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1.
Radiol Cardiothorac Imaging ; 6(3): e230252, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38842454

RESUMEN

Purpose To assess the correlation between noninvasive cardiac MRI-derived parameters with pressure-volume (PV) loop data and evaluate changes in left ventricular function after myocardial infarction (MI). Materials and Methods Sixteen adult female swine were induced with MI, with six swine used as controls and 10 receiving platelet-derived growth factor-AB (PDGF-AB). Load-independent measures of cardiac function, including slopes of end-systolic pressure-volume relationship (ESPVR) and preload recruitable stroke work (PRSW), were obtained on day 28 after MI. Cardiac MRI was performed on day 2 and day 28 after infarct. Global longitudinal strain (GLS) and global circumferential strain (GCS) were measured. Ventriculo-arterial coupling (VAC) was derived from PV loop and cardiac MRI data. Pearson correlation analysis was performed. Results GCS (r = 0.60, P = .01), left ventricular ejection fraction (LVEF) (r = 0.60, P = .01), and cardiac MRI-derived VAC (r = 0.61, P = .01) had a significant linear relationship with ESPVR. GCS (r = 0.75, P < .001) had the strongest significant linear relationship with PRSW, followed by LVEF (r = 0.67, P = .005) and cardiac MRI-derived VAC (r = 0.60, P = .01). GLS was not significantly correlated with ESPVR or PRSW. There was a linear correlation (r = 0.82, P < .001) between VAC derived from cardiac MRI and from PV loop data. GCS (-3.5% ± 2.3 vs 0.5% ± 1.4, P = .007) and cardiac MRI-derived VAC (-0.6 ± 0.6 vs 0.3 ± 0.3, P = .001) significantly improved in the animals treated with PDGF-AB 28 days after MI compared with controls. Conclusion Cardiac MRI-derived parameters of MI correlated with invasive PV measures, with GCS showing the strongest correlation. Cardiac MRI-derived measures also demonstrated utility in assessing therapeutic benefit using PDGF-AB. Keywords: Cardiac MRI, Myocardial Infarction, Pressure Volume Loop, Strain Imaging, Ventriculo-arterial Coupling Supplemental material is available for this article. © RSNA, 2024.


Asunto(s)
Modelos Animales de Enfermedad , Infarto del Miocardio , Animales , Femenino , Porcinos , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/fisiopatología , Imagen por Resonancia Magnética/métodos , Función Ventricular Izquierda/fisiología , Volumen Sistólico/fisiología , Daño por Reperfusión Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/diagnóstico por imagen , Imagen por Resonancia Cinemagnética/métodos
2.
Photodermatol Photoimmunol Photomed ; 40(4): e12978, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38845020

RESUMEN

BACKGROUND: Infections are complications in the wound healing process, and their treatment can lead to antibiotic overuse and bacterial resistance. Antimicrobial photodynamic therapy (aPDT) is used to treat infectious diseases caused by fungi, viruses, or bacteria. Methylene blue (MB) and its derivatives are commonly used dyes in antimicrobial photodynamic therapy (aPDT-MB). METHODS: This study is a PRISMA systematic review of animal models used to discuss the usefulness and therapeutic parameters of aPDT-MB or its derivatives for treating infected skin wounds. RESULTS: After an extensive literature review, 13 controlled trials totaling 261 animals were selected to evaluate skin infection by leishmaniasis and cutaneous bacterial and fungal infections. All studies found results favoring the use of aPDT-MB. Great variability in parameters was found for radiant exposure from 12 to 360 J/cm2, MB diluted in saline solution or distilled water, irradiation time from 40 to 3600 s, irradiance most commonly at a maximum of 100 mW/cm2, and wavelength used mainly in the 630-670 nm range. CONCLUSION: MB is a safe and promising agent used as a photosensitizer in aPDT for skin-infected lesions. There is great variability in the parameters found. Comparisons concerning concentration, irradiation time, and light intensity need to be performed.


Asunto(s)
Azul de Metileno , Fotoquimioterapia , Fármacos Fotosensibilizantes , Animales , Modelos Animales de Enfermedad , Azul de Metileno/farmacología , Azul de Metileno/uso terapéutico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico
3.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 36(5): 514-519, 2024 May.
Artículo en Chino | MEDLINE | ID: mdl-38845499

RESUMEN

OBJECTIVE: To investigate the effect of mild hypothermia on macrophage polarization in lipopolysaccharide (LPS)-induced acute lung injury (ALI) mice and to clarify its role in lung injury. METHODS: According to a random number table method, 18 male C57BL/6 mice were divided into sham operation group (Sham group), ALI normothermic model group (NT group) and ALI mild hypothermia treatment group (HT group), with 6 mice in each group. The ALI model in mice was established by the method of tracheal instillation of LPS, and temperature control was administered at 1 hour after surgery. The anus temperature in NT group was kept at 36-38?centigrade, while the anus temperature in HT group was kept at 32-34?centigrade. The target anus temperature in both groups were maintained for 6 hours and then slowly rewarmed to 36-38 centigrade. The Sham group was infused with an equal amount of physiological saline through the trachea without temperature control. After 24 hours of modeling, serum was collected and mice were sacrificed to obtain lung tissue. Pathological changes in lung tissue were observed under light microscopy and semi-quantitative lung injury score was performed. Enzyme linked immunosorbent assay (ELISA) was used to detect the serum levels of interleukins (IL-1ß, IL-10). Real-time quantitative polymerase chain reaction (RT-qPCR) was used to test the indicators of macrophage polarization, such as the mRNA expressions of CD86, IL-6, CD206 and arginase 1 (Arg1) in the lung tissue. The protein expression of M1 macrophage marker inducible nitric oxide synthase (iNOS) and M2 macrophage marker Arg1 were detected by Western blotting. RESULTS: Compared with the Sham group, the NT group appeared significant pulmonary hemorrhage and edema, thickened lung septum, inflammatory cell infiltration, and lung injury score was significantly increased; serum IL-1ß level was significantly elevated; IL-10 level was increased without statistical significance; the expressions of CD86 mRNA, IL-6 mRNA and iNOS protein were significantly elevated, and CD206 mRNA was significantly decreased; the mRNA and protein expressions of Arg1 decreased, but there were no significant differences. Compared with the NT group, the pathological injury of lung tissue in HT group was significantly reduced, and the lung injury score was significantly decreased (4.78±0.96 vs. 8.56±1.98, P < 0.01); serum IL-1ß level was decreased (ng/L: 13.52±1.95 vs. 27.18±3.87, P < 0.01), and IL-10 level was significantly increased (ng/L: 42.59±15.79 vs. 14.62±4.47, P < 0.01); IL-6 mRNA expression was decreased in lung tissue (2-ΔΔCt: 3.37±0.92 vs. 10.04±0.91, P < 0.05), the expression of M1 macrophage markers CD86 mRNA and iNOS protein were significantly decreased [CD86 mRNA (2-ΔΔCt): 0.52±0.16 vs. 1.95±0.33, iNOS protein (iNOS/ß-actin): 0.57±0.19 vs. 1.11±0.27, both P < 0.05], the expression of M2 macrophage markers CD206 mRNA, Arg1 mRNA and Arg1 protein were significantly increased [CD206 mRNA (2-ΔΔCt): 3.99±0.17 vs. 0.34±0.17, Arg1 mRNA (2-ΔΔCt): 2.33±0.73 vs. 0.94±0.23, Arg1 protein (Arg1/ß-actin): 0.96±0.09 vs. 0.31±0.11, all P < 0.05]. CONCLUSIONS: Mild hypothermia can alleviate the inflammatory response and protect lung tissue in ALI mice, which may be related to the inhibition of M1 macrophage polarization and promotion of M2 macrophage polarization.


Asunto(s)
Lesión Pulmonar Aguda , Lipopolisacáridos , Macrófagos , Ratones Endogámicos C57BL , Animales , Lesión Pulmonar Aguda/terapia , Masculino , Ratones , Macrófagos/metabolismo , Lipopolisacáridos/efectos adversos , Óxido Nítrico Sintasa de Tipo II/metabolismo , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Hipotermia Inducida , Interleucina-1beta/metabolismo , Modelos Animales de Enfermedad
4.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 36(5): 491-495, 2024 May.
Artículo en Chino | MEDLINE | ID: mdl-38845495

RESUMEN

OBJECTIVE: To investigate the effect of nuclear factor E2-related factor 2 (Nrf2) protein on ferroptosis in mice with sepsis-associated liver injury (SALI). METHODS: he male Sprague-Dawley (SD) mice were divided into 6 groups according to the random number table method, with 6 mice in each group. The SALI model of mice was established by cecal ligation and puncture (CLP), and the Sham group was only treated with laparotomy. CLP+Fer-1 group, CLP+Erastin group, CLP+ML385 group and CLP+Curcumin group were intraperitoneally injected with iron death inhibitor Ferrostatin-1 (Fer-1) 10 mg×kg-1×d-1, iron death activator Erastin 20 mg×kg-1×d-1, Nrf2 inhibitor ML385 30 mg×kg-1×d-1 and Nrf2 activator Curcumin 100 mg×kg-1×d-1 after CLP, respectively; Sham group and CLP group were given normal saline 10 mg×kg-1×d-1, each group was administered continuously for 10 days. Ten days after operation, the serum and liver tissues of mice were collected to detect the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, and the levels of malondialdehyde (MDA), glutathione (GSH) and Fe2+; in liver homogenate. The pathological changes of liver tissue were observed under light microscope after hematoxylin-eosin (HE) staining. The shape and length of mitochondria in liver cells were observed under transmission electron microscope. The protein expressions of Nrf2, glutathione peroxidase 4 (GPX4) and prostaglandin-endoperoxide synthase 2 (PTGS2) in liver tissue were detected by Western blotting. RESULTS: Compared with Sham group, the serum levels of ALT and AST in the CLP group were significantly increased; histologically, the hepatic cord was disordered, the cells were swollen and necrotic, and the length of mitochondria was significantly shortened; the levels of MDA and Fe2+ in liver tissue increased significantly, and the content of GSH decreased significantly; the protein expressions of Nrf2 and GPX4 in liver tissue decreased, and the protein expression of PTGS2 increased significantly. Compared with CLP group, the serum levels of ALT and AST in CLP+Fer-1 group and CLP+Curcumin group were significantly decreased [ALT (U/L): 80.65±19.44, 103.45±20.52 vs. 283.50±37.12, AST (U/L): 103.33±11.90, 127.33±15.79 vs. 288.67±36.82, all P < 0.05]; microscopically, the hepatic cord was irregular, the cells were slightly swollen, and the mitochondrial length was significantly increased (µm: 1.42±0.09, 1.43±0.21 vs. 1.07±0.25, both P < 0.05); the levels of MDA and Fe2+; in liver tissue decreased significantly, and the content of GSH increased significantly [MDA (mol/g): 0.87±0.23, 1.85±0.43 vs. 4.47±0.95, Fe2+ (µg/g): 63.80±7.15, 67.48±6.28 vs. 134.52±14.32, GSH (mol/g): 1.95±0.29, 1.95±0.45 vs. 0.55±0.29, all P < 0.05]; the protein expressions of Nrf2 and GPX4 in liver tissue were significantly increased, and the protein expression of PTGS2 was significantly decreased (Nrf2/GAPDH: 1.80±0.28, 2.10±0.43 vs. 0.70±0.24, GPX4/GAPDH: 0.80±0.06, 0.93±0.07 vs. 0.48±0.02, PTGS2/GAPDH: 0.76±0.05, 0.84±0.01 vs. 1.02±0.09, all P < 0.05). However, the results of the above indexes in the CLP+Erastin group and CLP+ML385 group were opposite, and the serum levels of ALT and AST were significantly increased [ALT (U/L): 344.52±40.79, 321.70±21.10 vs. 283.50±37.12, AST (U/L): 333.50±27.90, 333.00±16.67 vs. 288.67±36.82, all P < 0.05]; microscopically, the arrangement of hepatic cords was disordered, the cells were obviously swollen and necrotic, and the length of mitochondria was significantly shortened (µm: 0.78±0.13, 0.67±0.07 vs. 1.07±0.25, both P < 0.05); the levels of MDA and Fe2+ in liver tissue increased significantly, and the content of GSH decreased significantly [MDA (mol/g): 5.92±1.06, 5.62±0.56 vs. 4.47±0.95, Fe2+ (µg/g): 151.40±8.03, 151.88±8.68 vs. 134.52±14.32, GSH (mol/g): 0.25±0.08, 0.23±0.11 vs. 0.55±0.29, all P < 0.05]; the protein expressions of Nrf2 and GPX4 in liver tissue were significantly decreased, and the protein expression of PTGS2 was significantly increased (Nrf2/GAPDH: 0.46±0.09, 0.46±0.11 vs. 0.70±0.24, GPX4/GAPDH: 0.34±0.05, 0.40±0.01 vs. 0.48±0.02, PTGS2/GAPDH: 1.24±0.13, 1.16±0.11 vs. 1.02±0.09, all P < 0.05). CONCLUSIONS: CLP-induced SALI can lead to ferroptosis in mice hepatocytes, and Nrf2 protein in liver tissue can mediate SALI by regulating ferroptosis.


Asunto(s)
Ferroptosis , Factor 2 Relacionado con NF-E2 , Sepsis , Animales , Masculino , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Sepsis/metabolismo , Sepsis/complicaciones , Modelos Animales de Enfermedad , Hígado/metabolismo , Ratas Sprague-Dawley , Hepatopatías/etiología , Hepatopatías/metabolismo , Glutatión Peroxidasa/metabolismo , Malondialdehído/metabolismo , Curcumina/farmacología , Fenilendiaminas/farmacología , Ciclohexilaminas
5.
Fa Yi Xue Za Zhi ; 40(2): 172-178, 2024 Apr 25.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-38847033

RESUMEN

OBJECTIVES: To explore the biomarkers and potential mechanisms of chronic restraint stress-induced myocardial injury in hyperlipidemia ApoE-/- mice. METHODS: The hyperlipidemia combined with the chronic stress model was established by restraining the ApoE-/- mice. Proteomics and bioinformatics techniques were used to describe the characteristic molecular changes and related regulatory mechanisms of chronic stress-induced myocardial injury in hyperlipidemia mice and to explore potential diagnostic biomarkers. RESULTS: Proteomic analysis showed that there were 43 significantly up-regulated and 58 significantly down-regulated differentially expressed proteins in hyperlipidemia combined with the restraint stress group compared with the hyperlipidemia group. Among them, GBP2, TAOK3, TFR1 and UCP1 were biomarkers with great diagnostic potential. KEGG pathway enrichment analysis indicated that ferroptosis was a significant pathway that accelerated the myocardial injury in hyperlipidemia combined with restraint stress-induced model. The mmu_circ_0001567/miR-7a/Tfr-1 and mmu_circ_0001042/miR-7a/Tfr-1 might be important circRNA-miRNA-mRNA regulatory networks related to ferroptosis in this model. CONCLUSIONS: Chronic restraint stress may aggravate myocardial injury in hyperlipidemia mice via ferroptosis. Four potential biomarkers are selected for myocardial injury diagnosis, providing a new direction for sudden cardiac death (SCD) caused by hyperlipidemia combined with the restraint stress.


Asunto(s)
Apolipoproteínas E , Biomarcadores , Modelos Animales de Enfermedad , Hiperlipidemias , Restricción Física , Animales , Hiperlipidemias/metabolismo , Hiperlipidemias/complicaciones , Ratones , Biomarcadores/metabolismo , Apolipoproteínas E/genética , Proteómica/métodos , Estrés Psicológico/complicaciones , MicroARNs/metabolismo , MicroARNs/genética , Ferroptosis , Masculino , Miocardio/metabolismo , Miocardio/patología , Ratones Noqueados , Proteína Desacopladora 1/metabolismo , Biología Computacional
6.
Fa Yi Xue Za Zhi ; 40(2): 179-185, 2024 Apr 25.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-38847034

RESUMEN

OBJECTIVES: To detect the expression changes of interleukin-10 (IL-10) and transforming growth factor-ß1 (TGF-ß1) during the development of deep vein thrombosis in mice, and to explore the application value of them in thrombus age estimation. METHODS: The mice in the experimental group were subjected to ligation of inferior vena cava. The mice were sacrificed by excessive anesthesia at 1 d, 3 d, 5 d, 7 d, 10 d, 14 d and 21 d after ligation, respectively. The inferior vena cava segment with thrombosis was extracted below the ligation point. The mice in the control group were not ligated, and the inferior vena cava segment at the same position as the experimental group was extracted. The expression changes of IL-10 and TGF-ß1 were detected by immunohistochemistry (IHC), Western blotting and real-time qPCR. RESULTS: IHC results revealed that IL-10 was mainly expressed in monocytes in thrombosis and TGF-ß1 was mainly expressed in monocytes and fibroblast-like cells in thrombosis. Western blotting and real-time qPCR showed that the relative expression levels of IL-10 and TGF-ß1 in each experimental group were higher than those in the control group. The mRNA and protein levels of IL-10 reached the peak at 7 d and 10 d after ligation, respectively. The mRNA expression level at 7 d after ligation was 4.72±0.15 times that of the control group, and the protein expression level at 10 d after ligation was 7.15±0.28 times that of the control group. The mRNA and protein levels of TGF-ß1 reached the peak at 10 d and 14 d after ligation, respectively. The mRNA expression level at 10 d after ligation was 2.58±0.14 times that of the control group, and the protein expression level at 14 d after ligation was 4.34±0.19 times that of the control group. CONCLUSIONS: The expressions of IL-10 and TGF-ß1 during the evolution of deep vein thrombosis present time-dependent sequential changes, and the expression levels of IL-10 and TGF-ß1 can provide a reference basis for thrombus age estimation.


Asunto(s)
Modelos Animales de Enfermedad , Inmunohistoquímica , Interleucina-10 , Factor de Crecimiento Transformador beta1 , Vena Cava Inferior , Trombosis de la Vena , Animales , Interleucina-10/metabolismo , Interleucina-10/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Trombosis de la Vena/metabolismo , Trombosis de la Vena/etiología , Ratones , Vena Cava Inferior/metabolismo , Vena Cava Inferior/patología , Masculino , Factores de Tiempo , Monocitos/metabolismo , Western Blotting , ARN Mensajero/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Ligadura , Fibroblastos/metabolismo
7.
Artículo en Inglés | MEDLINE | ID: mdl-38847555

RESUMEN

This is an animal model study to investigate changes in hemostasis during endotoxemic shock and to determine whether the combination of inhaled nitric oxide (iNO) + intravenous hydrocortisone had an effect on clot formation and fibrinolysis. iNO selectively decreases pulmonary artery pressure, without affecting cardiac index or systemic vascular resistance; however, the results of studies on the possible consequences of iNO administration on coagulation are inconsistent and require further research. Thirty-four piglets were included. Administering endotoxin caused severe hypodynamic shock. Half of the animals received iNO (30 ppm) + hydrocortisone, starting 3 h after endotoxin infusion and continuing to the end of the study. All animals developed coagulation disorders, manifested by a tendency to hypocoagulation; at the same time, fibrinolysis was impaired. Coagulation and fibrinolysis disorders persisted after endotoxin infusion was discontinued, with worse severity in the animals that died before the study was terminated. Administering iNO + hydrocortisone did not cause further changes in coagulation and fibrinolysis parameters, either during or after the endotoxin challenge, suggesting that potential therapeutic interventions with iNO to lower pulmonary arterial pressure will not affect hemostasis.


Asunto(s)
Coagulación Sanguínea , Modelos Animales de Enfermedad , Fibrinólisis , Hidrocortisona , Óxido Nítrico , Choque Séptico , Tromboelastografía , Animales , Hidrocortisona/administración & dosificación , Hidrocortisona/uso terapéutico , Hidrocortisona/farmacología , Óxido Nítrico/metabolismo , Fibrinólisis/efectos de los fármacos , Porcinos , Coagulación Sanguínea/efectos de los fármacos , Choque Séptico/tratamiento farmacológico , Administración por Inhalación , Endotoxinas/administración & dosificación , Humanos , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico
8.
Arch Dermatol Res ; 316(7): 338, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38847916

RESUMEN

Diabetic foot ulcer (DFU) is a predominant complication of diabetes mellitus with poor prognosis accompanied by high amputation and mortality rates. Dang-Gui-Si-Ni decoction (DSD), as a classic formula with a long history in China, has been found to improve DFU symptoms. However, mechanism of DSD for DFU therapy remains unclear with no systematic elaboration. In vivo, following establishment of DFU rat model, DSD intervention with low, medium and high doses was done, with Metformin (DM) as a positive control group. With wound healing detection, pathological changes by HE staining, inflammatory factor expression by ELISA and qRT-PCR, oxidative stress levels by ELISA, and AGEs/RAGE/TGF-ß/Smad2/3 expression by Western blot were performed. In vitro, intervention with LY2109761 (TGF-ß pathway inhibitor) based on DSD treatment in human dermal fibroblast-adult (HDF-a) cells was made. Cell viability by CCK8, migration ability by cell scratch, apoptosis by flow cytometry, and AGEs/RAGE/TGF-ß/Smad2/3 expression by Western blot were measured. DFU rats exhibited elevated AGEs/RAGE expression, whereas decreased TGF-ß1 and p-Smad3/Smad3 protein expression, accompanied by higher IL-1ß, IL-6, TNF-α levels, and oxidative stress. DSD intervention reversed above effects. Glucose induction caused lower cell viability, migration, TGF-ß1 and p-Smad3/Smad3 protein expression, with increased apoptosis and AGEs/RAGE expression in HDF-a cells. These effects were reversed after DSD intervention, and further LY2109761 intervention inhibited DSD effects in cells. DSD intervention may facilitate wound healing in DFU by regulating expression of AGEs/RAGE/TGF-ß/Smad2/3, providing scientific experimental evidence for DSD clinical application for DFU therapy.


Asunto(s)
Pie Diabético , Medicamentos Herbarios Chinos , Productos Finales de Glicación Avanzada , Proteína Smad2 , Proteína smad3 , Cicatrización de Heridas , Pie Diabético/tratamiento farmacológico , Pie Diabético/metabolismo , Pie Diabético/patología , Animales , Cicatrización de Heridas/efectos de los fármacos , Ratas , Medicamentos Herbarios Chinos/farmacología , Proteína Smad2/metabolismo , Humanos , Proteína smad3/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Masculino , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Ratas Sprague-Dawley , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos
9.
Technol Cancer Res Treat ; 23: 15330338241258570, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38832431

RESUMEN

Background: Colon adenocarcinoma (COAD) has increasing incidence and is one of the most common malignant tumors. The mitochondria involved in cell energy metabolism, oxygen free radical generation, and cell apoptosis play important roles in tumorigenesis and progression. The relationship between mitochondrial genes and COAD remains largely unknown. Methods: COAD data including 512 samples were set out from the UCSC Xena database. The nuclear mitochondrial-related genes (NMRGs)-related risk prognostic model and prognostic nomogram were constructed, and NMRGs-related gene mutation and the immune environment were analyzed using bioinformatics methods. Then, a liver metastasis model of colorectal cancer was constructed and protein expression was detected using Western blot assay. Results: A prognostic model for COAD was constructed. Comparing the prognostic model dataset and the validation dataset showed considerable correlation in both risk grouping and prognosis. Based on the risk score (RS) model, the samples of the prognostic dataset were divided into high risk group and low risk group. Moreover, pathologic N and T stage and tumor recurrence in the two risk groups were significantly different. The four prognostic factors, including age and pathologic T stage in the nomogram survival model also showed excellent predictive performance. An optimal combination of nine differentially expressed NMRGs was finally obtained, including LARS2, PARS2, ETHE1, LRPPRC, TMEM70, AARS2, ACAD9, VARS2, and ATP8A2. The high-RS group had more inflamed immune features, including T and CD4+ memory cell activation. Besides, mitochondria-associated LRPPRC and LARS2 expression levels were increased in vivo xenograft construction and liver metastases assays. Conclusion: This study established a comprehensive prognostic model for COAD, incorporating nine genes associated with nuclear-mitochondrial functions. This model demonstrates superior predictive performance across four prognostic factors: age, pathological T stage, tumor recurrence, and overall prognosis. It is anticipated to be an effective model for enhancing the prognosis and treatment of COAD.


Asunto(s)
Adenocarcinoma , Biomarcadores de Tumor , Neoplasias del Colon , Regulación Neoplásica de la Expresión Génica , Humanos , Pronóstico , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias del Colon/mortalidad , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/secundario , Ratones , Animales , Biomarcadores de Tumor/genética , Nomogramas , Biología Computacional/métodos , Genes Mitocondriales , Modelos Animales de Enfermedad , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/patología , Perfilación de la Expresión Génica , Estadificación de Neoplasias , Masculino , Bases de Datos Genéticas , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Femenino
10.
Sci Rep ; 14(1): 12874, 2024 06 05.
Artículo en Inglés | MEDLINE | ID: mdl-38834629

RESUMEN

Atopic dermatitis is a chronic complex inflammatory skin disorder that requires sustainable treatment methods due to the limited efficacy of conventional therapies. Sargassum serratifolium, an algal species with diverse bioactive substances, is investigated in this study for its potential benefits as a therapeutic agent for atopic dermatitis. RNA sequencing of LPS-stimulated macrophages treated with ethanolic extract of Sargassum serratifolium (ESS) revealed its ability to inhibit a broad range of inflammation-related signaling, which was proven in RAW 264.7 and HaCaT cells. In DNCB-induced BALB/c or HR-1 mice, ESS treatment improved symptoms of atopic dermatitis within the skin, along with histological improvements such as reduced epidermal thickness and infiltration of mast cells. ESS showed a tendency to improve serum IgE levels and inflammation-related cytokine changes, while also improving the mRNA expression levels of Chi3l3, Ccr1, and Fcεr1a genes in the skin. Additionally, ESS compounds (sargachromanol (SCM), sargaquinoic acid (SQA), and sargahydroquinoic acid (SHQA)) mitigated inflammatory responses in LPS-treated RAW264.7 macrophages. In summary, ESS has an anti-inflammatory effect and improves atopic dermatitis, ESS may be applied as a therapeutics for atopic dermatitis.


Asunto(s)
Dermatitis Atópica , Dinitroclorobenceno , Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Sargassum , Animales , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/patología , Sargassum/química , Ratones , Células RAW 264.7 , Humanos , Etanol/química , Extractos Vegetales/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Piel/efectos de los fármacos , Piel/patología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Inmunoglobulina E/sangre , Citocinas/metabolismo
11.
Sci Rep ; 14(1): 12797, 2024 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-38834773

RESUMEN

The systemic inflammatory response syndrome can occur due to an inflammatory reaction to the release of cytokines, and it has been linked to the circulation of pro- and anti-inflammatory cytokines. The cardiopulmonary bypass (CPB) system is known to activate numerous inflammatory pathways. Applying CPB in large animals for an extended period may be useful as a controlled experimental model for systemic inflammatory responses. The authors hypothesized that 0.2 mg/kg NuSepin® would inhibit CBP-induced proinflammatory cytokine release, and attenuate CPB-induced vasoplegia. CPB was maintained for 2 h in 8 male Yorkshire pigs. Ten ml of saline was administered intravenously to the control group, while the study group received 10 ml of NuSepin® (0.2 mg/kg), before start of CPB. Blood samples were collected at four different time points to evaluating the level of cytokine (TNF-α, IL-1ß, IL-6, IL-8) release during and after CBP. All vital signals were recorded as continuous waveforms using the vital recorder®. Our study demonstrated that IL-6 increased in both groups during CPB remained unchanged. However, in the Nusepin group, IL-6 levels rapidly decreased when CPB was stopped and the proinflammatory reaction subsided. Furthermore, the dose of norepinephrine required to maintain a mean pressure of 60 mmHg was also lower in the Nusepin group.


Asunto(s)
Puente Cardiopulmonar , Citocinas , Animales , Puente Cardiopulmonar/efectos adversos , Porcinos , Citocinas/metabolismo , Citocinas/sangre , Proyectos Piloto , Masculino , Inflamasomas/metabolismo , Inflamasomas/antagonistas & inhibidores , Modelos Animales de Enfermedad , Administración Intravenosa , Vasoplejía/tratamiento farmacológico , Vasoplejía/etiología
12.
Sci Rep ; 14(1): 12826, 2024 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-38834813

RESUMEN

Lamin A/C gene (LMNA) mutations contribute to severe striated muscle laminopathies, affecting cardiac and skeletal muscles, with limited treatment options. In this study, we delve into the investigations of five distinct LMNA mutations, including three novel variants and two pathogenic variants identified in patients with muscular laminopathy. Our approach employs zebrafish models to comprehensively study these variants. Transgenic zebrafish expressing wild-type LMNA and each mutation undergo extensive morphological profiling, swimming behavior assessments, muscle endurance evaluations, heartbeat measurement, and histopathological analysis of skeletal muscles. Additionally, these models serve as platform for focused drug screening. We explore the transcriptomic landscape through qPCR and RNAseq to unveil altered gene expression profiles in muscle tissues. Larvae of LMNA(L35P), LMNA(E358K), and LMNA(R453W) transgenic fish exhibit reduced swim speed compared to LMNA(WT) measured by DanioVision. All LMNA transgenic adult fish exhibit reduced swim speed compared to LMNA(WT) in T-maze. Moreover, all LMNA transgenic adult fish, except LMNA(E358K), display weaker muscle endurance than LMNA(WT) measured by swimming tunnel. Histochemical staining reveals decreased fiber size in all LMNA mutations transgenic fish, excluding LMNA(WT) fish. Interestingly, LMNA(A539V) and LMNA(E358K) exhibited elevated heartbeats. We recognize potential limitations with transgene overexpression and conducted association calculations to explore its effects on zebrafish phenotypes. Our results suggest lamin A/C overexpression may not directly impact mutant phenotypes, such as impaired swim speed, increased heart rates, or decreased muscle fiber diameter. Utilizing LMNA zebrafish models for drug screening, we identify L-carnitine treatment rescuing muscle endurance in LMNA(L35P) and creatine treatment reversing muscle endurance in LMNA(R453W) zebrafish models. Creatine activates AMPK and mTOR pathways, improving muscle endurance and swim speed in LMNA(R453W) fish. Transcriptomic profiling reveals upstream regulators and affected genes contributing to motor dysfunction, cardiac anomalies, and ion flux dysregulation in LMNA mutant transgenic fish. These findings faithfully mimic clinical manifestations of muscular laminopathies, including dysmorphism, early mortality, decreased fiber size, and muscle dysfunction in zebrafish. Furthermore, our drug screening results suggest L-carnitine and creatine treatments as potential rescuers of muscle endurance in LMNA(L35P) and LMNA(R453W) zebrafish models. Our study offers valuable insights into the future development of potential treatments for LMNA-related muscular laminopathy.


Asunto(s)
Animales Modificados Genéticamente , Carnitina , Creatina , Lamina Tipo A , Músculo Esquelético , Mutación , Pez Cebra , Animales , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/efectos de los fármacos , Creatina/metabolismo , Carnitina/metabolismo , Modelos Animales de Enfermedad , Laminopatías/genética , Laminopatías/metabolismo , Natación , Transcriptoma , Humanos
13.
Stem Cell Res Ther ; 15(1): 160, 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38835014

RESUMEN

BACKGROUND: Metabolic syndrome (MetS) is a significant epidemiological problem worldwide. It is a pre-morbid, chronic and low-grade inflammatory disorder that precedes many chronic diseases. Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) could be used to treat MetS because they express high regenerative capacity, strong immunomodulatory properties and allogeneic biocompatibility. This study aims to investigate WJ-MSCs as a therapy against MetS in a rat model. METHODS: Twenty-four animals were fed with high-fat high-fructose (HFHF) diet ad libitum. After 16 weeks, the animals were randomised into treatment groups (n = 8/group) and received a single intravenous administration of vehicle, that is, 3 × 106 cells/kg or 10 × 106 cells/kg of WJ-MSCs. A healthy animal group (n = 6) fed with a normal diet received the same vehicle as the control (CTRL). All animals were periodically assessed (every 4 weeks) for physical measurements, serum biochemistry, glucose tolerance test, cardiovascular function test and whole-body composition. Post-euthanasia, organs were weighed and processed for histopathology. Serum was collected for C-reactive protein and inflammatory cytokine assay. RESULTS: The results between HFHF-treated groups and healthy or HFHF-CTRL did not achieve statistical significance (α = 0.05). The effects of WJ-MSCs were masked by the manifestation of different disease subclusters and continuous supplementation of HFHF diet. Based on secondary analysis, WJ-MSCs had major implications in improving cardiopulmonary morbidities. The lungs, liver and heart show significantly better histopathology in the WJ-MSC-treated groups than in the untreated CTRL group. The cells produced a dose-dependent effect (high dose lasted until week 8) in preventing further metabolic decay in MetS animals. CONCLUSIONS: The establishment of safety and therapeutic proof-of-concept encourages further studies by improving the current therapeutic model.


Asunto(s)
Modelos Animales de Enfermedad , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Síndrome Metabólico , Gelatina de Wharton , Animales , Síndrome Metabólico/terapia , Síndrome Metabólico/patología , Síndrome Metabólico/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/citología , Ratas , Gelatina de Wharton/citología , Trasplante de Células Madre Mesenquimatosas/métodos , Masculino , Inyecciones Intravenosas , Humanos , Dieta Alta en Grasa/efectos adversos
14.
J Neuroinflammation ; 21(1): 147, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38835057

RESUMEN

BACKGROUND: The gut microbiota plays a critical role in regulating brain function through the microbiome-gut-brain axis (MGBA). Dysbiosis of the gut microbiota is associated with neurological impairment in Traumatic brain injury (TBI) patients. Our previous study found that TBI results in a decrease in the abundance of Prevotella copri (P. copri). P. copri has been shown to have antioxidant effects in various diseases. Meanwhile, guanosine (GUO) is a metabolite of intestinal microbiota that can alleviate oxidative stress after TBI by activating the PI3K/Akt pathway. In this study, we investigated the effect of P. copri transplantation on TBI and its relationship with GUO-PI3K/Akt pathway. METHODS: In this study, a controlled cortical impact (CCI) model was used to induce TBI in adult male C57BL/6J mice. Subsequently, P. copri was transplanted by intragastric gavage for 7 consecutive days. To investigate the effect of the GUO-PI3K/Akt pathway in P. copri transplantation therapy, guanosine (GUO) was administered 2 h after TBI for 7 consecutive days, and PI3K inhibitor (LY294002) was administered 30 min before TBI. Various techniques were used to assess the effects of these interventions, including quantitative PCR, neurological behavior tests, metabolite analysis, ELISA, Western blot analysis, immunofluorescence, Evans blue assays, transmission electron microscopy, FITC-dextran permeability assay, gastrointestinal transit assessment, and 16 S rDNA sequencing. RESULTS: P. copri abundance was significantly reduced after TBI. P. copri transplantation alleviated motor and cognitive deficits tested by the NSS, Morris's water maze and open field test. P. copri transplantation attenuated oxidative stress and blood-brain barrier damage and reduced neuronal apoptosis after TBI. In addition, P. copri transplantation resulted in the reshaping of the intestinal flora, improved gastrointestinal motility and intestinal permeability. Metabolomics and ELISA analysis revealed a significant increase in GUO levels in feces, serum and injured brain after P. copri transplantation. Furthermore, the expression of p-PI3K and p-Akt was found to be increased after P. copri transplantation and GUO treatment. Notably, PI3K inhibitor LY294002 treatment attenuated the observed improvements. CONCLUSIONS: We demonstrate for the first time that P. copri transplantation can improve GI functions and alter gut microbiota dysbiosis after TBI. Additionally, P. copri transplantation can ameliorate neurological deficits, possibly via the GUO-PI3K/Akt signaling pathway after TBI.


Asunto(s)
Lesiones Traumáticas del Encéfalo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Animales , Ratones , Masculino , Rehabilitación Neurológica/métodos , Prevotella , Microbioma Gastrointestinal/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo
15.
Parasit Vectors ; 17(1): 247, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38835064

RESUMEN

BACKGROUND: The interplay between Toxoplasma gondii infection and tumor development is intriguing and not yet fully understood. Some studies showed that T. gondii reversed tumor immune suppression, while some reported the opposite, stating that T. gondii infection promoted tumor growth. METHODS: We created three mouse models to investigate the interplay between T. gondii and tumor. Model I aimed to study the effect of tumor growth on T. gondii infection by measuring cyst number and size. Models II and III were used to investigate the effect of different stages of T. gondii infection on tumor development via flow cytometry and bioluminescent imaging. Mouse strains (Kunming, BALB/c, and C57BL/6J) with varying susceptibilities to tumors were used in the study. RESULTS: The size and number of brain cysts in the tumor-infected group were significantly higher, indicating that tumor presence promotes T. gondii growth in the brain. Acute T. gondii infection, before or after tumor cell introduction, decreased tumor growth manifested by reduced bioluminescent signal and tumor size and weight. In the tumor microenvironment, CD4+ and CD8+ T cell number, including their subpopulations (cytotoxic CD8+ T cells and Th1 cells) had a time-dependent increase in the group with acute T. gondii infection compared with the group without infection. However, in the peripheral blood, the increase of T cells, including cytotoxic CD8+ T cells and Th1 cells, persisted 25 days after Lewis lung carcinoma (LLC) cell injection in the group with acute T. gondii. Chronic T. gondii infection enhanced tumor growth as reflected by increase in tumor size and weight. The LLC group with chronic T. gondii infection exhibited decreased percentages of cytotoxic CD8+ T cells and Th1 cells 25 days post-LLC injection as compared with the LLC group without T. gondii infection. At week 4 post-LLC injection, chronic T. gondii infection increased tumor formation rate [odds ratio (OR) 1.71] in both KM and BALB/c mice. CONCLUSIONS: Our research elucidates the dynamics between T. gondii infection and tumorigenesis. Tumor-induced immune suppression promoted T. gondii replication in the brain. Acute and chronic T. gondii infection had opposing effects on tumor development.


Asunto(s)
Modelos Animales de Enfermedad , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Toxoplasma , Animales , Ratones , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Toxoplasmosis/parasitología , Femenino , Linfocitos T CD8-positivos/inmunología , Encéfalo/parasitología , Encéfalo/patología , Enfermedad Crónica , Microambiente Tumoral , Neoplasias/parasitología , Enfermedad Aguda
16.
Parasites Hosts Dis ; 62(2): 243-250, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38835265

RESUMEN

We investigated organ specific Toxocara canis larval migration in mice infected with T. canis larvae. We observed the worm burden and systemic immune responses. Three groups of BALB/c mice (n=5 each) were orally administered 1,000 T. canis 2nd stage larvae to induce larva migrans. Mice were sacrificed at 1, 3, and 5 weeks post-infection. Liver, lung, brain, and eye tissues were collected. Tissue from 2 mice per group was digested for larval count, while the remaining 3 mice underwent histological analysis. Blood hematology and serology were evaluated and compared to that in a control uninfected group (n=5) to assess the immune response. Cytokine levels in bronchoalveolar lavage (BAL) fluid were also analyzed. We found that, 1 week post-infection, the mean parasite load in the liver (72±7.1), brain (31±4.2), lungs (20±5.7), and eyes (2±0) peaked and stayed constant until the 3 weeks. By 5-week post-infection, the worm burden in the liver and lungs significantly decreased to 10±4.2 and 9±5.7, respectively, while they remained relatively stable in the brain and eyes (18±4.2 and 1±0, respectively). Interestingly, ocular larvae resided in all retinal layers, without notable inflammation in outer retina. Mice infected with T. canis exhibited elevated levels of neutrophils, monocytes, eosinophils, and immunoglobulin E. At 5 weeks post-infection, interleukin (IL)-5 and IL-13 levels were elevated in BAL fluid. Whereas IL-4, IL-10, IL-17, and interferon-γ levels in BAL fluid were similar to that in controls. Our findings demonstrate that a small portion of T. canis larvae migrate to the eyes and brain within the first week of infection. Minimal tissue inflammation was observed, probably due to increase of anti-inflammatory cytokines. This study contributes to our understanding of the histological and immunological responses to T. canis infection in mice, which may have implications to further understand human toxocariasis.


Asunto(s)
Encéfalo , Citocinas , Larva , Hígado , Pulmón , Ratones Endogámicos BALB C , Toxocara canis , Toxocariasis , Animales , Toxocara canis/inmunología , Toxocariasis/inmunología , Toxocariasis/patología , Toxocariasis/parasitología , Larva/inmunología , Ratones , Citocinas/metabolismo , Pulmón/parasitología , Pulmón/inmunología , Pulmón/patología , Hígado/parasitología , Hígado/patología , Hígado/inmunología , Encéfalo/parasitología , Encéfalo/inmunología , Encéfalo/patología , Líquido del Lavado Bronquioalveolar/inmunología , Líquido del Lavado Bronquioalveolar/parasitología , Femenino , Carga de Parásitos , Ojo/parasitología , Ojo/inmunología , Ojo/patología , Modelos Animales de Enfermedad
17.
Front Immunol ; 15: 1397579, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38835755

RESUMEN

Background: Yersinia pestis is the etiological agent of plague, which can manifest as bubonic, septicemic, and/or pneumonic disease. Plague is a severe and rapidly progressing illness that can only be successfully treated with antibiotics initiated early after infection. There are no FDA-approved vaccines for plague, and some vaccine candidates may be less effective against pneumonic plague than bubonic plague. Y. pestis is not known to impact males and females differently in mechanisms of pathogenesis or severity of infection. However, one previous study reported sex-biased vaccine effectiveness after intranasal Y. pestis challenge. As part of developing a safe and effective vaccine, it is essential that potential sex differences are characterized. Methods: In this study we evaluated novel vaccines in male and female BALB/c mice using a heterologous prime-boost approach and monitored survival, bacterial load in organs, and immunological correlates. Our vaccine strategy consisted of two subcutaneous immunizations, followed by challenge with aerosolized virulent nonencapsulated Y. pestis. Mice were immunized with a combination of live Y. pestis pgm- pPst-Δcaf1, live Y. pestis pgm- pPst-Δcaf1/ΔyopD, or recombinant F1-V (rF1-V) combined with adjuvants. Results: The most effective vaccine regimen was initial priming with rF1-V, followed by boost with either of the live attenuated strains. However, this and other strategies were more protective in female mice. Males had higher bacterial burden and differing patterns of cytokine expression and serum antibody titers. Male mice did not demonstrate synergy between vaccination and antibiotic treatment as repeatedly observed in female mice. Conclusions: This study provides new knowledge about heterologous vaccine strategies, sex differences in plague-vaccine efficacy, and the immunological factors that differ between male and female mice.


Asunto(s)
Ratones Endogámicos BALB C , Vacuna contra la Peste , Peste , Yersinia pestis , Animales , Femenino , Peste/prevención & control , Peste/inmunología , Masculino , Yersinia pestis/inmunología , Vacuna contra la Peste/inmunología , Vacuna contra la Peste/administración & dosificación , Ratones , Anticuerpos Antibacterianos/sangre , Caracteres Sexuales , Factores Sexuales , Modelos Animales de Enfermedad , Eficacia de las Vacunas
18.
Front Immunol ; 15: 1405084, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38835771

RESUMEN

Introduction: Cynaroside exhibits various biological properties, including anti-inflammatory, antiviral, antitumor, and cardioprotective effects. However, its involvement in methotrexate (MTX)-induced intestinal inflammation remains inadequately understood. Thus, we investigated the impact of cynaroside on MTX-induced intestinal inflammation and its potential mechanisms. Methods: To assess the protective potential of cynaroside against intestinal inflammation, Sprague-Dawley rats were subjected to a regimen of 7 mg/kg MTX for 3 days, followed by treatment with cynaroside at varying doses (10, 20, or 40 mg/kg). Histopathological evaluations were conducted alongside measurements of inflammatory mediators to elucidate the involvement of the NLRP3 inflammasome in alleviating intestinal inflammation. Results: Administration of 7 mg/kg MTX resulted in decreased daily food intake, increased weight loss, and elevated disease activity index in rats. Conversely, treatment with cynaroside at 20 or 40 mg/kg ameliorated the reductions in body weight and daily food intake and suppressed the MTX-induced elevation in the disease activity index. Notably, cynaroside administration at 20 or 40 mg/kg attenuated inflammatory cell infiltration, augmented goblet cell numbers and lowered serum levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-18, as well as the CD68-positive cell rate in the intestines of MTX-induced rats. Furthermore, cynaroside downregulated the expression levels of NLRP3, cleaved caspase 1, and cleaved IL-1ß in MTX-induced rats. Discussion: Collectively, our findings indicated that cymaroside alleviates intestinal inflammatory injury by inhibiting the activation of NLRP3 inflammasome in MTX-induced rats.


Asunto(s)
Enteritis , Inflamasomas , Metotrexato , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas Sprague-Dawley , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Ratas , Masculino , Enteritis/inducido químicamente , Enteritis/tratamiento farmacológico , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Citocinas/metabolismo , Glucósidos/farmacología , Glucósidos/uso terapéutico , Modelos Animales de Enfermedad
19.
Front Immunol ; 15: 1391395, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38835773

RESUMEN

Sepsis is a clinical syndrome caused by uncontrollable immune dysregulation triggered by pathogen infection, characterized by high incidence, mortality rates, and disease burden. Current treatments primarily focus on symptomatic relief, lacking specific therapeutic interventions. The core mechanism of sepsis is believed to be an imbalance in the host's immune response, characterized by early excessive inflammation followed by late immune suppression, triggered by pathogen invasion. This suggests that we can develop immunotherapeutic treatment strategies by targeting and modulating the components and immunological functions of the host's innate and adaptive immune systems. Therefore, this paper reviews the mechanisms of immune dysregulation in sepsis and, based on this foundation, discusses the current state of immunotherapy applications in sepsis animal models and clinical trials.


Asunto(s)
Inmunoterapia , Sepsis , Sepsis/inmunología , Sepsis/terapia , Humanos , Animales , Inmunoterapia/métodos , Inmunidad Adaptativa , Inmunidad Innata , Modelos Animales de Enfermedad
20.
Front Cell Infect Microbiol ; 14: 1413787, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38836053

RESUMEN

Background: Trimethylamine-N-oxide (TMAO) is produced by hepatic flavin-containing monooxygenase 3 (FMO3) from trimethylamine (TMA). High TMAO level is a biomarker of cardiovascular diseases and metabolic disorders, and it also affects periodontitis through interactions with the gastrointestinal microbiome. While recent findings indicate that periodontitis may alter systemic TMAO levels, the specific mechanisms linking these changes and particular oral pathogens require further clarification. Methods: In this study, we established a C57BL/6J male mouse model by orally administering Porphyromonas gingivalis (P. gingivalis, Pg), Fusobacterium nucleatum (F. nucleatum, Fn), Streptococcus mutans (S. mutans, Sm) and PBS was used as a control. We conducted LC-MS/MS analysis to quantify the concentrations of TMAO and its precursors in the plasma and cecal contents of mice. The diversity and composition of the gut microbiome were analyzed using 16S rRNA sequencing. TMAO-related lipid metabolism and enzymes in the intestines and liver were assessed by qPCR and ELISA methods. We further explored the effect of Pg on FMO3 expression and lipid molecules in HepG2 cells by stimulating the cells with Pg-LPS in vitro. Results: The three oral pathogenic bacteria were orally administered to the mice for 5 weeks. The Pg group showed a marked increase in plasma TMAO, betaine, and creatinine levels, whereas no significant differences were observed in the gut TMAO level among the four groups. Further analysis showed similar diversity and composition in the gut microbiomes of both the Pg and Fn groups, which were different from the Sm and control groups. The profiles of TMA-TMAO pathway-related genera and gut enzymes were not significantly different among all groups. The Pg group showed significantly higher liver FMO3 levels and elevated lipid factors (IL-6, TG, TC, and NEFA) in contrast to the other groups. In vitro experiments confirmed that stimulation of HepG2 cells with Pg-LPS upregulated the expression of FMO3 and increased the lipid factors TC, TG, and IL-6. Conclusion: This study conclusively demonstrates that Pg, compared to Fn and Sm, plays a critical role in elevating plasma TMAO levels and significantly influences the TMA-TMAO pathway, primarily by modulating the expression of hepatic FMO3 and directly impacting hepatic lipid metabolism.


Asunto(s)
Microbioma Gastrointestinal , Metilaminas , Ratones Endogámicos C57BL , Oxigenasas , Porphyromonas gingivalis , Animales , Masculino , Metilaminas/metabolismo , Metilaminas/sangre , Humanos , Ratones , Oxigenasas/metabolismo , Porphyromonas gingivalis/metabolismo , Fusobacterium nucleatum/metabolismo , Redes y Vías Metabólicas , Células Hep G2 , Metabolismo de los Lípidos , Modelos Animales de Enfermedad , Periodontitis/microbiología , Periodontitis/metabolismo , Hígado/metabolismo , ARN Ribosómico 16S/genética , Espectrometría de Masas en Tándem , Boca/microbiología
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