Stem Cell Therapy for Erectile Dysfunction: A Step towards a Future Treatment.

Background: The improvement of absent or partial response in the medical treatment of erectile dysfunction (ED) has led to the development of minimally invasive new treatment modalities in the field of regenerative medicine. Methods: A literature review on stem cell therapy for the treatment of ED was performed. We searched for the terms "erectile dysfunction" and "stem cell therapy" in PubMed and Clinicaltrials.gov. Literature searching was conducted in English and included articles from 2010 to 2022. Results: New treatment modalities for ED involving stem cell therapy are not only conceived with a curative intent but also aim to avoid unnecessary adverse effects. Several sources of stem cells have been described, each with unique characteristics and potential applications, and different delivery methods have been explored. A limited number of interventional studies over the past recent years have provided evidence of a safety profile in their use and promising results for the treatment of ED, although there are not enough studies to generate an appropriate protocol, dose or cell lineage, or to determine a mechanism of action. Conclusions: Stem cell therapy is a novel treatment for ED with potential future applications. However, most urological societies agree that further research is required to conclusively prove its potential benefit.

Second-Generation Enamine-Type Schiff Bases as 2-Amino Acid-Derived Antifungals against Fusarium oxysporum: Microwave-Assisted Synthesis, In Vitro Activity, 3D-QSAR, and In Vivo Effect.

In this manuscript, the synthesis of enamine-type Schiff bases 1−48 derived from the amino acids L-Ala, L-Tyr, and L-Phe was carried out. Their in vitro activity and in vivo protective effect against Fusarium oxysporum were also evaluated through mycelial growth inhibition and disease severity reduction under greenhouse conditions. The in vitro activity of test compounds 1−48 showed half-maximal inhibitory concentrations (IC50) at different levels below the 40 mM range. Deep analysis of the IC50 variations indicated that the size of the substituent on the acetylacetone derivatives and the electronic character on the cyclohexane-3-one fragment influenced the antifungal effect. 3D-QSAR models based on atoms (atom-based approach) were built to establish the structure−activity relationship of the test Schiff bases, showing a good correlation and predictive consistency (R2 > 0.70 and Q2 > 0.60). The respective contour analysis also provided information about the structural requirements for potentiating their antifungal activity. In particular, the amino acid-related fragment and the alkyl ester residue can favor hydrophobic interactions. In contrast, the nitrogen atoms and enamine substituent are favorable regions as H-donating and electron-withdrawing moieties. The most active compounds (40 and 41) protected cape gooseberry plants against F. oxysporum infection (disease severity index < 2), involving adequate physiological parameters (stomatal conductance > 150 mmol/m2s) after 45 days of inoculation. These promising results will allow the design of novel Schiff base-inspired antifungals using 2-amino acids as precursors.

Chiral Alcohols from Alkenes and Water: Directed Evolution of a Styrene Hydratase.

Enantioselective synthesis of chiral alcohols through asymmetric addition of water across an unactivated alkene is a highly sought-after transformation and a big challenge in catalysis. Herein we report the identification and directed evolution of a fatty acid hydratase from Marinitoga hydrogenitolerans for the highly enantioselective hydration of styrenes to yield chiral 1-arylethanols. While directed evolution for styrene hydration was performed in the presence of heptanoic acid to mimic fatty acid binding, the engineered enzyme displayed remarkable asymmetric styrene hydration activity in the absence of the small molecule activator. The evolved styrene hydratase provided access to chiral alcohols from simple alkenes and water with high enantioselectivity (>99 : 1 e.r.) and could be applied on a preparative scale.

Selective Biocatalytic N-Methylation of Unsaturated Heterocycles.

Methods for regioselective N-methylation and -alkylation of unsaturated heterocycles with "off the shelf" reagents are highly sought-after. This reaction could drastically simplify synthesis of privileged bioactive molecules. Here we report engineered and natural methyltransferases for challenging N-(m)ethylation of heterocycles, including benzimidazoles, benzotriazoles, imidazoles and indazoles. The reactions are performed through a cyclic enzyme cascade that consists of two methyltransferases using only iodoalkanes or methyl tosylate as simple reagents. This method enables the selective synthesis of important molecules that are otherwise difficult to access, proceeds with high regioselectivity (r.r. up to >99 %), yield (up to 99 %), on a preparative scale, and with nearly equimolar concentrations of simple starting materials.

Synthesis (Z) vs (E) Selectivity, Antifungal Activity against Fusarium oxysporum, and Structure-Based Virtual Screening of Novel Schiff Bases Derived from l-Tryptophan.

Schiff bases are widely used molecules due to their potential biological activity. In this manuscript, we presented the synthesis and NMR study of new enamine Schiff bases derived from l-tryptophan, showing that the Z-form of the enamine is the main tautomeric form for aliphatic precursors. The DFT-B3LYP methodology at the 6-311+G**(d,p) level suggested that the tautomeric imine forms are less stable than the corresponding enamine forms. Their isomerism depends on the formation of intramolecular hydrogen bonds and steric factors associated with the starting carbonyl precursors. The in vitro biological activity tests against Fusarium oxysporum revealed that acetylacetone derivatives are the most active agents (IC50 < 0.9 mM); however, the antifungal activity could be disfavored by bulky groups on ester and enamine moieties. Finally, the structure-based virtual screening through molecular docking and MM-GBSA rescoring revealed that Schiff bases 3e, 3g, and 3j behave putatively as binders for target proteins involved in the life processes of F. oxysporum. In this sense, molecular dynamics analysis showed that the ligand-protein complexes have good stability with root-mean-square deviation (RMSD) values within the allowed range. Therefore, the present study paves the way for designing new antifungal compounds based on l-tryptophan-derived Schiff bases.

Substrate Profiling of Anion Methyltransferases for Promiscuous Synthesis of S-Adenosylmethionine Analogs from Haloalkanes.

Biocatalytic alkylation reactions can be performed with high chemo-, regio- and stereoselectivity using S-adenosyl-l-methionine (SAM)-dependent methyltransferases (MTs) and SAM analogs. Currently, however, this methodology is limited in application due to the rather laborious protocols to access SAM analogs. It has recently been shown that halide methyltransferases (HMTs) enable synthesis and recycling of SAM analogs with readily available haloalkanes as starting material. Here we expand this work by using substrate profiling of the anion MT enzyme family to explore promiscuous SAM analog synthesis. Our study shows that anion MTs are in general very promiscuous with respect to the alkyl chain as well as the halide leaving group. Substrate profiling further suggests that promiscuous anion MTs cluster in sequence space. Next to iodoalkanes, cheaper, less toxic, and more available bromoalkanes have been converted and several haloalkanes bearing short alkyl groups, alkyl rings, and functional groups such as alkene, alkyne and aromatic moieties are accepted as substrates. Further, we applied the SAM analogs as electrophiles in enzyme-catalyzed regioselective pyrazole allylation with 3-bromopropene as starting material.

Biocatalytic Alkylation Chemistry: Building Molecular Complexity with High Selectivity.

Biocatalysis has traditionally been viewed as a field that primarily enables access to chiral centers. This includes the synthesis of chiral alcohols, amines and carbonyl compounds, often through functional group interconversion via hydrolytic or oxidation-reduction reactions. This limitation is partly being overcome by the design and evolution of new enzymes. Here, we provide an overview of a recently thriving research field that we summarize as biocatalytic alkylation chemistry. In the past 3-4 years, numerous new enzymes have been developed that catalyze sp3 C-C/N/O/S bond formations. These enzymes utilize different mechanisms to generate molecular complexity by coupling simple fragments with high activity and selectivity. In many cases, the engineered enzymes perform reactions that are difficult or impossible to achieve with current small-molecule catalysts such as organocatalysts and transition-metal complexes. This review further highlights that the design of new enzyme function is particularly successful when off-the-shelf synthetic reagents are utilized to access non-natural reactive intermediates. This underscores how biocatalysis is gradually moving to a field that build molecules through selective bond forming reactions.

Highly sensitive scent-detection of COVID-19 patients in vivo by trained dogs.

Timely and accurate diagnostics are essential to fight the COVID-19 pandemic, but no test satisfies both conditions. Dogs can scent-identify the unique odors of volatile organic compounds generated during infection by interrogating specimens or, ideally, the body of a patient. After training 6 dogs to detect SARS-CoV-2 by scent in human respiratory secretions (in vitro diagnosis), we retrained 5 of them to search and find the infection by scenting the patient directly (in vivo screening). Then, efficacy trials were designed to compare the diagnostic performance of the dogs against that of the rRT-PCR in 848 human subjects: 269 hospitalized patients (COVID-19 prevalence 30.1%), 259 hospital staff (prevalence 2.7%), and 320 government employees (prevalence 1.25%). The limit of detection in vitro was lower than 10-12 copies ssRNA/mL. During in vivo efficacy experiments, our 5 dogs detected 92 COVID-19 positive patients among the 848 study subjects. The alert (lying down) was immediate, with 95.2% accuracy and high sensitivity (95.9%; 95% C.I. 93.6-97.4), specificity (95.1%; 94.4-95.8), positive predictive value (69.7%; 65.9-73.2), and negative predictive value (99.5%; 99.2-99.7) in relation to rRT-PCR. Seventy-five days after finishing in vivo efficacy experiments, a real-life study (in vivo effectiveness) was executed among the riders of the Metro System of Medellin, deploying the human-canine teams without previous training or announcement. Three dogs were used to examine the scent of 550 volunteers who agreed to participate, both in test with canines and in rRT-PCR testing. Negative predictive value remained at 99.0% (95% C.I. 98.3-99.4), but positive predictive value dropped to 28.2% (95% C.I. 21.1-36.7). Canine scent-detection in vivo is a highly accurate screening test for COVID-19, and it detects more than 99% of infected individuals independent of key variables, such as disease prevalence, time post-exposure, or presence of symptoms. Additional training is required to teach the dogs to ignore odoriferous contamination under real-life conditions.

A Compendium of the Most Promising Synthesized Organic Compounds against Several Fusarium oxysporum Species: Synthesis, Antifungal Activity, and Perspectives.

Vascular wilt caused by F. oxysporum (FOX) is one of the main limitations of producing several agricultural products worldwide, causing economic losses between 40% and 100%. Various methods have been developed to control this phytopathogen, such as the cultural, biological, and chemical controls, the latter being the most widely used in the agricultural sector. The treatment of this fungus through systemic fungicides, although practical, brings problems because the agrochemical agents used have shown mutagenic effects on the fungus, increasing the pathogen's resistance. The design and the synthesis of novel synthetic antifungal agents used against FOX have been broadly studied in recent years. This review article presents a compendium of the synthetic methodologies during the last ten years as promissory, which can be used to afford novel and potential agrochemical agents. The revision is addressed from the structural core of the most active synthetic compounds against FOX. The synthetic methodologies implemented strategies based on cyclo condensation reactions, radical cyclization, electrocyclic closures, and carbon-carbon couplings by metal-organic catalysis. This revision contributes significantly to the organic chemistry, supplying novel alternatives for the use of more effective agrochemical agents against F. oxysporum.

Clinicopathological relationship in Colombian patients with lupus nephritis / Relación clínicopatológica en pacientes colombianos con nefritis lúpica

ABSTRACT Background: There are several clinical and laboratory features for lupus nephritis diagnosis; however, renal biopsy remains as the gold standard. Different series have tried to establish the relationship between these findings, with conflicting results. Objective: To describe the correlation between clinical and laboratory variables with histo-logical biopsy-proven lupus nephritis. Methods: An analytical cross-sectional study was conducted, between January, 2004 and December, 2012. Qualitative variables were described using absolute and relative frequencies, while quantitative variables were assessed by medians with interquartile range. The relationship with clinical findings was explored using chi-square maximum likelihood test, adjusted standardized residuals, hierarchical Kruskal-Wallis test, homogeneity of variance in data, post hoc Dunn's test, Spearman's correlation coefficient, and Mann-Whitney test. Results: 132 patients were included. Proliferative lupus nephritis was the most frequent (74%). The most common clinical condition was nephritic syndrome (46%); proteinuria was observed in 80%. No relationship was found between clinical syndromes and histological types; only statistically significant differences were observed between proliferative and nonproliferative forms regarding hematuria (72.1 vs. 46.7%; p = 0.012), C3 hypocomplementemia (70.9 vs. 43.3%; p = 0.007), 24-h proteinuria (2560 vs 741 mg; p = 0.001), and serum creatinine (1 vs. 0.77 mg/dL; p = 0.006). We found positive correlations between activity index and serum creatinine values, 24-h proteinuria, C3 hypocomplementemia, along with positive anti-DNA antibodies. Conclusion: There is a clinicopathological relationship within proliferative types and certain laboratory features (hematuria, elevated 24-h protein excretion, serum creatinine level, and C3 hypocomplementemia) in a mestizo population with lupus nephritis; nonetheless, no association was found with any other variables.

RESUMEN Introducción: Existen varias características clínicas y de laboratorio para el diagnóstico de la nefritis lúpica; sin embargo, la biopsia renal sigue siendo el estándar de oro. Diferentes series han tratado de establecer la relación entre estos hallazgos, con resultados contradictorios. Objetivo: Describir la correlación entre variables clínicas y de laboratorio con los hallazgos histológicos de nefritis lúpica comprobados por biopsia. Métodos: Se realizó un estudio transversal analítico entre enero de 2004 y diciembre de 2012. Se describieron las variables cualitativas utilizando frecuencias absolutas y relativas, mientras que las variables cuantitativas fueron evaluadas por medianas con rango intercuartílico. La relación con los hallazgos clínicos se exploró utilizando: prueba de probabilidad máxima de Chi-cuadrado, residuos estandarizados ajustados, prueba jerárquica de Kruskal-Wallis, homogeneidad en los datos de la varianza, prueba de Dunn post hoc, coeficiente de correlación de Spearman y prueba de Mann-Whitney. Resultados: Se incluyeron 132 pacientes La nefritis lúpica proliferativa fue la más frecuente (74%). La condición clínica más común fue el síndrome nefrítico (46%); Se observó proteinuria en el 80%. No se encontró relación entre los síndromes clínicos y los tipos histológicos; solo se observaron diferencias estadísticamente significativas entre las formas proliferativa y no proliferativa con respecto a: hematuria (72,1 vs. 46,7%; p = 0,012), hipocomplementemia C3 (70,9 vs. 43,3%; p = 0,007), proteinuria de 24 h (2.560 vs. 741 mg; p = 0,001) y creatinina sérica (1 vs. 0,77 mg/dl; p = 0,006). Se encontraron correlaciones positivas entre el índice de actividad y los valores de creatinina sérica, proteinuria de 24 h, hipocomplementemia C3, junto con anticuerpos anti-DNA positivos. Conclusión: Existe una relación clínico-patológica entre los tipos proliferativos y ciertos hallazgos paraclínicos (hematuria, elevación de 24 h de proteína, nivel de creatinina sérica e hipocomplementemia C3) en una población mestiza con nefritis lúpica; sin embargo, no se encontró asociación con ninguna otra variable.

Perfil clínico y epidemiológico de pacientes atendidos por hipertiroidismo e hipotiroidismo en el servicio de endocrinología de una institución hospitalaria de Medellín (Colombia) entre 2013 y 2015 / Clinical and epidemiological profile of patients with hyperthyroidism and hypothyroidism that receive endocrinological services from a medical institution in Medellín (Colombia) between 2013 and 2015

Objetivo: determinar el perfil epidemiológico en pacientes hipertiroideos e hipotiroideos que acudieron al servicio de endocrinología de una institución hospitalaria de Medellín (Colombia) entre 2013 y 2015.Materiales y métodos: se realizó un estudio descriptivo retrospectivo y se incluyeron todas las historias clínicas de pacientes con diagnóstico de hipertiroidismo o hipotiroidismo. Se realizó un análisis univariado con estadística descriptiva por medio de frecuencias absolutas y proporciones en el programa IBM SPSS versión 19.0. Resultados: se estudiaron 149 pacientes: 131 con hipotiroidismo y 18 con hipertiroidismo, la media de edad fue 57,8±17,8 años y 48,2±15,1 años respectivamente. La frecuencia de sexo femenino fue mayor en hipotiroideos que en hipertiroideos (86,3% versus 66,7%). Las principales etiologías en los hipotiroideos fueron el hipotiroidismo postquirúrgico 11,5% y la enfermedad de Hashimoto 5,3%,mientras que en el hipertiroidismo estuvieron la enfermedad de Graves 33,3% y tirotoxicosis 22,2%. El síntoma más frecuente en los pacientes estudiados fue el bocio con un 14,5% en los hipotiroideos versus un 38,9% en los hipertiroideos. Los antecedentes personales más frecuentes en ambos grupos de pacientes fueron hipertensión arterial y Diabetes Mellitus. Conclusión: los resultados del presente estudio son acordes a la información existente en la literatura, la presentación de patologías tiroideas es más común en el sexo femenino; y la principal etiología es cirugía y enfermedad de Graves para hipo e hipertiroidismo respectivamente..(AU)

Objective: determine the epidemiological profile of hyperthyroid and hypothyroid patients that receive endocrinological services from a medical institution in Medellin (Colombia) between 2013 and 2015. Materials and Methods: a descriptive, retrospective study was conducted and included the clinical records of patients diagnosed with hyperthyroidism or hypothyroidism. A univariate analysis was applied using descriptive statistics by means of absolute frequencies and proportions in the IBM SPSS software, version 19.0. Results: a sample of 149 patients was obtained 131 patients with hypothyroidism and 18 with hyperthyroidism, the average age was 57,8±17,8 years and 48,2±15,1 years, respectively. The frequency of female sex with hypothyroidism was greater than those patients with hyperthyroidism (86,3% versus 66,7%). Post-surgery hypothyroidism had a high prevalence 11,5% followed by the Hashimoto disease 5,3%.The principal etiologies in hyperthyroidism were Graves disease 33,3% and thyrotoxicosis 22,2%. With relation to the signs and frequent symptoms in the studied patients,the goiter was common in 14,5% of the patients with hypothyroidism versus 38,9% of those patients with hyperthyroidism. The most frequent diseases on past medical history in both groups of patients were high blood pressure and Diabetes Mellitus. Conclusion: the results of the present study are in agreement with the information existing in the literature, the presentation of thyroid pathologies is more common in the female sex; and the main etiology is surgery and Graves' disease for hypo and hyperthyroidism respectively..(AU)

Synthesis of Positional Isomeric Phenylphenalenones.

A series of isomeric phenylphenalenones in which the phenyl ring is located at all possible peripheral positions of the phenalenone nuclei was synthesized. The structural characteristics of the series, in which topological variation is permitted with minimal electronic disturbance, could, in principle, allow for easy pharmacophore recognition when the compounds are aligned in steroidomimetic conformations.

Application of the Crystalline Sponge Method to Revise the Structure of the Phenalenone Fuliginone.

The structure of fuliginone was revised from a phenyl substituted phenalenone to a hydroxyl substituted phenalenone as a result of its re-purification via HPLC with subsequent NMR analysis together with an independent synthesis and analysis of the crystal structure, which was secured via the crystalline sponge method. On-flow High Performance Liquid Chromatography coupled to Nuclear Magnetic Resonance spectroscopy (HPLC-NMR) was employed to confirm the presence of the natural product in the plant extract and to monitor for any possible degradation or conversion of the compound.

Synthesis of 8-Phenylphenalenones: 2-Hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one from Eichhornia crassipes.

2-Hydroxy-8-(4-hydroxyphenyl)-1H-phenalen-1-one (1), the first reported 8-phenylphenalenone from the roots of Eichhornia crassipes (water hyacinth), was synthesized starting from 2-methoxynaphthalene in 11 steps and with an overall yield of 2%. A cascade Friedel-Crafts/Michael annulation reaction between acryloyl chloride and 2-methoxynaphthalene afforded 9-methoxyperinaphthanone that, after transformation to 9-methoxy-2-(4-methoxyphenyl)-1H-phenalen-1-one by means of standard Suzuki-Miyaura methodology, was subjected to a reductive carbonyl transposition to afford 8-(4-methoxyphenyl)perinaphthanone. Dehydrogenation, epoxidation, and demethylation of the latter afforded 1.

Factores de riesgo asociados a la hipertension durante el embarazo / Risk factors associated to hypertension during pregnancy

La importancia de la búsqueda exhaustiva de factores de riesgo relacionados con la hipertensión durante el embarazo condiciona un nuevo enfoque clínico epidemiológico acerca de las baterias necesarias para el estudio de una materna a través del embarazo. De importancia fundamental factores como edad, nivel socioeconómico, enfermedades renovasculares presentes o pasadas, aborto, paridad, estado nutricional y grupo étnico, que el médico debe conocer para así poder establecer a tiempo el riesgo de dicho embarazo con respecto a una futura hipertension durante el embarazo. Este estudio pretende mostrar la frecuencia de presentación de dichos factores mediante un estudio descriptivo realizado en el Centro de salud de Horizontes en un periodo de dos y medio años. Se estudiaron 124 pacientes que asistieron a control prenatal, encontrándose un predominio de maternas menores de 29 años de nivel socioeconómico bajo, multíparas, y en mínima proporción con alteraciones renovasculares; solo una paciente presentó enfermedad hipertensiva durante el embarazo, cuyo parto llego a feliz término gracias a la oportuna remisión al Hospital Regional Simón Bolivar para su seguimiento y atención