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1.
Microb Pathog ; 191: 106660, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38657710

RESUMEN

Endometritis is the inflammation of the endothelial lining of the uterine lumen and is multifactorial in etiology. Escherichia (E.) coli is a Gram-negative bacteria, generally considered as a primary causative agent for bovine endometritis. Bovine endometritis is characterized by the activation of Toll-like receptors (TLRs) by E. coli, which in turn triggers inflammation, oxidative stress, and apoptosis. The objective of this study was to investigate the gene expression of inflammatory, oxidative stress, and apoptotic markers related to endometritis in the uteri of cows. Twenty uterine tissues were collected from the abattoir. Histologically, congestion, edema, hyperemia, and hemorrhagic lesions with massive infiltration of neutrophil and cell necrosis were detected markedly (P < 0.05) in infected uterine samples. Additionally, we identify E. coli using the ybbW gene (177 base pairs; E. coli-specific gene) from infected uterine samples. Moreover, qPCR and western blot results indicated that TLR2, TLR4, proinflammatory mediators, and apoptosis-mediated genes upregulated except Bcl-2, which is antiapoptotic, and there were downregulations of oxidative stress-related genes in the infected uterine tissue. The results of our study suggested that different gene expression regimes related to the immune system reflex were activated in infected uteri. This research gives a novel understanding of active immunological response in bovine endometritis.


Asunto(s)
Apoptosis , Enfermedades de los Bovinos , Endometritis , Infecciones por Escherichia coli , Escherichia coli , Estrés Oxidativo , Regulación hacia Arriba , Útero , Bovinos , Animales , Femenino , Endometritis/veterinaria , Endometritis/microbiología , Endometritis/patología , Endometritis/metabolismo , Enfermedades de los Bovinos/microbiología , Enfermedades de los Bovinos/metabolismo , Enfermedades de los Bovinos/inmunología , Escherichia coli/genética , Escherichia coli/patogenicidad , Infecciones por Escherichia coli/veterinaria , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/patología , Útero/patología , Útero/microbiología , Útero/metabolismo , Inflamación , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Mediadores de Inflamación/metabolismo , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo
2.
Int J Mol Sci ; 23(18)2022 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-36142129

RESUMEN

Icariin (ICA) is a naturally occurring phytochemical agent primarily extracted from Epimedium Brevicornum Maxim (Family Berberidaceae) with a broad spectrum of bioactivities. Endometritis is a uterine disease that causes enormous losses in the dairy industry worldwide. In this study, anti-inflammatory and anti-oxidant properties of ICA were investigated against lipopolysaccharide (LPS)-induced endometritis in mice to investigate possible underlying molecular mechanisms. Sixty heathy female Kunming mice were randomly assigned to four groups (n = 15), namely control, LPS, LPS + ICA, and ICA groups. The endometritis was induced by intrauterine infusion of 50 µL of LPS (1 mg/mL). After 24 h of onset of LPS-induced endometritis, ICA groups were injected thrice by ICA intraperitoneally six hours apart. Histopathological examination, enzyme linked immunosorbent assay (ELISA), real time quantitative polymerase chain reaction (RT-qPCR), western blotting, and immunohistochemistry were used in this study. Histological alterations revealed that ICA markedly mitigated uterine tissue injury caused by LPS. The results showed that the ICA inhibited the production of pro-inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and boosted the production of anti-inflammatory cytokines (IL-10). Additionally, ICA modulated the expression of malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione peroxidase 1 (Gpx1) induced by LPS. The administration of ICA significantly (p < 0.05) improved the mRNA and protein expression of Toll-like receptor (TLR) 4. The western blotting and ELISA finding revealed that the ICA repressed LPS-triggered NF-κB pathway activation. Moreover, ICA improved the antioxidant defense system via activation of the Nrf2 pathway. The results revealed that ICA up-regulated the mRNA and protein expression of Nuclear erythroid-2-related factor (Nrf2), NAD(P)H: quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and glutamate-cysteine ligase catalytic subunit (GCLC) under LPS exposure. Conclusively, our findings strongly suggested that ICA protects endometritis caused by LPS by suppressing TLR4-associated NF-κB and Nrf2 pathways. Altogether, these innovative findings may pave the way for future studies into the therapeutic application of ICA to protect humans and animals against endometritis.


Asunto(s)
Endometritis , Lipopolisacáridos , Animales , Antiinflamatorios/farmacología , Antioxidantes/metabolismo , Catalasa/metabolismo , Citocinas/metabolismo , Endometritis/inducido químicamente , Endometritis/tratamiento farmacológico , Escherichia coli/metabolismo , Femenino , Flavonoides , Glutamato-Cisteína Ligasa/metabolismo , Hemo-Oxigenasa 1/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Lipopolisacáridos/efectos adversos , Malondialdehído , Ratones , NAD/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo , Quinonas/farmacología , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Superóxido Dismutasa-1/metabolismo , Receptor Toll-Like 4/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
3.
Pak J Med Sci ; 38(8): 2101-2106, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36415230

RESUMEN

Objectives: To evaluate the serum biochemical levels in celiac disease (CD) patients. Methods: It was a cross-sectional study carried out on 70 subjects, including 40 patients with CD and 30 healthy controls. This study was conducted at Jouf University from November, 2020 to October, 2021. The collected blood specimens were used to perform serum iron, serum lipids, liver enzymes, and human tissue transglutaminase IgA antibodies (anti-HTTG). The hematological parameters including hematocrit and MCV were determined to establish the diagnosis of iron deficiency. Results: Serum iron was significantly lower in patients as compared to the controls. Serum iron, serum HDL, blood hematocrit and MCV were significantly lower in patients than in controls (p = 0.000). Serum levels of liver enzymes (ALT and AST) and serum human tissue transglutaminase antibodies (anti-HTTG) were significantly higher in patients than in controls (p = 0.000). The correlation studies established the negative correlation of anti-HTTG IgA with serum iron (r = -0.991, p = 0.000), hematocrit (r = -0.967, p = 0.000) and MCV (r = -0.946, p = 0.000) in patients. Conclusion: The serum iron was remarkably reduced in CD patients. A negative correlation was found between anti-HTTG IgA and serum iron, while a positive serum iron was correlated with hematocrit and MCV in CD patients.

4.
Hum Mutat ; 42(8): 947-968, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33973684

RESUMEN

Mutations in Na-K-2Cl co-transporter, NKCC2, lead to type I Bartter syndrome (BS1), a life-threatening kidney disease. Yet, our knowledge of the molecular regulation of NKCC2 mutants remains poor. Here, we aimed to identify the molecular pathogenic mechanisms of one novel and three previously reported missense NKCC2 mutations. Co-immunolocalization studies revealed that all NKCC2 variants are not functional because they are not expressed at the cell surface due to retention in the endoplasmic reticulum (ER). Cycloheximide chase assays together with treatment by protein degradation and mannose trimming inhibitors demonstrated that the defect in NKCC2 maturation arises from ER retention and associated degradation (ERAD). Small interfering RNA (siRNA) knock-down experiments revealed that the ER lectin OS9 is involved in the ERAD of NKCC2 mutants. 4-phenyl butyric acid (4-PBA) treatment mimicked OS9 knock-down effect on NKCC2 mutants by stabilizing their immature forms. Importantly, out of the four studied mutants, only one showed an increased protein maturation upon treatment with glycerol. In summary, our study reveals that BS1 is among diseases linked to the ERAD pathway. Moreover, our data open the possibility that maturation of some ER retained NKCC2 variants is correctable by chemical chaperones offering, therefore, promising avenues in elucidating the molecular pathways governing the ERAD of NKCC2 folding mutants.


Asunto(s)
Síndrome de Bartter , Degradación Asociada con el Retículo Endoplásmico , Síndrome de Bartter/genética , Síndrome de Bartter/metabolismo , Retículo Endoplásmico/metabolismo , Humanos , Mutación , Miembro 1 de la Familia de Transportadores de Soluto 12/genética , Miembro 1 de la Familia de Transportadores de Soluto 12/metabolismo
5.
Microb Pathog ; 155: 104935, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33945855

RESUMEN

Pneumonia is the acute inflammation of lung tissue and is multi-factorial in etiology. Staphylococcus aureus (S. aureus) is a harmful pathogen present as a normal flora of skin and nares of dairy cattle. In bovine pneumonia, S. aureus triggers to activates Toll-Like Receptors (TLRs), that further elicits the activation of the inflammation via NF-κB pathway, oxidative stress and apoptotic pathways. In the current study, pathogen-associated gene expression of the pro-inflammatory cytokines, oxidative stress and apoptotic markers in the lung tissue of cattle was explored in bovine pneumonia. Fifty lung samples collected from abattoir located in Wuhan city, Hubei, China. Histopathologically, thickening of alveolar wall, accumulation of inflammatory cells and neutrophils in perivascular space, hyperemia, hemorrhages and edema were observed in infected lungs as compared to non-infected lung samples. Furthermore, molecular identification and characterization were carried by amplification of S. aureus-specific nuc gene (270 base pairs) from the infected and non-infected lung samples to identify the S. aureus. Moreover, qPCR results displayed that relative mRNA levels of TLR2, TLR4, pro-inflammatory gene (IL-1ß, IL-6 and TNF-α) and apoptosis-associated genes (Bax, caspase-3 and caspase-9) were up-regulated except Bcl-2, which is antiapoptotic in nature, and oxidative stress related genes (Nrf2, NQO1, HO-1 and GCLC) which was down-regulated in infected pulmonary group. The relative protein expression of NF-κB, mitochondria-mediated apoptosis gene was up-regulated while Bcl-2 and Nrf2 pathway genes were downregulated in infected cattle lungs. Our findings revealed that genes expression levels of inflammatory mediators, oxidative stress and apoptosis were associated with host immunogenic regulatory mechanisms in the lung tissue during infection. Conclusively, the present study provides insights of active immune response via TLRs-mediated inflammatory, oxidative damage, and apoptotic paradox.


Asunto(s)
Citocinas , Neumonía , Animales , Apoptosis , Bovinos , China , Citocinas/genética , Expresión Génica , FN-kappa B/genética , FN-kappa B/metabolismo , Estrés Oxidativo , Neumonía/genética , Neumonía/veterinaria , Staphylococcus aureus/metabolismo
6.
Ecotoxicol Environ Saf ; 219: 112353, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34034046

RESUMEN

Acute lung injury (ALI) is acute uncontrolled inflammation of lung tissue that leads to high fatality both in human and animals. Staphylococcus aureus (S. aureus) could be an opportunistic, versatile bacterial etiology of ALI. Ginsenoside Rb1 (Rb1) is extracted from the Panax ginseng, which displays a wide range of biological and pharmacological effects. However, protective effects of Rb1 in S. aureus-induced ALI though endoplasmic reticulum (ER) stress and death receptor-mediated pathways have not yet been reported. Therefore, present study was planned with the aims to investigate the antioxidant and anti-apoptotic properties of Rb1 through regulation of ER stress as well as death receptor-mediated pathways in ALI induced by S. aureus in mice. In this study, four groups of healthy Kunming mice (n = 48) were used. The S. aureus (80 µl; 1 ×107 CFU/10 µl) was administered intranasally to establish mice model of ALI. After 24 h of onset of S. aureus-induced ALI, the mice were injected thrice with Rb1 (40 mg/kg) intraperitoneally six hours apart. Histopathology, enzyme linked immunosorbent assay (ELISA), real time quantitative polymerase chain reaction (RT-qPCR), Immunohistochemistry and western blotting assay were employed in the current study. Our results suggested that Rb1 administration save lungs from pulmonary injury by reducing wet to dry (W/D) ratio, protein levels, total cells, neutrophilic count, reactive oxygen species (ROS), myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (Gpx)1 depletion. Meanwhile, Rb1 therapy ameliorated histopathology alteration of lung tissue and pro-inflammatory cytokines secretion. The gene expression of ER stress marker (PERK, AFT-6, IRE1 and CHOP) were upregulated markedly (P < .05) in S. aureus-instilled groups, which was reduced by Rb1 administration that is reveled from the result findings of the RT-qPCR and immunoblot assay. The results of immunohistochemistry for CHOP indicated the increased expression in S. aureus groups which in turn ameliorated by Rb1 treatment. The mRNA expression demonstrated that death receptor-associated genes (FasL, Fas, FADD and caspase-8) showed up-regulation in S. aureus group. The similar findings were observed for the protein expression of caspase-8, FADD and Fas. Rb1 treatment markedly (P < .05) reversed protein and mRNA expression levels of these death receptor-associated genes when compared to the S. aureus group. Taken together, Rb1 attenuated S. aureus-induced oxidative damage via the ER stress-mediated pathway and apoptosis through death receptor-mediated pathway. Conclusively, our findings provide an insight into preventive mechanism of Rb1 in ALI caused by S. aureus and hence proven a scientific baseline for the therapeutic application of Rb1.


Asunto(s)
Antioxidantes/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ginsenósidos/farmacología , Estrés Oxidativo/efectos de los fármacos , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/genética , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Glutatión Peroxidasa , Pulmón/metabolismo , Malondialdehído/metabolismo , Ratones , Panax , Especies Reactivas de Oxígeno/metabolismo , Receptores de Muerte Celular/metabolismo , Proteínas de Unión a Retinoblastoma , Infecciones Estafilocócicas , Staphylococcus aureus , Superóxido Dismutasa/metabolismo , Ubiquitina-Proteína Ligasas , Glutatión Peroxidasa GPX1
7.
Molecules ; 26(23)2021 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-34885671

RESUMEN

Endometritis is the inflammatory response of the endometrial lining of the uterus and is associated with low conception rates, early embryonic mortality, and prolonged inter-calving intervals, and thus poses huge economic losses to the dairy industry worldwide. Ginsenoside Rb1 (GnRb1) is a natural compound obtained from the roots of Panax ginseng, having several pharmacological and biological properties. However, the anti-inflammatory properties of GnRb1 in lipopolysaccharide (LPS)-challenged endometritis through the TLR4-mediated NF-κB signaling pathway has not yet been researched. This study was planned to evaluate the mechanisms of how GnRb1 rescues LPS-induced endometritis. In the present research, histopathological findings revealed that GnRb1 ameliorated LPS-triggered uterine injury. The ELISA and RT-qPCR assay findings indicated that GnRb1 suppressed the expression level of pro-inflammatory molecules (TNF-α, IL-1ß and IL-6) and boosted the level of anti-inflammatory (IL-10) cytokine. Furthermore, the molecular study suggested that GnRb1 attenuated TLR4-mediated NF-κB signaling. The results demonstrated the therapeutic efficacy of GnRb1 in the mouse model of LPS-triggered endometritis via the inhibition of the TLR4-associated NF-κB pathway. Taken together, this study provides a baseline for the protective effect of GnRb1 to treat endometritis in both humans and animals.


Asunto(s)
Antiinflamatorios/administración & dosificación , Endometritis/inducido químicamente , Endometritis/tratamiento farmacológico , Ginsenósidos/administración & dosificación , Lipopolisacáridos/efectos adversos , FN-kappa B/metabolismo , Panax/química , Fitoquímicos/administración & dosificación , Fitoterapia/métodos , Extractos Vegetales/administración & dosificación , Transducción de Señal/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Animales , Citocinas/metabolismo , Endometritis/metabolismo , Femenino , Ratones , Ratones Endogámicos BALB C , Resultado del Tratamiento
8.
Microb Pathog ; 143: 104109, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32171710

RESUMEN

Acute lung injury (ALI) is considered as an uncontrolled inflammatory response that can leads to acute respiratory distress syndrome (ARDS), which limits the therapeutic strategies. Ginsenosides Rb1 (Rb1), an active ingredient obtained from Panax ginseng, possesses a broad range of pharmacological and medicinal properties, comprising the anti-inflammatory, anti-oxidant, and anti-tumor activities. Therefore, the purpose of the present study was to investigate the protective effects of Rb1 against S. aureus-induced (ALI) through regulation of Nuclear factor erythroid 2-related factor 2 (Nrf2) and mitochondrial-mediated apoptotic pathways in mice (in-vivo), and RAW264.7 cells (in-vitro). For that purpose, forty Kunming mice were randomly assigned into four treatment groups; (1) Control group (phosphate buffer saline (PBS); (2) S. aureus group; (3) S. aureus + Rb1 (20 mg/kg) group; and (4) Rb1 (20 mg/kg) group. The 20 µg/mL dose of Rb1 was used in RAW264.7 cells. In the present study, we found that Rb1 treatment reduced ALI-induced oxidative stress via suppressing the accumulation of malondialdehyde (MDA) and myeloperoxidase (MPO) and increase the antioxidant enzyme activities of superoxidase dismutase 1 (SOD1), Catalase (CAT), and glutathione peroxidase 1 (Gpx1). Similarly, Rb1 markedly increased messenger RNA (mRNA) expression of antioxidant genes (SOD1, CAT and Gpx1) in comparison with ALI group. The histopathological results showed that Rb1 treatment ameliorated ALI-induced hemorrhages, hyperemia, perivascular edema and neutrophilic infiltration in the lungs of mice. Furthermore, Rb1 enhanced the antioxidant defense system through activating the Nrf2 signaling pathway. Our findings showed that Rb1 treated group significantly up-regulated mRNA and protein expression of Nrf2 and its downstream associated genes down-regulated by ALI in vivo and in vitro. Moreover, ALI significantly increased the both mRNA and protein expression of mitochondrial-apoptosis-related genes (Bax, caspase-3, caspase-9, cytochrome c and p53), while decreased the Bcl-2. In addition, Rb1 therapy significantly reversed the mRNA and protein expression of these mitochondrial-apoptosis-related genes, as compared to the ALI group in vivo and in vitro. Taken together, Rb1 alleviates ALI-induced oxidative injury and apoptosis by modulating the Nrf2 and mitochondrial signaling pathways in the lungs of mice.


Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Ginsenósidos/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Infecciones Estafilocócicas/complicaciones , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/patología , Animales , Ginsenósidos/química , Ratones , Panax/química , Células RAW 264.7 , Reacción en Cadena en Tiempo Real de la Polimerasa
9.
Microb Pathog ; 132: 302-312, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31059756

RESUMEN

Acute lung injury (ALI) is clinically characterized by excessive inflammation leading to acute respiratory distress syndrome (ARDS), having high morbidity and mortality both in human and animals. Ginsenoside Rb1 (Rb1) is a major primary bioactive component extracted by Panax ginseng, which has numerous pharmacological functions such as anti-cancer, anti-inflammatory, and antioxidant. However, the anti-inflammatory effects of Rb1 in Staphylococcus aureus (S. aureus)-induced ALI in mice have not been investigated. The aim of the current study was to determine the anti-inflammatory influence of Rb1 on S. aureus-induced ALI in mice, and to explore its possible underlying principle mechanisms in RAW 264.7 macrophage cells. The results of physical morphology, histopathological variation and wet-to-dry weight ratio of lungs revealed that Rb1 significantly attenuated S. aureus-induced lung injury. Furthermore, qPCR results displayed that Rb1 inhibited IL-1ß, IL-6 and TNF-α production both in vivo and in vitro. The activation of Toll-like receptor 2 (TLR2) by S. aureus was inhibited by application of Rb1 as confirmed by results of immunofluorescence assay. The expression of NF-kB and MAPK signaling proteins revealed that Rb1 significantly attenuated the phosphorylation of p65, ERK, as well as JNK. Altogether, the results of this experiment presented that Rb1 has ability to protect S. aureus-induced ALI in mice by attenuating TLR-2-mediated NF-kB and MAPK signaling pathways. Consequently, Rb-1 might be a potential medicine in the treatment of S. aureus-induced lung inflammation.


Asunto(s)
Lesión Pulmonar Aguda/microbiología , Ginsenósidos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/metabolismo , Staphylococcus aureus/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Pulmón/patología , Masculino , Ratones , Panax/química , Neumonía , Células RAW 264.7/efectos de los fármacos , ARN Mensajero/metabolismo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo
10.
Acta Trop ; 255: 107236, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38692450

RESUMEN

Endometritis reduces reproductive effectiveness and leads to significant financial losses in the dairy sector. Luteolin is a natural phyto-flavonoid compound with many biological activities. However, the therapeutic effect of Luteolin against lipopolysaccharides (LPS)-induced endometritis has not yet been explored. A total of eighty female Kunming mice were randomly assigned into four treatment groups (n = 20). Following a successful initiation of the endometritis model by LPS, Luteolin was intraperitoneally administered three times, at six-hour intervals between each injection in the Luteolin groups. The histopathological findings revealed that Luteolin significantly alleviated uterine injury induced by LPS. Moreover, Luteolin suppressed the synthesis of pro-inflammatory mediators [interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α] while promoting the synthesis of an anti-inflammatory mediator (IL-10) altered by LPS. Furthermore, Luteolin significantly mitigated the LPS-induced oxidative stress by scavenging malondialdehyde (MDA) and reactive oxygen species (ROS), accumulation and boosting the capacity of antioxidant enzyme activities such as superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione peroxidase 1 (Gpx1) in the uterine tissue of mice. Additionally, injection of Luteolin markedly increased the expression of Toll-like receptors (TLR) 4 both at mRNA and protein levels under LPS stimulation. Western blotting and ELISA findings demonstrated that Luteolin suppressed the activation of the NF-κB pathway in response to LPS exposure in the uterine tissue of mice. Notably, Luteolin enhanced the anti-oxidant defense system by activating the Nrf2 signaling pathway under LPS exposure in the uterine tissue of mice. Conclusively, our findings demonstrated that Luteolin effectively alleviated LPS-induced endometritis via modulation of TLR4-associated Nrf2 and NF-κB signaling pathways.


Asunto(s)
Lipopolisacáridos , Luteolina , Estrés Oxidativo , Luteolina/farmacología , Luteolina/uso terapéutico , Animales , Femenino , Ratones , Estrés Oxidativo/efectos de los fármacos , Endometritis/tratamiento farmacológico , Escherichia coli , Antiinflamatorios/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Especies Reactivas de Oxígeno/metabolismo , Útero/efectos de los fármacos , Útero/patología , Antioxidantes/farmacología , FN-kappa B/metabolismo , Inflamación/tratamiento farmacológico , Animales no Consanguíneos
11.
Pharmaceuticals (Basel) ; 15(9)2022 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-36145285

RESUMEN

This research was designed to identify thermodynamically and kinetically stable lipidic self-emulsifying formulations through simple energy dynamics in addition to highlighting and clarifying common ambiguities in the literature in this regard. Proposing a model study, this research shows how most of the professed energetically stable systems are actually energetically unstable, subjected to indiscriminate and false characterization, leading to significant effects for their pharmaceutical applications. A self-emulsifying drug delivery system (SEDDS) was developed and then solidified (S-SEDDS) using a model drug finasteride. Physical nature of SEDDS was identified by measuring simple dynamics which showed that the developed dispersion was thermodynamically unstable. An in vivo study of albino rats showed a three-fold enhanced bioavailability of model drug with SEDDS as compared to the commercial tablets. The study concluded that measuring simple energy dynamics through inherent properties can distinguish between thermodynamically stable and unstable lipidic systems. It might lead to correct identification of a specific lipidic formulation and the application of appropriate characterization techniques accordingly. Future research strategies include improving their pharmaceutical applications and understanding the basic differences in their natures.

12.
Clin Infect Pract ; 10: 100042, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32999997

RESUMEN

BACKGROUND: Covid-19 is a novel disease caused by the severe acute respiratory coronavirus (SARS-CoV2). We discuss a gentleman who presented with an atraumatic rupture of the spleen secondary to this infection. BRIEF SUMMARY OF PRESENTATION: A 57-year-old service engineer was brought into the emergency department after having collapsed at home. RT-PCR was positive for covid-19 infection. CT scan showed evidence of haemoperitoneum and splenic rupture. He underwent splenic artery embolisation and required ventilatory and circulatory support on ITU. He made a full recovery and was discharged home 3 weeks later. DISCUSSION AND RELEVANCE: Atraumatic splenic rupture is a rare, potentially fatal condition which has been described as a complication of haematological and non-haematological malignancies, inflammatory disorders and infections. There is emerging evidence to suggest that covid-19 has a direct destructive impact on the spleen, causing lymphoid follicle attrition and nodular atrophy in addition to microvascular thrombosis and necrosis. This is the first report of atraumatic splenic rupture secondary to covid-19 infection, to our knowledge.

13.
J Community Hosp Intern Med Perspect ; 9(2): 168-170, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31044051

RESUMEN

Uterine leiomyoma is the most common benign pelvic tumor of the myometrium, as the prevalence could be as high as 70%. Major risk factors include age between 40-60 years and African descent. It usually presents with abnormal uterine bleeding and/or pelvic pain or pressure. Extra-uterine cases of leiomyoma have been reported including Leiomyomatosis Peritonealis Disseminata (LPD), in which multiple nodules are found in the pelvis, peritoneum, or intestine. The term parasitic leiomyoma has been used in literature to describe a non-disseminating pattern . There is no clear explanation for pathogenesis; however, some reports linked it to previous uterine procedures. We are presenting here a case report of an unusual presentation of extra-uterine leiomyoma in a patient with a remote history of hysterectomy for uterine fibroids.

14.
Oncotarget ; 10(34): 3166-3182, 2019 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-31139331

RESUMEN

Chondrosarcoma is a highly agressive cancer with currently no effective therapies when unresectable or metastasized, thus the outcome remains poor. High-grade chordrosarcomas are resistant to conventional chemotherapy and radiotherapy and surgical resection remains the only treatment for the majority of chondrosarcomas. Constitutive activation of receptor tyrosine kinases has been shown to be important for malignant transformation and tumour proliferation. Here, we investigated the activation status of EGFR in chondrosarcoma tumor biopsies and cell lines. We found that EGFR is activated in grade II and grade III chondrosarcoma tumors but not in grade I tumors, suggesting a role in tumor progression. Interestingly, we showed that EGFR is activated through an autocrine loop and that inhibition of the EGFR by the TKI, tyrphostin AG1478 or EGFR neutralizing antibodies strongly reduced activation of oncogenic ERK1/2 and mTOR/AKT downstream pathways. Importantly, inhibition of EGFR profoundly reduces cell proliferation and migration, inhibits the expression of MMP13 and MMP3 and enhances cell death. Taken together, these data support the blocking of EGFR as new potential treatment for high-grade chondrosarcoma tumors.

15.
Hum Pathol ; 84: 18-25, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30266251

RESUMEN

Rat sarcoma (RAS) and RAS-associated pathways play important roles in the pathogenesis of lung cancers and in the development of targeted therapies. However, the clinical significance of RAS pathways is still not fully understood. We investigated the RAS-associated molecular aberrations in primary lung adenocarcinomas and correlated molecular findings with clinicopathological characteristics of tumors. A total of 220 surgically resected tumors were identified for which a lung cancer molecular panel (testing 7 genes by next-generation sequencing and 3 genes for rearrangement by fluorescence in situ hybridization) had been performed. The overall molecular alterations were detected in 143 cases (65.00%), including 58 cases (26.36%) of KRAS, 40 cases (18.18%) of EGFR, 24 cases (10.91%) of BRAF, 8 cases (3.64%) of PIK3CA, 7 cases (3.18%) of NRAS, 6 cases (2.73%) of ALK alterations. KRAS, BRAF, NRAS, and PIK3CA mutations were more commonly seen in smokers and occurred with much higher rates than previously published data. BRAFV600E mutations were commonly seen in female smokers, whereas, BRAFnon-V600E mutations were seen in both male and female smokers with moderately to poorly differentiated tumors. PIK3CA mutations were predominantly occurred in p.E545K and p.E542K on exon 9 in moderately to poorly differentiated tumors.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad
16.
Artículo en Inglés | MEDLINE | ID: mdl-30559951

RESUMEN

Fetal Hemoglobin (HbF, α2γ2) is produced from the eighth week of gestation, constitutes 60 - 80 % of total hemoglobin by birth, which is then replaced with adult Hemoglobin A1 (HbA1: α2ß2) by 6-12 months. Hereditary Persistence of Fetal Hemoglobin (HPFH) is a rare benign asymptomatic genetic disorder where the HbF persists, and incidentally discovered on screening for other hemoglobinopathies. In adults, the variation in HbF levels could also be associated with other disease states, including hemoglobinopathies, leukemias and bone marrow failure syndromes. Here we present a case of a young asymptomatic female with the incidental finding of HPFH who was misdiagnosed as the sickle cell disease. It is important to have awareness about HPFH and should be distinguished from other causes of elevated HbF.

17.
Case Rep Oncol Med ; 2018: 6469591, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30310702

RESUMEN

Objective. GATA3-positive sarcomatoid carcinoma has never been documented in the past. It is a case of aggressive tumor, positive for GATA3, which should be further studied for its prognostic and therapeutic significance.

18.
Asian Pac J Cancer Prev ; 19(4): 1119-1125, 2018 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-29699373

RESUMEN

The miRNAs nuclear export protein XPO5 has been previously studied in several individual malignancies. In our recent study we have demonstrated that excess levels of XPO5 enhanced the proliferation of prostate cancer cells. Similarly, there are studies to support the inhibitory role of XPO5 in cancers. In order to evaluate discrepancies in the expression levels of XPO5 in differential tumor types, we quantified the expression of XPO5 using gene expression RNA-seq data for several tumor types which were independently confirmed by immunohistochemistry in multiple organs cancer tissue microarray (TMAs) experiment. We found that while some tumors (Breast, Bladder, Lymph-node, Lung, Esophagus and Ovary) showed higher differences between normal and malignant tumors in XPO5 expression, there were tissues (Kidney and Brain) that have a significantly lower XPO5 expression in malignant tumors. We further studies these observations of overexpression and down-regulation of XPO5 in breast and kidney cancer cell lines and found that XPO5 might have a dual role in promoting or inhibiting tumor growth in different cancer tissue types.


Asunto(s)
Carcinogénesis/genética , Genes Supresores de Tumor/fisiología , Carioferinas/genética , Oncogenes/genética , Línea Celular , Línea Celular Tumoral , Proliferación Celular/genética , Regulación hacia Abajo/genética , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Células HEK293 , Humanos , Células MCF-7 , MicroARNs/genética
19.
Cell Death Differ ; 25(8): 1442-1456, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29352270

RESUMEN

Dysregulation of Wnt signaling has been implicated in developmental defects and in the pathogenesis of many diseases such as osteoarthritis; however, the underlying mechanisms are poorly understood. Here, we report that non-canonical Wnt signaling induced loss of chondrocyte phenotype through activation of Fz-6/DVL-2/SYND4/CaMKIIα/B-raf/ERK1/2 cascade. We show that in response to Wnt-3a, Frizzled 6 (Fz-6) triggers the docking of CaMKIIα to syndecan 4 (SYND4) and that of B-raf to DVL-2, leading to the phosphorylation of B-raf by CaMKIIα and activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling, which leads to chondrocyte de-differentiation. We demonstrate that CaMKIIα associates and phosphorylates B-raf in vitro and in vivo. Our study reveals the mechanism by which non-canonical Wnt activates ERK1/2 signaling that induces loss of chondrocyte phenotype, and demonstrates a direct functional relationship between CaMKIIα and B-raf during chondrocyte de-differentiation. The identification of Fz-6, SYND4, and B-raf as novel physiological regulators of chondrocyte phenotype may provide new potential anti-osteoarthritic targets.


Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Desdiferenciación Celular , Proteínas Dishevelled/metabolismo , Receptores Frizzled/metabolismo , Proteínas Proto-Oncogénicas B-raf/metabolismo , Sindecano-4/metabolismo , Proteínas Wnt/metabolismo , Células Cultivadas , Condrocitos/citología , Condrocitos/metabolismo , Proteínas Dishevelled/antagonistas & inhibidores , Proteínas Dishevelled/genética , Receptores Frizzled/antagonistas & inhibidores , Receptores Frizzled/genética , Humanos , Sistema de Señalización de MAP Quinasas , Osteoartritis/metabolismo , Osteoartritis/patología , Fenotipo , Fosforilación , Proteínas Proto-Oncogénicas B-raf/genética , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Sindecano-4/antagonistas & inhibidores , Sindecano-4/genética , beta Catenina/antagonistas & inhibidores , beta Catenina/genética , beta Catenina/metabolismo
20.
PLoS One ; 11(1): e0146499, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26751072

RESUMEN

Stimulation of proteoglycan (PG) synthesis and deposition plays an important role in the pathophysiology of fibrosis and is an early and dominant feature of pulmonary fibrosis. Transforming growth factor-ß1 (TGF-ß1) is a major cytokine associated with fibrosis that induces excessive synthesis of matrix proteins, particularly PGs. Owing to the importance of PGs in matrix assembly and in mediating cytokine and growth factor signaling, a strategy based on the inhibition of PG synthesis may prevent excessive matrix PG deposition and attenuates profibrotic effects of TGF-ß1 in lung fibroblasts. Here, we showed that 4-MU4-deoxy-ß-D-xylopyranoside, a competitive inhibitor of ß4-galactosyltransferase7, inhibited PG synthesis and secretion in a dose-dependent manner by decreasing the level of both chondroitin/dermatan- and heparin-sulfate PG in primary lung fibroblasts. Importantly, 4-MU4-deoxy-xyloside was able to counteract TGF-ß1-induced synthesis of PGs, activation of fibroblast proliferation and fibroblast-myofibroblast differentiation. Mechanistically, 4-MU4-deoxy-xyloside treatment inhibited TGF-ß1-induced activation of canonical Smads2/3 signaling pathway in lung primary fibroblasts. The knockdown of ß4-galactosyltransferase7 mimicked 4-MU4-deoxy-xyloside effects, indicating selective inhibition of ß4-galactosyltransferase7 by this compound. Collectively, this study reveals the anti-fibrotic activity of 4-MU4-deoxy-xyloside and indicates that inhibition of PG synthesis represents a novel strategy for the treatment of lung fibrosis.


Asunto(s)
Himecromona/análogos & derivados , Pulmón/fisiopatología , Proteoglicanos/biosíntesis , Fibrosis Pulmonar/fisiopatología , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Diferenciación Celular , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Citocinas/metabolismo , Dermatán Sulfato/química , Inhibidores Enzimáticos/química , Matriz Extracelular/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Galactosiltransferasas/antagonistas & inhibidores , Glicósidos/química , Heparina/análogos & derivados , Heparina/biosíntesis , Humanos , Himecromona/química , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Pulmón/citología , Pulmón/metabolismo , N-Acetil-Lactosamina Sintasa/antagonistas & inhibidores , Fenotipo , Fibrosis Pulmonar/tratamiento farmacológico , ARN Interferente Pequeño/metabolismo , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal
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