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Introduction: Increasing evidence shows that hyperactive aryl hydrocarbon receptor (AHR) signalling is involved in renal disease. However, no currently available intervention strategy is effective in halting disease progression by targeting the AHR signalling. Our previous study showed that barleriside A (BSA), a major component of Plantaginis semen, exhibits renoprotective effects. Methods: In this study, we determined the effects of BSA on AHR expression in 5/6 nephrectomized (NX) rats. We further determined the effect of BSA on AHR, nuclear factor kappa B (NF-ƙB), and the nuclear factor erythroid 2-related factor 2 (Nrf2) signalling cascade in zymosan-activated serum (ZAS)-stimulated MPC5 cells. Results: BSA treatment improved renal function and inhibited intrarenal nuclear AHR protein expression in NX-treated rats. BSA mitigated podocyte lesions and suppressed AHR mRNA and protein expression in ZAS-stimulated MPC5 cells. BSA inhibited inflammation by improving the NF-ƙB and Nrf2 pathways in ZAS-stimulated MPC5 cells. However, BSA did not markedly upregulate the expression of podocyte-specific proteins in the ZAS-mediated MPC5 cells treated with CH223191 or AHR siRNA compared to untreated ZAS-induced MPC5 cells. Similarly, the inhibitory effects of BSA on nuclear NF-ƙB p65, Nrf2, and AHR, as well as cytoplasmic cyclooxygenase-2, heme oxygenase-1, and AHR, were partially abolished in ZAS-induced MPC5 cells treated with CH223191 or AHRsiRNA compared with untreated ZAS-induced MPC5 cells. These results indicated that BSA attenuated the inflammatory response, partly by inhibiting AHR signalling. Discussion: Both pharmacological and siNRA findings suggested that BSA mitigated podocyte lesions by improving the NF-ƙB and Nrf2 pathways via inhibiting AHR signalling. Therefore, BSA is a high-affinity AHR antagonist that abolishes oxidative stress and inflammation.

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BACKGROUND: Despite cisplatin's long history as a cornerstone in cancer therapy, both acquired chemoresistance and significant impacts on healthy tissues limit its use. Hepatotoxicity is one of its side effects. Adjunct therapies have shown promise in not only attenuating liver damage caused by cisplatin but also in enhancing the efficacy of chemotherapy. In this context, a new quaternary ammonium chitosan Schiff base (QACSB) was synthesized and applied as an encapsulating agent for the in-situ synthesis of QACSB-ZnO nanocomposite. MATERIAL AND METHODS: Thirty male albino rats were classified into Group 1 (control) distilled water, Group 2 (Cisplatin-treated) (12 mg/kg, i.p), and Group 3 (QACSB-ZnO NCs/cisplatin-treated) (150 mg/kg/day QACSB-ZnO NCs, i.p) for 14 days + a single dose of cisplatin. Liver functions, tissue TNF-α, MDA, and GSH were measured as well as histopathological and immunohistochemical studies were performed. RESULTS: The QACSB-ZnO NCs significantly restore liver functions, tissue TNF-α, MDA, and GSH levels (p < 0.001). Histopathological examination showed patchy necrosis in the cisplatin-treated group versus other groups. The QACSB-ZnO NCs showed a weak TGF-ß1 (score = 4) and a moderate Bcl-2 immunohistochemistry expression (score = 6) versus the CP group. CONCLUSIONS: QACSB-ZnO NCs have been shown to protect the liver from cisplatin-induced hepatotoxicity.

Asunto(s)

Quitosano , Cisplatino , Nanocompuestos , Compuestos de Amonio Cuaternario , Bases de Schiff , Óxido de Zinc , Animales , Cisplatino/efectos adversos , Bases de Schiff/química , Bases de Schiff/farmacología , Quitosano/química , Quitosano/farmacología , Ratas , Nanocompuestos/química , Masculino , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/farmacología , Óxido de Zinc/química , Óxido de Zinc/farmacología , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Glutatión/metabolismo , Sustancias Protectoras/farmacología , Sustancias Protectoras/química , Factor de Necrosis Tumoral alfa/metabolismo , Malondialdehído/metabolismo

RESUMEN

Intrahepatic cholestasis is a common clinical form of hepatobiliary injury characterized by the intrahepatic accumulation of toxic bile acids. Besides its antidiabetic activity, the dipeptidyl peptidase IV inhibitor sitagliptin (SG) has been recently assigned diverse pharmacological activities and therapeutic potential against different disorders owing to its emerging antioxidant and anti-inflammatory properties. The current study explored the potential hepatoprotective effect of SG on α-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury (CLI) in mice and investigate its possible targeted signaling pathways. Mice received SG (10 and 20 mg/kg) for four consecutive days, two days before and after a single oral administration of ANIT (75 mg/kg). Our results revealed that SG administration remarkably prevented ANIT-induced histopathological lesions in the liver and maintained hepatic functions and oxidative/antioxidant balance. Ultimately, SG counteracted the inflammatory response in the liver, as indicated by the marked suppression of hepatic expression of NF-κB, TNF-α, and IL-6. Moreover, it inhibited the endoplasmic reticulum (ER) stress response in the liver. These beneficial effects of SG were accompanied by upregulation of SIRT1, p-AMPK, and Nrf2 expressions while downregulating keap1 expression in the liver. In conclusion, this study is the first to demonstrate the ability of SG to protect against ANIT-induced CLI through modulating multiple signaling cascades, including SIRT1/AMPK, Nrf2/keap1, and NF-кB, which resulted in enhanced antioxidant capacity and repressed inflammatory and ER stress responses in the liver.

Asunto(s)

1-Naftilisotiocianato , Proteínas Quinasas Activadas por AMP , Estrés del Retículo Endoplásmico , Factor 2 Relacionado con NF-E2 , FN-kappa B , Estrés Oxidativo , Sirtuina 1 , Fosfato de Sitagliptina , Animales , Sirtuina 1/metabolismo , Estrés Oxidativo/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Fosfato de Sitagliptina/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Masculino , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , FN-kappa B/metabolismo , 1-Naftilisotiocianato/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Inflamación/prevención & control , Inflamación/metabolismo , Colestasis Intrahepática/inducido químicamente , Colestasis Intrahepática/tratamiento farmacológico , Colestasis Intrahepática/prevención & control , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología

RESUMEN

OBJECTIVE: V-set and immunoglobulin domain containing 4 (VSIG4) inhibits neurological dysfunction, microglial M1 polarization, and inflammation to participate in the progression of neurological disorders, but evidence regarding Parkinson's disease (PD) is scarce. The present study intended to investigate the engagement of VSIG4 in PD progression, and the potential mechanism. METHODS: BV-2 cells were treated with 1-Methyl-4-phenylpyridinium (MPP+) to establish PD model. MPP+ treated BV-2 cells were infected with VSIG4 overexpression adenovirus-associated virus (AAV) (oeVSIG4) and negative control AAV (oeNC), and AZD1480 (JAK2 inhibitor) was added to these cells. RESULTS: MPP+ reduced VSIG4 mRNA (P < 0.05) and protein (P < 0.05) in BV-2 cells. Interestingly, VSIG4 reduced malondialdehyde (P < 0.01), reactive oxygen species (P < 0.01), NOD-like receptor family pyrin domain containing 3 (P < 0.05), cleaved-caspase1 (P < 0.05), tumor necrosis factor-α (P < 0.05), and interleukin-1ß (P < 0.05), but increased glutathione (P < 0.05), mitochondrial membrane potential (P < 0.05), phosphorylation (p)-JAK2 (P < 0.05), and p-STAT3 (P < 0.01) in MPP+ treated BV-2 cells, which indicated that VSIG4 inhibited oxidative stress, mitochondrial dysfunction, and inflammation, as well as activated the JAK2/STAT3 pathway in PD model. Moreover, AZD1480 inhibited the JAK2/STAT3 pathway and aggravated oxidative stress, mitochondrial dysfunction, and inflammation in PD model (all P < 0.05). Importantly, AZD1480 attenuated the influence of VSIG4 on oxidative stress, mitochondrial dysfunction, inflammation, and the JAK2/STAT3 pathway in PD model (all P < 0.05). CONCLUSION: VSIG4 suppresses oxidative stress, mitochondrial dysfunction, and inflammation by activating the JAK2/STAT3 pathway, which may be helpful in attenuating PD progression.

Asunto(s)

Progresión de la Enfermedad , Janus Quinasa 2 , Estrés Oxidativo , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Ratones , Línea Celular , Inflamación/metabolismo , Janus Quinasa 2/metabolismo , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Pirazoles/farmacología , Pirimidinas/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Factor de Transcripción STAT3/metabolismo

RESUMEN

Diabetic encephalopathy (DE) is a complication of diabetes, especially type 2 diabetes (T2D), characterized by damage in the central nervous system and cognitive impairment, which has gained global attention. Despite the extensive research aimed at enhancing our understanding of DE, the underlying mechanism of occurrence and development of DE has not been established. Mounting evidence has demonstrated a close correlation between DE and various factors, such as Alzheimer's disease-like pathological changes, insulin resistance, inflammation, and oxidative stress. Of interest, nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor with antioxidant properties that is crucial in maintaining redox homeostasis and regulating inflammatory responses. The activation and regulatory mechanisms of NRF2 are a relatively complex process. NRF2 is involved in the regulation of multiple metabolic pathways and confers neuroprotective functions. Multiple studies have provided evidence demonstrating the significant involvement of NRF2 as a critical transcription factor in the progression of DE. Additionally, various molecules capable of activating NRF2 expression have shown potential in ameliorating DE. Therefore, it is intriguing to consider NRF2 as a potential target for the treatment of DE. In this review, we aim to shed light on the role and the possible underlying mechanism of NRF2 in DE. Furthermore, we provide an overview of the current research landscape and address the challenges associated with using NRF2 activators as potential treatment options for DE.

RESUMEN

Transportation noise is a ubiquitous urban exposure. In 2018, the World Health Organization concluded that chronic exposure to road traffic noise is a risk factor for ischemic heart disease. In contrast, they concluded that the quality of evidence for a link to other diseases was very low to moderate. Since then, several studies on the impact of noise on various diseases have been published. Also, studies investigating the mechanistic pathways underlying noise-induced health effects are emerging. We review the current evidence regarding effects of noise on health and the related disease-mechanisms. Several high-quality cohort studies consistently found road traffic noise to be associated with a higher risk of ischemic heart disease, heart failure, diabetes, and all-cause mortality. Furthermore, recent studies have indicated that road traffic and railway noise may increase the risk of diseases not commonly investigated in an environmental noise context, including breast cancer, dementia, and tinnitus. The harmful effects of noise are related to activation of a physiological stress response and nighttime sleep disturbance. Oxidative stress and inflammation downstream of stress hormone signaling and dysregulated circadian rhythms are identified as major disease-relevant pathomechanistic drivers. We discuss the role of reactive oxygen species and present results from antioxidant interventions. Lastly, we provide an overview of oxidative stress markers and adverse redox processes reported for noise-exposed animals and humans. This position paper summarizes all available epidemiological, clinical, and preclinical evidence of transportation noise as an important environmental risk factor for public health and discusses its implications on the population level.

Asunto(s)

Isquemia Miocárdica , Ruido del Transporte , Animales , Humanos , Ruido del Transporte/efectos adversos , Exposición a Riesgos Ambientales/efectos adversos , Estudios de Cohortes , Oxidación-Reducción

RESUMEN

Cell-based therapies have great promise in accelerating and improving burn wound healing. It is a growing need to scale their competence to meet the clinical demands. In this study, the bone marrow mesenchymal stem cells (BMSCs) and platelet-rich plasma (PRP) were tested on the repair of induced burn wounds in a murine model. After the induction of thermal injury, rats were injected with BMSCs and/or PRP in the burn area. After 4 weeks of post-burn, our findings revealed that local treatment of burnt skin with BMSCs and/or PRP offered substantial outcomes when compared with the untreated group. Injected burn with BMSCs and/or PRP enhanced the wound contraction rate and decreased the burn area and period of epithelization. Significant increases in VEGF together with declines in MMP-9 and TGF-ß1 were observed in burnt areas after being treated with BMSCs and/or PRP therapy that indicated improved angiogenesis, and re-epithelization. Furthermore, both MSCs and PRP modulated the burn's oxidative and inflammatory microenvironment as indicated by increases in SOD, CAT, and GSH besides declines in MDA, IL-6, TNF-α, NF-κB, NO, and iNOS. Notable increases in Bcl-2 levels and decreases in Cas-3 and Bax levels were recorded in burnt skin that received both agents concomitantly. Interestingly, the histopathological examination validates the healing power of BMSCs and/or PRP. Collectively, BMSCs and PRP have pioneered therapeutics candidates for clinical application in burn healing possibly via antioxidant, anti-inflammatory, and anti-apoptotic mechanisms along with regulating angiogenesis and scar formation.

RESUMEN

Introduction: Despite the prevalence of the perception that electronic cigarettes (e-cig) are a safer alternative to tobacco smoke, growing concern about their potential toxic impact warrants adequate investigation focusing on special populations like maternal and pediatric groups. This study evaluated the consequences of maternal e-cig use on neonatal neuroinflammation, oxidative stress, and mitochondrial function in primary cultured neurons and postnatal day (PD) 7 and 90 brain. Methodology: Pregnant CD1 mice were exposed to e-cig vapor (2.4% nicotine) from gestational day 5 (E5) till PD7, and the primary neurons were isolated from pups at E16/17. Cellular total reactive oxygen species (ROS) and mitochondrial superoxide were measured in primary neurons using CM-H2DCFDA and Mitosox red, respectively. Mitochondrial function was assessed by Seahorse XF Cell Mitostress analysis. The level of pro-inflammatory cytokines was measured in primary neurons and PD7 and PD90 brains by RT-PCR and immunobead assay. Western blot analysis evaluated the expression of antioxidative markers (SOD-2, HO-1, NRF2, NQO1) and that of the proinflammatory modulator NF-κB. Results: Significantly higher level of total cellular ROS (p < 0.05) and mitochondrial superoxide (p < 0.01) was observed in prenatally e-cig-exposed primary neurons. We also observed significantly reduced antioxidative marker expression and increased proinflammatory modulator and cytokines expression in primary neurons and PD7 (p < 0.05) but not in PD90 postnatal brain. Conclusion: Our findings suggest that prenatal e-cig exposure induces postnatal neuroinflammation by promoting oxidative stress (OS), increasing cytokines' levels, and disrupting mitochondrial function. These damaging events can alter the fetal brain's immune functions, making such offspring more vulnerable to brain insults.

RESUMEN

Large epidemiological studies have shown that traffic noise promotes the development of cardiometabolic diseases. It remains to be established how long these adverse effects of noise may persist in response to a noise-off period. We investigated the effects of acute aircraft noise exposure (mean sound level of 72 dB(A) applied for 4d) on oxidative stress and inflammation mediating vascular dysfunction and increased blood pressure in male C57BL/6 J mice. 1, 2 or 4d of noise cessation after a 4d continuous noise exposure period completely normalized noise-induced endothelial dysfunction of the aorta (measured by acetylcholine-dependent relaxation) already after a 1d noise pause. Vascular oxidative stress and the increased blood pressure were partially corrected, while markers of inflammation (VCAM-1, IL-6 and leukocyte oxidative burst) showed a normalization within 4d of noise cessation. In contrast, endothelial dysfunction, oxidative stress, and inflammation of the cerebral microvessels of noise-exposed mice did not improve at all. These data demonstrate that the recovery from noise-induced damage is more complex than expected demonstrating a complete restoration of large conductance vessel function but persistent endothelial dysfunction of the microcirculation. These findings also imply that longer noise pauses are required to completely reverse noise-induced vascular dysfunction including the resistance vessels.

RESUMEN

The world population is aging rapidly, and by some estimates, the number of people older than 60 will double in the next 30 years. With the increase in life expectancy, adverse effects of environmental exposures start playing a more prominent role in human health. Air pollution is now widely considered the most detrimental of all environmental risk factors, with some studies estimating that almost 20% of all deaths globally could be attributed to poor air quality. Cardiovascular diseases are the leading cause of death worldwide and will continue to account for the most significant percentage of non-communicable disease burden. Cardiovascular aging with defined pathomechanisms is a major trigger of cardiovascular disease in old age. Effects of environmental risk factors on cardiovascular aging should be considered in order to increase the health span and reduce the burden of cardiovascular disease in older populations. In this review, we explore the effects of air pollution on cardiovascular aging, from the molecular mechanisms to cardiovascular manifestations of aging and, finally, the age-related cardiovascular outcomes. We also explore the distinction between the effects of air pollution on healthy aging and disease progression. Future efforts should focus on extending the health span rather than the lifespan.

Asunto(s)

Contaminación del Aire , Enfermedades Cardiovasculares , Sistema Cardiovascular , Humanos , Anciano , Envejecimiento , Longevidad

RESUMEN

Membranous nephropathy (MN) patients are diagnosed by the presence of phospholipase A2 receptor (PLA2R) before they progress to renal failure. However, the subepithelium-like immunocomplex deposit-mediated downstream molecular pathways are poorly understood. The aryl hydrocarbon receptor (AHR), NF-ƙB and Nrf2 pathways play central roles in the pathogenesis and progression of chronic kidney disease. However, their mutual effects on MN require further examination. Thus, we investigated the effect of AHR signalling on the NF-ƙB and Nrf2 pathways in IMN patients, cationic bovine serum albumin (CBSA)-injected rats and zymosan activation serum (ZAS)-treated podocytes. IMN patients show significantly decreased serum total protein and albumin levels, increased urine protein levels and intrarenal IgG4 and PLA2R protein expression in glomeruli compared with controls. IMN patients exhibited increased mRNA expression of intrarenal AHR and its target genes, including CYP1A1, CYP1A2, CYP1B1 and COX-2. This increase was accompanied by significantly upregulated protein expression of CD3, NF-ƙB p65 and COX-2 and significantly downregulated Nrf2 and HO-1 expression. Similarly, CBSA-induced rats showed severe proteinuria and activated intrarenal AHR signalling. This was accompanied by significantly upregulated protein expression of intrarenal p-IκBα, NF-κB p65 and its gene products, including COX-2, MCP-1, iNOS, 12-LOX, p47phox and p67phox, and significantly downregulated protein expression of Nrf2 and its gene products, including HO-1, catalase, GCLC, GCLM, MnSOD and NQO1. These results were further verified in ZAS-induced podocytes. Treatment with the AHR antagonist CH223191 and AHRsiRNA significantly preserved podocyte-specific protein expression and improved the NF-ƙB and Nrf2 pathways in ZAS-induced podocytes. In contrast, similar results were obtained in ZAS-induced podocytes treated with the NF-ƙB inhibitor BAY 11-7082 and NF-κBp65 siRNA. However, neither method had a significant effect on AHR signalling. Collectively, these results indicate that the NF-ƙB pathway is a downstream target of AHR signalling. Our findings suggest that blocking AHR signalling inhibits oxidative stress and inflammation, thereby improving proteinuria and renal injury.

Asunto(s)

Glomerulonefritis Membranosa , Animales , Ratas , Ciclooxigenasa 2/metabolismo , Glomerulonefritis Membranosa/genética , Glomerulonefritis Membranosa/metabolismo , Glomerulonefritis Membranosa/patología , Inflamación/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Proteinuria , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Humanos , Podocitos/metabolismo

RESUMEN

Thioredoxin interacting protein (TXNIP) is a potential drug target for type 2 diabetes mellitus (T2DM) treatment. A series of quinazoline derivatives were designed, synthesised, and evaluated to inhibit TXNIP expression and protect from palmitate (PA)-induced ß cell injury. In vitro cell viability assay showed that compounds D-2 and C-1 could effectively protect ß cell from PA-induced apoptosis, and subsequent results showed that these two compounds decreased TXNIP expression by accelerating its protein degradation. Mechanistically, compounds D-2 and C-1 reduced intracellular reactive oxygen species (ROS) production and modulated TXNIP-NLRP3 inflammasome signalling, and thus alleviating oxidative stress injury and inflammatory response under PA insult. Besides, these two compounds were predicted to possess better drug-likeness properties using SwissADME. The present study showed that compounds D-2 and C-1, especially compound D-2, were potent pancreatic ß cell protective agents to inhibit TXNIP expression and might serve as promising lead candidates for the treatment of T2DM.

Asunto(s)

Diabetes Mellitus Tipo 2 , Proteína con Dominio Pirina 3 de la Familia NLR , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Línea Celular , Inflamasomas/metabolismo , Inflamasomas/farmacología , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Proteínas Portadoras/metabolismo , Proteínas Portadoras/farmacología

RESUMEN

Renal ischemia-reperfusion (IR) injury triggers a cascade of signaling reactions involving an increase in Ca2 + charge and reactive oxygen species (ROS) levels resulting in necrosis, inflammation, apoptosis, and subsequently acute kidney injury (AKI).Transient receptor potential (TRP) channels include an essential class of Ca2+ permeable cation channels, which are segregated into six main channels: the canonical channel (TRPC), the vanilloid-related channel (TRPV), the melastatin-related channel (TRPM), the ankyrin-related channel (TRPA), the mucolipin-related channel (TRPML) and polycystin-related channel (TRPP) or polycystic kidney disease protein (PKD2). TRP channels are involved in adjusting vascular tone, vascular permeability, cell volume, proliferation, secretion, angiogenesis and apoptosis.TRPM channels include eight isoforms (TRPM1-TRPM8) and TRPM2 is the second member of this subfamily that has been expressed in various tissues and organs such as the brain, heart, kidney and lung. Renal TRPM2 channels have an important role in renal IR damage. So that TRPM2 deficient mice are resistant to renal IR injury. TRPM2 channels are triggered by several chemicals including hydrogen peroxide, Ca2+, and cyclic adenosine diphosphate (ADP) ribose (cADPR) that are generated during AKI caused by IR injury, as well as being implicated in cell death caused by oxidative stress, inflammation, and apoptosis.

Asunto(s)

Lesión Renal Aguda , Daño por Reperfusión , Canales Catiónicos TRPM , Canales de Potencial de Receptor Transitorio , Ratones , Animales , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismo , Daño por Reperfusión/metabolismo , Riñón/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Lesión Renal Aguda/metabolismo , Inflamación/metabolismo , Estrés Oxidativo , Calcio/metabolismo

RESUMEN

Benzo[a]pyrene (BaP) as a carcinogen induces oxidative stress and inflammation, causing health problems including liver damage. Puerarin (a natural flavonoid) is traditionally used to provide hepatoprotective effects. This research was established to meet the rising demand for effective therapies/treatments against hepatic diseases and investigate the mechanism underlying the protective actions of puerarin against BaP-induced liver damage. In mice, puerarin combated effectively the detrimental changes in liver weight, color and function indices caused by BaP. In HepG2 cells, puerarin alleviated BaP-induced cell death, oxidative stress and inflammation, and such effects were positively correlated with puerarin's concentration (12.5-50 µM). Mechanistic studies revealed that BaP induced low Sirt1 expression and high miR-34a-5p expression, and puerarin treatment alleviated these changes. Oxidative stress and inflammation induced by BaP were almost eliminated when miR-34a-5p was silenced. Inhibiting miR-34a-5p or overexpressing Sirt1 had a similar effect to puerain treatment. Overexpression of miR-34a-5p and inhibition of Sirt1 reduced the protective effect of puerarin. Collectively, miR-34a-5p participates in the regulation of puerarin's protective function against BaP-induced injury through targeting Sirt1. There is a novel pathway for suppressing oxidative stress and inflammation via miR-34a-5p/Sirt1 axis in puerarin-mediated hepatoprotection, which opens up a new avenue for alternative therapies.

Asunto(s)

MicroARNs , Sirtuina 1 , Animales , Benzo(a)pireno/toxicidad , Inflamación , Isoflavonas , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo

RESUMEN

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that induces the expression of a broad range of downstream genes such as cytochromes P450 enzymes and cyclooxygenase-2. Recent research focuses are shifting from AhR activation induced by xenobiotics to its response patterns to physiological ligands that expand our understanding of how endogenous metabolites as ligands to modulate AhR signaling pathway under homeostasis and pathological conditions. With increasing interest in AhR and its endogenous ligands, it would seem advisable to summarize a variety of endogenous ligands especially host/gut microbiota-derived tryptophan metabolites. Mounting evidence has indicated that AhR play a critical role in the regulation of redox homeostasis and immune responses. In this review, we outline the canonical and non-canonical AhR signalling pathway that is mediated by host/gut microbiota-derived tryptophan metabolites. Through several typical endogenous AhR ligands, we investigated the molecular mechanisms of AhR-induced oxidative stress and inflammation in the pathological milieu, including diabetes, diabetic kidney disease and end-stage renal disease. Finally, we summarize and emphasize the limitations and breakthrough of endogenous AhR ligands from host/microbial tryptophan catabolites. This review might provide novel diagnostic and prognostic approach for refractory human diseases and establish new therapeutic strategies for AhR activation.

Asunto(s)

Microbioma Gastrointestinal , Receptores de Hidrocarburo de Aril , Humanos , Inflamación , Ligandos , Estrés Oxidativo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Transducción de Señal , Triptófano/metabolismo

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases without effective pharmacological intervention. Liensinine (LIEN), a plant-derived isoquinoline alkaloid, exerts key roles in regulating various cellular processes. However, its potential on NAFLD progression has not been reported. In the study, we attempted to explore the regulatory effects of LIEN on fatty liver, and the underlying molecular mechanisms. Our in vitro experiments showed that LIEN treatments significantly reduced the lipid deposition in palmitate acid (PA)-treated cells by improving AMP-activated protein kinase (AMPK) activation. Additionally, excessive reactive oxygen species (ROS) generation was also strongly down-regulated by LIEN in cells upon PA stimulation through enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation. Moreover, PA-triggered inflammatory response was markedly restrained by LIEN via the blockage of TGF-ß-activating kinase 1/nuclear factor-κB (TAK1/NF-κB) signaling. Intriguingly, we further found that LIEN-prohibited ROS production, lipid disorder and inflammation were largely dependent on AMPK activation through repressing TAK1. Consistently, our in vivo experiments confirmed that LIEN treatments efficiently improved the metabolic disorder, insulin resistance, dyslipidemia in high fat diet (HFD)-fed mice. Furthermore, HFD-triggered oxidative stress and inflammation in liver were greatly meliorated by LIEN administration by mediating Nrf2 and TAK1 signaling pathways, respectively. Collectively, all these findings demonstrated that LIEN exerted anti-dyslipidemia, anti-oxidant and anti-inflammatory effects to alleviate NAFLD progression mainly through modulating TAK1/AMPK signaling, and thus could be considered as a promising therapeutic strategy.

Asunto(s)

Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Isoquinolinas/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Fenoles/uso terapéutico , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Línea Celular , Citocinas/genética , Dieta Alta en Grasa , Dislipidemias/tratamiento farmacológico , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Hipolipemiantes/farmacología , Isoquinolinas/farmacología , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Quinasas Quinasa Quinasa PAM/metabolismo , Masculino , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patología , Estrés Oxidativo/efectos de los fármacos , Ácido Palmítico/farmacología , Fenoles/farmacología , Especies Reactivas de Oxígeno/metabolismo

RESUMEN

Galangin is a natural flavonoid isolated from ginger, honey and propolis. AIMS: To investigate the effect of galangin on blood pressure, vascular changes, sympathoexcitation, oxidative stress and inflammation in rats treated with NG-nitro-l-arginine methyl ester (l-NAME). MATERIALS AND METHODS: Male Wistar rats (220-250 g) were given l-NAME (0.5 mg/mL in drinking water) to induce hypertension for 5 weeks. They were treated with vehicle, galangin (30 or 60 mg/kg), or amlodipine (10 mg/kg) for the final two weeks (n = 6/group). KEY FINDINGS: Galangin significantly reduced blood pressure and improved the impairment of endothelium-dependent vasodilation in hypertensive rats. Sympathoexcitation, including enhancement of contractile responses to electrical field stimulation, increases in intensity of tyrosine hydroxylase and plasma norepinephrine concentration in hypertensive rats, was attenuated by galangin treatment. Galangin also reduced systemic and vascular oxidative damage and increased plasma nitric oxide levels in the hypertensive groups. Aortic remodelling accompanied by aortic wall hypertrophy and fibrosis observed in hypertensive rats were alleviated by galangin treatment. Furthermore, galangin exhibited an anti-inflammatory effect by suppressing the upregulation of tumour necrosis factor receptor 1 (TNF-R1), phospho-nuclear factor kappa B (p-NF-κB) and vascular cell adhesion protein 1 (VCAM-1) in aortic tissue and reducing plasma tumour necrosis factor alpha (TNF-α) in l-NAME rats. In conclusion, galangin had antihypertensive effects that were relevant to attenuating endothelial dysfunction, sympathoexcitation and vascular remodelling. These effects might be contributed by antioxidant and anti-inflammatory capacities and modulation of the TNF-R1, p-NF-κB and VCAM-1 pathways in hypertensive rats.

Asunto(s)

Antiinflamatorios no Esteroideos/farmacología , Antihipertensivos/farmacología , Antioxidantes/farmacología , Flavonoides/farmacología , Hipertensión/metabolismo , FN-kappa B/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo , Remodelación Vascular/efectos de los fármacos , Amlodipino/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Masculino , NG-Nitroarginina Metil Éster , Ratas , Ratas Wistar

RESUMEN

Diabetic kidney disease (DKD) is the primary cause of chronic kidney disease that inevitably progress to end-stage kidney disease. Intervention strategies such as blood glucose control is effective for preventing DKD, but many patients with DKD still reach end-stage kidney disease. Although comprehensive mechanisms shed light on the progression of DKD, the most compelling evidence has highlighted that hyperglycemia-related advanced glycation end products (AGEs) formation plays a central role in the pathogenesis of DKD. Pathologically, accumulation of AGEs-mediated receptor for AGEs (RAGE) triggers oxidative stress and inflammation, which is the major deleterious effect of AGEs in host and intestinal microenvironment of diabetic and ageing conditions. The activation of AGEs-mediated RAGE could evoke nicotinamide adenine dinucleotide phosphate oxidase-induced reactive oxygen and nitrogen species production and subsequently give rise to oxidative stress in DKD and ageing kidney. Therefore, targeting RAGE with its ligands mediated oxidative stress and chronic inflammation is considered as an additional intervention strategy for DKD and ageing kidney. In this review, we summarize AGEs/RAGE-mediated oxidative stress and inflammation signaling pathways in DKD and ageing kidney, discussing opportunities and challenges of targeting at AGEs/RAGE-induced oxidative stress that could hold the promising potential approach for improving DKD and ageing kidney.

Asunto(s)

Diabetes Mellitus , Nefropatías Diabéticas , Envejecimiento , Productos Finales de Glicación Avanzada/metabolismo , Humanos , Riñón/metabolismo , Estrés Oxidativo , Receptor para Productos Finales de Glicación Avanzada/metabolismo

RESUMEN

Berberine (BBR) is a promising anti-diabetic isoquinoline alkaloid from Rhizoma coptidis, while its bioavailability was extremely low. Here, the existing form and pharmacokinetics of BBR were comparatively characterized in conventional and antibiotic-induced pseudo germ-free (PGF) rats. Furthermore, we comparatively investigated the antidiabetic effect and potential mechanism of BBR and its intestinal oxidative metabolite oxyberberine (OBB) in STZ-induced diabetic rats. Results showed that BBR and OBB existed mainly as protein-bound form in blood, while protein-bound OBB was significantly depleted in PGF rats. Treatment with OBB and BBR effectively decreased clinical symptoms of diabetic rats, reduced blood glucose level, ameliorated the pancreatic damage, and mitigated oxidative stress and inflammatory markers. However, the anti-diabetes effect of BBR was obviously compromised by antibiotics. In addition, OBB exerted superior anti-diabetes effect to BBR of the same dose, significantly up-regulated the mRNA expression of Nrf2 signaling pathway and substantially promoted the pancreatic levels of PI3K/Akt signaling pathway. In conclusion, BBR and its absorbed oxidative metabolite OBB were mainly presented and transported in the protein-bound form in vivo. The gut microbiota may play an important role in the anti-diabetes effect of BBR through transforming itself into the superior hypoglycemic metabolite OBB. OBB possessed favorable hypoglycemic and pancreatic ß-cells protective effects, which may stand a huge potential to be further developed into a promising anti-diabetes candidate.

Asunto(s)

Berberina/análogos & derivados , Berberina/farmacología , Hipoglucemiantes/farmacología , Factor 2 Relacionado con NF-E2/efectos de los fármacos , Proteína Oncogénica v-akt/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Antiinflamatorios no Esteroideos/farmacología , Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Simulación del Acoplamiento Molecular , Estrés Oxidativo/efectos de los fármacos , Páncreas/patología , Ratas , Ratas Sprague-Dawley

RESUMEN

Oxidative stress and inflammation are important and critical mediators in the development and progression of chronic kidney disease (CKD) and its complications. Shenkang injection (SKI) has been widely used to treat patients with CKD. Although the anti-oxidative and anti-inflammatory activity was involved in SKI against CKD, its bioactive components and underlying mechanism remain enigmatic. A rat model of adenine-induced chronic renal failure (CRF) is associated with, and largely driven by, oxidative stress and inflammation. Hence, we identified the anti-oxidative and anti-inflammatory components of SKI and further revealed their underlying mechanism in the adenine-induced CRF rats. Compared with control rats, the levels of creatinine, urea, uric acid, total cholesterol, triglyceride, and low-density lipoprotein cholesterol in serum were significantly increased in the adenine-induced CRF rats. However, treatment with SKI and its three anthraquinones including chrysophanol, emodin, and rhein could reverse these aberrant changes. They could significantly inhibit pro-fibrotic protein expressions including collagen I, α-SMA, fibronectin, and vimentin in the kidney tissues of the adenine-induced CRF rats. Of note, SKI and rhein showed the stronger inhibitory effect on these pro-fibrotic protein expressions than chrysophanol and emodin. Furthermore, they could improve dysregulation of IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways. Chrysophanol and emodin showed the stronger inhibitory effect on the NF-κB p65 protein expression than SKI and rhein. Rhein showed the strongest inhibitory effect on p65 downstream target gene products including NAD(P)H oxidase subunits (p47phox, p67phox, and gp91phox) and COX-2, MCP-1, iNOS, and 12-LO in the kidney tissues. However, SKI and rhein showed the stronger inhibitory effect on the significantly downregulated anti-inflammatory and anti-oxidative protein expression nuclear Nrf2 and its target gene products including HO-1, catalase, GCLC, and NQO1 in the Keap1/Nrf2 signaling pathway than chrysophanol and emodin. This study first demonstrated that SKI and its major components protected against renal fibrosis by inhibiting oxidative stress and inflammation via simultaneous targeting IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways, which illuminated the potential molecular mechanism of anti-oxidative and anti-inflammatory effects of SKI.