Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73–93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (μ), chemical hardness (η), and electrophilicity (ω) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29–31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.Fil: Santana Romo, Fabián. Pontificia Universidad Católica de Chile; ChileFil: Lagos, Carlos F.. Universidad San Sebastián; ChileFil: Duarte, Yorley. Universidad Andrés Bello; ChileFil: Castillo, Francisco. Pontificia Universidad Católica de Chile; ChileFil: Moglie, Yanina Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Maestro, Miguel A.. University of A Coruña; EspañaFil: Charbe, Nitin. Pontificia Universidad Católica de Chile; ChileFil: Zacconi, Flavia Cristina Milagro. Pontificia Universidad Católica de Chile; Chil

Biomedical applications of three‐dimensional bioprinted craniofacial tissue engineering

Abstract Anatomical complications of the craniofacial regions often present considerable challenges to the surgical repair or replacement of the damaged tissues. Surgical repair has its own set of limitations, including scarcity of the donor tissues, immune rejection, use of immune suppressors followed by the surgery, and restriction in restoring the natural aesthetic appeal. Rapid advancement in the field of biomaterials, cell biology, and engineering has helped scientists to create cellularized skeletal muscle‐like structures. However, the existing method still has limitations in building large, highly vascular tissue with clinical application. With the advance in the three‐dimensional (3D) bioprinting technique, scientists and clinicians now can produce the functional implants of skeletal muscles and bones that are more patient‐specific with the perfect match to the architecture of their craniofacial defects. Craniofacial tissue regeneration using 3D bioprinting can manage and eliminate the restrictions of the surgical transplant from the donor site. The concept of creating the new functional tissue, exactly mimicking the anatomical and physiological function of the damaged tissue, looks highly attractive. This is crucial to reduce the donor site morbidity and retain the esthetics. 3D bioprinting can integrate all three essential components of tissue engineering, that is, rehabilitation, reconstruction, and regeneration of the lost craniofacial tissues. Such integration essentially helps to develop the patient‐specific treatment plans and damage site‐driven creation of the functional implants for the craniofacial defects. This article is the bird's eye view on the latest development and application of 3D bioprinting in the regeneration of the skeletal muscle tissues and their application in restoring the functional abilities of the damaged craniofacial tissue. We also discussed current challenges in craniofacial bone vascularization and gave our view on the future direction, including establishing the interactions between tissue‐engineered skeletal muscle and the peripheral nervous system

Small interfering RNA for cancer treatment: overcoming hurdles in delivery

© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences In many ways, cancer cells are different from healthy cells. A lot of tactical nano-based drug delivery systems are based on the difference between cancer and healthy cells. Currently, nanotechnology-based delivery systems are the most promising tool to deliver DNA-based products to cancer cells. This review aims to highlight the latest development in the lipids and polymeric nanocarrier for siRNA delivery to the cancer cells. It also provides the necessary information about siRNA development and its mechanism of action. Overall, this review gives us a clear picture of lipid and polymer-based drug delivery systems, which in the future could form the base to translate the basic siRNA biology into siRNA-based cancer therapies

Hypoxia-inducible factor (HIF): fuel for cancer progression

Hypoxia is an integral part of the tumor microenvironment, caused primarily due to rapidly multiplying tumor cells and a lack of proper blood supply. Among the major hypoxic pathways, HIF-1 transcription factor activation is one of the widely investigated pathways in the hypoxic tumor microenvironment (TME). HIF-1 is known to activate several adaptive reactions in response to oxygen deficiency in tumor cells. HIF-1 has two subunits, HIF-1β (constitutive) and HIF-1α (inducible). The HIF-1α expression is largely regulated via various cytokines (through PI3K-ACT-mTOR signals), which involves the cascading of several growth factors and oncogenic cascades. These events lead to the loss of cellular tumor suppressant activity through changes in the level of oxygen via oxygen-dependent and oxygenindependent pathways. The significant and crucial role of HIF in cancer progression and its underlying mechanisms have gained much attention lately among the translational researchers in the fields of cancer and biological sciences, which have enabled them to correlate these mechanisms with various other disease modalities. In the present review, we have summarized the key findings related to the role of HIF in the progression of tumors

Biomedical applications of three-dimensional bioprinted craniofacial tissue engineering.

Anatomical complications of the craniofacial regions often present considerable challenges to the surgical repair or replacement of the damaged tissues. Surgical repair has its own set of limitations, including scarcity of the donor tissues, immune rejection, use of immune suppressors followed by the surgery, and restriction in restoring the natural aesthetic appeal. Rapid advancement in the field of biomaterials, cell biology, and engineering has helped scientists to create cellularized skeletal muscle-like structures. However, the existing method still has limitations in building large, highly vascular tissue with clinical application. With the advance in the three-dimensional (3D) bioprinting technique, scientists and clinicians now can produce the functional implants of skeletal muscles and bones that are more patient-specific with the perfect match to the architecture of their craniofacial defects. Craniofacial tissue regeneration using 3D bioprinting can manage and eliminate the restrictions of the surgical transplant from the donor site. The concept of creating the new functional tissue, exactly mimicking the anatomical and physiological function of the damaged tissue, looks highly attractive. This is crucial to reduce the donor site morbidity and retain the esthetics. 3D bioprinting can integrate all three essential components of tissue engineering, that is, rehabilitation, reconstruction, and regeneration of the lost craniofacial tissues. Such integration essentially helps to develop the patient-specific treatment plans and damage site-driven creation of the functional implants for the craniofacial defects. This article is the bird's eye view on the latest development and application of 3D bioprinting in the regeneration of the skeletal muscle tissues and their application in restoring the functional abilities of the damaged craniofacial tissue. We also discussed current challenges in craniofacial bone vascularization and gave our view on the future direction, including establishing the interactions between tissue-engineered skeletal muscle and the peripheral nervous system

Predicting needlestick and sharps injuries in nursing students: Development of the SNNIP scale

Aim: To develop an instrument to investigate knowledge and predictive factors of needlestick and sharps injuries (NSIs) in nursing students during clinical placements. Design: Instrument development and cross-sectional study for psychometric testing. Methods: A self-administered instrument including demographic data, injury epidemiology and predictive factors of NSIs was developed between October 2018–January 2019. Content validity was assessed by a panel of experts. The instrument's factor structure and discriminant validity were explored using principal components analysis. The STROBE guidelines were followed. Results: Evidence of content validity was found (S-CVI 0.75; I-CVI 0.50–1.00). A three-factor structure was shown by exploratory factor analysis. Of the 238 participants, 39% had been injured at least once, of which 67.3% in the second year. Higher perceptions of “personal exposure” (4.06, SD 3.78) were reported by third-year students. Higher scores for “perceived benefits” of preventive behaviours (13.6, SD 1.46) were reported by second-year students

Modelos de combustibles para arbustales de la Región Andina de las provincias de Río Negro, Chubut y Santa Cruz

En este folleto de divulgación, se dan a conocer las principales herramientas para el modelado de los combustibles vegetales en relación con sus respuestas al fuego.  Está escrito de una manera sencilla para que pueda ser interpretado por jefes de cuadrillas o de brigadas de combatientes de incendios forestales.  En el mismo de describe una metodología común y replicable para la obtención de los llamados "modelos de combustible".   Se dan ejemplos de 6 de estos modelos desarrollados para arbustales del ecotono bosque-estepa de la Patagonia. en base a información científica y empírica.Fil: Rey, Marcelo A.. Provincia de Río Negro. Servicio Provincial de Lucha contra Incendios Forestales; ArgentinaFil: Cuevas, Jorge. Provincia de Río Negro. Servicio Provincial de Lucha contra Incendios Forestales; ArgentinaFil: Sales, Bruno. Provincia de Río Negro. Servicio Provincial de Lucha contra Incendios Forestales; ArgentinaFil: Muñoz, Miriam M.. Provincia de Santa Cruz. Consejo Agrario; ArgentinaFil: Méndez, Mario. Provincia de Santa Cruz. Consejo Agrario; ArgentinaFil: Antequera, Silvio. Provincia de Chubut. Dirección General de Bosques y Parques; ArgentinaFil: Casas, Ángel Leandro. Provincia de Chubut. Dirección General de Bosques y Parques; ArgentinaFil: Lencinas, José Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Provincia del Chubut. Centro de Investigación y Extensión Forestal Andino Patagónico; ArgentinaFil: Mohr Bell, Diego Alejandro. Provincia del Chubut. Centro de Investigación y Extensión Forestal Andino Patagónico; ArgentinaFil: Gómez, Mariano. Provincia del Chubut. Centro de Investigación y Extensión Forestal Andino Patagónico; ArgentinaFil: Defossé, Guillermo Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centro de Investigación y Extensión Forestal Andino Patagónico; Argentina. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ingeniería - Sede Esquel. Departamento de Ingeniería Forestal; ArgentinaFil: Bianchi, Lucas Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rodríguez, Norberto. Universidad Nacional de la Patagonia "San Juan Bosco"; ArgentinaFil: Díaz, María Cecilia. Plan Nacional de Manejo del Fuego; ArgentinaFil: Dentoni, María del Carmen. Plan Nacional de Manejo del Fuego; ArgentinaFil: Zacconi, Gabriel. Plan Nacional de Manejo del Fuego; Argentin

Modelos de combustibles para arbustales de la Región Andina de las provincias de Río Negro, Chubut y Santa Cruz

En este folleto de divulgación, se dan a conocer las principales herramientas para el modelado de los combustibles vegetales en relación con sus respuestas al fuego.  Está escrito de una manera sencilla para que pueda ser interpretado por jefes de cuadrillas o de brigadas de combatientes de incendios forestales.  En el mismo de describe una metodología común y replicable para la obtención de los llamados "modelos de combustible".   Se dan ejemplos de 6 de estos modelos desarrollados para arbustales del ecotono bosque-estepa de la Patagonia. en base a información científica y empírica.Fil: Rey, Marcelo A.. Provincia de Río Negro. Servicio Provincial de Lucha contra Incendios Forestales; ArgentinaFil: Cuevas, Jorge. Provincia de Río Negro. Servicio Provincial de Lucha contra Incendios Forestales; ArgentinaFil: Sales, Bruno. Provincia de Río Negro. Servicio Provincial de Lucha contra Incendios Forestales; ArgentinaFil: Muñoz, Miriam M.. Provincia de Santa Cruz. Consejo Agrario; ArgentinaFil: Méndez, Mario. Provincia de Santa Cruz. Consejo Agrario; ArgentinaFil: Antequera, Silvio. Provincia de Chubut. Dirección General de Bosques y Parques; ArgentinaFil: Casas, Ángel Leandro. Provincia de Chubut. Dirección General de Bosques y Parques; ArgentinaFil: Lencinas, José Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Provincia del Chubut. Centro de Investigación y Extensión Forestal Andino Patagónico; ArgentinaFil: Mohr Bell, Diego Alejandro. Provincia del Chubut. Centro de Investigación y Extensión Forestal Andino Patagónico; ArgentinaFil: Gómez, Mariano. Provincia del Chubut. Centro de Investigación y Extensión Forestal Andino Patagónico; ArgentinaFil: Defossé, Guillermo Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centro de Investigación y Extensión Forestal Andino Patagónico; Argentina. Universidad Nacional de la Patagonia "San Juan Bosco". Facultad de Ingeniería - Sede Esquel. Departamento de Ingeniería Forestal; ArgentinaFil: Bianchi, Lucas Osvaldo. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rodríguez, Norberto. Universidad Nacional de la Patagonia "San Juan Bosco"; ArgentinaFil: Díaz, María Cecilia. Plan Nacional de Manejo del Fuego; ArgentinaFil: Dentoni, María del Carmen. Plan Nacional de Manejo del Fuego; ArgentinaFil: Zacconi, Gabriel. Plan Nacional de Manejo del Fuego; Argentin