pharmacology methods identified the active ingredients, target proteins, and pathways affected by XCHD in the context of SIC. We conducted in vivo experiments using mice with lipopolysaccharide-induced SIC, evaluating cardiac function through echocardiography and histology. XCHD-containing serum was analyzed to determine its principal active components using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The effects of XCHD-containing serum on SIC were further tested in vitro in LPS-treated H9c2 cardiac cells. Protein expression levels were quantified via Western blotting and enzyme-linked immunosorbent assay (ELISA). Additionally, molecular docking was performed between the active components and ZBP1, a potential target protein. Overexpression of ZBP1 in H9c2 cells allowed for a deeper exploration of its role in modulating SIC-associated gene expression. RESULTS: UPLC-MS/MS identified 31 shared XCHD and XCHD-containing serum components. These included organic acids, terpenoids, and flavonoids, which have been identified as the active components of XCHD. Our findings revealed that XCHD alleviated LPS-induced myocardial injury, improved cardiac function, and preserved cardiomyocyte morphology in mice. In vitro studies, we demonstrated that XCHD-containing serum significantly suppressed the expression of inflammatory cytokines (IL-6, IL-1ß, and TNF-α) in LPS-induced H9c2 cells. Mechanistic investigations showed that XCHD downregulated genes associated with PANoptosis, a novel cell death pathway, suggesting its protective role in sepsis-damaged hearts. Conversely, overexpression of ZBP1 abolished the protective effects of XCHD and amplified PANoptosis-related gene expression. CONCLUSIONS: Our study provides the first evidence supporting the protective effects of XCHD against SIC, both in vitro and in vivo. The underlying mechanism involves the inhibition of ZBP1-initiated PANoptosis, offering new insights into treating SIC using XCHD.

Asunto(s)

Cardiomiopatías , Medicamentos Herbarios Chinos , Sepsis , Animales , Medicamentos Herbarios Chinos/farmacología , Sepsis/tratamiento farmacológico , Sepsis/complicaciones , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/metabolismo , Ratones , Masculino , Línea Celular , Ratones Endogámicos C57BL , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Lipopolisacáridos/toxicidad , Farmacología en Red , Ratas , Modelos Animales de Enfermedad , Espectrometría de Masas en Tándem

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Shuangdan Jiedu Decoction (SJD) is a formula composed of six Chinese herbs with heat-removing and detoxifying, antibacterial, and anti-inflammatory effects, which is clinically used in the therapy of various inflammatory diseases of the lungs including COVID-19, but the therapeutic material basis of its action as well as its molecular mechanism are still unclear. AIM OF THE STUDY: The study attempted to determine the therapeutic effect of SJD on LPS-induced acute lung injury (ALI), as well as to investigate its mechanism of action and assess its therapeutic potential for the cure of inflammation-related diseases in the clinical setting. MATERIALS AND METHODS: We established an ALI model by tracheal drip LPS, and after the administration of SJD, we collected the bronchoalveolar lavage fluid (BALF) and lung tissues of mice and examined the expression of inflammatory factors in them. In addition, we evaluated the effects of SJD on the cyclic guanosine monophosphate-adenosine monophosphate synthase -stimulator of interferon genes (cGAS-STING) and inflammasome by immunoblotting and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: We demonstrated that SJD was effective in alleviating LPS-induced ALI by suppressing the levels of pro-inflammatory cytokines in the BALF, improving the level of lung histopathology and the number of neutrophils, as well as decreasing the inflammatory factor-associated gene expression. Importantly, we found that SJD could inhibit multiple stimulus-driven activation of cGAS-STING and inflammasome. Further studies showed that the Chinese herbal medicines in SJD had no influence on the cGAS-STING pathway and inflammasome alone at the formulated dose. By increasing the concentration of these herbs, we observed inhibitory effects on the cGAS-STING pathway and inflammasome, and the effect exerted was maximal when the six herbs were combined, indicating that the synergistic effects among these herbs plays a crucial role in the anti-inflammatory effects of SJD. CONCLUSIONS: Our research demonstrated that SJD has a favorable protective effect against ALI, and its mechanism of effect may be associated with the synergistic effect exerted between six Chinese medicines to inhibit the cGAS-STING and inflammasome abnormal activation. These results are favorable for the wide application of SJD in the clinic as well as for the development of drugs for ALI from herbal formulas.

Asunto(s)

Lesión Pulmonar Aguda , Medicamentos Herbarios Chinos , Inflamasomas , Lipopolisacáridos , Proteínas de la Membrana , Nucleotidiltransferasas , Transducción de Señal , Animales , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lipopolisacáridos/toxicidad , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Nucleotidiltransferasas/metabolismo , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Ratones , Masculino , Transducción de Señal/efectos de los fármacos , Ratones Endogámicos C57BL , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Modelos Animales de Enfermedad , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/metabolismo , Líquido del Lavado Bronquioalveolar/citología

RESUMEN

Pro-inflammatory cytokines in muscle play a pivotal role in physiological responses and in the pathophysiology of inflammatory disease and muscle atrophy. Lactobacillus delbrueckii (LD), as a kind of probiotics, has inhibitory effects on pro-inflammatory cytokines associated with various inflammatory diseases. This study was conducted to explore the effect of dietary LD on the lipopolysaccharide (LPS)-induced muscle inflammation and atrophy in piglets and to elucidate the underlying mechanism. A total of 36 weaned piglets (Duroc × Landrace × Large Yorkshire) were allotted into three groups with six replicates (pens) of two piglets: (1) Nonchallenged control; (2) LPS-challenged (LPS); (3) 0.2% LD diet and LPS-challenged (LD+LPS). On d 29, the piglets were injected intraperitoneally with LPS or sterilized saline, respectively. All piglets were slaughtered at 4 h after LPS or saline injection, the blood and muscle samples were collected for further analysis. Our results showed that dietary supplementation of LD significantly attenuated LPS-induced production of pro-inflammatory cytokines IL-6 and TNF-α in both serum and muscle of the piglets. Concomitantly, pretreating the piglets with LD also clearly inhibited LPS-induced nuclear translocation of NF-κB p65 subunits in the muscle, which correlated with the anti-inflammatory effects of LD on the muscle of piglets. Meanwhile, LPS-induced muscle atrophy, indicated by a higher expression of muscle atrophy F-box, muscle RING finger protein (MuRF1), forkhead box O 1, and autophagy-related protein 5 (ATG5) at the transcriptional level, whereas pretreatment with LD led to inhibition of these upregulations, particularly genes for MuRF1 and ATG5. Moreover, LPS-induced mRNA expression of endoplasmic reticulum stress markers, such as eukaryotic translational initiation factor 2α (eIF-2α) was suppressed by pretreatment with LD, which was accompanied by a decrease in the protein expression levels of IRE1α and GRP78. Additionally, LD significantly prevented muscle cell apoptotic death induced by LPS. Taken together, our data indicate that the anti-inflammatory effect of LD supply on muscle atrophy of piglets could be likely regulated by inhibiting the secretion of pro-inflammatory cytokines through the inactivation of the ER stress/NF-κB singling pathway, along with the reduction in protein degradation.

Asunto(s)

Estrés del Retículo Endoplásmico , Lactobacillus delbrueckii , Lipopolisacáridos , Atrofia Muscular , Animales , Lipopolisacáridos/toxicidad , Porcinos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Atrofia Muscular/inducido químicamente , Atrofia Muscular/metabolismo , Atrofia Muscular/prevención & control , Atrofia Muscular/patología , Destete , Proteolisis , Probióticos/farmacología , Inflamación/metabolismo , Miositis/inducido químicamente , Miositis/metabolismo , Miositis/patología , Citocinas/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/efectos de los fármacos

RESUMEN

OBJECTIVE: The study will be to observe the effect of Sodium butyrate (NaB) on bone loss in lipopolysaccharide (LPS)-treated rats. METHODS: In the rat model, we observed that changes in the expression of oxidative stress regulators, inflammatory markers and target genes were measured by immunofluorescence and RT-PCR after treatment. Changes in viability and osteogenesis of MC3T3-E1, osteoclast differentiation in RAW264.7 cells in the presence of LPS were evaluated using CCK-8, ALP staining, RES staining, and TRAP staining. RESULTS: In vitro experiments have shown that LPS-induced inhibition of JC-1, SIRT1, GPX1 and SOD2 is associated with increased levels of inflammation and oxidative stress. In addition, NaB has been found to suppress oxidative stress, inflammation and Mito SOX, promote osteogenic differentiation, and inhibit osteoclast differentiation. In addition, NaB significantly promoted SITR1 expression, repaired impaired bone metabolism, and improved bone strength and bone mineral density. CONCLUSION: Given all this experimental evidence, the results strongly suggest that NaB can restore osteogenic activity in the presence of LPS by reducing intracellular ROS, inhibiting osteoclast differentiation and reducing bone loss in LPS-treated rat models.

Asunto(s)

Ácido Butírico , Inflamación , Lipopolisacáridos , Estrés Oxidativo , Animales , Lipopolisacáridos/toxicidad , Lipopolisacáridos/farmacología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ácido Butírico/farmacología , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Ratones , Células RAW 264.7 , Osteogénesis/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Diferenciación Celular/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Masculino , Ratas Sprague-Dawley , Huesos/efectos de los fármacos , Huesos/metabolismo

RESUMEN

Minocycline (Min), as an antibiotic, possesses various beneficial properties such as anti-inflammatory, antioxidant, and anti-apoptotic effects. Despite these known qualities, the precise cardioprotective effect and mechanism of Min in protecting against sepsis-induced cardiotoxicity (SIC) remain unspecified. To address this, our study sought to assess the protective effects of Min on the heart. Lipopolysaccharide (LPS) was utilized to establish a cardiotoxicity model both in vivo and in vitro. Min was pretreated in the models. In the in vivo setting, evaluation of heart tissue histopathological injury was performed using hematoxylin and eosin (H&E) staining and TUNEL. Immunohistochemistry (IHC) was employed to evaluate the expression levels of NLRP3 and Caspase-1 in the heart tissue of mice. During in vitro experiments, the viability of H9c2 cells was gauged utilizing the CCK8 assay kit. Intracellular ROS levels in H9c2 cells were quantified using a ROS assay kit. Both in vitro and in vivo settings were subjected to measurement of oxidative stress indexes, encompassing glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) levels. Additionglly, myocardial injury markers like lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB) activity were quantified using appropriate assay kits. Western blotting (WB) analysis was conducted to detect the expression levels of NOD-like receptor protein-3 (NLRP3), caspase-1, IL-18, and IL-1ß, alongside apoptosis-related proteins such as Bcl-2 and Bax, and antioxidant proteins including superoxide dismutase-1 (SOD-1) and antioxidant proteins including superoxide dismutase-1 (SOD-2), both in H9c2 cells and mouse heart tissues. In vivo, Min was effective in reducing LPS-induced inflammation in cardiac tissue, preventing cell damage and apoptosis in cardiomyocytes. The levels of LDH and CK-MB were significantly reduced with Min treatment. In vitro studies showed that Min improved the viability of H9C2 cells, reduced apoptosis, and decreased ROS levels in these cells. Further analysis indicated that Min decreased the protein levels of NLRP3, Caspase-1, IL-18, and IL-1ß, while increasing the levels of SOD-1 and SOD-2 both in vivo and in vitro. Min alleviates LPS-induced SIC by suppressing the NLRP3/Caspase-1 signalling pathway in vivo and in vitro.

Asunto(s)

Cardiotoxicidad , Caspasa 1 , Lipopolisacáridos , Minociclina , Proteína con Dominio Pirina 3 de la Familia NLR , Transducción de Señal , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Transducción de Señal/efectos de los fármacos , Lipopolisacáridos/toxicidad , Caspasa 1/metabolismo , Cardiotoxicidad/metabolismo , Cardiotoxicidad/tratamiento farmacológico , Ratones , Minociclina/farmacología , Masculino , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Línea Celular , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Ratones Endogámicos C57BL , Ratas

RESUMEN

OBJECTIVE: Environmental factors such as noise and music can significantly impact physiological responses, including inflammation. This study explored how environmental factors like noise and music affect lipopolysaccharide (LPS)-induced inflammation, with a focus on systemic and organ-specific responses. MATERIALS AND METHODS: 24 Wistar rats were divided into four groups (n = 6 per group): Control group, LPS group, noise-exposed group, and music-exposed group. All rats, except for the Control group, received 10 mg/kg LPS intraperitoneally. The rats in the noise-exposed group were exposed to 95 dB noise, and the music-exposed group listened to Mozart's K. 448 music (65-75 dB) for 1 h daily over 7 days. An enzyme-linked immunosorbent assay was utilized to detect the levels of inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), in serum and tissues (lung, liver, and kidney). Western blot examined the phosphorylation levels of nuclear factor-κB (NF-κB) p65 in organ tissues. RESULTS: Compared with the Control group, LPS-induced sepsis rats displayed a significant increase in the levels of TNF-α and IL-1ß in serum, lung, liver, and kidney tissues, as well as a remarkable elevation in the p-NF-κB p65 protein expression in lung, liver, and kidney tissues. Noise exposure further amplified these inflammatory markers, while music exposure reduced them in LPS-induced sepsis rats. CONCLUSION: Noise exposure exacerbates inflammation by activating the NF-κB pathway, leading to the up-regulation of inflammatory markers during sepsis. On the contrary, music exposure inhibits NF-κB signaling, indicating a potential therapeutic effect in reducing inflammation.

Asunto(s)

Lipopolisacáridos , Música , Ruido , Ratas Wistar , Sepsis , Animales , Lipopolisacáridos/toxicidad , Sepsis/inmunología , Sepsis/complicaciones , Ruido/efectos adversos , Masculino , Interleucina-1beta/sangre , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Inflamación , Hígado/metabolismo , Ratas , Riñón/metabolismo , FN-kappa B/metabolismo , Citocinas/sangre , Citocinas/metabolismo

RESUMEN

BACKGROUND: Inflammation-induced testicular damage is a significant contributing factor to the increasing incidence of infertility. Traditional treatments during the inflammatory phase often fail to achieve the desired fertility outcomes, necessitating innovative interventions such as cell therapy. METHODS: We explored the in vivo properties of intravenously administered Sertoli cells (SCs) in an acute lipopolysaccharide (LPS)-induced inflammatory mouse model. Infiltrating and resident myeloid cell phenotypes were assessed using flow cytometry. The impact of SC administration on testis morphology and germ cell quality was evaluated using computer-assisted sperm analysis (CASA) and immunohistochemistry. RESULTS: SCs demonstrated a distinctive migration pattern, importantly they preferentially concentrated in the testes and liver. SC application significantly reduced neutrophil infiltration as well as preserved the resident macrophage subpopulations. SCs upregulated MerTK expression in both interstitial and peritubular macrophages. Applied SC treatment exhibited protective effects on sperm including their motility and kinematic parameters, and maintained the physiological testicular morphology. CONCLUSION: Our study provides compelling evidence of the therapeutic efficacy of SC transplantation in alleviating acute inflammation-induced testicular damage. These findings contribute to the expanding knowledge on the potential applications of cell-based therapies for addressing reproductive health challenges and offer a promising approach for targeted interventions in male infertility.

Asunto(s)

Inflamación , Células de Sertoli , Espermatozoides , Masculino , Animales , Células de Sertoli/metabolismo , Ratones , Inflamación/patología , Inflamación/terapia , Espermatozoides/metabolismo , Lipopolisacáridos/toxicidad , Ratones Endogámicos C57BL , Testículo , Tirosina Quinasa c-Mer/metabolismo , Tirosina Quinasa c-Mer/genética , Motilidad Espermática , Macrófagos/metabolismo

RESUMEN

Newborn lambs are susceptible to pathogenic bacterial infections leading to enteritis, which affects their growth and development and causes losses in sheep production. It has been reported that N6-methyladenosine (m6A) is closely related to innate immunity, but the effect of m6A on sheep small intestinal epithelial cells (IECs) and the mechanism involved have not been elucidated. Here, we investigated the effects of m6A on lipopolysaccharide (LPS)-induced inflammatory responses, apoptosis and oxidative stress in primary sheep IECs. First, the extracted IECs were identified by immunofluorescence using the epithelial cell signature protein cytokeratin 18 (CK18), and the cellular activity of IECs induced by different concentrations of LPS was determined by the CCK8 assay. Meanwhile, LPS could induce the upregulation of mRNA and protein levels of IECs cytokines IL1ß, IL6 and TNFα and the apoptosis marker genes caspase-3, caspase-9, Bax, and apoptosis rate, reactive oxygen species (ROS) levels and mRNA levels of CAT, Mn-SOD and CuZn-SOD, and METTL3 were found to be upregulated during induction. It was hypothesized that METTL3 may have a potential effect on the induction of IECs by LPS. Overexpression and knockdown of METTL3 in IECs revealed that a low-level expression of METTL3 could reduce the inflammatory response, apoptosis and ROS levels in LPS-induced IECs to some extent. The results suggest that METTL3 may be a genetic marker for potential resistance to cellular damage.

Asunto(s)

Apoptosis , Células Epiteliales , Intestino Delgado , Lipopolisacáridos , Metiltransferasas , Animales , Lipopolisacáridos/toxicidad , Ovinos , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Metiltransferasas/metabolismo , Metiltransferasas/genética , Apoptosis/efectos de los fármacos , Apoptosis/genética , Intestino Delgado/metabolismo , Intestino Delgado/efectos de los fármacos , Intestino Delgado/patología , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Adenosina/análogos & derivados , Adenosina/metabolismo , Citocinas/metabolismo , Citocinas/genética , Células Cultivadas

RESUMEN

This study investigates the underlying mechanism through which dietary supplementation of pyrroloquinoline quinone disodium (PQQ) alleviates intestinal inflammation and cell apoptosis in piglets challenged with lipopolysaccharide (LPS). Seventy-two barrows were divided into three groups: control (CTRL), LPS challenged (LPS), and LPS challenged with PQQ supplementation (PQQ + LPS). On d 7, 11, and 14, piglets received intraperitoneal injections of LPS or 0.9% of NaCl (80 µg/kg). After a 4 h interval following the final LPS injection on d 14, blood samples were obtained, and all piglets were euthanized for harvesting jejunal samples. The results showed that dietary supplementation of PQQ improved the damage of intestinal morphology, increased the down-regulated tight junction proteins, and reduced the increase of serum diamine oxidase activity, the intestinal fatty acid binding protein, and TNF-α levels in piglets challenged with LPS (p < 0.05). The proteomics analysis revealed a total of 141 differentially expressed proteins (DEPs), consisting of 64 up-regulated DEPs and 77 down-regulated DEPs in the PQQ + LPS group compared to the LPS group. The KEGG pathway analysis indicated enrichment of the tight junction pathway and the apoptosis pathway (p < 0.05). Compared to the LPS group, the piglets in the PQQ + LPS group had increased levels of Bcl-2 protein, reduced positive apoptosis signals, and a decrease in the abundance of MKK 3/6 and p-p38 proteins (p < 0.05). In conclusion, dietary supplementation of PQQ could alleviate jejunal inflammatory damage and cell apoptosis in piglets challenged with LPS through the MKK3/6-p38 signaling pathway.

Asunto(s)

Apoptosis , Lipopolisacáridos , Cofactor PQQ , Animales , Apoptosis/efectos de los fármacos , Porcinos , Cofactor PQQ/farmacología , Cofactor PQQ/uso terapéutico , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/toxicidad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Modelos Animales de Enfermedad , MAP Quinasa Quinasa 3/metabolismo , Suplementos Dietéticos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Proteínas de Uniones Estrechas/metabolismo , Intestinos/efectos de los fármacos , Intestinos/patología

RESUMEN

Background: Dental pulp inflammation, often initiated by Gram-negative microorganisms and lipopolysaccharides (LPS), can lead to pulpitis and, subsequently, dental pulp necrosis, compromising tooth structure and increasing susceptibility to fracture. Asiatic acid, derived from Centella asiatica, has demonstrated pharmacological properties, including anti-inflammatory and antioxidant effects, making it a potential candidate for mitigating LPS-induced pulp inflammation. This in vivo study aims to investigate the impact of Asiatic acid on the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in Rattus norvegicus with LPS-induced pulp inflammation. Methods: This quasi-laboratory experimental in vivo study employed a post-test-only control group design to investigate the effects of Asiatic acid on LPS-induced pulp inflammation in Wistar rats. Thirty rats were randomly divided into six groups subjected to various interventions. LPS was administered to all groups for 6 h except the standard control group (CG, n = 5). The negative control group (NCG, n = 5) received only glass ionomer cement. The positive control group (PCG, n = 5) received Eugenol with glass ionomer cement. Intervention groups 1, 2, and 3 (IG1, IG2, IG3; n = 5 each) received Asiatic acid at concentrations of 0.5%, 1%, and 2%, respectively, with glass ionomer cement. Dental pulp inflammation was confirmed through immunological (tumor necrosis factor alpha (TNF-α) levels), histopathological (inflammatory parameters), and physiological (pain assessment using the rat grimace scale) analyses. Additionally, Nrf2 levels were examined using enzyme-linked immunosorbent assay (ELISA). Results: Asiatic acid administration significantly influenced Nrf2 levels in rats with LPS-induced pulp inflammation. Nrf2 levels were significantly higher in groups treated with 0.5% (IG1) (8.810 ± 1.092 ng/mL; p = 0.047), 1.0% (IG2) (9.132 ± 1.285 ng/mL; p = 0.020), and 2.0% (IG3) (11.972 ± 1.888 ng/mL; p = 0.000) Asiatic acid compared to NCG (7.146 ± 0.706). Notably, Nrf2 levels were also significantly higher in the 2.0% Asiatic acid group (IG3) compared to the PCG treated with Eugenol (8.846 ± 0.888 ng/mL; p = 0.001), as well as IG1 (p = 0.001) and IG2 (p = 0.002). However, no significant difference was observed between administering 0.5% Asiatic acid (IG1), 1.0% Asiatic acid (IG2), and Eugenol (PCG). Conclusion: This research showed that Asiatic acid significantly impacted the Nrf2 levels in rats with LPS-induced pulp inflammation. This suggests that it has the potential to be used as a therapeutic agent for reducing dental pulp inflammation. These findings support the need to further explore Asiatic acid as a promising intervention for maintaining dental pulp health.

Asunto(s)

Lipopolisacáridos , Factor 2 Relacionado con NF-E2 , Triterpenos Pentacíclicos , Pulpitis , Ratas Wistar , Animales , Triterpenos Pentacíclicos/farmacología , Triterpenos Pentacíclicos/uso terapéutico , Lipopolisacáridos/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Ratas , Pulpitis/tratamiento farmacológico , Pulpitis/patología , Pulpitis/metabolismo , Pulpitis/inducido químicamente , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Pulpa Dental/efectos de los fármacos , Pulpa Dental/metabolismo , Pulpa Dental/patología , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/inducido químicamente

RESUMEN

The impact of Sodium Houttuyniae (SH) on lipopolysaccharide (LPS)-induced ALI has been investigated extensively. However, it remains ambiguous whether ferroptosis participates in this process. This study aimed to find out the impacts and probable mechanisms of SH on LPS-induced ferroptosis. A rat ALI model and type II alveolar epithelial (ATII) cell injury model were treated with LPS. Enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (HE) staining, and Giemsa staining were executed to ascertain the effects of SH on LPS-induced ALI. Moreover, Transmission electron microscopy, Cell Counting Kit-8 (CCK8), ferrous iron colorimetric assay kit, Immunohistochemistry, Immunofluorescence, Reactive oxygen species assay kit, western blotting (Wb), and qRT-PCR examined the impacts of SH on LPS-induced ferroptosis and ferroptosis-related pathways. Theresults found that by using SH treatment, there was a remarkable attenuation of ALI by suppressing LPS-induced ferroptosis. Ferroptosis was demonstrated by a decline in the levels of glutathione peroxidase 4 (GPX4), FTH1, and glutathione (GSH) and a surge in the accumulation of malondialdehyde (MDA), reactive oxygen species (ROS), NOX1, NCOA4, and Fe2+, and disruption of mitochondrial structure, which were reversed by SH treatment. SH suppressed ferroptosis by regulating TRAF6-c-Myc in ALI rats and rat ATII cells. The results suggested that SH treatment attenuated LPS-induced ALI by repressing ferroptosis, and the mode of action can be linked to regulating the TRAF6-c-Myc signaling pathway in vivo and in vitro.

Asunto(s)

Lesión Pulmonar Aguda , Medicamentos Herbarios Chinos , Ferroptosis , Lipopolisacáridos , Proteínas Proto-Oncogénicas c-myc , Transducción de Señal , Factor 6 Asociado a Receptor de TNF , Animales , Masculino , Ratas , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Ferroptosis/efectos de los fármacos , Lipopolisacáridos/toxicidad , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/genética

RESUMEN

The pathological role of interferon signaling is emerging in neuroinflammatory disorders, yet, the specific role of Interferon Regulatory Factor 3 (IRF3) in neuroinflammation remains poorly understood. Here, we show that global IRF3 deficiency delays TLR4-mediated signaling in microglia and attenuates the hallmark features of LPS-induced inflammation such as cytokine release, microglial reactivity, astrocyte activation, myeloid cell infiltration, and inflammasome activation. Moreover, expression of a constitutively active IRF3 (S388D/S390D: IRF3-2D) in microglia induces a transcriptional program reminiscent of the Activated Response Microglia and the expression of genes associated with Alzheimer's disease, notably apolipoprotein-e. Using bulk-RNAseq of IRF3-2D brain myeloid cells, we identified Z-DNA binding protein-1 (ZBP1) as a target of IRF3 that is relevant across various neuroinflammatory disorders. Lastly, we show IRF3 phosphorylation and IRF3-dependent ZBP1 induction in response to Aß in primary microglia cultures. Together, our results identify IRF3 as an important regulator of LPS and Aß -mediated neuroinflammatory responses and highlight IRF3 as a central regulator of disease-specific gene activation in different neuroinflammatory diseases.

Asunto(s)

Enfermedad de Alzheimer , Factor 3 Regulador del Interferón , Microglía , Enfermedades Neuroinflamatorias , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/genética , Animales , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Ratones , Enfermedades Neuroinflamatorias/genética , Enfermedades Neuroinflamatorias/metabolismo , Microglía/metabolismo , Lipopolisacáridos/farmacología , Lipopolisacáridos/toxicidad , Ratones Endogámicos C57BL , Regulación de la Expresión Génica/efectos de los fármacos , Células Cultivadas , Humanos , Ratones Noqueados

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Feining keli (FNKL) is herbal preparation mainly made from Senecio cannabifolius Less., In recent years, more and more studies have found that FNKL has excellent therapeutic effects on chronic bronchitis (CB). Nevertheless, its pharmacodynamic material basis and mechanism of action are still unknown. AIM OF THE STUDY: This study aimed to explore the pharmacodynamic material basis and mechanism of action of FNKL in treating CB. MATERIALS AND METHODS: The CB rat model was induced using nasal drops of lipopolysaccharide (LPS) in combination with smoking. Various assessments including behavioral and body mass examination, lung index measurement, enzyme linked immunosorbent assay (ELISA), as well as histological analyses using hematoxylin and eosin (H&E) and Masson staining were conducted to validate the reliability of the CB model. The serum components of FNKL in CB rats were identified using ultra-high-performance liquid chromatography Orbitrap Exploris mass spectrometer (UHPLC-OE-MS). Network pharmacology was used to predict the network of action of the active ingredients in FNKL based on these serum components. Signaling pathways were enriched and analyzed, and molecular docking was conducted for key targets. Molecular dynamics simulations were performed using GROMACS software. The mechanism was confirmed through a series of experiments including Western blot (WB), immunofluorescence (IF), and reverse transcription (RT)-PCR. Additionally, untargeted metabolomics was employed to identify biomarkers and relevant metabolic pathways associated with the treatment of CB with FNKL. RESULTS: In CB rats, FNKL improved body mass, lung index, and pathological damage of lung tissues. It also decreased interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), malonaldehyde (MDA) levels, and percentage of lung collagen fiber area. Furthermore, FNKL increased IL-10 and superoxide dismutase (SOD) levels, which helped alleviate bronchial inflammation in the lungs. A total of 70 FNKL chemical components were identified in CB rat serum. Through network pharmacology analysis, 5 targets, such as PI3K, AKT, NF-κB, HIF-1α, and MYD88, were identified as key targets of FNKL in the treatment of CB. Additionally, the key signaling pathways identified were PI3K/AKT pathway、NF-κB/MyD88 pathway、HIF-1α pathway. WB, IF, and RT-PCR experiments were conducted to confirm the findings. Molecular docking studies demonstrated successful docking of 16 potential active components with 5 key targets. Additionally, molecular dynamics simulations indicated the stability of quercetin-3-galactoside and HIF-1α. Metabolomics analysis revealed that FNKL primarily regulated pathways related to alpha-linolenic acid metabolism, primary bile acid biosynthesis, bile secretion, arachidonic acid metabolism, neuroactive ligand-receptor interaction, and folate biosynthesis. Furthermore, the expression levels of traumatic acid, traumatin, alpha linolenic acid, cholic acid, 2-arachidonoylglycerol, deoxycholic acid, 7,8-dihydroneopterin, and other metabolites were found to be regulated. CONCLUSION: FNKL exhibits positive therapeutic effects on CB, with quercetin-3-galactoside identified as a key active component. The mechanism of FNKL's therapeutic action on CB involves reducing inflammatory response, oxidative stress, and regulating metabolism, and its molecular mechanism was better elucidated in a holistic manner. This study serves as a reference for understanding the pharmacodynamic material basis and mechanism of action of FNKL in treating CB, and provides avenues for exploring the effects of compounded herbal medicines on CB.

Asunto(s)

Bronquitis Crónica , Medicamentos Herbarios Chinos , Metabolómica , Simulación del Acoplamiento Molecular , Farmacología en Red , Ratas Sprague-Dawley , Animales , Masculino , Metabolómica/métodos , Bronquitis Crónica/tratamiento farmacológico , Bronquitis Crónica/metabolismo , Ratas , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Lipopolisacáridos/toxicidad , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Notopterygium incisum Ting ex H. T. Chang, also called 'Qianghuo', is a distinct umbelliferae plant in China. The rhizomes and roots of Notopterygium incisum have long been used to treat headaches, colds, analgesia and rheumatoid arthritis. It is a main traditional Chinese medicine in Qianghuo Yufeng Decoction, which was used to treat diseases such as liver and kidney insufficiency, mental paralysis and dementia. AIM OF THIS STUDY: As the most common dementia, Alzheimer's disease (AD) has a complicated pathogenesis. So far, there is no effective drug to prevent its pathological process. Previous research has shown that Notopterygium incisum root extract (NRE) may inhibit the release of Aß and the activation of tau in mice with AD. However, the effect of NRE on the pathological process of neuroinflammation is still unclear. MATERIALS AND METHODS: We determined the pro-inflammatory cytokines levels in BV2 cells exposed to LPS/Aß42 after treated with NRE. APP/PS1 and LPS-induced C57BL/6 neuroinflammatory mice were given NRE for 8 weeks and 5 days respectively to detect the pathological changes of neuroinflammation. RESULTS: The findings showed that NRE had a notable inhibitory effect on the levels of TNF-α and IL-1ß in BV2 cells induced by LPS/Aß42. The results of in vivo experiments show that following NRE treatment, there was a notable decrease in the number of activated microglia in the hippocampus of APP/PS1 mice as indicated by immunofluorescence results. Sholl analysis showed that microglia branches increased in NRE group, indicating that M1 microglia activation was inhibited. In the mice model injected with LPS in the tail vein, PCR and Western Blot results confirmed the anti-inflammatory effect of NRE, Nissl staining showed the protective effect of NRE on neurons, and immunofluorescence results also indicated that the activation of M1 microglia was inhibited. CONCLUSION: These results suggest that long term oral administration of NRE may inhibit neuroinflammation in the progression of AD.

Asunto(s)

Enfermedad de Alzheimer , Apiaceae , Ratones Endogámicos C57BL , FN-kappa B , Extractos Vegetales , Raíces de Plantas , Receptor Toll-Like 4 , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Receptor Toll-Like 4/metabolismo , Raíces de Plantas/química , Apiaceae/química , FN-kappa B/metabolismo , Extractos Vegetales/farmacología , Ratones , Transducción de Señal/efectos de los fármacos , Masculino , Lipopolisacáridos/toxicidad , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Microglía/efectos de los fármacos , Microglía/metabolismo , Línea Celular , Ratones Transgénicos , Péptidos beta-Amiloides/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/aislamiento & purificación , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/metabolismo

RESUMEN

The hypothalamus receives serotonergic projections from the raphe nucleus in a sex-specific manner. During systemic inflammation, hypothalamic levels of serotonin (5-hydroxytryptamine [5-HT]) decrease in male rats. The present study evaluated the involvement of endothelin-1 (ET-1) in the febrile response, hypolocomotion, and changes in hypothalamic 5-HT levels during systemic inflammation in male and female rats. An intraperitoneal injection of lipopolysaccharide (LPS) induced a febrile response and hypolocomotion in both male and female rats. However, although LPS reduced hypothalamic levels of 5-HT and its metabolite 5-hydroxyindol acetic acid (5-HIAA) in male rats, it increased these levels in female rats. An intracerebroventricular injection of the endothelin-B receptor antagonist BQ788 significantly reduced LPS-induced fever and hypolocomotion and changes in hypothalamic 5-HT and 5-HIAA levels in both male and female rats. The i.c.v. administration of ET-1 induced a significant fever and hypolocomotion, but reduced the hypothalamic levels of 5-HT and 5-HIAA in both males and females. These results suggest an important sexual dimorphism during systemic inflammation regarding the release of 5-HT in the hypothalamus. Moreover, ET-1 arises as an important mediator involved in the changes in hypothalamic 5-HT levels in both male and female rats.

Asunto(s)

Endotelina-1 , Hipotálamo , Inflamación , Piperidinas , Ratas Wistar , Serotonina , Caracteres Sexuales , Animales , Masculino , Femenino , Endotelina-1/metabolismo , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Ratas , Inflamación/metabolismo , Inflamación/inducido químicamente , Serotonina/metabolismo , Piperidinas/farmacología , Lipopolisacáridos/toxicidad , Oligopéptidos/farmacología , Ácido Hidroxiindolacético/metabolismo , Antagonistas de los Receptores de Endotelina/farmacología , Fiebre/metabolismo , Fiebre/inducido químicamente

RESUMEN

Xanthoxylin, a bioactive phenolic compound extracted from the traditional herbal medicine Penthorum Chinense Pursh, is renowned for its anti-inflammatory effects. While previous studies have highlighted the anti-inflammatory and antioxidant properties of Xanthoxylin, its precise mechanisms, particularly concerning immune response and organ protection, remain underexplored. This study aimed to elucidate the effects of Xanthoxylin on inflammation and associated signaling pathways in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced via intratracheal administration of LPS, followed by intraperitoneal injections of Xanthoxylin at doses of 1, 2.5, 5, and 10 mg/kg, administered 30 min post-LPS exposure. Lung tissues were harvested for analysis 6 h after LPS challenge. Xanthoxylin treatment significantly mitigated lung tissue damage, pathological alterations, immune cell infiltration, and the production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Additionally, Xanthoxylin modulated the expression of key proteins in the protein kinase B (Akt)/hypoxia-inducible factor 1-alpha (HIF-1α)/nuclear factor-kappa B (NF-κB) signaling pathway, as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and oxidative markers such as superoxide dismutase (SOD) and malondialdehyde (MDA) in the context of LPS-induced injury. This study demonstrates that Xanthoxylin exerts protective and anti-inflammatory effects by down-regulating and inhibiting the Akt/HIF-1α/NF-κB pathways, suggesting its potential as a therapeutic target for the prevention and treatment of ALI or acute respiratory distress syndrome (ARDS).

Asunto(s)

Lesión Pulmonar Aguda , Subunidad alfa del Factor 1 Inducible por Hipoxia , Lipopolisacáridos , Factor 2 Relacionado con NF-E2 , FN-kappa B , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , FN-kappa B/metabolismo , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Transducción de Señal/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Estrés Oxidativo/efectos de los fármacos

RESUMEN

Data on the participation of microbiota in the development of Parkinson's disease allow us to discuss the ability of bacterial preparations to influence the processes leading to neurodegeneration. We studied the effect of oral administration of Limosilactobacillus fermentum U-21 lyophilisate on a model of Parkinson's disease in rats induced by combined intranigral injection of LPS and systemic administration of paraquat. The toxins significantly increased the number of missteps in the "narrowing beam walking" test, but a tendency to a decrease in this parameter was shown after treatment with U-21. It should be noted that U-21 did not reduce the neuronal death in the substantia nigra, but mitigated the inflammatory glial response, decreased the accumulation of phosphorylated α-synuclein and complement protein C3. Our study demonstrated the efficiency of the combined model of parkinsonism and reduction of proinflammatory changes under the influence of pharmabiotic without changes in the nigral neuronal death and motor deficits.

Asunto(s)

Modelos Animales de Enfermedad , Lipopolisacáridos , Sustancia Negra , alfa-Sinucleína , Animales , Ratas , alfa-Sinucleína/metabolismo , Masculino , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Lipopolisacáridos/farmacología , Lipopolisacáridos/toxicidad , Paraquat , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Ratas Wistar , Complemento C3/metabolismo , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/tratamiento farmacológico

RESUMEN

Endothelial progenitor cells (EPCs) play a crucial role in maintaining vascular health and aiding in the repair of damaged blood vessels. However, the specific impact of EPCs-derived exosomes on vascular endothelial cell injury caused by lipopolysaccharide (LPS) remains inadequately understood. This study aims to explore the potential benefits of EPC-exosomes in mitigating LPS-induced vascular injury and to elucidate the underlying mechanism. Initially, EPCs were isolated from mouse peripheral blood, and their identity was confirmed through flow cytometry and immunocytochemistry. Subsequently, the exosomes derived from EPCs were identified using transmission electron microscopy (TEM) and western blot analysis. A sepsis model was induced by subjecting brain microvascular endothelial cells (BMECs) to LPS-induced injury. Both EPC and their exosomes demonstrated a significant increase in BMECs proliferation, reduced apoptosis, decreased levels of pro-inflammatory factors (TNF-α, IL-6, and caspase-3), and enhanced sprouting and angiogenesis of BMECs. Notable, the Exosomes demonstrated a more pronounced impact on these parameters. Furthermore, both EPCs and Exosomes exhibited significantly increased levels of miR-126a-5p, with the Exosomes showing a more substantial enhancement. These findings suggest that supplementing exosomal miR-126a-5p from EPCs can provide protective effects on BMECs, offering a potential therapeutic option for treating sepsis-induced microvascular endothelial cell injury.

Asunto(s)

Encéfalo , Células Endoteliales , Células Progenitoras Endoteliales , Exosomas , Lipopolisacáridos , MicroARNs , Exosomas/metabolismo , Animales , Células Progenitoras Endoteliales/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Lipopolisacáridos/toxicidad , Ratones , Encéfalo/metabolismo , Encéfalo/patología , Células Endoteliales/metabolismo , Apoptosis , Proliferación Celular , Microvasos/metabolismo , Masculino , Sepsis/metabolismo , Ratones Endogámicos C57BL