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The COVID-19 pandemic has had a significant impact on the health and economy of the global population. Even after recovery from the disease, post-COVID-19 symptoms, such as pulmonary fibrosis, continue to be a concern. This narrative review aims to address pulmonary fibrosis (PF) from various perspectives, including the fibrotic mechanisms involved in idiopathic and COVID-19-induced pulmonary fibrosis. On the other hand, we also discuss the current therapeutic drugs in use, as well as those undergoing clinical or preclinical evaluation. Additionally, this article will address various biomarkers with usefulness for PF prediction, diagnosis, treatment, prognosis, and severity assessment in order to provide better treatment strategies for patients with this disease.
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COVID-19 , Fibrosis Pulmonar Idiopática , Humanos , Pandemias , COVID-19/complicaciones , Fibrosis Pulmonar Idiopática/diagnóstico , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/etiología , Fibrosis , Biomarcadores , Prueba de COVID-19RESUMEN
BACKGROUND: Epidemiological data on patients with COVID-19 referred to specialized weaning centers (SWCs) are sparse, particularly in low- and middle-income countries. Our aim was to describe clinical features, epidemiology, and outcomes of subjects admitted to SWCs in Argentina. METHODS: We conducted a prospective, multi-center, observational study between July 2020-December 2021 in 12 SWCs. We collected demographic characteristics, laboratory results, pulmonary function, and dependence on mechanical ventilation at admission, decannulation, weaning from mechanical ventilation, and status at discharge. A multiple logistic model was built to predict home discharge. RESULTS: We enrolled 568 tracheostomized adult subjects after the acute COVID-19 phase who were transferred to SWCs. Age was 62 [52-71], males 70%, Charlson comorbidity index was 2 [0-3], and length of stay in ICU was 42 [32-56] d. Of the 315 ventilator-dependent subjects, 72.4% were weaned, 427 (75.2%) were decannulated, and 366 subjects (64.5%) were discharged home. The mortality rate was 6.0%. In multivariate analysis, age (odds ratio 0.30 [95% CI 0.16-0.56], P < .001), Charlson comorbidity index (odds ratio 0.43 [95% CI 0.22-0.84], P < .01), mechanical ventilation duration in ICU (odds ratio 0.80 [95% CI 0.72-0.89], P < .001), renal failure (odds ratio 0.40 [95% CI 0.22-0.73], P = .003), and expiratory muscle weakness (odds ratio 0.35 [95% CI 0.19-0.62], P < .001) were independently associated with home discharge. CONCLUSIONS: Most subjects with COVID-19 transferred to SWCs were weaned, achieved decannulation, and were discharged to home. Age, high-comorbidity burden, prolonged mechanical ventilation in ICU, renal failure at admission, and expiratory muscle weakness were inversely associated with home discharge.
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COVID-19 , Insuficiencia Renal , Humanos , Masculino , COVID-19/epidemiología , Debilidad Muscular , Estudios Prospectivos , Respiración Artificial , Desconexión del Ventilador , Femenino , Persona de Mediana Edad , AncianoRESUMEN
The present study highlighted the repositioning of the drug dapsone (DDS) for cancer therapy. Due to its mechanism of action, DDS has a dual effect as an antibiotic and as an anti-inflammatory/immunomodulator; however, at high doses, it has important adverse effects. The derivative DDS-13 [N,N'-(sulfonyl bis (4,1-phenylene)) dioctanamide] was synthesized through an N-acylation reaction to compare it with DDS. Its cytotoxic effects in cancer cells (DU145 and HeLa) and non-cancer cells (HDFa) were observed at concentrations ranging 0.01-100 µM and its physicochemical/pharmacokinetic properties were analyzed using the SwissADME tool. The objectives of the present study were to evaluate the anticancer activity of both DDS and DDS-13 and to identify the physicochemical and pharmacokinetic properties of DDS-13. The results showed that DDS-13 presented a cytotoxic effect in the DU145 cell line (IC50=19.06 µM), while DDS showed a cytotoxic effect on both the DU145 (IC50=11.11 µM) and HeLa (IC50=13.07 µM) cell lines. DDS-13 appears to be a good cytotoxic candidate for the treatment of prostate cancer, while DDS appears to be a good candidate for both cervical and prostate cancer. Neither candidate showed a cytotoxic effect in non-cancerous cells. The different pharmacokinetic properties of DDS-13 make it a new candidate for evaluation in preclinical models for the treatment of cancer.
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The appearance of a new coronavirus, SARS-CoV-2, in 2019 kicked off an international public health emergency. Although rapid progress in vaccination has reduced the number of deaths, the development of alternative treatments to overcome the disease is still necessary. It is known that the infection begins with the interaction of the spike glycoprotein (at the virus surface) and the angiotensin-converting enzyme 2 cell receptor (ACE2). Therefore, a straightforward solution for promoting virus inhibition seems to be the search for molecules capable of abolishing such attachment. In this work, we tested 18 triterpene derivatives as potential inhibitors of SARS-CoV-2 against the receptor-binding domain (RBD) of the spike protein by means of molecular docking and molecular dynamics simulations, modeling the RBD S1 subunit from the X-ray structure of the RBD-ACE2 complex (PDB ID: 6M0J). Molecular docking revealed that at least three triterpene derivatives of each type (i.e., oleanolic, moronic and ursolic) present similar interaction energies as the reference molecule, i.e., glycyrrhizic acid. Molecular dynamics suggest that two compounds from oleanolic and ursolic acid, OA5 and UA2, can induce conformational changes capable of disrupting the RBD-ACE2 interaction. Finally, physicochemical and pharmacokinetic properties simulations revealed favorable biological activity as antivirals.
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COVID-19 , SARS-CoV-2 , Humanos , Enzima Convertidora de Angiotensina 2 , Simulación del Acoplamiento Molecular , Glicoproteína de la Espiga del Coronavirus , Simulación de Dinámica Molecular , Unión ProteicaRESUMEN
The use of derivatives of natural and synthetic origin has gained attention because of their therapeutic effects against human diseases. Coumarins are one of the most common organic molecules and are used in medicine for their pharmacological and biological effects, such as anti-inflammatory, anticoagulant, antihypertensive, anticonvulsant, antioxidant, antimicrobial, and neuroprotective, among others. In addition, coumarin derivates can modulate signaling pathways that impact several cell processes. The objective of this review is to provide a narrative overview of the use of coumarin-derived compounds as potential therapeutic agents, as it has been shown that substituents on the basic core of coumarin have therapeutic effects against several human diseases and types of cancer, including breast, lung, colorectal, liver, and kidney cancer. In published studies, molecular docking has represented a powerful tool to evaluate and explain how these compounds selectively bind to proteins involved in various cellular processes, leading to specific interactions with a beneficial impact on human health. We also included studies that evaluated molecular interactions to identify potential biological targets with beneficial effects against human diseases.
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Antiinfecciosos , Antineoplásicos , Neoplasias , Humanos , Simulación del Acoplamiento Molecular , Cumarinas/farmacología , Neoplasias/tratamiento farmacológico , Antiinfecciosos/farmacología , Antiinflamatorios/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
Dapsone (DDS) is an antibacterial drug with well-known antioxidant properties. However, the antioxidant behavior of its derivatives has not been well explored. In the present work, the antioxidant activity of 10 dapsone derivatives 4-substituted was determined by an evaluation in two in vitro models (DPPH radical scavenging assay and ferric reducing antioxidant power). These imine derivatives 1-10 were obtained through condensation between DDS and the corresponding aromatic aldehydes 4-substuited. Three derivatives presented better results than DDS in the determination of DPPH (2, 9, and 10). Likewise, we have three compounds with better reducing activity than dapsone (4, 9, and 10). In order to be more insight, the redox process, a conceptual DFT analysis was carried out. Molecular descriptors such as electronic distribution, the total charge accepting/donating capacity (I/A), and the partial charge accepting/donating capacity (ω+/ω-) were calculated to analyze the relative donor-acceptor capacity through employing a donor acceptor map (DAM). The DFT calculation allowed us to establish a relationship between GAPHOMO-LUMO and DAM with the observed antioxidant effects. According to the results, we concluded that compounds 2 and 3 have the lowest Ra values, representing a good antioxidant behavior observed experimentally in DPPH radical capturing. On the other hand, derivatives 4, 9, and 10 display the best reducing capacity activity with the highest ω- and Rd values. Consequently, we propose these compounds as the best antireductants in our DDS imine derivative series.
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Antioxidantes/síntesis química , Dapsona/química , Iminas/síntesis química , Antioxidantes/química , Antioxidantes/farmacología , Simulación por Computador , Teoría Funcional de la Densidad , Iminas/química , Iminas/farmacología , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Since the appearance of the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 in China, diabetes mellitus (DM) and hyperglycemia in patients infected with SARS-CoV, represent independent predictors of mortality. Therefore, metabolic control has played a major role in the prognosis of these patients. In the current pandemic of coronavirus disease 19 (COVID-19), multiple studies have shown that DM is one of the main comorbidities associated with COVID-19 and higher risk of complications and death. The incidence and prevalence of COVID-19 complications and death related with hyperglycemia in patients with or without DM are high. There are many hypotheses related with worse prognosis and death related to COVID-19 and/or hyperglycemia. However, the information about the interplay between hyperglycemia and angiotensin-converting enzyme 2 (ACE2), the critical receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in the context of SARS-CoV-2 infection, is almost null, but there is enough information to consider the possible participation of hyperglycemia in the glycation of this protein, unleashing a pool of reactions leading to acute respiratory distress syndrome and death in patients with COVID-19. In this document we investigated the current evidence related with ACE2 as a key element within the pathophysiological mechanism related with hyperglycemia extrapolating it to context of SARS-CoV-2 infection and its relationship with worse prognosis and death for COVID-19.
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The increase of insecurity levels in Mexico, as well as the fact that violence is a frequent experience among health personnel, motivated this study whose purpose was to evaluate the perception of security and violence that social service medical interns (SSMI) had on the institutions and localities where they carried out their social work and make visible the main types of violence to which they were exposed. This was a cross-sectional study, based on a perception survey self-administered to 157 SSMI from Zacatecas, in Mexico. A high proportion of the participants (75.8%) stated that they were victims of violence, describing 134 incidents; however, only 33.6% of SSMI made an official report. The reported incidents were related to organized crime (31.9%), verbal violence (20.6%), violence by the authorities (14.7%) and sexual harassment (11.8%). One hundred percent of the victims of sexual harassment were women (p = 0.039). According to the above, it is a priority to generate strategies to prevent and reduce the risk of exposure to the violence generated in the medical units and communities where SSMI carry out their activities as medical graduates, as well as, to efficiently process formal violence reports to promote a safe environment that favors the fulfillment of the practice of SSMIs in Mexico.
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Servicio Social , Violencia , Estudios Transversales , Femenino , Humanos , México , PercepciónRESUMEN
Background and objectives: Pytiriasis alba (PA) is a common skin disorder which affects 80% of children between six and 16 years. The etiology of PA is unclear, but hypo-pigmented patches in photo-exposed zones characterize the disease. Because the high ultraviolet exposition of the skin promotes an acute inflammatory response and an increase of oxidative stress (OS), this study aimed to evaluate the expression levels of inflammatory and OS-related genes in skin biopsies, and their association with PA. Materials and Methods: A cross-sectional study was carried out. Skin biopsies of the lesion sites and healthy skin (controls) from 16 children with PA were evaluated. The tissue expression of IL-4, IL-6, IL-17A, TNFα, INFγ, IL-1ß, SOD1, and HMOX1 was analyzed by qRT-PCR, using SYBR Green and glyceraldehyde-3-phosphate dehydrogenase gene as the endogenous control. Results: There were differences in the ΔCq values of HMOX1, SOD1, IL-6, and IFNγ between tissue with lesions and healthy skin (p < 0.05). Compared with healthy skin, IL-6, IFNγ, HMOX1, and SOD1 were predominantly under-expressed in the lesion sites. However, 25% of skin biopsies with lesions showed over-expression of these four genes. Positive correlations between the expression of IL-6 and HMOX1, SOD1, and IFNγ (p < 0.05) were also observed. Conclusions: Our results suggest the presence of molecular stages of PA, defined according to the over-expression (first stage) or under-expression (second stage) of the HMOX1, SOD1, IL-6, and IFNγ genes in abnormal skin tissue. These findings may have implications for the selection of treatment for PA-related lesions.
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Biopsia/estadística & datos numéricos , Inflamación/sangre , Pitiriasis/patología , Piel/fisiopatología , Biopsia/métodos , Niño , Estudios Transversales , Femenino , Humanos , Inflamación/genética , Masculino , México/epidemiología , Estrés Oxidativo/fisiología , Pitiriasis/epidemiología , Piel/químicaRESUMEN
The antileukemia cancer activity of organic compounds analogous to ellipticine representes a critical endpoint in the understanding of this dramatic disease. A molecular modeling simulation on a dataset of 23 compounds, all of which comply with Lipinski's rules and have a structure analogous to ellipticine, was performed using the quantitative structure activity relationship (QSAR) technique, followed by a detailed docking study on three different proteins significantly involved in this disease (PDB IDs: SYK, PI3K and BTK). As a result, a model with only four descriptors (HOMO, softness, AC1RABAMBID, and TS1KFABMID) was found to be robust enough for prediction of the antileukemia activity of the compounds studied in this work, with an R2 of 0.899 and Q2 of 0.730. A favorable interaction between the compounds and their target proteins was found in all cases; in particular, compounds 9 and 22 showed high activity and binding free energy values of around -10 kcal/mol. Theses compounds were evaluated in detail based on their molecular structure, and some modifications are suggested herein to enhance their biological activity. In particular, compounds 22_1, 22_2, 9_1, and 9_2 are indicated as possible new, potent ellipticine derivatives to be synthesized and biologically tested.
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Antineoplásicos/síntesis química , Elipticinas/síntesis química , Leucemia/metabolismo , Quinasa Syk/metabolismo , Agammaglobulinemia Tirosina Quinasa/química , Agammaglobulinemia Tirosina Quinasa/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Teoría Funcional de la Densidad , Elipticinas/química , Elipticinas/farmacología , Humanos , Leucemia/tratamiento farmacológico , Modelos Moleculares , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Relación Estructura-Actividad Cuantitativa , Quinasa Syk/químicaRESUMEN
Diabetic foot ulcers (DFUs) are very important diabetes-related lesions that can lead to serious physical consequences like amputations of limbs and equally severe social, psychological, and economic outcomes. It is reported that up to 25% of patients with diabetes develop a DFU in their lifetime, and more than half of them become infected. Therefore, it is essential to manage infection and ulcer recovery to prevent negatives outcomes. The available information plays a significant role in keeping both physicians and patients aware of the emerging therapies against DFUs. The purpose of this review is to compile the currently available approaches in the managing and treatment of DFUs, including molecular and regenerative medicine, antimicrobial and energy-based therapies, and the use of plant extracts, antimicrobial peptides, growth factors, ozone, devices, and nano-medicine, to offer an overview of the assessment of this condition.
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Hit, Lead & Candidate Discovery Protein tyrosine phosphatase 1B (PTP-1B) has attracted interest as a novel target for the treatment of type 2 diabetes, this because its role in the insulin-signaling pathway as a negative regulator. Thus, the aim of current work was to obtain seven ursolic acid derivatives as potential antidiabetic agents with PTP-1B inhibition as main mechanism of action. Furthermore, derivatives 1-7 were submitted in vitro to enzymatic PTP-1B inhibition being 3, 5, and 7 the most active compounds (IC50 = 5.6, 4.7, and 4.6 µM, respectively). In addition, results were corroborated with in silico docking studies with PTP-1B orthosteric site A and extended binding site B, showed that 3 had polar and Van der Waals interactions in both sites with Lys120, Tyr46, Ser216, Ala217, Ile219, Asp181, Phe182, Gln262, Val49, Met258, and Gly259, showing a docking score value of -7.48 Kcal/mol, being more specific for site A. Moreover, compound 7 showed polar interaction with Gln262 and Van der Waals interactions with Ala217, Phe182, Ile219, Arg45, Tyr46, Arg47, Asp48, and Val49 with a predictive docking score of -6.43 kcal/mol, suggesting that the potential binding site could be localized in the site B adjacent to the catalytic site A. Finally, derivatives 2 and 7 (50 mg/kg) were selected to establish their in vivo antidiabetic effect using a noninsulin-dependent diabetes mice model, showing significant blood glucose lowering compared with control group (p < .05).
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Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Triterpenos , Animales , Glucemia/efectos de los fármacos , Simulación por Computador , Diabetes Mellitus Experimental/sangre , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Masculino , Ratones , Conformación Molecular , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteína Tirosina Fosfatasa no Receptora Tipo 1/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Triterpenos/química , Triterpenos/farmacología , Triterpenos/uso terapéutico , Ácido UrsólicoRESUMEN
PURPOSE: To perform serum microRNA expression profiling to identify members of chromosome 19 miRNA cluster involved in preeclampsia development. METHODS: Serum chromosome 19 miRNA cluster microRNA expression profiling was evaluated at 12, 16, and 20 gestational weeks and at the time of preeclampsia diagnosis, in women who developed preeclampsia (WWD-PE; n = 16) and controls (n = 18) using TaqMan low density array plates. RESULTS: A total of 51 chromosome 19 microRNA cluster members were evaluated. The circulating hsa-miRs 512-3p, 518f-3p, 520c-3p, and 520d-3p, were differentially expressed between groups (P < 0.05). Compared with controls, serum levels of hsa-miR-518f-3p at 20 GW were useful for identifying WWD-Mild-PE (P = 0.035) and WWD-Severe-PE (P = 0.007). CONCLUSIONS: Serum hsa-miRs 512-3p, 518f-3p, 520c-3p, and 520d-3p, are differentially expressed between WWD-PE and controls and their role in the development of preeclampsia should be investigated further.
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Cromosomas Humanos Par 19 , Perfilación de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , Placenta/metabolismo , Preeclampsia/sangre , Estudios de Casos y Controles , Femenino , Regulación del Desarrollo de la Expresión Génica , Humanos , Preeclampsia/genética , Preeclampsia/metabolismo , EmbarazoRESUMEN
Despite the implementation of programmes to improve maternal health, maternal and foetal mortality rates still remain high. The presence of maternal distress and its association with the development of pregnancy hypertensive disorders is not well established. The aim of this study was to evaluate the association between maternal distress and the development of hypertensive disorders in pregnancy in a prospective cohort of 321 Mexican women. Symptoms of maternal distressing were evaluated at week 20th of gestation using the General Health Questionnaire. The presence of acute somatic symptoms, social dysfunction, anxiety and insomnia increased the odds of developing a pregnancy hypertensive disorder by 5.1-26.4 times in study population (p values < .05). Our results support the participation of maternal distress in the development of hypertensive disorders of pregnancy. The implementation of effective programmes prioritising risk factors during pregnancy including the presence of maternal distressing factors is recommended. Impact statement What is already known on this subject: Changes in the nervous, endocrine, and immune systems have been observed in pregnant women with distress conditions leading to gestational disorders. What do the results of this study add: The presence of acute somatic symptoms, social dysfunction, anxiety and insomnia increased the developing of hypertensive disorders in Mexican population. What are the implications of these findings for clinical practice and/or further research: These findings may contribute to a better understanding of the role of the maternal stress in the development of hypertensive disorders of pregnancy, and in the implementation of effective programmes for clinical practice prioritising risk factors during pregnancy, including the presence of maternal distressing factors.
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Hipertensión Inducida en el Embarazo/epidemiología , Trastornos Mentales/complicaciones , Trastornos Mentales/epidemiología , Complicaciones del Embarazo/psicología , Adolescente , Adulto , Ansiedad/complicaciones , Ansiedad/epidemiología , Estudios de Cohortes , Femenino , Humanos , Relaciones Interpersonales , Salud Materna , México/epidemiología , Embarazo , Estudios Prospectivos , Factores de Riesgo , Trastornos del Inicio y del Mantenimiento del Sueño/complicaciones , Trastornos del Inicio y del Mantenimiento del Sueño/epidemiología , Encuestas y CuestionariosRESUMEN
Six derivatives (1-6) of moronic acid were semi-synthesized and their in vitro protein tyrosine phosphatase 1B (PTP-1B) inhibition activity assessed. Derivatives 2 (IC50=10.8 ± 0.5 µM) and 6 (IC50=7.5 ± 0.1 µM) displayed the most potent inhibitory activity. Therefore, they (50mg/Kg) were tested for their antidiabetic effect in vivo using a non-insulin dependent diabetes mellitus rat model. The results indicated that they decrease plasma glucose levels during all the experiment (p <0.05). Docking analysis of 2 and 6 with PTP-1B orthosteric site A and allosteric site B, showed that 2 had polar and Van der Waals interactions in both sites with Val49, Gln262, Met258, Phe182, Ala217, Ile219 and Gly259, displaying more affinity for site A. Compound 6 showed polar interaction with Gln262 and Van der Waals with Val49, Ile219, Gly259, Arg254, Ala27, Phe52, Met258, Asp48 and Phe182, suggesting that the potential binding site is localized in site B, close to the catalytic site A. Therefore, derivatives 2 and 6 have potential for the development of antidiabetic agents.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/enzimología , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ácido Oleanólico/análogos & derivados , Proteína Tirosina Fosfatasa no Receptora Tipo 1/antagonistas & inhibidores , Animales , Glucemia/efectos de los fármacos , Simulación por Computador , Relación Dosis-Respuesta a Droga , Hipoglucemiantes/síntesis química , Simulación del Acoplamiento Molecular , Estructura Molecular , Ácido Oleanólico/síntesis química , Ácido Oleanólico/química , Ácido Oleanólico/farmacología , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Non-insulin dependent diabetes mellitus is a multifactorial disease that links different metabolic routes; a point of convergence is the enzyme PTP-1B which turns off insulin and leptin receptors involved in glucose and lipid metabolism, respectively. Pentacyclic acid triterpenes such as oleanolic acid (OA) have proved to be excellent PTP-1B inhibitors, thus, the purpose of current work was to generate a series of derivatives that improve the pharmacological effect of OA. Our findings suggest that the presence of the carboxylic acid and/or its corresponding reduction product carbinol derivative (H-bond donor) in C-28 is required to maintain the inhibitory activity; moreover, this is further enhanced by ester or ether formation on C-3. The most active derivatives were cinnamoyl ester (6) and ethyl ether (10). Compound 6 showed potent in vitro inhibitory activity and significantly decrease of blood glucose levels on in vivo experiments. Meanwhile, 10 showed contrasting outcomes, since it was the compound with higher inhibitory activity and selectivity over PTP-1B and has improved interaction with site B, according with docking studies, the in vivo antidiabetic effect was similar to oleanolic acid. In conclusion, oleanolic acid derivatives have revealed an enhanced inhibitory effect over PTP-1B activity by increasing molecular interactions with either catalytic or allosteric sites and producing a hypoglycaemic effect on non insulin dependent diabetes mellitus rat model.