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1.
Biomed Pharmacother ; 173: 116341, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428309

RESUMO

Obesity is a significant risk factor for several chronic diseases. However, pre-menopausal females are protected against high-fat diet (HFD)-induced obesity and its adverse effects. The pregnane X receptor (PXR, NR1I2), a xenobiotic-sensing nuclear receptor, promotes short-term obesity-associated liver disease only in male mice but not in females. Therefore, the current study investigated the metabolic and pathophysiological effects of a long-term 52-week HFD in female wild-type (WT) and PXR-KO mice and characterized the PXR-dependent molecular pathways involved. After 52 weeks of HFD ingestion, the body and liver weights and several markers of hepatotoxicity were significantly higher in WT mice than in their PXR-KO counterparts. The HFD-induced liver injury in WT female mice was also associated with upregulation of the hepatic mRNA levels of peroxisome proliferator-activated receptor gamma (Pparg), its target genes, fat-specific protein 27 (Fsp27), and the liver-specific Fsp27b involved in lipid accumulation, apoptosis, and inflammation. Notably, PXR-KO mice displayed elevated hepatic Cyp2a5 (anti-obesity gene), aldo-keto reductase 1b7 (Akr1b7), glutathione-S-transferase M3 (Gstm3) (antioxidant gene), and AMP-activated protein kinase (AMPK) levels, contributing to protection against long-term HFD-induced obesity and inflammation. RNA sequencing analysis revealed a general blunting of the transcriptomic response to HFD in PXR-KO compared to WT mice. Pathway enrichment analysis demonstrated enrichment by HFD for several pathways, including oxidative stress and redox pathway, cholesterol biosynthesis, and glycolysis/gluconeogenesis in WT but not PXR-KO mice. In conclusion, this study provides new insights into the molecular mechanisms by which PXR deficiency protects against long-term HFD-induced severe obesity and its adverse effects in female mice.


Assuntos
Dieta Hiperlipídica , Fígado , Masculino , Feminino , Camundongos , Animais , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BL , Aumento de Peso , Obesidade/metabolismo , Inflamação/metabolismo , Camundongos Knockout
2.
Biomed Pharmacother ; 173: 116359, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38430633

RESUMO

Inflammatory responses are linked to cardiovascular diseases (CVDs) in various forms. Tregs, members of CD4+ T cells, play important roles in regulating immune system and suppressing inflammatory response, thus contributing to maintaining immune homeostasis. However, Tregs exert their powerful suppressive function relying on the stable phenotype and function. The stability of Tregs primarily depends on the FOXP3 (Forkhead box P3) expression and epigenetic regulation. Although Tregs are quite stable under physiological conditions, prolonged exposure to inflammatory cues, Tregs may lose suppressive function and require proinflammatory phenotype, namely plastic Tregs or ex-Tregs. There are extensive researches have established the beneficial role of Tregs in CVDs. Nevertheless, the potential risks of dysfunctional Tregs lack deep research. Anti-inflammatory and immunological modulation have been hotspots in the treatment of CVDs. Tregs are appealing because of their crucial role in resolving inflammation and promoting tissue repair. If alleviating inflammatory response through modulating Tregs could be a new therapeutic strategy for CVDs, the next step to consider is how to prevent the formation of dysfunctional Tregs or reverse detrimental Tregs to normal phenotype.


Assuntos
Doenças Cardiovasculares , Linfócitos T Reguladores , Humanos , Epigênese Genética , Doenças Cardiovasculares/metabolismo , Imunoterapia , Inflamação/metabolismo , Fatores de Transcrição Forkhead/genética
3.
Int Immunopharmacol ; 130: 111749, 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38430804

RESUMO

AIMS: Saikosaponin F (SsF) is one of the major active ingredients of Radix Bupleuri, an herb widely used in the treatment of depression. Studies have shown that dry eye disease often occurs together with depression. The aim of this study is to investigate whether SsF can improve depression-associated dry eye disease and explore the underlying mechanism. METHODS: Behavioral test was used to verify the effect of SsF on CUMS-induced depression-like behaviors in mice. Corneal fluorescein staining, phenol red cotton thread test and periodic acid-Schiff (PAS) staining were used to observe the effect of SsF on depression-associated dry eye disease. Western blot (WB) was performed to observe the expression of TAK1 protein and key proteins of NF-κB and MAPK (P38) inflammatory pathways in the hippocampus and cornea. Immunohistochemical staining was used to observe the expression of microglia, and immunoprecipitation was used to observe K63-linked TAK1 ubiquitination. Subsequently, we constructed a viral vector sh-TAK1 to silence TAK1 protein to verify whether SsF exerted its therapeutic effect based on TAK1. The expression of inflammatory factors such as IL-1ß, TNF-α and IL-18 in hippocampus and cornea were detected by ELISA. Overexpression of TRIM8 (OE-TRIM8) by viral vector was used to verify whether SsF improved depression-associated dry eye disease based on TRIM8. RESULTS: SsF treatment significantly improved the depression-like behavior, increased tear production and restored corneal injury in depression-related dry eye model mice. SsF treatment downregulated TAK1 expression and TRIM8-induced K63-linked TAK1 polyubiquitination, while inhibiting the activation of NF-κB and MAPK (P38) inflammatory pathways and microglial expression. In addition, selective inhibition of TAK1 expression ameliorated depression-associated dry eye disease, while overexpression of TRIM8 attenuated the therapeutic effect of SsF on depression-associated dry eye disease. CONCLUSION: SsF inhibited the polyubiquitination of TAK1 by acting on TRIM8, resulting in the downregulation of TAK1 expression, inhibition of inflammatory response, and improvement of CUMS-induced depression-associated dry eye disease.


Assuntos
Antidepressivos , Depressão , Síndromes do Olho Seco , MAP Quinase Quinase Quinases , NF-kappa B , Ácido Oleanólico , Saponinas , Ubiquitina-Proteína Ligases , Animais , Masculino , Camundongos , Depressão/complicações , Depressão/tratamento farmacológico , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/etiologia , Inflamação/tratamento farmacológico , MAP Quinase Quinase Quinases/metabolismo , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso , NF-kappa B/metabolismo , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Saponinas/uso terapêutico , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/efeitos dos fármacos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico
4.
Biomark Med ; 18(5): 181-190, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38440887

RESUMO

Objective: This study aimed to investigate the prognostic potency of LRG1 in acute ischemic stroke (AIS) patients. Methods: Plasma LRG1 levels were detected at admission and on days 3, 7 and 30 in 150 AIS patients. Results: LRG1 positively correlated with total cholesterol (p = 0.016), triglycerides (p = 0.046), C-reactive protein (p < 0.001), TNF-α (p = 0.001) and IL-6 (p = 0.004). After admission, LRG1 showed a decreasing trend (p < 0.001). Interestingly, LRG1 levels at admission (p = 0.014), day 3 (p = 0.027), day 7 (p = 0.008) and day 30 (p = 0.002) were higher in patients with modified Rankin scale score ≥2 versus those with scores <2. The LRG1 levels at day 7 (p = 0.032) and day 30 (p = 0.023) were higher in patients with recurrence versus no recurrence. Conclusion: LRG1 correlates with blood lipids, inflammation and short-term prognosis of AIS.


Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Prognóstico , Glicoproteínas/metabolismo , Inflamação , Proteína C-Reativa , Acidente Vascular Cerebral/diagnóstico
5.
Sci Rep ; 14(1): 5382, 2024 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-38443436

RESUMO

Telomerase activity is restricted in humans and telomere attrition occurs in several tissues accompanying natural aging. Critically short telomeres trigger DNA damage responses and activate p53 which leads to apoptosis or replicative senescence. These processes reduce cell proliferation and disrupt tissue homeostasis, thus contributing to systemic aging. Similarly, zebrafish have restricted telomerase expression, and telomeres shorten to critical length during their lifespan. Telomerase-deficient zebrafish (tert -/-) is a premature model of aging that anticipates aging phenotypes due to early telomere shortening. tert -/- zebrafish have impaired cell proliferation, accumulation of DNA damage markers and p53 response. These cellular defects lead to disruption of tissue homeostasis, resulting in premature infertility, gastrointestinal atrophy, sarcopenia and kyphosis. Such consequences contribute to its premature death. Here we reveal a genetic interdependence between tp53 and telomerase function. Mutation of tp53 abrogates premature aging of tert -/- zebrafish, prolonging male fertility and lifespan. However, it does not fully rescue healthspan. tp53mut tert -/- zebrafish retain high levels of inflammation and increased spontaneous cancer incidence. Conversely, loss of telomerase prolongs the lifespan of tp53mut single mutants. Lack of telomerase reduces two-fold the cancer incidence in double mutants and increases lifetime survival. Thus, we observe a reciprocal rescue of tp53mut and tert -/- that ameliorates lifespan but not spontaneous cancer incidence of tp53mut, likely due to higher levels of inflammation.


Assuntos
Neoplasias , Telomerase , Humanos , Animais , Masculino , Longevidade/genética , Peixe-Zebra/genética , Telomerase/genética , Incidência , Proteína Supressora de Tumor p53/genética , Inflamação , Neoplasias/genética
6.
Stroke ; 55(4): 1075-1085, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38445502

RESUMO

BACKGROUND: Ischemic stroke is often accompanied by oxidative stress and inflammatory response, both of which work synergistically to exacerbate the disruption of the blood-brain barrier and ischemic brain injury. ALK (anaplastic lymphoma kinase), a cancer-associated receptor tyrosine kinase, was found to play a role in oxidative stress and inflammation. In this study, we investigated the role of ALK inhibition in a murine model of ischemic stroke. METHODS: Focal cerebral ischemia was induced by temporary occlusion of the right middle cerebral artery in mice with a filament. The ALK inhibitor alectinib was administered following the stroke. ALOX15 (arachidonic acid 15-lipoxygenase) was overexpressed by adenovirus injection. The immunohistochemistry, Western blot, oxidative stress, inflammation, blood-brain barrier leakage, infarct volume, and functional outcomes were determined. RESULTS: We found that the expression of ALK was markedly increased in the neurovascular unit after cerebral ischemia. Treatment with the ALK inhibitor alectinib reduced the accumulation of reactive oxygen species, lipid peroxidation, and oxidative DNA, increased the vascular levels of antioxidant enzymes, inactivated the vascular NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome pathway, and reduced vascular inflammation (ICAM-1 [intercellular adhesion molecule-1] and MCP-1 [monocyte chemoattractant protein-1]) after ischemia. Moreover, alectinib reduced the loss of cerebrovascular integrity and blood-brain barrier damage, consequently decreasing brain infarction and neurological deficits. Furthermore, alectinib reduced stroke-evoked ALOX15 expression, whereas virus-mediated overexpression of ALOX15 abolished alectinib-dependent inhibition of oxidative stress and vascular inflammation, blood-brain barrier protection, and neuroprotection, suggesting the protective effects of alectinib for stroke may involve ALOX15. CONCLUSIONS: Our findings demonstrated that alectinib protects from stroke by regulating ischemic signaling cascades and suggest that ALK may be a novel therapeutic target for ischemic stroke.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Camundongos , Quinase do Linfoma Anaplásico/metabolismo , Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/patologia , Infarto da Artéria Cerebral Média/patologia , Inflamação/patologia , AVC Isquêmico/complicações , Inibidores de Proteínas Quinases/farmacologia
7.
Coron Artery Dis ; 35(3): 179-185, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38451553

RESUMO

BACKGROUND: Increased levels of inflammatory markers have been found in association with the severity of coronary atherosclerosis. Systemic immuneinflammation index (SII), which is calculated by multiplying neutrophil and platelet counts and then dividing the result by the lymphocyte count, can also be used as a prognostic indicator in different cardiovascular diseases. In this study, we investigated SII levels and long-term mortality of patients with non-ST segment elevation myocardial infarction (NSTEMI). METHODS: This is an observational, single-center study. Two hundred-eight patients who underwent coronary angiography for NSTEMI were included in the study. Patients were divided into 3 tertiles based on SII levels. We researched the relationship between level level and 1, 3 and 5 years mortality (NSTEMI). RESULTS: One-year mortality of the patients was significantly higher among patients in the upper SII tertile when compared with the lower and middle SII tertile groups [11 (15.9%) vs. 2 (2.9%) and 6 (8.7%); P  = 0.008, P  = 0.195, respectively). Three-year mortality of the patients was significantly higher among patients in the upper SII tertile when compared with the lower and middle SII tertile groups [21 (30.4%) vs. 5 (7.1%) and 12 (17.4%); P  < 0.001, P  = 0.072, respectively). Five-year mortality of the patients was significantly higher among patients in the upper SII tertile when compared with the lower and middle SII tertile groups [26 (37.7%) vs. 8 (11.4%) and 15 (21.7%); P  < 0.001, P  = 0.040, respectively). CONCLUSION: Our study showed that NSTEMI patients with higher SII had worse long-term mortality.


Assuntos
Sistema Cardiovascular , Infarto do Miocárdio sem Supradesnível do Segmento ST , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico por imagem , Prognóstico , Inflamação
8.
Biomed Pharmacother ; 173: 116379, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38452656

RESUMO

BACKGROUND: Microglia-mediated neuroinflammation is an important pathological feature in many neurological diseases; thus, suppressing microglial activation is considered a possible therapeutic strategy for reducing neuronal damage. Oxyimperatorin (OIMP) is a member of furanocoumarin, isolated from the medicinal herb Glehnia littoralis. However, it is unknown whether OIMP can suppress the neuroinflammation. PURPOSE: To investigate the neuroprotective activity of oxyimperatorin (OIMP) in LPS-induced neuroinflammation in vitro and in vivo models. METHODS: In vitro inflammation-related assays were performed with OIMP in LPS-induced BV-2 microglia. In addition, intraperitoneal injection of LPS-induced microglial activation in the mouse brain was used to validate the anti-neuroinflammatory activity of OIMP. RESULTS: OIMP was found to suppress LPS-induced neuroinflammation in vitro and in vivo. OIMP significantly attenuated LPS-induced the production of free radicals, inducible nitric oxide synthase, cyclooxygenase-2, and pro-inflammatory cytokines in BV-2 microglia without causing cytotoxicity. In addition, OIMP could reduce the M1 pro-inflammatory transition in LPS-stimulated BV-2 microglia. The mechanistic study revealed that OIMP inhibited LPS-induced NF-κB p65 phosphorylation and nuclear translocation. However, OIMP did not affect LPS-induced IκB phosphorylation and degradation. In addition, OIMP also was able to reduce LPS-induced microglial activation in mice brain. CONCLUSION: Our findings suggest that OIMP suppresses microglia activation and attenuates the production of pro-inflammatory mediators and cytokines via inhibition of NF-κB p65 signaling.


Assuntos
Microglia , NF-kappa B , Animais , Camundongos , NF-kappa B/metabolismo , Microglia/metabolismo , Lipopolissacarídeos/farmacologia , Doenças Neuroinflamatórias , Linhagem Celular , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Citocinas/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico/metabolismo
9.
Biomed Pharmacother ; 173: 116369, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38452657

RESUMO

Anandamide (AEA) is an important modulator of nociception in the spinal dorsal horn, acting presynaptically through Cannabinoid (CB1) and Transient receptor potential vanilloid (TRPV1) receptors. The role of AEA (1 µM, 10 µM, and 30 µM) application on the modulation of nociceptive synaptic transmission under control and inflammatory conditions was studied by recording miniature excitatory postsynaptic currents (mEPSCs) from neurons in spinal cord slices. Inhibition of the CB1 receptors by PF514273, TRPV1 by SB366791, and the fatty acid amide hydrolase (FAAH) by URB597 was used. Under naïve conditions, the AEA application did not affect the mEPSCs frequency (1.43±0.12 Hz) when all the recorded neurons were considered. The mEPSC frequency increased (180.0±39.2%) only when AEA (30 µM) was applied with PF514273 and URB597. Analysis showed that one sub-population of neurons had synaptic input inhibited (39.1% of neurons), the second excited (43.5%), whereas 8.7% showed a mixed effect and 8.7% did not respond to the AEA. With inflammation, the AEA effect was highly inhibitory (72.7%), while the excitation was negligible (9.1%), and 18.2% were not modulated. After inflammation, more neurons (45.0%) responded even to low AEA by mEPSC frequency increase with PF514273/URB597 present. AEA-induced dual (excitatory/inhibitory) effects at the 1st nociceptive synapse should be considered when developing analgesics targeting the endocannabinoid system. These findings contrast the clear inhibitory effects of the AEA precursor 20:4-NAPE application described previously and suggest that modulation of endogenous AEA production may be more favorable for analgesic treatments.


Assuntos
Ácidos Araquidônicos , Benzamidas , Carbamatos , Endocanabinoides , Nociceptividade , Humanos , Endocanabinoides/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Corno Dorsal da Medula Espinal , Analgésicos/farmacologia , Inflamação/tratamento farmacológico , Amidoidrolases
10.
Sci Total Environ ; 923: 171475, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38453063

RESUMO

Climbazole is an azole biocide that has been widely used in formulations of personal care products. Climbazole can cause developmental toxicity and endocrine disruption as well as gut disturbance in aquatic organisms. However, the mechanisms behind gut toxicity induced by climbazole still remain largely unclear in fish. Here, we evaluate the gut effects by exposing grass carp (Ctenopharyngodon idella) to climbazole at levels ranging from 0.2 to 20 µg/L for 42 days by evaluating gene transcription and expression, biochemical analyses, correlation network analysis, and molecular docking. Results showed that climbazole exposure increased cyp1a mRNA expression and ROS level in the three treatment groups. Climbazole also inhibited Nrf2 and Keap1 transcripts as well as proteins, and suppressed the transcript levels of their subordinate antioxidant molecules (cat, sod, and ho-1), increasing oxidative stress. Additionally, climbazole enhanced NF-κB and iκBα transcripts and proteins, and the transcripts of NF-κB downstream pro-inflammatory factors (tnfα, and il-1ß/6/8), leading to inflammation. Climbazole increased pro-apoptosis-related genes (fadd, bad1, and caspase3), and decreased anti-apoptosis-associated genes (bcl2, and bcl-xl), suggesting a direct reaction to apoptosis. The molecular docking data showed that climbazole could form stable hydrogen bonds with CYP1A. Mechanistically, our findings suggested that climbazole can induce inflammation and oxidative stress through CYP450s/ROS/Nrf2/NF-κB pathways, resulting in cell apoptosis in the gut of grass carp.


Assuntos
Carpas , Suplementos Nutricionais , Imidazóis , Animais , Suplementos Nutricionais/análise , Dieta , NF-kappa B , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Imunidade Inata , Azóis/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Simulação de Acoplamento Molecular , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Inflamação/induzido quimicamente , Inflamação/veterinária , Estresse Oxidativo , Apoptose , Carpas/metabolismo
11.
J Transl Med ; 22(1): 254, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459588

RESUMO

BACKGROUND: Although hepatitis B virus (HBV) infection is a major risk factor for hepatic cancer, the majority of HBV carriers do not develop this lethal disease. Additional molecular alterations are thus implicated in the process of liver tumorigenesis. Since phosphatase and tensin homolog (PTEN) is decreased in approximately half of liver cancers, we investigated the significance of PTEN deficiency in HBV-related hepatocarcinogenesis. METHODS: HBV-positive human liver cancer tissues were checked for PTEN expression. Transgenic HBV, Alb-Cre and Ptenfl/fl mice were inter-crossed to generate WT, HBV, Pten-/- and HBV; Pten-/- mice. Immunoblotting, histological analysis and qRT-PCR were used to study these livers. Gp73-/- mice were then mated with HBV; Pten-/- mice to illustrate the role of hepatic tumor biomarker golgi membrane protein 73 (GP73)/ golgi membrane protein 1 (GOLM1) in hepatic oncogenesis. RESULTS: Pten deletion and HBV transgene synergistically aggravated liver injury, inflammation, fibrosis and development of mixed hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). GP73 was augmented in HBV; Pten-/- livers. Knockout of GP73 blunted the synergistic effect of deficient Pten and transgenic HBV on liver injury, inflammation, fibrosis and cancer development. CONCLUSIONS: This mixed HCC-ICC mouse model mimics liver cancer patients harboring HBV infection and PTEN/AKT signaling pathway alteration. Targeting GP73 is a promising therapeutic strategy for cancer patients with HBV infection and PTEN alteration.


Assuntos
Carcinoma Hepatocelular , Hepatite B , Neoplasias Hepáticas , PTEN Fosfo-Hidrolase , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/patologia , Fibrose , Hepatite B/complicações , Vírus da Hepatite B , Inflamação/patologia , Fígado/patologia , Neoplasias Hepáticas/patologia , Proteínas de Membrana/metabolismo , Camundongos Knockout , PTEN Fosfo-Hidrolase/metabolismo
12.
Biomed Pharmacother ; 173: 116407, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38460367

RESUMO

Acute kidney injury frequently occurs after cardiac surgery, and is primarily attributed to renal ischemia-reperfusion (I/R) injury and inflammation from surgery and cardiopulmonary bypass. Vitamin C, an antioxidant that is often depleted in critically ill patients, could potentially mitigate I/R-induced oxidative stress at high doses. We investigated the effectiveness of high-dose vitamin C in preventing I/R-induced renal injury. The ideal time and optimal dosage for administration were determined in a two-phase experiment on Sprague-Dawley rats. The rats were assigned to four groups: sham, IRC (I/R + saline), and pre- and post-vitC (vitamin C before and after I/R, respectively), with vitamin C administered at 200 mg/kg. Additional groups were examined for dose modification based on the optimal timing determined: V100, V200, and V300 (100, 200, and 300 mg/kg, respectively). Renal I/R was achieved through 45 min of ischemia followed by 24 h of reperfusion. Vitamin C administration during reperfusion significantly reduced renal dysfunction and tubular damage, more than pre-ischemic administration. Doses of 100 and 200 mg/kg during reperfusion reduced oxidative stress markers, including myeloperoxidase and inflammatory responses by decreasing high mobility group box 1 release and nucleotide-binding and oligomerization domain-like receptor 3 inflammasome. Overall beneficial effect was most prominent with 200 mg/kg. The 300 mg/kg dose, however, showed no additional benefits over the IRC group regarding serum blood urea nitrogen and creatinine levels and histological evaluation. During reperfusion, high-dose vitamin C administration (200 mg/kg) significantly decreased renal I/R injury by effectively attenuating the major triggers of oxidative stress and inflammation.


Assuntos
Injúria Renal Aguda , Antineoplásicos , Traumatismo por Reperfusão , Humanos , Ratos , Animais , Ratos Sprague-Dawley , Rim , Estresse Oxidativo , Injúria Renal Aguda/metabolismo , Ácido Ascórbico/farmacologia , Ácido Ascórbico/uso terapêutico , Ácido Ascórbico/metabolismo , Traumatismo por Reperfusão/patologia , Antineoplásicos/farmacologia , Inflamação/metabolismo , Isquemia/metabolismo , Creatinina
13.
Biomed Pharmacother ; 173: 116387, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38471276

RESUMO

BACKGROUND: The induction of intestinal inflammation as a result of abdominal surgery is an essential factor in postoperative ileus (POI) development. Electroacupuncture (EA) at ST36 has been demonstrated to relieve intestinal inflammation and restore gastrointestinal dysmotility in POI. This study aims to elucidate the neuroimmune pathway involved in the anti-inflammatory properties of EA in POI. METHODS: After intestinal manipulation (IM) was performed to induce POI, intestinal inflammation and motility were assessed 24 h post-IM, by evaluating gastrointestinal transit (GIT), cytokines expression, and leukocyte infiltration. Experimental surgery, pharmacological intervention, and genetic knockout mice were used to elucidate the neuroimmune mechanisms of EA. RESULTS: EA at ST36 significantly improved GIT and reduced the expression of pro-inflammatory cytokines and leukocyte infiltration in the intestinal muscularis following IM in mice. The anti-inflammatory effectiveness of EA treatment was abolished by sub-diaphragmatic vagotomy, whereas splenectomy did not hinder the anti-inflammatory benefits of EA treatment. The hexamethonium chloride (HEX) administration contributes to a notable reduction in the EA capacity to suppress inflammation and enhance motility dysfunction, and EA is ineffective in α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice. CONCLUSIONS: EA at ST36 prevents intestinal inflammation and dysmotility through a neural circuit that requires vagal innervation but is independent of the spleen. Further findings revealed that the process involves enteric neurons mediating the vagal signal and requires the presence of α7nAChR. These findings suggest that utilizing EA at ST36 may represent a possible therapeutic approach for POI and other immune-related gastrointestinal diseases.


Assuntos
Eletroacupuntura , Íleus , Camundongos , Animais , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Íleus/terapia , Inflamação/metabolismo , Citocinas/metabolismo , Transdução de Sinais , Anti-Inflamatórios , Camundongos Knockout , Complicações Pós-Operatórias/terapia
14.
Biomed Pharmacother ; 173: 116419, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38479178

RESUMO

BACKGROUND: Repetitive mild traumatic brain injury (rmTBI) can lead to somatic, emotional, and cognitive symptoms that persist for years after the initial injury. Although the ability of various treatments to promote recovery after rmTBI has been explored, the optimal time window for early intervention after rmTBI is unclear. Previous research has shown that hydrogen-rich water (HRW) can diffuse through the blood-brain - barrier, attenuate local oxidative stress, and reduce neuronal apoptosis in patients with severe traumatic brain injury. However, research on the effect of HRW on rmTBI is scarce. AIMS: The objectives of this study were to explore the following changes after rmTBI and HRW treatment: (i) temporal changes in inflammasome activation and oxidative stress-related protein expression through immunoblotting, (ii) temporal changes in neuron/myelin-related metabolite concentrations in vivo through magnetic resonance spectroscopy, (iii) myelin structural changes in late-stage rmTBI via immunofluorescence, and (iv) postinjury anxiety/depression-like behaviors and spatial learning and memory impairment. RESULTS: NLRP-3 expression in the rmTBI group was elevated at 7 and 14 DPI, and inflammasome marker levels returned to normal at 30 DPI. Oxidative stress persisted throughout the first month postinjury. HRW replacement significantly decreased Nrf2 expression in the prefrontal cortex and hippocampal CA2 region at 14 and 30 DPI, respectively. Edema and local gliosis in the hippocampus and restricted diffusion in the thalamus were observed on MR-ADC images. The tCho/tCr ratio in the rmTBI group was elevated, and the tNAA/tCr ratio was decreased at 30 DPI. Compared with the mice in the other groups, the mice in the rmTBI group spent more time exploring the open arms in the elevated plus maze (P < 0.05) and were more active in the maze (longer total distance traveled). In the sucrose preference test, the rmTBI group exhibited anhedonia. In the Morris water maze test, the latency to find the hidden platform in the rmTBI group was longer than that in the sham and HRW groups (P < 0.05). CONCLUSION: Early intervention with HRW can attenuate inflammasome assembly and reduce oxidative stress after rmTBI. These changes may restore local oligodendrocyte function, promote myelin repair, prevent axonal damage and neuronal apoptosis, and alleviate depression-like behavior and cognitive impairment.


Assuntos
Concussão Encefálica , Disfunção Cognitiva , Camundongos , Humanos , Animais , Bainha de Mielina/metabolismo , Depressão , Inflamassomos/metabolismo , Aprendizagem em Labirinto , Estresse Oxidativo , Disfunção Cognitiva/metabolismo , Inflamação/metabolismo , Receptores de Antígenos de Linfócitos T , Modelos Animais de Doenças
15.
Biomed Pharmacother ; 173: 116357, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38479179

RESUMO

BACKGROUND & OBJECTIVES: This study aimed to: 1) analyze the inflammatory profile of Rheumatoid Arthritis (RA) patients, identifying clinical phenotypes associated with cardiovascular (CV) risk; 2) evaluate biologic and targeted-synthetic disease-modifying antirheumatic drugs (b-DMARDs and ts-DMARDs': TNFi, IL6Ri, JAKinibs) effects; and 3) characterize molecular mechanisms in immune-cell activation and endothelial dysfunction. PATIENTS & METHODS: A total of 387 RA patients and 45 healthy donors were recruited, forming three cohorts: i) 208 RA patients with established disease but without previous CV events; ii) RA-CVD: 96 RA patients with CV events, and iii) 83 RA patients treated with b-DMARDs/ts-DMARDs for 6 months. Serum inflammatory profiles (cytokines/chemokines/growth factors) and NETosis/oxidative stress-linked biomolecules were evaluated. Mechanistic in vitro studies were performed on monocytes, neutrophils and endothelial cells (EC). RESULTS: In the first RA-cohort, unsupervised clustering unveiled three distinct groups: cluster 3 (C3) displayed the highest inflammatory profile, significant CV-risk score, and greater atheroma plaques prevalence. In contrast, cluster 1 (C1) exhibited the lowest inflammatory profile and CV risk score, while cluster 2 (C2) displayed an intermediate phenotype. Notably, 2nd cohort RA-CVD patients mirrored C3's inflammation. Treatment with b-DMARDs or ts-DMARDs effectively reduced disease-activity scores (DAS28) and restored normal biomolecules levels, controlling CV risk. In vitro, serum from C3-RA or RA-CVD patients increased neutrophils activity and CV-related protein levels in cultured monocytes and EC, which were partially prevented by pre-incubation with TNFi, IL6Ri, and JAKinibs. CONCLUSIONS: Overall, analyzing circulating molecular profiles in RA patients holds potential for personalized clinical management, addressing CV risk and assisting healthcare professionals in tailoring treatment, ultimately improving outcomes.


Assuntos
Antirreumáticos , Artrite Reumatoide , Produtos Biológicos , Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Células Endoteliais , Fatores de Risco , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Antirreumáticos/uso terapêutico , Inflamação/tratamento farmacológico , Fatores de Risco de Doenças Cardíacas , Produtos Biológicos/uso terapêutico
17.
ACS Nano ; 18(12): 9019-9030, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38483200

RESUMO

Urinary tract infections (UTIs), common bacterial infections in communities and medical facilities, are mainly mediated by FimH. The glycan sites of the uromodulin protein play a crucial role in protecting against UTIs by interacting with FimH. A bioinspired approach using glycan-FimH interactions may effectively reduce bacteria through an antiadhesive mechanism, thereby curbing bacterial resistance. However, typical antiadhesive therapy alone fails to address the excessive reactive oxygen species and inflammatory response during UTIs. To bridge this gap, antioxidant nanozymes with antiadhesive ability were developed as nanodecoys to counter bacteria and inflammation. Specifically, ultrasmall dextran-coated ceria (DEC) was engineered to address UTIs, with dextran blocking FimH adhesion and ceria exhibiting anti-inflammatory properties. DECs, metabolizable by the kidneys, reduced bacterial content in the urinary tract, mitigating inflammation and tissue damage. In murine models, DECs successfully treated acute UTIs, repeated infections, and catheter-related UTIs. This dual approach not only highlights the potential of nanozymes for UTIs but also suggests applicability to other FimH-induced infections in the lungs and bowels, marking a significant advancement in nanozyme-based clinical approaches.


Assuntos
Adesinas de Escherichia coli , Infecções Urinárias , Camundongos , Humanos , Animais , Adesinas de Escherichia coli/metabolismo , Proteínas de Fímbrias/metabolismo , Dextranos , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Inflamação , Antibacterianos
18.
Front Immunol ; 15: 1281263, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38487535

RESUMO

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Due to its high infectivity, the pandemic has rapidly spread and become a global health crisis. Emerging evidence indicates that endothelial dysfunction may play a central role in the multiorgan injuries associated with COVID-19. Therefore, there is an urgent need to discover and validate novel therapeutic strategies targeting endothelial cells. PIEZO1, a mechanosensitive (MS) ion channel highly expressed in the blood vessels of various tissues, has garnered increasing attention for its potential involvement in the regulation of inflammation, thrombosis, and endothelial integrity. This review aims to provide a novel perspective on the potential role of PIEZO1 as a promising target for mitigating COVID-19-associated endothelial dysfunction.


Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Células Endoteliais , Inflamação , Endotélio , Canais Iônicos
19.
Biomed Pharmacother ; 173: 116425, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38490155

RESUMO

Depression is a common mental health disorder, and in recent years, the incidence of various forms of depression has been on the rise. Most medications for depression are highly dependency-inducing and can lead to relapse upon discontinuation. Therefore, novel treatment modalities and therapeutic targets are urgently required. Traditional Chinese medicine (TCM) offers advantages in the treatment of depression owing to its multi-target, multi-dimensional approach that addresses the root cause of depression by regulating organ functions and balancing Yin and Yang, with minimal side effects. Cynaroside (CNS), an extract from the traditional Chinese herb honeysuckle, is a flavonoid compound with antioxidant properties. In this study, network pharmacology identified 44 potential targets of CNS associated with depression and several highly correlated inflammatory signaling pathways. CNS alleviated LPS-induced M1 polarization and the release of inflammatory factors in BV-2 cells. Transcriptomic analysis and validation revealed that CNS reduced inflammatory polarization, lipid peroxidation, and ferroptosis via the IRF1/SLC7A11/GPX4 signaling pathway. In vivo experiments showed that CNS treatment had effects similar to those of fluoxetine (FLX). It effectively ameliorated anxiety-, despair-, and anhedonia-like states in chronic unpredictable mild stress (CUMS)-induced mice and reduced microglial activation in the hippocampus. Thus, we conclude that CNS exerts its therapeutic effect on depression by inhibiting microglial cells from polarizing into the M1 phenotype and reducing inflammation and ferroptosis levels. This study provides further evidence that CNS is a potential antidepressant, offering new avenues for the treatment of depression.


Assuntos
Depressão , Ferroptose , Glucosídeos , Luteolina , Camundongos , Animais , Depressão/tratamento farmacológico , Depressão/metabolismo , Microglia/metabolismo , Hipocampo , Comportamento Animal , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Estresse Psicológico/tratamento farmacológico , Modelos Animais de Doenças
20.
Nat Commun ; 15(1): 2627, 2024 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-38521787

RESUMO

IgG4-related disease (IgG4-RD) has complex clinical manifestations ranging from fibrosis and inflammation to deregulated metabolism. The molecular mechanisms underpinning these phenotypes are unclear. In this study, by using IgG4-RD patient peripheral blood mononuclear cells (PBMCs), IgG4-RD cell lines and Usp25 knockout mice, we show that ubiquitin-specific protease 25 (USP25) engages in multiple pathways to regulate fibrotic and inflammatory pathways that are characteristic to IgG4-RD. Reduced USP25 expression in IgG4-RD leads to increased SMAD3 activation, which contributes to fibrosis and induces inflammation through the IL-1ß inflammatory axis. Mechanistically, USP25 prevents ubiquitination of RAC1, thus, downregulation of USP25 leads to ubiquitination and degradation of RAC1. Decreased RAC1 levels result in reduced aldolase A release from the actin cytoskeleton, which then lowers glycolysis. The expression of LYN, a component of the B cell receptor signalosome is also reduced in USP25-deficient B cells, which might result in B cell activation deficiency. Altogether, our results indicate a potential anti-inflammatory and anti-fibrotic role for USP25 and make USP25 a promising diagnostic marker and potential therapeutic target in IgG4-RD.


Assuntos
Doença Relacionada a Imunoglobulina G4 , Animais , Camundongos , Humanos , Leucócitos Mononucleares/metabolismo , Inflamação , Linfócitos B/metabolismo , Fibrose , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo
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