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Oxidative stress and the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome have been linked to insulin resistance in skeletal muscle. In immune cells, the exacerbated generation of reactive oxygen species (ROS) activates the NLRP3 inflammasome, by facilitating the interaction between thioredoxin interacting protein (TXNIP) and NLRP3. However, the precise role of ROS/TXNIP-dependent NLRP3 inflammasome activation in skeletal muscle during obesity-induced insulin resistance remains undefined. Here, we induced insulin resistance in C57BL/6J mice by feeding them for 8 weeks with a high-fat diet (HFD) and explored whether the ROS/TXNIP/NLRP3 pathway was involved in the induction of insulin resistance in skeletal muscle. Skeletal muscle fibers from insulin-resistant mice exhibited increased oxidative stress, as evidenced by elevated malondialdehyde levels, and altered peroxiredoxin 2 dimerization. Additionally, these fibers displayed augmented activation of the NLRP3 inflammasome, accompanied by heightened ROS-dependent proximity between TXNIP and NLRP3, which was abolished by the antioxidant N-acetylcysteine (NAC). Inhibition of the NLRP3 inflammasome with MCC950 or suppressing the ROS/TXNIP/NLRP3 pathway with NAC restored insulin-dependent glucose uptake in muscle fibers from insulin-resistant mice. These findings provide insights into the mechanistic link between oxidative stress, NLRP3 inflammasome activation, and obesity-induced insulin resistance in skeletal muscle.
Assuntos
Proteínas de Transporte , Dieta Hiperlipídica , Glucose , Resistência à Insulina , Músculo Esquelético , Proteína 3 que Contém Domínio de Pirina da Família NLR , Obesidade , Estresse Oxidativo , Espécies Reativas de Oxigênio , Transdução de Sinais , Tiorredoxinas , Animais , Masculino , Camundongos , Proteínas de Transporte/metabolismo , Proteínas de Transporte/genética , Dieta Hiperlipídica/efeitos adversos , Furanos/farmacologia , Glucose/metabolismo , Indenos/farmacologia , Inflamassomos/metabolismo , Insulina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Obesos , Músculo Esquelético/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Obesidade/metabolismo , Obesidade/patologia , Espécies Reativas de Oxigênio/metabolismo , Sulfonamidas , Tiorredoxinas/metabolismo , Tiorredoxinas/genéticaRESUMO
This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients.
El objetivo del presente trabajo fue conocer qué tratamientos mostraron efectividad contra COVID-19, para lo cual se revisan y discuten los resultados de 37 estudios clínicos iniciados durante 2020 y concluidos en 2021. Estos fueron seleccionados de bases de datos, excluyendo vacunas, estudios computacionales, in silico, in vitro y con sueros hiperinmunes de pacientes recuperados. Se documentaron 34 fármacos, una vitamina y un remedio herbolario, con actividad farmacológica ante COVID-19 sintomático. Estos redujeron la mortalidad, el progreso de la enfermedad, o el tiempo de recuperación. Para cada tratamiento se presenta identificador y tipo de estudio, la gravedad de la enfermedad, patrocinador, país donde se realizó, así como sus resultados. Los fármacos se clasificaron de acuerdo con su mecanismo de acción. Varios fármacos que redujeron la mortalidad también disminuyeron la inflamación en los casos más graves. Esto incluyendo algunos no considerados antiinflamatorios, como el aviptadil, el bromuro de piridostigmina, el anakinra, el imatinib, el baricitinib y el bevacizumab, así como la combinación de ivermectina, aspirina, dexametasona y enoxaparina. También se reportaron con actividad terapéutica las semillas de Nigella sativa con miel. Además, resultaron efectivos el tofacitinib, el novaferón con ritonavir y lopinavir, así como los antivirales en terapias combinadas como el danoprevir con ritonavir. Los productos naturales colchicina y vitamina D3, solo tuvieron actividad en los pacientes en estado leve a moderado de la COVID-19, así como la hidroxicloroquina. El reposicionamiento de fármacos fue la principal herramienta para buscar terapias efectivas ampliando las opciones farmacológicas accesibles a los pacientes.
Assuntos
Produtos Biológicos , COVID-19 , Humanos , Ritonavir/uso terapêutico , Antivirais/uso terapêutico , Antivirais/farmacologia , SARS-CoV-2 , PandemiasRESUMO
Abstract This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients.
Resumen El objetivo del presente trabajo fue conocer qué tratamientos mostraron efectividad contra COVID-19, para lo cual se revisan y discuten los resultados de 37 estudios clínicos iniciados durante 2020 y concluidos en 2021. Estos fueron seleccionados de bases de datos, excluyendo vacunas, estudios computacionales, in silico, in vitro y con sueros hiperinmunes de pacientes recuperados. Se documentaron 34 fármacos, una vitamina y un remedio herbolario, con actividad farmacológica ante COVID-19 sintomático. Estos redujeron la mortalidad, el progreso de la enfermedad, o el tiempo de recuperación. Para cada tratamiento se presenta identificador y tipo de estudio, la gravedad de la enfermedad, patrocinador, país donde se realizó, así como sus resultados. Los fármacos se clasificaron de acuerdo con su mecanismo de acción. Varios fármacos que redujeron la mortalidad también disminuyeron la inflamación en los casos más graves. Esto incluyendo algunos no considerados antiinflamatorios, como el aviptadil, el bromuro de piridostigmina, el anakinra, el imatinib, el baricitinib y el bevacizumab, así como la combinación de ivermectina, aspirina, dexametasona y enoxaparina. También se reportaron con actividad terapéutica las semillas de Nigella sativa con miel. Además, resultaron efectivos el tofacitinib, el novaferón con ritonavir y lopinavir, así como los antivirales en terapias combinadas como el danoprevir con ritonavir. Los productos naturales colchicina y vitamina D3, solo tuvieron actividad en los pacientes en estado leve a moderado de la COVID-19, así como la hidroxicloroquina. El reposicionamiento de fármacos fue la principal herramienta para buscar terapias efectivas ampliando las opciones farmacológicas accesibles a los pacientes.
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Patients with bone diseases often experience increased bone fragility. When bone injuries exceed the body's natural healing capacity, they become significant obstacles. The global rise in the aging population and the escalating obesity pandemic are anticipated to lead to a notable increase in acute bone injuries in the coming years. Our research developed a novel DLP resin for 3D printing, utilizing poly(ethylene glycol diacrylate) (PEGDA) and various monomers through the PET-RAFT polymerization method. To enhance the performance of bone scaffolds, triply periodic minimal surfaces (TPMS) were incorporated into the printed structure, promoting porosity and pore interconnectivity without reducing the mechanical resistance of the printed piece. The gyroid TPMS structure was the one that showed the highest mechanical resistance (0.94 ± 0.117 and 1.66 ± 0.240 MPa) for both variants of resin composition. Additionally, bioactive particles were introduced to enhance the material's biocompatibility, showcasing the potential for incorporating active compounds for specific applications. The inclusion of bioceramic particles produces an increase of 13% in bioactivity signal for osteogenic differentiation (alkaline phosphatase essay) compared to that of control resins. Our findings highlight the substantial improvement in printing precision and resolution achieved by including the photoabsorber, Rose Bengal, in the synthesized resin. This enhancement allows for creating intricately detailed and accurately defined 3D-printed parts. Furthermore, the TPMS gyroid structure significantly enhances the material's mechanical resistance, while including bioactive compounds significantly boosts the polymeric resin's biocompatibility and bioactivity (osteogenic differentiation).
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Diabetes mellitus (DM) is considered one of the major health diseases worldwide, one that requires immediate alternatives to allow treatments for DM to be more effective and less costly for patients and also for health-care systems. Recent approaches propose treatments for DM based on that; in addition to focusing on reducing hyperglycemia, they also consider multitargets, as in the case of plants. Among these, we find the plant known as chia to be highlighted, a crop native to Mexico and one cultivated in Mesoamerica from pre-Hispanic times. The present work contributes to the review of the antidiabetic effects of chia for the treatment of DM. The antidiabetic effects of chia are effective in different mechanisms involved in the complex pathogenesis of DM, including hypoglycemic, antioxidant, and anti-inflammatory mechanisms, and the inhibition of the enzymes α-glucosidase and α-amylase, as well as in the prevention of the risk of cardiovascular disease. The tests reviewed included 16 in vivo assays on rodent models, 13 clinical trials, and 4 in vitro tests. Furthermore, chia represents advantages over other natural products due to its availability and its acceptance and, in addition, as a component of the daily diet worldwide, especially due to its omega-3 fatty acids and its high concentration of dietary fiber. Thus, chia in the present work represents a source of antidiabetic agents that would perhaps be useful in novel clinical treatments.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus , Salvia , Humanos , alfa-Amilases , alfa-Glucosidases , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Salvia hispanica , SementesRESUMO
Essential oils (EOs) are complex mixtures of volatile natural compounds. We have extensively studied the EO of Bursera morelensis, which demonstrates antibacterial, antifungal, anti-inflammatory, and wound-healing activities. The objective of this work was to determine the effect of this EO on fibroblast migration in a three-dimensional in vitro model. For the three-dimensional in vitro model, a series of fibrin hydrogel scaffolds (FSs) were built in which fibroblasts were cultured and subsequently stimulated with fibroblast growth factor (FGF) or EO. The results demonstrated that these FSs are appropriate for fibroblast culture, since no decrease in cell viability or changes in cell proliferation were found. The results also showed that this EO promotes cell migration four hours after stimulation, and the formation of cell projections (filopodia) outside the SF was observed. From these results, we confirmed that part of the mechanism of action of the essential oil of B. morelensis during the healing process is the stimulation of fibroblast migration to the wound site.
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Bursera , Óleos Voláteis , Óleos Voláteis/farmacologia , Projetos de Pesquisa , Movimento Celular , Fatores de Crescimento de Fibroblastos , FibroblastosRESUMO
Phytochemical bio-guided studies are used to find compounds with biological activity. Flavonoids from seeds of Leucaena species have antimicrobial activity in strains of medical interest, therefore, fresh seeds were collected from the town of Tlayacapan, Morelos, Mexico. The methanolic extracts were obtained by the maceration technique, targeted fractionation was performed using adsorption and molecular exclusion chromatographic techniques; to observe the antimicrobial activity, agar diffusion techniques were used; spectrometric and spectroscopic techniques were used for the characterization of D-pinitol, resulting from the fractionation of L. leucocephala. Antimicrobial activity was found on strains of Escherichia coli CUSI and Staphylococcus aureus ATCC 29213 of the most polar fractions, identifying the responsible compounds by HPLC: caffeic acid, gallic acid, p-coumaric acid, quercetin, catechin and apigenin, these compounds can inhibit the activation enzymatic, synthesis of nucleic acids and proteins, chelating with different ions, etc.
Los estudios biodirigidos fitoquímicos son empleados para encontrar compuestos con actividad biológica. Los flavonoides de semillas de especies de Leucaena son reportados por tener actividad antimicrobiana sobre cepas de interés médico, por tanto, se colectaron semillas frescas de la localidad de Tlayacapan, Morelos, México. Se obtuvieron los extractos metanólicos mediante la técnica de maceración, el fraccionamiento dirigido se realizó empleando técnicas cromatográficas de adsorción y exclusión molecular; la actividad antimicrobiana se determinó mediante técnicas de difusión en agar; se utilizaron técnicas espectrométricas y espectroscópicas para la caracterización del D-pinitol, resultado del fraccionamiento de L. leucocephala. Se encontró actividad antimicrobiana sobre cepas de Escherichia coli CUSI y Staphylococcus aureus ATCC 29213 de las fracciones más polares, identificando los compuestos responsables vía HPLC: ácido caféico, ácido gálico, ácido p-cumárico quercetina, catequina y apigenina, dichos compuestos pueden inhibir activación enzimática, síntesis de ácidos nucleicos y proteínas, quelarse con diferentes iones, etc.
Assuntos
Cromatografia/métodos , Fabaceae/química , Anti-Infecciosos/química , Plantas Medicinais/química , Fracionamento Químico , MéxicoRESUMO
In Mexico, Diabetes mellitus (DM) is a serious health problem, and although the current pharmacological treatments for DM such as insulin and oral hypoglycemics are available, the Mexican population continues to use medicinal plants in the treatment of DM. The antidiabetic properties of the plant species that belong to the Cucurbitaceae family has already been recognized worldwide. Since Mexico is one of the most important centers of diversity of Cucurbitaceae, the present work contributes to the review of the most used species of Cucurbitaceae in the treatment of DM in Mexico. The reviewed species (Cucurbita ficifolia, C. maxima, C. moschata, C. pepo, Ibervillea sonorae, Sechium edule, Citrullus lanatus, Cucumis melo, and C. sativus) revealed that the antidiabetic effects exerted are effective in a number of mechanisms involved in the complex pathogenesis of DM: hypoglycemic, antioxidant, anti-inflammatory, anti-obesity, protective effects on diverse organs and cells, as well as in the control of dyslipidemias; furthermore, the select species of the Cucurbitaceae family could also be essential components of diets for the control of DM in patients with the disease. Thus, the Cucurbitaceae species selected in the present work represent a source of antidiabetic agents that perhaps establish the bases for novel clinical treatments.
Assuntos
Cucurbitaceae , Diabetes Mellitus , Diabetes Mellitus/tratamento farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Insulina , MéxicoRESUMO
Low-grade chronic inflammation plays a pivotal role in the pathogenesis of insulin resistance (IR), and skeletal muscle has a central role in this condition. NLRP3 inflammasome activation pathways promote low-grade chronic inflammation in several tissues. However, a direct link between IR and NLRP3 inflammasome activation in skeletal muscle has not been reported. Here, we evaluated the NLRP3 inflammasome components and their role in GLUT4 translocation impairment in skeletal muscle during IR. Male C57BL/6J mice were fed with a normal control diet (NCD) or high-fat diet (HFD) for 8 weeks. The protein levels of NLRP3, ASC, caspase-1, gasdermin-D (GSDMD), and interleukin (IL)-1ß were measured in both homogenized and isolated fibers from the flexor digitorum brevis (FDB) or soleus muscle. GLUT4 translocation was determined through GLUT4myc-eGFP electroporation of the FBD muscle. Our results, obtained using immunofluorescence, showed that adult skeletal muscle expresses the inflammasome components. In the FDB and soleus muscles, homogenates from HFD-fed mice, we found increased protein levels of NLRP3 and ASC, higher activation of caspase-1, and elevated IL-1ß in its mature form, compared to NCD-fed mice. Moreover, GSDMD, a protein that mediates IL-1ß secretion, was found to be increased in HFD-fed-mice muscles. Interestingly, MCC950, a specific pharmacological NLRP3 inflammasome inhibitor, promoted GLUT4 translocation in fibers isolated from the FDB muscle of NCD- and HFD-fed mice. In conclusion, we found increased NLRP3 inflammasome components in adult skeletal muscle of obese insulin-resistant animals, which might contribute to the low-grade chronic metabolic inflammation of skeletal muscle and IR development.
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Transportador de Glucose Tipo 4/metabolismo , Inflamassomos/metabolismo , Resistência à Insulina/fisiologia , Interleucina-1beta/metabolismo , Músculo Esquelético/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Caspase 1/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Furanos/farmacologia , Indenos/farmacologia , Inflamassomos/química , Interleucina-1beta/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Obesidade/induzido quimicamente , Obesidade/metabolismo , Proteínas de Ligação a Fosfato/metabolismo , Sulfonamidas/farmacologiaRESUMO
In men, 70% of circulating testosterone binds with high affinity to plasma sex hormone binding globulin (SHBG), which determines its bioavailability in their target cells. In recent years, a growing body of evidence has shown that circulating SHBG not only is a passive carrier for steroid hormones but also actively regulates testosterone signaling through putative plasma membrane receptors and by local expression of androgen-binding proteins apparently to reach local elevated testosterone concentrations in specific androgen target tissues. Circulating SHBG levels are influenced by metabolic and hormonal factors, and they are reduced in obesity and insulin resistance, suggesting that SHBG may have a broader clinical utility in assessing the risk for cardiovascular diseases. Importantly, plasma SHBG levels are strongly correlated with testosterone concentrations, and in men, low testosterone levels are associated with an adverse cardiometabolic profile. Although obesity and insulin resistance are associated with an increased incidence of cardiovascular disease, whether they lead to abnormal expression of circulating SHBG or its interaction with androgen signaling remains to be elucidated. SHBG is produced mainly in the liver, but it can also be expressed in several tissues including the brain, fat tissue, and myocardium. Expression of SHBG is controlled by peroxisome proliferator-activated receptor γ (PPARγ) and AMP-activated protein kinase (AMPK). AMPK/PPAR interaction is critical to regulate hepatocyte nuclear factor-4 (HNF4), a prerequisite for SHBG upregulation. In cardiomyocytes, testosterone activates AMPK and PPARs. Therefore, the description of local expression of cardiac SHBG and its circulating levels may shed new light to explain physiological and adverse cardiometabolic roles of androgens in different tissues. According to emerging clinical evidence, here, we will discuss the potential mechanisms with cardioprotective effects and SHBG levels to be used as an early metabolic and cardiovascular biomarker in men.
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Diabetes mellitus (DM) is cited as a serious worldwide health problem that occupies second place in causes of annual mortality in Mexico. Among Mexican flora, nearly 300 plant species have been employed as hypoglycemic in popular use. Thus, their study entertains great relevance In this context, this work contributes a clear and timely review of the plant species utilized in Traditional Mexican Medicine and experimental biological models in which not only have the hypoglycemic properties of the extracts and the isolated compounds been considered, but also the anti-inflammatory and antioxidant properties, taking into account an integral focus based on the complex mechanisms involved in the pathogenesis and physiopathology of DM. Among the species reviewed, we highlight Psacalium decompositum (Asteraceae), due to the potent hypoglycemic, anti-inflammatory, and antioxidant activity of the sesquiterpenes identified as majority compounds isolated from the root, such as cacalol and cacalone that also possess the capacity of increasing insulin levels. In this manner, the present manuscript attempts to contribute necessary information for the future study of bioactive molecules that are useful in the treatment of DM, as well as also being a contribution to the knowledge and diffusion of Mexican Traditional Medicine.
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Diabetes Mellitus/terapia , Plantas Medicinais/química , Psacalium/química , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Modelos Animais de Doenças , Humanos , MéxicoRESUMO
Among multiple mechanisms, low-grade inflammation is critical for the development of insulin resistance as a feature of type 2 diabetes. The nucleotide-binding oligomerization domain-like receptor family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome has been linked to the development of insulin resistance in various tissues; however, its role in the development of insulin resistance in the skeletal muscle has not been explored in depth. Currently, there is limited evidence that supports the pathological role of NLRP3 inflammasome activation in glucose handling in the skeletal muscle of obese individuals. Here, we have centered our focus on insulin signaling in skeletal muscle, which is the main site of postprandial glucose disposal in humans. We discuss the current evidence showing that the NLRP3 inflammasome disturbs glucose homeostasis. We also review how NLRP3-associated interleukin and its gasdermin D-mediated efflux could affect insulin-dependent intracellular pathways. Finally, we address pharmacological NLRP3 inhibitors that may have a therapeutical use in obesity-related metabolic alterations.
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Inflamassomos/metabolismo , Inflamação/etiologia , Inflamação/metabolismo , Resistência à Insulina , Músculo Esquelético/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Animais , Transporte Biológico , Doença Crônica , Glucose/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Interleucina-1beta/metabolismo , Metabolismo dos Lipídeos , Músculo Esquelético/patologia , Obesidade/tratamento farmacológico , Obesidade/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
Bursera morelensis is used in Mexican folk medicine to treat wounds on the skin. Recently, it was shown that the essential oil (EO) of B. morelensis has wound healing activity, accelerating cutaneous wound closure and generating scars with good tensile strength. α-pinene (PIN) and α-phellandrene (FEL) are terpenes that have been found in this EO, and it has been shown in different studies that both have anti-inflammatory activity. The aim of this study was to determine the wound healing activity of these two terpenes. The results of in vitro tests demonstrate that PIN and FEL are not cytotoxic at low concentrations and that they do not stimulate fibroblast cell proliferation. In vivo tests showed that the terpenes produce stress-resistant scars and accelerate wound contraction, due to collagen deposition from the early stages, in wounds treated with both terpenes. Therefore, we conclude that both α-pinene and α-phellandrene promote the healing process; this confirms the healing activity of the EO of B. morelensis, since having these terpenes as part of its chemical composition explains part of its demonstrated activity.
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Monoterpenos Bicíclicos/farmacologia , Monoterpenos Cicloexânicos/farmacologia , Extratos Vegetais/farmacologia , Cicatrização/efeitos dos fármacos , Monoterpenos Bicíclicos/química , Bursera/química , Monoterpenos Cicloexânicos/química , Humanos , México , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Extratos Vegetais/química , Pele/química , Terpenos/química , Terpenos/farmacologiaRESUMO
BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake-via AMP-activated protein kinase (AMPK)-after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.
Assuntos
Proteínas Quinases Ativadas por AMP , Glucose/metabolismo , Miócitos Cardíacos , Receptores Androgênicos/metabolismo , Testosterona/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Células Cultivadas , Hipertrofia , Masculino , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Transdução de SinaisRESUMO
Resumen Los informes iniciales sugirieron que los pacientes con antecedentes o malignidad activa podrían tener un mayor riesgo de contraer el coronavirus 2 del síndrome respiratorio agudo grave (SARS-CoV-2) y desarrollar complicaciones relacionadas con la enfermedad por coronavirus 2019 (COVID-19). Pacientes con patologías hematológicas benignas y malignas pueden estar inmunocomprometidos por los efectos de la terapia antineoplásica, medicamentos de apoyo como los esteroides y las propiedades inmunosupresoras del cáncer en sí. También podrían tener una respuesta inmunitaria aumentada a la infección secundaria a fármacos inmunomoduladores. Se espera que la COVID-19, causada por el SARS-CoV-2, sea una infección devastadora en muchos pacientes con enfermedades hematológicas. En México se reportaron los primeros casos confirmados el 1 de marzo de 2020; en nuestro servicio de hematología el primer caso reportado y confirmado fue en abril de 2020. Realizamos un estudio de serie de casos de 33 pacientes hospitalizados con patologías benignas y malignas que desarrollaron COVID-19. Las tasas de casos de COVID-19 en sujetos hospitalizados con patologías hematológicas fue del 15.7%. La mortalidad por COVID-19 fue del 54.54%. En pacientes con patologías hematológicas parece deberse principalmente a que los pacientes con cáncer activo sin respuesta completa que recibieron quimioterapia citotóxica u otro tratamiento contra el cáncer tienen un mayor riesgo de mortalidad por la COVID-19 en comparación con aquellos que no reciben tratamiento activo, pacientes de novo sin quimioterapia, pero en estadios avanzados de la enfermedad con comorbilidades y asociadas principalmente con coinfecciones bacterianas.
Abstract Initial reports suggested that patients with a history or active malignancy may be at increased risk of contracting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and developing complications related to coronavirus disease 2019 (COVID-19). Patients with benign and malignant hematological pathologies may be immunocompromised by the effects of antineoplastic therapy, supportive medications such as steroids, and the immunosuppressive properties of the cancer itself. They may also have an increased immune response to infection secondary to immunomodulatory drugs. COVID-19, caused by SARS-CoV-2, is expected to be an infection devastating in many patients with hematologic diseases. The first confirmed cases in Mexico were on March 1, 2020; In our hematology service, the first case reported and confirmed was in April 2020. We conducted a case series study of 33 hospitalized patients with benign and malignant pathologies that developed COVID-19. The COVID-19 case rates in hospitalized subjects with hematological pathologies was 15.7%. The mortality from COVID-19 was 54.54%. In patients with hematological pathologies it seems to be mainly due to the fact that patients with active cancer without a complete response who received cytotoxic chemotherapy or other anti-cancer treatment cancer have a higher risk of mortality from COVID-19 compared to those who do not receive active treatment, patients de novo without chemotherapy, but in advanced stages of the disease with comorbidities and associated mainly with bacterial coinfections.
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Resumen La infección por coronavirus 2 del síndrome respiratorio agudo grave condiciona un gran número de anormalidades pulmonares y sistémicas que basan su fisiopatogenia en la inmunotrombosis. Específicamente para el área de la hematología desde los primeros estudios de caracterización clínica y paraclínica se identificaron anormalidades hematológicas y de la hemostasia que se han documentado de forma consistente en diferentes publicaciones y cuyo conocimiento es trascendente desde el punto de vista de pronóstico. Durante el curso de la enfermedad, la evaluación longitudinal de algunos parámetros hematológicos es primordial para la identificación temprana de pacientes potencialmente complicables. El conteo absoluto de leucocitos, la depleción linfoide y la trombocitopenia son los marcadores hematológicos principalmente alterados. La linfopenia severa es un hallazgo cardinal en la fase temprana de la infección y su persistencia durante la progresión de la enfermedad tiene mayor impacto pronóstico adverso. La determinación de los índices hemáticos neutrófilo:linfocito y linfocito:plaqueta también ha demostrado su utilidad como predictores de complicaciones respiratorias y mortalidad. Un estado de hipercoagulabilidad demostrado por niveles altos de dímero D y/o productos de degradación de fibrinógeno y diversas alteraciones hemostásicas en el perfil de coagulación se asocian a una mayor tasa de morbimortalidad. Otros biomarcadores inflamatorios, incluidos proteína C reactiva, procalcitonina y ferritina, podrían identificar tempranamente aquellos casos que requieren de soporte ventilatorio y/o hemodinámico avanzado. En esta revisión se abordan los antecedentes históricos de la patología y las principales alteraciones hematológicas y de la hemostasia y sus implicaciones pronósticas.
Abstract Severe acute respiratory syndrome coronavirus 2 infection conditions a large number of pulmonary and systemic abnormalities that base its physiopathogenesis on immunothrombosis. Specifically, for the area of hematology, from the first clinical and paraclinical characterization studies, hematological and hemostasis abnormalities have been identified that have been consistently documented through different publications and whose knowledge is transcendent from the prognostic point of view. During the course of the disease, longitudinal evaluation of some hematological parameters is essential for the early identification of potentially complicated patients. Absolute leukocyte count, lymphoid depletion, and thrombocytopenia are the principally altered hematologic markers. Severe lymphopenia is a cardinal finding in the early phase of infection, and its persistence during disease progression has a greater adverse prognostic impact. The determination of the neutrophil/ lymphocyte and lymphocyte/ platelet hematic indices have also shown their usefulness as predictors of respiratory complications and mortality. A state of hypercoagulability demonstrated by high levels of D-dimer and or fibrinogen degradation products and various hemostatic alterations in the coagulation profile are associated with a higher rate of morbidity and mortality. Other inflammatory biomarkers including C-Reactive Protein, procalcitonin and ferritin can early identify those cases that require advanced ventilatory and/or hemodynamic support. In this review, the historical antecedents of the pathology and the main hematological and hemostasis alterations and their prognostic implications are addressed.
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BACKGROUND: Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptakevia AMP-activated protein kinase (AMPK)after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). METHODS: Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of ß-myosin heavy chain (ß-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). RESULTS: Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated ß-mhc, Hk2 and Pfk2 mRNA levels. CONCLUSION: These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.
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Animais , Masculino , Ratos , Testosterona/farmacologia , Receptores Androgênicos/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Glucose/metabolismo , Transdução de Sinais , Células Cultivadas , Hipertrofia , Miocárdio/patologiaRESUMO
The prevalence of cardiovascular mortality is higher in men than in age-matched premenopausal women. Gender differences are linked to circulating sex-related steroid hormone levels and their cardio-specific actions, which are critical factors involved in the prevalence and features of age-associated cardiovascular disease. In women, estrogens have been described as cardioprotective agents, while in men, testosterone is the main sex steroid hormone. The effects of testosterone as a metabolic regulator and cardioprotective agent in aging men are poorly understood. With advancing age, testosterone levels gradually decrease in men, an effect associated with increasing fat mass, decrease in lean body mass, dyslipidemia, insulin resistance and adjustment in energy substrate metabolism. Aging is associated with a decline in metabolism, characterized by modifications in cardiac function, excitation-contraction coupling, and lower efficacy to generate energy. Testosterone deficiency -as found in elderly men- rapidly becomes an epidemic condition, associated with prominent cardiometabolic disorders. Therefore, it is highly probable that senior men showing low testosterone levels will display symptoms of androgen deficiency, presenting an unfavorable metabolic profile and increased cardiovascular risk. Moreover, recent reports establish that testosterone replacement improves cardiomyocyte bioenergetics, increases glucose metabolism and reduces insulin resistance in elderly men. Thus, testosterone-related metabolic signaling and gene expression may constitute relevant therapeutic target for preventing, or treating, age- and gender-related cardiometabolic diseases in men. Here, we will discuss the impact of current evidence showing how cardiac metabolism is regulated by androgen levels in aging men.
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Envelhecimento/patologia , Androgênios/metabolismo , Doenças Cardiovasculares/patologia , Idoso , Androgênios/administração & dosagem , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/metabolismo , Humanos , MasculinoRESUMO
Bursera morelensis is used in Mexican folk medicine to treat wounds on the skin. It is an endemic tree known as "aceitillo", and the antibacterial and antifungal activity of its essential oil has been verified; it also acts as an anti-inflammatory. All of these reported biological activities make the essential oil of B. morelensis a candidate to accelerate the wound-healing process. The objective was to determine the wound-healing properties of B. morelensis' essential oil on a murine model. The essential oil was obtained by hydro-distillation, and the chemical analysis was performed by gas chromatography-mass spectrometry (GC-MS). In the murine model, wound-healing efficacy (WHE) and wound contraction (WC) were evaluated. Cytotoxic activity was evaluated in vitro using peritoneal macrophages from BALB/c mice. The results showed that 18 terpenoid-type compounds were identified in the essential oil. The essential oil had remarkable WHE regardless of the dose and accelerated WC and was not cytotoxic. In vitro tests with fibroblasts showed that cell viability was dose-dependent; by adding 1 mg/mL of essential oil (EO) to the culture medium, cell viability decreased below 80%, while, at doses of 0.1 and 0.01 mg/mL, it remained around 90%; thus, EO did not intervene in fibroblast proliferation, but it did influence fibroblast migration when wound-like was done in monolayer cultures. The results of this study demonstrated that the essential oil was a pro-wound-healing agent because it had good healing effectiveness with scars with good tensile strength and accelerated repair. The probable mechanism of action of the EO of B. morelensis, during the healing process, is the promotion of the migration of fibroblasts to the site of the wound, making them active in the production of collagen and promoting the remodeling of this collagen.
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Bursera/química , Óleos Voláteis/farmacologia , Óleos de Plantas/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Cromatografia Gasosa-Espectrometria de Massas , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óleos Voláteis/química , Compostos Fitoquímicos/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Óleos de Plantas/química , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/patologiaRESUMO
Introducción: Pteridium aquilinum es un helecho heliófilo ampliamente distribuido en México. Es una especie pionera que usualmente se encuentra en hábitats alterados y tiene gran relevancia ecológica por sus propiedades alelopáticas, su resistencia al fuego y a condiciones de sequía. Objetivo: Realizar una descripción integral de la forma y ornamentación de las esporas de P. aquilinum, así como de la morfogénesis del gametofito, incluyendo el tipo de germinación y el desarrollo protálico (resaltando su morfología). Además, describir la anatomía del esporofito joven desarrollado en condiciones in vitro. Metodología: Se utilizó microscopía electrónica de barrido y técnica histológica de parafina para la descripción de las fases del gametofito y esporofito. Resultados: Las esporas son globulares y el trilete tiene ornamentación granulada, mientras que su germinación fue de tipo Vittaria y el desarrollo protálico correspondió al tipo Adiantum. Los anteridios se observaron 13 días después de la siembra, mientras que los arquegonios surgieron al día 17. La primera hoja del esporofito apareció entre los días 60 y 70. Al cuarto mes, la fase esporofítica desarrollada in vitro mostró la anatomía típica de la especie a esta edad, dado que no presentó vitrificación. El análisis histológico del rizoma, la base del peciolo, el raquis de primer orden y la lámina mostraron los sistemas de tres tejidos bien diferenciados. Las modificaciones anatómicas observadas in vitro, como una dictiostela monocíclica y sólo una banda de esclerénquima en el rizoma, podrían atribuirse a la edad de los individuos. Por otra parte, los estomas están presentes en la superficie adaxial de la lámina, que corresponde al tipo anomocítico. Aunque estos estomas se formaron en condiciones in vitro, es importante resaltar que son completamente funcionales. Conclusiones: Nuestro trabajo describe por primera vez la morfo-anatomía de las fases gametofítica y esporofítica del ciclo de vida de P. aquilinum en condiciones in vitro. Nuestros resultados posiblemente permitan la exploración con mayor profundidad de las propiedades biológicas, fisiológicas y ecológicas de la especie.
Introduction: Pteridium aquilinum is a heliophilous fern widely distributed in Mexico. It is a pioneer species usually found within disturbed habitats with high ecological relevance because of its allelopathic properties, its resistance to fire and drought conditions. Objective: Provide an integrative description regarding P. aquilinum spores shape and ornamentation, and also on gametophyte morphogenesis, including the type of germination and the prothallic development (highlighting its morphology). Furthermore, the anatomy of young sporophyte grown under in vitro conditions was described. Methods: We used scanning electron microscopy and histological paraffin technique to describe the gametophytic and sporophytic phases. Results: The evaluation of the spores showed the presence of globular morphology and triletes with granulated ornamentation; while their germination was Vittaria-type, the prothallic development corresponded to the Adiantum-type. The antheridia were observed 13 days following to the sowing, whereas archegonia arose at day 17. The first leaf of the sporophyte appeared between days 60 and 70. At fourth month, the in vitro grown sporophyte showed the typical anatomy of the individuals of the species at this age, since it did not exhibit vitrification. The histological analysis of rhizome, the petiole base, first order rachis and lamina showed the three tissue systems well differentiated. The anatomical modifications observed in vitro, such as a non-polycyclic dictyostele and just one band sclerenchyma in the rhizome, may be attributed to the individuals age. Moreover, the stomata are present on the adaxial surface of lamina, corresponding to the anomocytic type. Although these stomata were developed under in vitro conditions, it is important to highlight that they are completely functional. Conclusions: Our work describes for the first time the morpho-anatomy of both the gametophytic and the sporophytic phases in the life cycle of P. aquilinum under in vitro conditions. Our results indicate that this method will allow deeper exploration of biological, physiological and ecological properties of the species.