HP0953 - hypothetical virulence factor overexpresion and localization during Helicobacter pylori infection of gastric epithelium.

BACKGROUND: The high prevalence and persistence of Helicobacter pylori (H. pylori) infection, as well as the diversity of pathologies related to it, suggest that the virulence factors used by this microorganism are varied. Moreover, as its proteome contains 340 hypothetical proteins, it is important to investigate them to completely understand the mechanisms of its virulence and survival. We have previously reported that the hypothetical protein HP0953 is overexpressed during the first hours of adhesion to inert surfaces, under stress conditions, suggesting its role in the environmental survival of this bacterium and perhaps as a virulence factor. AIM: To investigate the expression and localization of HP0953 during adhesion to an inert surface and against gastric (AGS) cells. METHODS: Expression analysis was performed for HP0953 during H. pylori adhesion. HP0953 expression at 0, 3, 12, 24, and 48 h was evaluated and compared using the Kruskal-Wallis equality-of-populations rank test. Recombinant protein was produced and used to obtain polyclonal antibodies for immunolocalization. Immunogold technique was performed on bacterial sections during adherence to inert surfaces and AGS cells, which was analyzed by transmission electron microscopy. HP0953 protein sequence was analyzed to predict the presence of a signal peptide and transmembrane helices, both provided by the ExPASy platform, and using the GLYCOPP platform for glycosylation sites. Different programs, via, I-TASSER, RaptorX, and HHalign-Kbest, were used to perform three-dimensional modeling. RESULTS: HP0953 exhibited its maximum expression at 12 h of infection in gastric epithelium cells. Immunogold technique revealed HP0953 localization in the cytoplasm and accumulation in some peripheral areas of the bacterial body, with greater expression when it is close to AGS cells. Bioinformatics analysis revealed the presence of a signal peptide that interacts with the transmembrane region and then allows the release of the protein to the external environment. The programs also showed a similarity with the Tip-alpha protein of H. pylori. Tip-alpha is an exotoxin that penetrates cells and induces tumor necrosis factor alpha production, and HP0953 could have a similar function as posttranslational modification sites were found; modifications in turn require enzymes located in eukaryotic cells. Thus, to be functional, HP0953 may necessarily need to be translocated inside the cell where it can trigger different mechanisms producing cellular damage. CONCLUSION: The location of HP0953 around infected cells, the probable posttranslational modifications, and its similarity to an exotoxin suggest that this protein is a virulence factor.

Evolution of the Inhibitory and Non-Inhibitory ε, ζ, and IF1 Subunits of the F1FO-ATPase as Related to the Endosymbiotic Origin of Mitochondria.

The F1FO-ATP synthase nanomotor synthesizes >90% of the cellular ATP of almost all living beings by rotating in the "forward" direction, but it can also consume the same ATP pools by rotating in "reverse." To prevent futile F1FO-ATPase activity, several different inhibitory proteins or domains in bacteria (ε and ζ subunits), mitochondria (IF1), and chloroplasts (ε and γ disulfide) emerged to block the F1FO-ATPase activity selectively. In this study, we analyze how these F1FO-ATPase inhibitory proteins have evolved. The phylogeny of the α-proteobacterial ε showed that it diverged in its C-terminal side, thus losing both the inhibitory function and the ATP-binding/sensor motif that controls this inhibition. The losses of inhibitory function and the ATP-binding site correlate with an evolutionary divergence of non-inhibitory α-proteobacterial ε and mitochondrial δ subunits from inhibitory bacterial and chloroplastidic ε subunits. Here, we confirm the lack of inhibitory function of wild-type and C-terminal truncated ε subunits of P. denitrificans. Taken together, the data show that ζ evolved to replace ε as the primary inhibitor of the F1FO-ATPase of free-living α-proteobacteria. However, the ζ inhibitory function was also partially lost in some symbiotic α-proteobacteria and totally lost in some strictly parasitic α-proteobacteria such as the Rickettsiales order. Finally, we found that ζ and IF1 likely evolved independently via convergent evolution before and after the endosymbiotic origin mitochondria, respectively. This led us to propose the ε and ζ subunits as tracer genes of the pre-endosymbiont that evolved into the actual mitochondria.

Abo Blood Group, Atherothrombotic Comorbidities, and COVID-19: A Case-Control Study of their Association in the Mexican Population.

BACKGROUND: COVID-19 has been associated with negative results in patients with A blood group and with a better evolution in O blood group individuals. AIM: Because the evidence regarding ABO blood groups and COVID was empirically not that clear in our country, we tested the association regarding COVID-19 and blood groups. MATERIAL AND METHODS: Adult patients were enrolled in this prospective, case-control, observational multicenter study. Patients with a confirmed diagnosis of COVID-19 were assigned to one of three groups based on the clinical presentation of the infection. Age, gender, ABO and Rh blood groups, body mass index, history of diabetes mellitus or high blood pressure, and smoking were recorded directly or from their clinical charts. ABO blood group was obtained from 5,000 blood donors (50% each gender). Atherothrombotic variables were compared with a nation-wide data collection. RESULTS: A total of 2,416 patients with COVID-19 were included (women:39.6%; men:60.4%). There were no significant differences between cases and controls in terms of age. O blood group was the most frequently found in healthy donors and COVID-19 patients, but this blood group was significantly higher in COVID-19 patients vs. healthy donors. ABO blood group was not associated with the final health status in COVID-19 patients. Obesity, diabetes mellitus, hypertension and smoking were significantly more frequent among COVID-19 patients. CONCLUSION: The proposed protective effect of the O blood group in COVID-19 patients could not be reproduced in the Mexican population while some atherothrombotic risk factors had a significant effect on the clinical evolution.

Analysis of the quality of anticoagulation with vitamin K antagonists in three clinical scenarios in Mexico.

INTRODUCTION: Vitamin K antagonists (VKA) are a therapeutic alternative in patients with venous thromboembolic disease; however, numerous factors affect their pharmacology. OBJECTIVE: To evaluate the quality of VKA anticoagulation at three different time periods in Mexico. METHODS: Prospective study, nested in patient cohorts at three different clinical scenarios between 2013 and 2019. Outpatients with indication for treatment with VKAs for at least 12 months were included. Patients were managed according to the criteria of the treating physician. RESULTS: Patient general characteristics were similar between groups, except for the VKA indication. The results of 4,148 patients and 38,548 INR assessments were analyzed. The times in therapeutic range during the three phases of the study and pooled data were significantly higher for the anticoagulation clinic. Only the number of patient visits was significantly associated with the results, unlike age, gender, and type of VKA. CONCLUSIONS: VKAs are widely used, but it is difficult for therapeutic goals to be achieved, especially in non-specialized clinical services. Creation of anticoagulation clinics is an urgent need for the Mexican health system.

INTRODUCCIÓN: Los antagonista de la vitamina K (AVK) son una alternativa terapéutica en los pacientes con enfermedad tromboembólica venosa; sin embargo, numerosos factores afectan su farmacología. OBJETIVO: Evaluar la calidad de la anticoagulación AVK durante tres diferentes periodos en México. MÉTODOS: Estudio prospectivo, anidado en cohortes de pacientes en tres escenarios clínicos entre los años 2013-2019. Se incluyeron pacientes no hospitalizados con indicación para recibir AVK por al menos 12 meses, quienes fueron manejados de acuerdo con el criterio del médico tratante. RESULTADOS: Las características generales de los pacientes fueron similares entre los grupos, excepto por la indicación para usar los AVK. Se analizaron los resultados de 4148 pacientes y 38 548 evaluaciones de INR. Los tiempos en rango terapéutico durante las tres fases del estudio y los datos acumulados fueron significativamente mayores en la clínica de anticoagulación. Solo el número de visitas de control de los pacientes se asoció significativamente con los resultados, a diferencia de la edad, el sexo y el tipo de AVK. CONCLUSIONES: Los AVK se utilizan ampliamente, pero es difícil alcanzar la meta terapéutica, sobre todo en servicios clínicos no especializados. La creación de clínicas de anticoagulación es una necesidad urgente en el sistema mexicano de salud.

Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients.

Lamivudine, also widely known as 3TC belongs to a family of nucleotide/nucleoside analogues of cytidine or cytosine that inhibits the Reverse Transcriptase (RT) of retroviruses such as HIV. Lamivudine is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection or for chronic Hepatitis B (HBV) virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. HBV reactivation in patients with HBV infections who receive anticancer chemotherapy can be a life-threatening complication during and after the completion of chemotherapy. Lamivudine is used, as well as other antiretrovirals, to prevent the reactivation of the Hepatitis B virus during and after chemotherapy. In addition, Lamivudine has been shown to sensitize cancer cells to chemotherapy. Lamivudine and other similar analogues also have direct positive effects in the prevention of cancer in hepatitis B or HIV positive patients, independently of chemotherapy or radiotherapy. Recently, it has been proposed that Lamivudine might be also repurposed against SARS-CoV-2 in the context of the COVID-19 pandemic. In this review we first examine recent reports on the re-usage of Lamivudine or 3TC against the SARS-CoV-2, and we present docking evidence carried out in silico suggesting that Lamivudine may bind and possibly work as an inhibitor of the SARS-CoV-2 RdRp RNA polymerase. We also evaluate and propose assessment of repurposing Lamivudine as anti-SARS-CoV-2 and anti-COVID-19 antiviral. Secondly, we summarize the published literature on the use of Lamivudine or (3TC) before or during chemotherapy to prevent reactivation of HBV, and examine reports of enhanced effectiveness of radiotherapy in combination with Lamivudine treatment against the cancerous cells or tissues. We show that the anti-cancer properties of Lamivudine are well established, whereas its putative anti-COVID effect is under investigation. The side effects of lamivudine and the appearance of resistance to 3TC are also discussed.

Análisis de la calidad de la anticoagulación con antagonistas de la vitamina K en tres escenarios clínicos en México / Analysis of the quality of anticoagulation with vitamin K antagonists in three clinical scenarios in Mexico

Resumen Introducción: Los antagonista de la vitamina K (AVK) son una alternativa terapéutica en los pacientes con enfermedad tromboembólica venosa; sin embargo, numerosos factores afectan su farmacología. Objetivo: Evaluar la calidad de la anticoagulación AVK durante tres diferentes periodos en México. Métodos: Estudio prospectivo, anidado en cohortes de pacientes en tres escenarios clínicos entre los años 2013-2019. Se incluyeron pacientes no hospitalizados con indicación para recibir AVK por al menos 12 meses, quienes fueron manejados de acuerdo con el criterio del médico tratante. Resultados: Las características generales de los pacientes fueron similares entre los grupos, excepto por la indicación para usar los AVK. Se analizaron los resultados de 4148 pacientes y 38 548 evaluaciones de INR. Los tiempos en rango terapéutico durante las tres fases del estudio y los datos acumulados fueron significativamente mayores en la clínica de anticoagulación. Solo el número de visitas de control de los pacientes se asoció significativamente con los resultados, a diferencia de la edad, el sexo y el tipo de AVK. Conclusiones: Los AVK se utilizan ampliamente, pero es difícil alcanzar la meta terapéutica, sobre todo en servicios clínicos no especializados. La creación de clínicas de anticoagulación es una necesidad urgente en el sistema mexicano de salud.

Abstract Introduction: Vitamin K antagonists (VKA) are a therapeutic alternative in patients with venous thromboembolic disease; however, numerous factors affect their pharmacology. Objective: To evaluate the quality of VKA anticoagulation at three different time periods in Mexico. Methods: Prospective study, nested in patient cohorts at three different clinical scenarios between 2013 and 2019. Outpatients with indication for treatment with VKAs for at least 12 months were included. Patients were managed according to the criteria of the treating physician. Results: Patient general characteristics were similar between groups, except for the VKA indication. The results of 4,148 patients and 38,548 INR assessments were analyzed. The times in therapeutic range during the three phases of the study and pooled data were significantly higher for the anticoagulation clinic. Only the number of patient visits was significantly associated with the results, unlike age, gender, and type of VKA. Conclusions: VKAs are widely used, but it is difficult for therapeutic goals to be achieved, especially in non-specialized clinical services. Creation of anticoagulation clinics is an urgent need for the Mexican health system.

Comparación de cuatro técnicas quirúrgicas para el manejo de la espondilitis tuberculosa de la columna torácica en adultos.

OBJETIVO: Comparar la eficiencia de las cuatro técnicas quirúrgicas más utilizadas para el manejo de la espondilitis tuberculosa. MÉTODO: Estudio retrospectivo en el que se incluyeron pacientes adultos con diagnóstico confirmado de espondilitis tuberculosa, afectación de dos niveles vertebrales o menos y sin deformidad vertebral grave. Se recopilaron y revisaron los expedientes médicos, los estudios de imagen y los datos demográficos de los pacientes intervenidos para analizar retrospectivamente los resultados clínicos y funcionales de cada grupo. Las variables primarias fueron la erradicación de la infección, la fusión vertebral y las complicaciones. Entre las variables secundarias se estudiaron el sangrado intraoperatorio, la estancia hospitalaria y el tiempo quirúrgico. RESULTADOS: Entre los grupos analizados no hubo diferencias significativas (p ≥ 0.05) en la mayoría de las variables analizadas, pero sí (p ≤ 0.001) respecto al sangrado, el tiempo quirúrgico, la estancia intrahospitalaria y las complicaciones, a favor del abordaje posterior único. CONCLUSIONES: El abordaje posterior único logró una eficacia clínica similar a la del resto de los abordajes en términos de erradicación de la infección y fusión vertebral; sin embargo, se asoció a menores tiempo quirúrgico, sangrado, estancia hospitalaria y complicaciones. OBJECTIVE: To compare the efficiency of the 4 most used surgical techniques for the management of tuberculous spondylitis. METHOD: Retrospective study in which adult patients with a confirmed diagnosis of tuberculous spondylitis, involvement of two vertebral levels or less, and without severe vertebral deformity were included. The medical records, imaging studies, and demographic data of the operated patients were collected and reviewed to retrospectively analyze the clinical results of each group. The primary variables were cure of infection, spinal fusion, and complications. The secondary variables included intraoperative bleeding, hospital stay, and surgical time. RESULTS: There were no significant differences (p ≥ 0.05) in most of the variables analyzed, however, there were (p ≤ 0.001) regarding bleeding, surgical time, hospital stay and complications between the groups analyzed, with a lower result in all cases for the single posterior approach. CONCLUSIONS: The single posterior approach obtained a clinical efficacy similar to the rest of the approaches in terms of eradication of the infection and vertebral fusion, however, it was associated with less surgical invasion (surgical time and bleeding), a shorter hospital stay and complications.

Automatic selection and feature extraction of motor-evoked potentials by transcranial magnetic stimulation in stroke patients.

Transcranial magnetic stimulation (TMS) allows the assessment of stroke patients' cortical excitability and corticospinal tract integrity, which provide information regarding motor function recovery. However, the extraction of features from motor-evoked potentials (MEP) elicited by TMS, such as amplitude and latency, is performed manually, increasing variability due to observer-dependent subjectivity. Therefore, an automatic methodology could improve MEP analysis, especially in stroke, which increases the difficulty of manual MEP measurements due to brain lesions. A methodology based on time-frequency features of stroke patients' MEPs that allows to automatically select and extract MEP amplitude and latency is proposed. The method was validated using manual measurements, performed by three experts, computed from patients' affected and unaffected hemispheres. Results showed a coincidence of 58.3 to 80% between automatic and manual MEP selection. There were no significant differences between the amplitudes and latencies computed by two of the experts with those obtained with the automatic method, for most comparisons. The median relative error of amplitudes and latencies computed by the automatic method was 5% and 23%, respectively. Therefore, the proposed method has the potential to reduce processing time and improve the computation of MEP features, by eliminating observer-dependent variability due to the subjectivity of manual measurements.

Effects on the Post-translational Modification of H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 Levels in Cerebral Cortex, Hypothalamus and Pons of Rats after a Systemic Administration of Cannabidiol: A Preliminary Study.

BACKGROUND: Cannabidiol (CBD), a non-psychotropic constituent of Cannabis sativa, has shown therapeutic promises by modulating several pathological conditions, including pain, epilepsy autism, among others. However, the molecular mechanism of action of CBD remains unknown and recent data suggest the engagement on CBD´s effects of nuclear elements, such as histone activity. AIM: This study assessed the changes in the post-translational modification (PTM) on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions of rats after the administration of CBD (20 mg/Kg/i.p.). OBJECTIVE: To evaluate the effects on the PTM of histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels in the cerebral cortex, hypothalamus and pons of CBD-treated rats. METHODS: Ten adult rats were randomly assigned into 2 groups: Control or CBD (20 mg/Kg/i.p). Animals were sacrificed after treatments and brains were collected for dissections of the cerebral cortex, hypothalamus and pons. Samples were analyzed for PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 levels by Western blot procedure. RESULTS: CBD increased the PTM levels on the histones H3K4Me3, H3K9ac, and H3K27Me3 in the cerebral cortex whereas no significant differences were found in H3K9Me2 and H3K36Me2. In addition, in the hypothalamus, CBD decreased the contents of H3K9ac while no significant effects were observed in H3K4Me3, H3K9Me2, H3K27Me3, and H3K36Me2. Lastly, in the pons, CBD- treated rats showed a significant decline on the PTM levels of H3K4Me3 whereas no statistical differences were found in H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2. CONCLUSION: The study showed that CBD induced differential effects in levels of PTM on the histones H3K4Me3, H3K9ac, H3K9Me2, H3K27Me3, and H3K36Me2 in several brain regions.

Regulation of bacterial ATP synthase activity: A gear-shifting or a pawl-ratchet mechanism?

The F1 Fo -ATP synthase, a widely distributed nanomotor responsible of ATP synthesis, rotates its central rotor reversibly: In the clockwise direction when viewed from the Fo (with the observer facing the positive side of the energy transducing membrane and looking down into the negative side of the membrane), it functions as ATP synthase, while in counterclockwise sense, it operates as a proton-pumping ATP hydrolase. Regulation exerted by naturally occurring inhibitory proteins of the enzyme appears to function by avoiding ATP hydrolysis while preserving ATP synthesis. The work of Liu et al. describes an unbiased, elegant analytical pipeline that provides important insights into the inhibitory role of the ε-subunit of the bacterial F1 Fo -ATP synthase in vivo. We discuss if a gear-shifting versus a pawl-ratchet mechanism may explain the regulatory role of the ε-subunit.

Cadmium-dependent expression of a new metallothionein identified in Trichomonas vaginalis.

Metallothioneins (MTs) have been identified in a wide variety of organisms from bacteria to humans. The biological functions of these MTs have a key role in metalloregulatory metabolism and its expression is induced in response to different stimuli, particularly by divalent metal cations. Also, the action of MTs have been implicated in the survival of pathogens in presence of microbicidal concentration of divalent cations, which allows the establishment of the infection. Trichomonas vaginalis is a protozoan parasite that adapts to the microenvironment of the male urogenital tract, where cations such as zinc (Zn2+) and cadmium (Cd2+) are present. Nevertheless, the molecular mechanisms of metal tolerance and homeostasis is not yet dilucidated in this parasite. In this study, we have identified 4 potential MT-like sequences (tvmt´s) in T. vaginalis genome. Because tvmt-2, -3, and -4 corresponds to truncated partial genes, we characterized the trichomonad tvmt-1 gene. The bioinformatic analyses and the predicted protein (TvMT-1) show similar properties to the reported in other MTs. The expression patterns of tvmt-1 in the presence of several divalent cations (Fe2+, Mn2+, Zn2+ and Cd2+) were analyzed and we demonstrated that Cd2+ induce significantly their expression. By indirect immunofluorescence assays, we corroborated this positive regulation of TvMT-1 in the cytoplasm of parasites grown in the presence of Cd2+. The tvmt-1 promoter contains putative metal responsive elements, which are probably the responsible for the Cd2+-dependent expression of this gene. Our results suggest that tvmt-1 gene encode a metallothionein that may be responsible for the homeostatis and detoxification of Cd+2 in T. vaginalis.

Validation of a Cell Proliferation Assay to Assess the Potency of a Dialyzable Leukocyte Extract Intended for Batch Release.

Transferon® is a blood product with immunomodulatory properties constituted by a complex mixture of peptides obtained from a human dialyzable leukocyte extract (DLE). Due to its complex nature, it is necessary to demonstrate batch consistency in its biological activity. Potency is the quantitative measure of biological activity and is also a quality attribute of drugs. Here we developed and validated a proliferation assay using Jurkat cells exposed to azathioprine, which is intended to determine the potency of Transferon® according to international guidelines for pharmaceuticals. The assay showed a linear response (2.5 to 40 µg/mL), coefficients of variation from 0.7 to 13.6% demonstrated that the method is precise, while r2 = 0.97 between the nominal and measured values obtained from dilutional linearity showed that the method is accurate. We also demonstrated that the cell proliferation response was specific for Transferon® and was not induced by its vehicle nor by other peptide complex mixtures (glatiramer acetate or hydrolyzed collagen). The bioassay validated here was used to assess the relative potency of eight released batches of Transferon® with respect to a reference standard, showing consistent results. The collective information from the validation and the assessment of several batches indicate that the bioassay is suitable for the release of Transferon®.

Microencapsulated Pomegranate Reverts High-Density Lipoprotein (HDL)-Induced Endothelial Dysfunction and Reduces Postprandial Triglyceridemia in Women with Acute Coronary Syndrome.

(1) Background: the composition of high-density lipoproteins (HDL) becomes altered during the postprandial state, probably affecting their functionality vis-à-vis the endothelium. Since acute coronary syndrome (ACS) in women is frequently associated with endothelial dysfunction, it is likely that HDL are unable to improve artery vasodilation in these patients. Therefore, we characterized HDL from women with ACS in fasting and postprandial conditions. We also determined whether microencapsulated pomegranate (MiPo) reverts the HDL abnormalities, since previous studies have suggested that this fruit improves HDL functionality. (2) Methods: Eleven women with a history of ACS were supplemented daily with 20 g of MiPo, for 30 days. Plasma samples were obtained during fasting and at different times, after a lipid load test to determine the lipid profile and paraoxonase-1 (PON1) activity. HDL were isolated by sequential ultracentrifugation to determine their size distribution and to assess their effect on endothelial function, by using an in vitro model of rat aorta rings. (3) Results: MiPo improved the lipid profile and increased PON1 activity, as previously reported, with fresh pomegranate juice. After supplementation with MiPo, the incremental area under the curve of triglycerides decreased to half of the initial values. The HDL distribution shifted from large HDL to intermediate and small-size particles during the postprandial period in the basal conditions, whereas such a shift was no longer observed after MiPo supplementation. Consistently, HDL isolated from postprandial plasma samples hindered the vasodilation of aorta rings, and this endothelial dysfunction was reverted after MiPo consumption. (4) Conclusions: MiPo exhibited the same beneficial effects on the lipid profile and PON1 activity as the previously reported fresh pomegranate. In addition, MiPo supplementation reverted the negative effects of HDL on endothelial function generated during the postprandial period in women with ACS.

Antibacterial mechanism of gold nanoparticles on Streptococcus pneumoniae.

Streptococcus pneumoniae is a causal agent of otitis media, pneumonia, meningitis and severe cases of septicemia. This human pathogen infects elderly people and children with a high mortality rate of approximately one million deaths per year worldwide. Antibiotic-resistance of S. pneumoniae strains is an increasingly serious health problem; therefore, new therapies capable of combating pneumococcal infections are indispensable. The application of gold nanoparticles has emerged as an option in the control of bacterial infections; however, the mechanism responsible for bacterial cell lysis remains unclear. Specifically, it has been observed that gold nanoparticles are capable of crossing different structures of the S. pneumoniae cells, reaching the cytosol where inclusion bodies of gold nanoparticles are noticed. In this work, a novel process for the separation of such inclusion bodies that allowed the analysis of the biomolecules such as carbohydrates, lipids and proteins associated with the gold nanoparticles was developed. Then, it was possible to separate and identify proteins associated with the gold nanoparticles, which were suggested as possible candidates that facilitate the interaction and entry of gold nanoparticles into S. pneumoniae cells.

Tumor de Buschke-Löwenstein: tratamiento quirúrgico en el embarazo. Reporte de un caso y revisión de la bibliografía / Buschke-Löwenstein tumor: surgical treatment in pregnancy. Case report and literature review

Resumen ANTECEDENTES: El tratamiento del tumor de Buschke-Löwenstein durante el embarazo aún se discute, por lo que se prefiere iniciarlo en el puerperio. OBJETIVO: Reportar un caso de tumor de Buschke-Löwenstein, además de conocer y ampliar su protocolo de tratamiento, pues se considera un reto, debido a la recidiva, alto grado de malignidad y escasa bibliografía relacionada con la enfermedad durante el embarazo. CASO CLÍNICO: Paciente de 17 años, con embarazo previable y diagnóstico de infección de VPH de bajo riesgo, con condiloma genital incipiente, sin tratamiento, inadecuado control prenatal y sin inmunodepresión. Ingresó a la unidad hospitalaria con embarazo pretérmino, por pérdida del bienestar fetal en el tercer trimestre. Mediante ultrasonido se descartó la afectación fetal; sin embargo, se encontró anemia materna y fetidez genital, por lo que se decidió efectuar la resección de la tumoración. El procedimiento transcurrió sin contratiempos. Hasta la fecha no muestra recidiva. El embarazo llegó a término y finalizó por vía abdominal, sin complicaciones. CONCLUSIONES: El tumor de Buschke-Löwenstein es una neoplasia poco común relacionada con inmunodepresión, raramente aparece durante el embarazo y se prefiere iniciar el tratamiento en el puerperio. Se considera un factor de riesgo por la amenaza de parto pretérmino, el efecto proinflamatorio y la afectación materna-fetal, debido al sangrado materno crónico. Es importante considerar el tratamiento durante el embarazo, evaluando el riesgo-beneficio.

Abstract BACKGROUND: The management of the Buschke-Löwenstein tumor in pregnancy is controversial, preferring its treatment in the puerperium. OBJECTIVE: A clinical case report, know and expand the management of the Buschke-Löwenstein tumor, since this is considered a therapeutic challenge due to its important recurrence, high degree of malignancy and its scarce bibliography in which management is carried out during pregnancy. CLINICAL CASE: A 17-years old patient with preventable pregnancy and diagnosis of low risk HPV infection, presents incipient genital condyloma, which does not want any management, antecedent of inadequate prenatal control and without conditions that indicate immunosuppression. Later, she entered with preterm pregnancy due to loss of fetal well-being in the third trimester, fetal involvement was ruled out, however, maternal anemia and genital stinking were found, so it was decided to successfully resect the tumor, without recurrence and ending pregnancy. Ending the pregnancy by abdominal route. CONCLUSIONS: Buschke-Löwenstein tumor is a rare pathology related to immunosuppression, rarely occurs in pregnancy and its resolution is preferred in the puerperium. It can become a risk factor for the threat of preterm delivery due to its proinflammatory effect and generate a compromise of the binomial due to chronic maternal bleeding. It is important not to rule out your treatment during pregnancy by assessing risk benefit.

Control of rotation of the F1FO-ATP synthase nanomotor by an inhibitory α-helix from unfolded ε or intrinsically disordered ζ and IF1 proteins.

The ATP synthase is a ubiquitous nanomotor that fuels life by the synthesis of the chemical energy of ATP. In order to synthesize ATP, this enzyme is capable of rotating its central rotor in a reversible manner. In the clockwise (CW) direction, it functions as ATP synthase, while in counter clockwise (CCW) sense it functions as an proton pumping ATPase. In bacteria and mitochondria, there are two known canonical natural inhibitor proteins, namely the ε and IF1 subunits. These proteins regulate the CCW F1FO-ATPase activity by blocking γ subunit rotation at the αDP/ßDP/γ subunit interface in the F1 domain. Recently, we discovered a unique natural F1-ATPase inhibitor in Paracoccus denitrificans and related α-proteobacteria denoted the ζ subunit. Here, we compare the functional and structural mechanisms of ε, IF1, and ζ, and using the current data in the field, it is evident that all three regulatory proteins interact with the αDP/ßDP/γ interface of the F1-ATPase. In order to exert inhibition, IF1 and ζ contain an intrinsically disordered N-terminal protein region (IDPr) that folds into an α-helix when inserted in the αDP/ßDP/γ interface. In this context, we revised here the mechanism and role of the ζ subunit as a unidirectional F-ATPase inhibitor blocking exclusively the CCW F1FO-ATPase rotation, without affecting the CW-F1FO-ATP synthase turnover. In summary, the ζ subunit has a mode of action similar to mitochondrial IF1, but in α-proteobacteria. The structural and functional implications of these intrinsically disordered ζ and IF1 inhibitors are discussed to shed light on the control mechanisms of the ATP synthase nanomotor from an evolutionary perspective.

Distribución espacial de la probabilidad de ocurrencia de verdolaga silvestre (Portulaca oleracea L) en la Región Lagunera de Coahuila, México / Spatial distribution of the probability of occurrence of wild purslane (Portulaca oleracea L.) in the Lagunera Region of Coahuila, Mexico

El interés por introducir verdolaga (Portulaca oleracea L.) como planta cultivable se ha incrementado paulatinamente debido a sus propiedades medicinales. Sin embargo, estudios acerca de su distribución espacial y relación con el tipo de suelo son escasos. Los objetivos del presente trabajo fueron determinar la probabilidad de ocurrencia de verdolaga, así como la relación entre su distribución espacial y las características edáficas en la Región Lagunera. Se obtuvieron datos de presencia/ausencia de esta planta y muestras de suelo superficial de sitios en distintas clases de tierra, y se determinaron las características físicas y químicas de los suelos. Los datos obtenidos se utilizaron para estimar la probabilidad de ocurrencia de verdolaga con una regresión logística y se cartografiaron. Los resultados muestran que la arena, la conductividad eléctrica y el pH influyen en la presencia de la verdolaga y su distribución espacial es diferente, donde los suelos de tierras blancas arenosas tuvieron la mayor probabilidad de ocurrencia.

pVHL suppresses Akt/ß-catenin-mediated cell proliferation by inhibiting 14-3-3ζ expression.

The mechanisms controlling degradation of cytosolic ß-catenin are important for regulating ß-catenin co-transcriptional activity. Loss of von Hippel-Lindau protein (pVHL) has been shown to stabilize ß-catenin, increasing ß-catenin transactivation and ß-catenin-mediated cell proliferation. However, the role of phosphoinositide 3-kinase (PI3K)/Akt in the regulation of ß-catenin signaling downstream from pVHL has never been addressed. Here, we report that hyperactivation of PI3K/Akt in cells lacking pVHL contributes to the stabilization and nuclear accumulation of active ß-catenin. PI3K/Akt hyperactivation is facilitated by the up-regulation of 14-3-3ζ and the down-regulation of 14-3-3ε, 14-3-3η and 14-3-3θ. Up-regulation of 14-3-3ζ in response to pVHL is important for the recruitment of PI3K to the cell membrane and for stabilization of soluble ß-catenin. In contrast, 14-3-3ε and 14-3-3η enhanced PI3K/Akt signaling by inhibiting PI3K and PDK1, respectively. Thus, our results demonstrated that 14-3-3 family members enhance PI3K/Akt/ß-catenin signaling in order to increase proliferation. Inhibition of Akt activation and/or 14-3-3 function strongly reduces ß-catenin signaling and decreases cell proliferation. Thus, inhibition of Akt and 14-3-3 function efficiently reduces cell proliferation in 786-0 cells characterized by hyperactivation of ß-catenin signaling due to pVHL loss.

Mitochondrial proteomic profile of complex IV deficiency fibroblasts: rearrangement of oxidative phosphorylation complex/supercomplex and other metabolic pathways / Perfil proteómico mitocondrial de los fibroblastos con deficiencia del complejo IV: reordenamiento del complejo/supercomplejo de la fosforilación oxidativa y otras vías metabólicas

Abstract: Background: Mitochondriopathies are multisystem diseases affecting the oxidative phosphorylation (OXPHOS) system. Skin fibroblasts are a good model for the study of these diseases. Fibroblasts with a complex IV mitochondriopathy were used to determine the molecular mechanism and the main affected functions in this disease. Methods: Skin fibroblast were grown to assure disease phenotype. Mitochondria were isolated from these cells and their proteome extracted for protein identification. Identified proteins were validated with the MitoMiner database. Results: Disease phenotype was corroborated on skin fibroblasts, which presented a complex IV defect. The mitochondrial proteome of these cells showed that the most affected proteins belonged to the OXPHOS system, mainly to the complexes that form supercomplexes or respirosomes (I, III, IV, and V). Defects in complex IV seemed to be due to assembly issues, which might prevent supercomplexes formation and efficient substrate channeling. It was also found that this mitochondriopathy affects other processes that are related to DNA genetic information flow (replication, transcription, and translation) as well as beta oxidation and tricarboxylic acid cycle. Conclusions: These data, as a whole, could be used for the better stratification of these diseases, as well as to optimize management and treatment options.

Resumen: Introducción: Las mitocondriopatías son enfermedades multisistémicas que afectan el funcionamiento de la fosforilación oxidativa (OXPHOS). Un buen modelo de estudio para estas enfermedades es el cultivo primario de fibroblastos. En este trabajo se utilizaron fibroblastos con mitocondriopatía del complejo IV para determinar cuáles son las principales funciones afectadas en esta enfermedad. Métodos: Se realizaron cultivos primarios de fibroblastos para corroborar el fenotipo de la enfermedad. Las mitocondrias se aislaron de estas células y se extrajo su proteoma para su identificación. Las proteínas identificadas se validaron con la base de datos de MitoMiner. Resultados: Los fibroblastos conservaron el fenotipo de la enfermedad que incluye un defecto del complejo IV. El proteoma mitocondrial de estas células mostró que las proteínas más afectadas pertenecen al sistema de OXPHOS, principalmente los complejos que forman supercomplejos o respirosomas (I, III, IV y V). El defecto en el complejo IV al parecer se debió a problemas de ensamblaje que pueden evitar la formación de los supercomplejos y la eficiente canalización de sustratos. También se observó que esta mitocondriopatía afecta otros procesos relacionados con el flujo de información genética del DNA (replicación, transcripción y traducción), así como con la beta oxidación y el ciclo de los ácidos tricarboxílicos (TCA). Conclusiones: En conjunto, estos datos podrían utilizarse para una mejor clasificación de estas enfermedades, así como para la optimización de las opciones de manejo y tratamiento.

The Endocannabinoid System Modulating Levels of Consciousness, Emotions and Likely Dream Contents.

BACKGROUND & OBJECTIVE: Cannabinoids are derivatives that are either compounds occurring naturally in the plant, Cannabis sativa or synthetic analogs of these molecules. The first and most widely investigated of the cannabinoids is Δ9-tetrahydrocannabinol (Δ9-THC), which is the main psychotropic constituent of cannabis and undergoes significant binding to cannabinoid receptors. These cannabinoid receptors are seven-transmembrane receptors that received their name from the fact that they respond to cannabinoid compounds, including Δ9-THC. The cannabinoid receptors have been described in rat, human and mouse brains and they have been named the CB1 and CB2 cannabinoid receptors. Later, an endogenous molecule that exerts pharmacological effects similar to those described by Δ9-THC and binds to the cannabinoid receptors was discovered. This molecule, named anandamide, was the first of five endogenous cannabinoid receptor agonists described to date in the mammalian brain and other tissues. Of these endogenous cannabinoids or endocannabinoids, the most thoroughly investigated to date have been anandamide and 2-arachidonoylglycerol (2-AG). Over the years, a significant number of articles have been published in the field of endogenous cannabinoids, suggesting a modulatory profile in multiple neurobiological roles of endocannabinoids. The general consensus accepts that the endogenous cannabinoid system includes natural ligands (such as anandamide and 2- AG), receptors (CB1 and CB2), and the main enzymes responsible for the hydrolysis of anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) as well as the anandamide membrane transporter (AMT). To date, diverse pieces of evidence have shown that the endocannabinoid system controls multiple functions such as feeding, pain, learning and memory and has been linked with various disturbances, such as Parkinson´s disease. Among the modulatory properties of the endocannabinoid system, current data indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness, whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity. Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams. Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. CONCLUSION: Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences.