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1.
Int J Nanomedicine ; 16: 2461-2475, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33814910

RESUMEN

Aim: To explore the effects of Radix Sophorae Flavescentis carbonisata-based carbon dots (RSFC-CDs) on an ethanol-induced acute gastric ulcer rat model. Methods: The structure, optical properties, functional groups and elemental composition of RSFC-CDs synthesized by one-step pyrolysis were characterized. The gastric protective effects of RSFC-CDs were evaluated and confirmed by applying a rat model of ethanol-induced acute gastric ulcers. The underlying mechanisms were investigated through the nuclear factor-kappa B (NF-κB) signalling pathway and oxidative stress. Results: RSFC-CDs with a diameter ranging from 2-3 nm mainly showed gastric protective effects by reducing the levels of NF-κB, tumour necrosis factor-α (TNF-α), interleukin (IL)-6, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), glutathione (GSH), malondialdehyde (MDA) and inducible nitric oxide synthase (iNOS) to inhibit ethanol-induced inflammation and oxidative stress. Conclusion: RSFC-CDs have anti-inflammatory and anti-oxidative effects, making them promising for application in ethanol-induced gastric injury.


Asunto(s)
Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Carbono/química , Medicamentos Herbarios Chinos/uso terapéutico , Sustancias Protectoras/uso terapéutico , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológico , Enfermedad Aguda , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Regulación hacia Abajo/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Etanol/efectos adversos , Interleucina-6/metabolismo , Masculino , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo/efectos de los fármacos , Espectroscopía de Fotoelectrones , Sustancias Protectoras/farmacología , Ratas Sprague-Dawley , Úlcera Gástrica/patología , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/efectos de los fármacos
2.
Int J Mol Sci ; 22(6)2021 Mar 20.
Artículo en Inglés | MEDLINE | ID: mdl-33804769

RESUMEN

SARS-CoV-2 infection can cause cytokine storm and may overshoot immunity in humans; however, it remains to be determined whether virus-induced soluble mediators from infected cells are carried by exosomes as vehicles to distant organs and cause tissue damage in COVID-19 patients. We took an unbiased proteomic approach for analyses of exosomes isolated from plasma of healthy volunteers and COVID-19 patients. Our results revealed that tenascin-C (TNC) and fibrinogen-ß (FGB) are highly abundant in exosomes from COVID-19 patients' plasma compared with that of healthy normal controls. Since TNC and FGB stimulate pro-inflammatory cytokines via the Nuclear factor-κB (NF-κB) pathway, we examined the status of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-C motif chemokine ligand 5 (CCL5) expression upon exposure of hepatocytes to exosomes from COVID-19 patients and observed significant increase compared with that from healthy subjects. Together, our results demonstrate that TNC and FGB are transported through plasma exosomes and potentially trigger pro-inflammatory cytokine signaling in cells of distant organ.


Asunto(s)
/sangre , Exosomas/química , Exosomas/genética , Fibrinógeno/metabolismo , Inflamación/metabolismo , Tenascina/metabolismo , Anciano , Línea Celular , Quimiocina CCL5/metabolismo , Exosomas/metabolismo , Exosomas/ultraestructura , Femenino , Hepatocitos/metabolismo , Humanos , Inflamación/etiología , Interleucina-6/metabolismo , Masculino , Espectrometría de Masas , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , FN-kappa B/metabolismo , Mapas de Interacción de Proteínas , Proteoma/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
3.
Int J Mol Sci ; 22(4)2021 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-33671213

RESUMEN

Palmitoylethanolamide (PEA), a fatty acid amide, has been widely investigated for its analgesic and anti-inflammatory properties. The ultra-micronized formulation of PEA (um-PEA), that has an enhanced rate of dissolution, is extensively used. Acetyl-l-carnitine (LAC), employed for the treatment of neuropathic pain in humans, is able to cause analgesia by up-regulating type-2 metabotropic glutamate (mGlu2) receptors. In the present study, we tested different associations of um-PEA, LAC and non-micronized PEA (non-m-PEA) in a rat model of carrageenan (CAR)-induced paw edema. Intraplantar injection of CAR into the hind paw of animals caused edema, thermal hyperalgesia, accumulation of infiltrating inflammatory cells and augmented myeloperoxidase (MPO) activity. All these parameters were decreased in a significantly manner by oral administration of a compound constituted by a mixture of um-PEA and LAC in relation 1:1 (5 mg/kg), but not with the association of single compounds administered one after the other. These findings showed the superior anti-inflammatory and anti-nociceptive action displayed by oral administration of um-PEA and LAC versus LAC plus, separate but consecutive, um-PEA in the rat paw CAR model of inflammatory pain.


Asunto(s)
Acetilcarnitina/uso terapéutico , Amidas/uso terapéutico , Etanolaminas/uso terapéutico , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Ácidos Palmíticos/uso terapéutico , Acetilcarnitina/farmacología , Amidas/farmacología , Animales , Carragenina , Recuento de Células , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Edema/complicaciones , Edema/tratamiento farmacológico , Edema/patología , Etanolaminas/farmacología , Hiperalgesia/complicaciones , Hiperalgesia/tratamiento farmacológico , Inflamación/complicaciones , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-1beta/metabolismo , Masculino , Mastocitos/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Dolor/complicaciones , Dolor/patología , Ácidos Palmíticos/farmacología , Peroxidasa/metabolismo , Ratas Sprague-Dawley , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismo
4.
Methods Mol Biol ; 2269: 167-174, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33687679

RESUMEN

Three-dimensional (3D) cell cultures combining multipotent mesenchymal stromal cells (MSC), tendon extracellular matrix scaffolds, and mechanical stimulation by a bioreactor have been used to induce tenogenic differentiation in vitro. Yet, these conditions alone do not mimic the environment of acute inflammatory tendon disease adequately, thus the results of such studies are not representatives for tendon regeneration after acute injury. In this chapter, we describe two different approaches to introduce inflammatory stimuli, comprising co-culture with leukocytes and supplementation with the cytokines IL-1 ß and TNF-α. The presented in vitro model of inflammatory tendon disease could be used to study musculoskeletal pathophysiology and regeneration in more depth.


Asunto(s)
Células Madre Mesenquimatosas/metabolismo , Modelos Biológicos , Tendinopatía/metabolismo , Tendones/metabolismo , Andamios del Tejido/química , Animales , Humanos , Inflamación/metabolismo , Inflamación/patología , Interleucina-1beta/metabolismo , Células Madre Mesenquimatosas/patología , Tendinopatía/patología , Tendones/patología , Factor de Necrosis Tumoral alfa/metabolismo
5.
Int J Mol Sci ; 22(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673381

RESUMEN

Tumor necrosis factor (TNF) is known to activate the epithelial Na+ channel (ENaC) in A549 cells. A549 cells are widely used model for ENaC research. The role of δ-ENaC subunit in TNF-induced activation has not been studied. In this study we hypothesized that δ-ENaC plays a major role in TNF-induced activation of ENaC channel in A549 cells which are widely used model for ENaC research. We used CRISPR/Cas 9 approach to knock down (KD) the δ-ENaC in A549 cells. Western blot and immunofluorescence assays were performed to analyze efficacy of δ-ENaC protein KD. Whole-cell patch clamp technique was used to analyze the TNF-induced activation of ENaC. Overexpression of wild type δ-ENaC in the δ-ENaC KD of A549 cells restored the TNF-induced activation of whole-cell Na+ current. Neither N-linked glycosylation sites nor carboxyl terminus domain of δ-ENaC was necessary for the TNF-induced activation of whole-cell Na+ current in δ-ENaC KD of A549 cells. Our data demonstrated that in A549 cells the δ-ENaC plays a major role in TNF-induced activation of ENaC.


Asunto(s)
Sistemas CRISPR-Cas , Canales Epiteliales de Sodio , Factor de Necrosis Tumoral alfa/metabolismo , Células A549 , Canales Epiteliales de Sodio/genética , Canales Epiteliales de Sodio/metabolismo , Humanos , Factor de Necrosis Tumoral alfa/genética
6.
Int J Mol Sci ; 22(5)2021 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-33668718

RESUMEN

BACKGROUND: Status epilepticus (SE) is a neurological disorder characterized by a prolonged epileptic activity followed by subsequent epileptogenic processes. The aim of the present study was to evaluate the early effects of topiramate (TPM) and lacosamide (LCM) treatment on oxidative stress and inflammatory damage in a model of pilocarpine-induced SE. METHODS: Male Wistar rats were randomly divided into six groups and the two antiepileptic drugs (AEDs), TPM (40 and 80 mg/kg, i.p.) and LCM (10 and 30 mg/kg, i.p.), were injected three times repeatedly after pilocarpine administration. Rats were sacrificed 24 h post-SE and several parameters of oxidative stress and inflammatory response have been explored in the hippocampus. RESULTS: The two drugs TPM and LCM, in both doses used, succeeded in attenuating the number of motor seizures compared to the SE-veh group 30 min after administration. Pilocarpine-induced SE decreased the superoxide dismutase (SOD) activity and reduced glutathione (GSH) levels while increasing the catalase (CAT) activity, malondialdehyde (MDA), and IL-1ß levels compared to the control group. Groups with SE did not affect the TNF-α levels. The treatment with a higher dose of 30 mg/kg LCM restored to control level the SOD activity in the SE group. The two AEDs, in both doses applied, also normalized the CAT activity and MDA levels to control values. In conclusion, we suggest that the antioxidant effect of TPM and LCM might contribute to their anticonvulsant effect against pilocarpine-induced SE, whereas their weak anti-inflammatory effect in the hippocampus is a consequence of reduced SE severity.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Inflamación/patología , Lacosamida/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológico , Topiramato/uso terapéutico , Animales , Anticonvulsivantes/farmacología , Biomarcadores/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipocampo/fisiopatología , Interleucina-1beta/metabolismo , Lacosamida/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Pilocarpina , Ratas Wistar , Convulsiones/fisiopatología , Estado Epiléptico/fisiopatología , Topiramato/farmacología , Factor de Necrosis Tumoral alfa/metabolismo
7.
Life Sci ; 272: 119233, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33600863

RESUMEN

Aim Increasing evidence demonstrated circular RNAs (circRNAs) are involved in the development of various diseases, including sepsis-induced AKI. Although CIRC-Ttc3 has been proved to regulate cardiac function after myocardial infarction, its role in sepsis-induced AKI remains unclear. MATERIALS AND METHODS: The AKI rat model was firstly induced by sepsis through cecal ligation puncture (CLP). Serum levels of creatinine, BUN, NGAL, TNF-α, IL-6, SOD, MDA and IL-1ß were measured through appropriate kits. The pathological alteration and renal microvascular permeability in renal tissues were determined by HE staining and Evans Blue assays. Cell apoptosis was detected by TUNEL assay. The expression levels of CIRC-Ttc3, miR-148a, TNF-α, IL-1ß and iNOS in rats' renal samples were tested by qRT-PCR or/and western blot. The binding ability between CIRC-Ttc3 and miR-148a was evaluated through luciferase reporter, RIP and RNA pull-down assays. KEY FINDINGS: Kidney injury was found in CLP-treated rats. CIRC-Ttc3 expression was down-regulated, and upregulation of CIRC-Ttc3 improved inflammatory responses and oxidative stress in AKI rats. Mechanismly, CIRC-Ttc3 was confirmed to bind to and negatively regulate miR-148a. Further rescue assays revealed that overexpression of miR-148a rescued the improvement of CIRC-Ttc3 on sepsis-induced AKI. Then, it was illustrated that CIRC-Ttc3 regulated Rcan2 expression by binding to miR-148a. Finally, knockdown of Rcan2 reversed the effects of miR-148a inhibition on sepsis-induced AKI. SIGNIFICANCE: CIRC-Ttc3 relieved inflammation and oxidative stress through regulating the miR-148a/Rcan2 axis in rats with AKI induced by sepsis. Therefore, CIRC-Ttc3 may be a potential therapeutic target for sepsis-induced AKI.


Asunto(s)
Lesión Renal Aguda/genética , ARN Circular/genética , Lesión Renal Aguda/metabolismo , Animales , Apoptosis/genética , China , Modelos Animales de Enfermedad , Inflamación/genética , Riñón/metabolismo , Riñón/patología , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Estrés Oxidativo/genética , ARN Circular/metabolismo , ARN Largo no Codificante/genética , Ratas , Ratas Sprague-Dawley , Sepsis/complicaciones , Sepsis/genética , Factor de Necrosis Tumoral alfa/metabolismo
8.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artículo en Inglés | MEDLINE | ID: mdl-33540902

RESUMEN

Human epidermal keratinocytes are constantly exposed to UV radiation. As a result, there is a significant need for safe and effective compounds to protect skin cells against this environmental damage. This study aimed to analyze the effect of phytocannabinoid-cannabinoid (CBD)-on the proteome of UVA/B irradiated keratinocytes. The keratinocytes were cultured in a three-dimensional (3D) system, designed to mimic epidermal conditions closely. The obtained results indicate that CBD protected against the harmful effects of UVA/B radiation. CBD decreased the expression of proinflammatory proteins, including TNFα/NFκB and IκBKB complex and decreased the expression of proteins involved in de novo protein biosynthesis, which are increased in UVA/B-irradiated cells. Additionally, CBD enhanced the UV-induced expression of 20S proteasome subunits. CBD also protected protein structures from 4-hydroxynonenal (HNE)-binding induced by UV radiation, which primarily affects antioxidant enzymes. CBD-through its antioxidant/anti-inflammatory activity and regulation of protein biosynthesis and degradation-protects skin cells against UVA/B-induced changes. In the future, its long-term use in epidermal cells should be investigated.


Asunto(s)
Cannabidiol/farmacología , Queratinocitos/efectos de los fármacos , Proteoma/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Rayos Ultravioleta , Aldehídos/farmacología , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Cannabidiol/química , Técnicas de Cultivo de Célula , Células Cultivadas , Evaluación Preclínica de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de la radiación , Humanos , Quinasa I-kappa B/metabolismo , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Estructura Molecular , Complejos Multiproteicos/metabolismo , FN-kappa B/metabolismo , Análisis de Componente Principal , Proteoma/efectos de la radiación , Transducción de Señal/efectos de la radiación , Factor de Necrosis Tumoral alfa/metabolismo
9.
Life Sci ; 270: 119120, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33545204

RESUMEN

BACKGROUND AND AIMS: C-X-C ligand 16 (CXCL16) is an exceptional chemokine that is expressed as transmembrane and soluble forms. Our aim is to shed lights on the role of CXCL16/ADAM10 (a disintegrin and metalloproteinase) in cisplatin (CP)-induced renal toxicity as well as possible protective effect of enoxaparin. MAIN METHODS: Male albino mice were injected with CP (30 mg/kg, i.p.) in the presence or absence of enoxaparin (ENOX) (5 mg/kg, i.p.). Renal toxicity markers, serum level of cystatin-c, complete blood count (CBC), prothrombin time (Pt) and tissue expression of CXCL16, ADAM10, cluster of differentiation 3 (CD3), fibrinogen, tissue factor (TF), nuclear factor-κB (NF-κB) and tumour necrosis factor α (TNF-α) were measured. Besides, serum CXCL16 and histopathology were also analyzed. KEY FINDINGS: CP increased renal toxicity markers, renal expression of CXCL16/ADAM10, fibrinogen, TF and CD3 tissue expression in a time-dependent manner, and elevated serum cystatin-c, CXCL16 and tissue TNF-α, NF-κB. Alternatively, ENOX restored the deteriorated parameters and reduced tissue level of NF-κB. SIGNIFICANCE: This report, for the first time, showed that soluble CXCL16 resulting from ADAM10 cleavage may recruit T-cells to the renal glomeruli and tubules in CP toxicity. Furthermore, TF and fibrin, have similar expression and location pattern like CXCL16 and ADAM10 suggesting their possible interrelation. ENOX successfully restored the deteriorated parameters suggesting it may be an effective nephroprotective adjuvant therapy.


Asunto(s)
Quimiocina CXCL16/metabolismo , Enoxaparina/farmacología , Proteínas ADAM/metabolismo , Proteína ADAM10/efectos de los fármacos , Proteína ADAM10/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Línea Celular Tumoral , Quimiocina CXCL16/efectos de los fármacos , Quimiocinas CXC/metabolismo , Cisplatino/efectos adversos , Cisplatino/farmacología , Enoxaparina/metabolismo , Riñón/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , FN-kappa B/metabolismo , Linfocitos T/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
10.
Life Sci ; 272: 119194, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33609541

RESUMEN

AIM: The aim of the present study was to investigate the anti-inflammatory response mediated of the M1 muscarinic acetylcholine receptor (mAChR) during experimental colitis. MATERIAL AND METHODS: After the induction of 6% acetic acid colitis, mice were treated with McN-A-343 0.5, 1.0, and 1.5 mg/kg or dexamethasone (DEXA, 2.0 mg/kg) or pirenzepine (PIR, 10 mg/kg; M1 mAChR antagonist). Colonic inflammation was assessed by macroscopic and microscopic lesion scores, colonic wet weight, myeloperoxidase (MPO) activity, interleukin-1 beta (IL1-ß) levels and tumor necrosis factor alpha (TNF-α), glutathione (GSH), malondialdehyde (MDA) and nitrate and nitrite (NO3/NO2), mRNA expression of IKKα, nuclear factor kappa beta (NF-kB) and cyclooxygenase-2 (COX-2), as well protein expression of NF-kB and COX-2. RESULTS: Treatment with McN-A-343 at a concentration of 1.5 mg/kg showed a significant reduction in intestinal damage as well as a decrease in wet weight, MPO activity, pro-inflammatory cytokine concentration, markers of oxidative stress and expression of inflammatory mediators. The action of the M1 agonist by the administration of pirenzepine, which promoted the blocking of the mAChR M1-mediated anti-inflammatory response, has also been proven. CONCLUSION: The results suggest that peripheral colonic M1 mAChR is involved in reversing the pro-inflammatory effect of experimentally induced colitis, which may represent a promising therapeutic alternative for patients with ulcerative colitis.


Asunto(s)
Cloruro de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamonio/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Cloruro de (4-(m-Clorofenilcarbamoiloxi)-2-butinil)trimetilamonio/metabolismo , Animales , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Dexametasona/farmacología , Modelos Animales de Enfermedad , Glutatión/metabolismo , Inflamación/patología , Mediadores de Inflamación/metabolismo , Interleucina-1beta/metabolismo , Masculino , Malondialdehído/metabolismo , Ratones , Agonistas Muscarínicos/farmacología , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Receptor Muscarínico M1 , Factor de Necrosis Tumoral alfa/metabolismo
11.
Adv Exp Med Biol ; 1275: 1-33, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33539010

RESUMEN

Protein kinases are intracellular signaling enzymes that catalyze the phosphorylation of specific residues in their target substrate proteins. They play important role for regulation of life and death decisions. The complexity of the relationship between death receptors and protein kinases' cell death decision-making mechanisms create many difficulties in the treatment of various diseases. The most of fifteen different cell death pathways, which are reported by Nomenclature Committee on Cell Death (NCCD) are protein kinase signal transduction-mediated negative or positive selections. Tumor necrosis factor (TNF) as a main player of death pathways is a dual-functioning molecule in that it can promote both cell survival or cell death. All apoptotic and necrotic signal transductions are conveyed through death domain-containing death receptors, which are expressed on the surface of nearly all human cells. In humans, eight members of the death receptor family have been identified. While the interaction of TNF with TNF Receptor 1 (TNFR1) activates various signal transduction pathways, different death receptors activate three main signal transduction pathways: nuclear factor kappa B (NF-ĸB)-mediated differentiation or pro-inflammatory cytokine synthesis, mitogen-activated protein kinase (MAPK)-mediated stress response and caspase-mediated apoptosis. The link between the NF-ĸB and the c-Jun NH2-terminal kinase (JNK) pathways comprise another check-point to regulate cell death. TNF-α also promotes the "receptor-interacting serine/threonine protein kinase 1" (RIPK1)/RIPK3/ mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necrosis. Thus, necrosome is mainly comprised of MLKL, RIPK3 and, in some cases, RIPK1. In fact, RIPK1 is at the crossroad between life and death, downstream of various receptors as a regulator of endoplasmic reticulum stress-induced death. TNFR1 signaling complex (TNF-RSC), which contains multiple kinase activities, promotes phosphorylation of transforming growth factor ß-activated kinase 1 (TAK1), inhibitor of nuclear transcription factor κB (IκB) kinase (IKK) α/IKKß, IκBα, and NF-κB. IKKs affect cell-survival pathways in NF-κB-independent manner. Toll-like receptor (TLR) stimulation triggers various signaling pathways dependent on myeloid differentiation factor-88 (MyD88), Interleukin-1 receptor (IL-1R)-associated kinase (IRAK1), IRAK2 and IRAK4, lead to post-translational activation of nucleotide and oligomerization domain (NLRP3). Thereby, cell fate decisions following TLR signaling is parallel with death receptor signaling. Inhibition of IKKα/IKKß or its upstream activators sensitize cells to death by inducing RIPK1-dependent apoptosis or necroptosis. During apoptosis, several kinases of the NF-κB pathway, including IKK1 and NF-κB essential modulator (NEMO), are cleaved by cellular caspases. This event can terminate the NF-κB-derived survival signals. In both canonical and non-canonical pathways, IKK is key to NF-κB activation. Whereas, the activation process of IKK, the functions of NEMO ubiquitination, IKK-related non-canonical pathway and the nuclear transportation of NEMO and functions of IKKα are still debated in cell death. In addition, cluster of differentiation 95 (CD95)-mediated non-apoptotic signaling and CD95- death-inducing signaling complex (DISC) interactions are waiting for clarification.


Asunto(s)
Quinasa I-kappa B , Proteínas Quinasas , Apoptosis , Humanos , Quinasa I-kappa B/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Fosforilación , Proteínas Quinasas/genética , Transducción de Señal , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
12.
Biomed Res Int ; 2021: 6694572, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33521129

RESUMEN

Allanblackia floribunda has been used to treat an upset stomach in African traditional medicine, but its efficacy and safety have not been scientifically studied. The present research is aimed at assessing the antiulcer property of the seed extract of the plant to validate its traditional claim. Rats were pretreated with three doses of aqueous extract of A. floribunda (AFE) at 30, 100, and 300 mg/kg or omeprazole 10 mg/kg for 1 hr before the acute gastric ulcer was induced by oral administration of 5 mL/kg of 98% ethanol. The animals were sacrificed under anesthesia, and the stomach and blood were collected. The gross histology of the stomach, percentage protection conferred by the treatment, gastric pH, and serum TNF-α and INF-γ were assessed as well as the expression of Ki67 antigens. The antioxidant properties as well as the acute toxicity profile of the plant extract were also assessed. The results show that A. floribunda conferred significant protection on the rats against gastric ulceration with % protection of 46.15, 57.69, and 65.38 for AFE 30, 100, and 300 mg/kg, respectively, as well as 69.23% for omeprazole 10 mg/kg. The plant extract caused marked reductions in gastric pH, TNF-α, and INF-γ with statistical significance (p < 0.001) for AFE 300 mg/kg and omeprazole 10 mg/kg. Also, the plant showed good antioxidant activity comparable to gallic acid. Furthermore, the plant extract modulated the expression of Ki67 antigens. All animals survived the 14-day delayed toxicity test with no significant differences in physical, hematological, and biochemical parameters between rats orally administered with supratherapeutic doses of AFE (5000 mg/kg) or normal saline. The study established that the gastroprotective effect of the seed extract of A. floribunda is attributable to its antisecretory, antioxidant, and anti-inflammatory properties. Additionally, the plant was found to promote ulcer healing via the modulation of the expression Ki67 and was safe at supratherapeutic doses.


Asunto(s)
Clusiaceae/química , Etanol/toxicidad , Interferón gamma/metabolismo , Antígeno Ki-67/metabolismo , Semillas/química , Úlcera Gástrica/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antiinflamatorios/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Compuestos de Bifenilo/química , Quelantes/farmacología , Modelos Animales de Enfermedad , Depuradores de Radicales Libres , Concentración 50 Inhibidora , Masculino , Óxido Nítrico/metabolismo , Fitoterapia , Picratos/química , Ratas , Ratas Sprague-Dawley , Úlcera Gástrica/inducido químicamente
13.
Exp Parasitol ; 223: 108079, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33524381

RESUMEN

Chagas disease is caused by Trypanosoma cruzi, and it is an important cause of morbidity and mortality in Latin America. There are no vaccines, and the chemotherapy available to treat this infection has serious side effects. In a search for alternative treatments, we determined the in vitro susceptibility of epimastigote and trypomastigote forms of T. cruzi and the cytotoxic effects on peripheral blood mononuclear cells (PBMCs) of ethanolic extracts obtained from six different plant species. The ethanolic extracts of Ageratina vacciniaefolia, Clethra fimbriata and Siparuna sessiliflora showed antiprotozoal activity against epimastigotes and low cytotoxicity in mammalian cells. However, only the ethanolic extract of C. fimbriata showed activity against T. cruzi trypomastigotes, and it had low cytotoxicity in PBMCs. An analysis on the phytochemical composition of C. fimbriata extract showed that its metabolites were primarily represented by two families of compounds: flavonoids and terpenoids. Lastly, we analyzed whether the A. vacciniaefolia, C. fimbriata, or S. sessiliflora ethanolic extracts induced IFN-γ or TNF-α production. Significantly, ethanolic extracts of C. fimbriata induced TNF-α production and S. sessiliflora induced both cytokines. In addition, C. fimbriata and S. sessiliflora induced the simultaneous secretion of IFN-γ and TNF-α in CD8+ T cells. The antiprotozoal and immunomodulatory activity of C. fimbriata may be related to the presence of flavonoid and triterpene compounds in the extract. Thus, these findings suggest that C. fimbriata may represent a valuable source of new bioactive compounds for the therapeutic treatment of Chagas disease that combines trypanocidal activity with the capacity to boost the immune response.


Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Leucocitos Mononucleares/efectos de los fármacos , Extractos Vegetales/química , Extractos Vegetales/farmacología , Trypanosoma cruzi/efectos de los fármacos , Adulto , Ageratina/química , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Cromatografía Líquida de Alta Presión , Clethraceae/química , Colombia , Femenino , Citometría de Flujo , Humanos , Concentración 50 Inhibidora , Interferón gamma/metabolismo , Laurales/química , Masculino , Medicina Tradicional , Extractos Vegetales/toxicidad , Espectrometría de Masa por Ionización de Electrospray , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven
14.
Nat Commun ; 12(1): 819, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547302

RESUMEN

Regulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIPS into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.


Asunto(s)
Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/química , Caspasa 8/química , Proteína de Dominio de Muerte Asociada a Fas/química , Proteína Serina-Treonina Quinasas de Interacción con Receptores/química , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/genética , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/metabolismo , Caspasa 8/genética , Caspasa 8/metabolismo , Dominio Catalítico , Clonación Molecular , Microscopía por Crioelectrón , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/química , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/genética , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteína de Dominio de Muerte Asociada a Fas/genética , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Células HEK293 , Humanos , Modelos Moleculares , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Dominios y Motivos de Interacción de Proteínas , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Multimerización de Proteína , Proteína Serina-Treonina Quinasas de Interacción con Receptores/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Muerte Celular Regulada/genética , Factor de Necrosis Tumoral alfa/química , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
15.
Viruses ; 13(2)2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33546489

RESUMEN

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprises mild courses of disease as well as progression to severe disease, characterised by lung and other organ failure. The immune system is considered to play a crucial role for the pathogenesis of COVID-19, although especially the contribution of innate-like T cells remains poorly understood. Here, we analysed the phenotype and function of mucosal-associated invariant T (MAIT) cells, innate-like T cells with potent antimicrobial effector function, in patients with mild and severe COVID-19 by multicolour flow cytometry. Our data indicate that MAIT cells are highly activated in patients with COVID-19, irrespective of the course of disease, and express high levels of proinflammatory cytokines such as IL-17A and TNFα ex vivo. Of note, expression of the activation marker HLA-DR positively correlated with SAPS II score, a measure of disease severity. Upon MAIT cell-specific in vitro stimulation, MAIT cells however failed to upregulate expression of the cytokines IL-17A and TNFα, as well as cytolytic proteins, that is, granzyme B and perforin. Thus, our data point towards an altered cytokine expression profile alongside an impaired antibacterial and antiviral function of MAIT cells in COVID-19 and thereby contribute to the understanding of COVID-19 immunopathogenesis.


Asunto(s)
/inmunología , Activación de Linfocitos , Células T Invariantes Asociadas a Mucosa/inmunología , Inmunidad Adaptativa , Citocinas/metabolismo , Femenino , Granzimas/metabolismo , Antígenos HLA-DR , Humanos , Interleucina-17/metabolismo , Células Asesinas Naturales/inmunología , Masculino , Células T Invariantes Asociadas a Mucosa/metabolismo , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
16.
J Cell Mol Med ; 25(4): 2279-2284, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33421348

RESUMEN

Obesity increases the morbidity and severity of asthma, with poor sensitivity to corticosteroid treatment. Metformin has potential effects on improving asthma airway inflammation. Regulatory T cells (Tregs) play a key role in suppressing the immunoreaction to allergens. We built an obese asthmatic mouse model by administering a high-fat diet (HFD) and ovalbumin (OVA) sensitization, with daily metformin treatment. We measured the body weight and airway inflammatory status by histological analysis, qRT-PCR, and ELISA. The percentage of Tregs was measured by flow cytometry. Obese asthmatic mice displayed more severe airway inflammation and more significant changes in inflammatory cytokines. Metformin reversed the obese situation and alleviated the airway inflammation and remodelling with increased Tregs and related transcript factors. The anti-inflammatory function of metformin may be mediated by increasing Tregs.


Asunto(s)
Antiinflamatorios/farmacología , Asma/tratamiento farmacológico , Hipoglucemiantes/farmacología , Metformina/farmacología , Obesidad/tratamiento farmacológico , Linfocitos T Reguladores/efectos de los fármacos , Animales , Asma/inmunología , Asma/patología , Peso Corporal/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Recuento de Linfocito CD4 , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Humanos , Inflamación , Interleucina-4/antagonistas & inhibidores , Interleucina-4/inmunología , Interleucina-4/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/patología , Ratones , Obesidad/inmunología , Obesidad/patología , Ovalbúmina/administración & dosificación , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/patología , Linfocitos T Reguladores/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo
17.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-33513808

RESUMEN

There is little known about the effect of the periodontopathogen Filifactor alocis on macrophages as key cells of the innate immune defense in the periodontium. Therefore, the aim of the present study was to investigate the effect of F. alocis and additionally of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNFα) on visfatin and other pro-inflammatory and proteolytic molecules associated with periodontitis in human macrophages. The presence of macrophage markers CD14, CD86, CD68, and CD163 was examined in gingival biopsies from healthy individuals and periodontitis patients. Human macrophages were incubated with F. alocis and TNFα for up to 2 d. The effects of both stimulants on macrophages were determined by real-time PCR, ELISA, immunocytochemistry, and immunofluorescence. F. alocis was able to significantly stimulate the synthesis of visfatin by human macrophages using TLR2 and MAPK pathways. In addition to visfatin, F. alocis was also able to increase the synthesis of cyclooxygenase 2, TNFα, and matrix metalloproteinase 1. Like F. alocis, TNFα was also able to stimulate the production of these proinflammatory and proteolytic molecules. Our results highlight the pathogenetic role of F. alocis in periodontal diseases and also underline the involvement of visfatin in the aetiopathogenesis of periodontitis.


Asunto(s)
Clostridiales/inmunología , Encía/metabolismo , Macrófagos/metabolismo , Nicotinamida Fosforribosiltransferasa/biosíntesis , Periodontitis/inmunología , Receptor Toll-Like 2/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Ciclooxigenasa 2/biosíntesis , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Encía/citología , Encía/patología , Humanos , Inmunohistoquímica , Receptores de Lipopolisacáridos/genética , Receptores de Lipopolisacáridos/metabolismo , Sistema de Señalización de MAP Quinasas/inmunología , Macrófagos/efectos de los fármacos , Metaloproteinasa 1 de la Matriz/biosíntesis , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/metabolismo , Nicotinamida Fosforribosiltransferasa/genética , Nicotinamida Fosforribosiltransferasa/metabolismo , Periodontitis/metabolismo , Periodontitis/microbiología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
18.
Int J Mol Sci ; 22(3)2021 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-33513830

RESUMEN

In advanced cirrhosis, the TNFα-mediated intestinal inflammation and bacteria dysbiosis are involved in the development of inflammation and vasoconstriction-related renal dysfunction. In colitis and acute kidney injury models, activation of SIRT1 attenuates the TNFα-mediated intestinal and renal abnormalities. This study explores the impacts of intestinal SIRT1 deficiency and TNFα-mediated intestinal abnormalities on the development of cirrhosis-related renal dysfunction. Systemic and renal hemodynamics, intestinal dysbiosis [cirrhosis dysbiosis ratio (CDR) as marker of dysbiosis], and direct renal vasoconstrictive response (renal vascular resistance (RVR) and glomerular filtration rate (GFR)) to cumulative doses of TNFα were measured in bile duct ligated (BDL)-cirrhotic ascitic mice. In SIRT1IEC-KO-BDL-ascitic mice, the worsening of intestinal dysbiosis exacerbates intestinal inflammation/barrier dysfunction, the upregulation of the expressions of intestinal/renal TNFα-related pathogenic signals, higher TNFα-induced increase in RVR, and decrease in GFR in perfused kidney. In intestinal SIRT1 knockout groups, the positive correlations were identified between intestinal SIRT1 activity and CDR. Particularly, the negative correlations were identified between CDR and RVR, with the positive correlation between CDR and GFR. In mice with advanced cirrhosis, the expression of intestinal SIRT1 is involved in the linkage between intestinal dysbiosis and vasoconstriction/hypoperfusion-related renal dysfunction through the crosstalk between intestinal/renal TNFα-related pathogenic inflammatory signals.


Asunto(s)
Inflamación/metabolismo , Mucosa Intestinal/metabolismo , Riñón/anomalías , Cirrosis Hepática/metabolismo , Sirtuina 1/deficiencia , Factor de Necrosis Tumoral alfa/metabolismo , Anomalías Urogenitales/metabolismo , Animales , Microbioma Gastrointestinal/genética , Tasa de Filtración Glomerular/genética , Inflamación/genética , Inflamación/patología , Mucosa Intestinal/microbiología , Mucosa Intestinal/fisiopatología , Intestinos/microbiología , Intestinos/fisiopatología , Riñón/metabolismo , Riñón/fisiopatología , Cirrosis Hepática/genética , Cirrosis Hepática/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Sirtuina 1/genética , Sirtuina 1/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Anomalías Urogenitales/genética , Anomalías Urogenitales/fisiopatología , Resistencia Vascular/genética
19.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-33451043

RESUMEN

Our aim was to investigate the subset distribution and function of circulating monocytes, proinflammatory cytokine levels, gut barrier damage, and bacterial translocation in chronic spinal cord injury (SCI) patients. Thus, 56 SCI patients and 28 healthy donors were studied. The levels of circulating CD14+highCD16-, CD14+highCD16+, and CD14+lowCD16+ monocytes, membrane TLR2, TLR4, and TLR9, phagocytic activity, ROS generation, and intracytoplasmic TNF-α, IL-1, IL-6, and IL-10 after lipopolysaccharide (LPS) stimulation were analyzed by polychromatic flow cytometry. Serum TNF-α, IL-1, IL-6 and IL-10 levels were measured by Luminex and LPS-binding protein (LBP), intestinal fatty acid-binding protein (I-FABP) and zonulin by ELISA. SCI patients had normal monocyte counts and subset distribution. CD14+highCD16- and CD14+highCD16+ monocytes exhibited decreased TLR4, normal TLR2 and increased TLR9 expression. CD14+highCD16- monocytes had increased LPS-induced TNF-α but normal IL-1, IL-6, and IL-10 production. Monocytes exhibited defective phagocytosis but normal ROS production. Patients had enhanced serum TNF-α and IL-6 levels, normal IL-1 and IL-10 levels, and increased circulating LBP, I-FABP, and zonulin levels. Chronic SCI patients displayed impaired circulating monocyte function. These patients exhibited a systemic proinflammatory state characterized by enhanced serum TNF-α and IL-6 levels. These patients also had increased bacterial translocation and gut barrier damage.


Asunto(s)
Susceptibilidad a Enfermedades , Inflamación/complicaciones , Enfermedades Intestinales/complicaciones , Traumatismos de la Médula Espinal/etiología , Traumatismos de la Médula Espinal/metabolismo , Adulto , Biomarcadores , Estudios de Casos y Controles , Enfermedad Crónica , Citocinas/metabolismo , Femenino , Homeostasis , Humanos , Mediadores de Inflamación/metabolismo , Masculino , Monocitos/inmunología , Monocitos/metabolismo , Fagocitos/inmunología , Fagocitos/metabolismo , Fagocitosis , Índice de Severidad de la Enfermedad , Traumatismos de la Médula Espinal/patología , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven
20.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33498456

RESUMEN

The urgency of the search for inexpensive and effective drugs with localized action for the treatment of rheumatoid arthritis continues unabated. In this study, for the first time we investigated the Cytos-11 antisense oligonucleotide suppression of TNF-α gene expression in a rat model of rheumatoid arthritis induced by complete Freund's adjuvant. Cytos-11 has been shown to effectively reduce peripheral blood concentrations of TNF-α, reduce joint inflammation, and reduce pannus development. The results achieved following treatment with the antisense oligonucleotide Cytos-11 were similar to those of adalimumab (Humira®); they also compared favorably with those results, which provides evidence of the promise of drugs based on antisense technologies in the treatment of this disease.


Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Oligonucleótidos Antisentido/uso terapéutico , Factor de Necrosis Tumoral alfa/genética , Animales , Silenciador del Gen , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismo
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