Nutritional and potential health benefits of chufa oil, olive oil, and anhydrous milk fat against gallstone disease in a C57BL/6N mouse model.

Dietary lipids play a major role in many diseases, particularly cardiovascular diseases. Recently, the health value of plant oils, particularly heart health, has been recognized. Despite these facts, limited information is available on the potential nutritional and anti-arteriolosclerosis effects of chufa oil, olive oil, and anhydrous milk fat in C57BL/6N mice. In the present study, the effects of olive oil (OO), chufa oil (CO), and anhydrous milk fat (AMF) on 4-week-old C57BL/6N male mice, a model for studies of diet-induced atherosclerosis, were investigated. The AIN-93G-based diet was supplemented with 15% of either OO, CO, or AMF. The final mixture of the diets contained 15% fat, approximately 1.25% cholesterol, and 0.5% sodium cholate. The data obtained showed that most mice had gallstone disease. The highest percentage of the gallstones formed were found in AMF groups (approximately 85.7% of the mice). However, the lowest one was found in the chufa oil group (42.9%), followed by the olive oil group (57.1%). Although the mice's food intake significantly differed, their body weights did not change during the feeding period. The diet supplemented with CO resulted in a significant reduction in serum cholesterol compared with the other groups. Livers from the CO-fed group showed higher triglyceride levels than those from the AMF group. No significant differences were found in atherosclerotic lesions in the aortic valve between the groups. Collectively, our results show no deleterious nutritional effects of the fats used on C57BL/6N mice fed cholesterol-rich diets. Chufa oil improved cholesterol metabolism and atherogenic index in mice. However, the major issue is the formation of gallstones in all mice, which is most prominent in AMF, followed by olive oil and chufa oil diets.

Short Communication: Novel Di- and Triselenoesters as Effective Therapeutic Agents Inhibiting Multidrug Resistance Proteins in Breast Cancer Cells.

Breast cancer has the highest incidence rate among all malignancies worldwide. Its high mortality is mainly related to the occurrence of multidrug resistance, which significantly limits therapeutic options. In this regard, there is an urgent need to develop compounds that would overcome this phenomenon. There are few reports in the literature that selenium compounds can modulate the activity of P-glycoprotein (MDR1). Therefore, we performed in silico studies and evaluated the effects of the novel selenoesters EDAG-1 and EDAG-8 on BCRP, MDR1, and MRP1 resistance proteins in MCF-7 and MDA-MB-231 breast cancer cells. The cytometric analysis showed that the tested compounds (especially EDAG-8) are inhibitors of BCRP, MDR1, and MRP1 efflux pumps (more potent than the reference compounds-novobiocin, verapamil, and MK-571). An in silico study correlates with these results, suggesting that the compound with the lowest binding energy to these transporters (EDAG-8) has a more favorable spatial structure affecting its anticancer activity, making it a promising candidate in the development of a novel anticancer agent for future breast cancer therapy.

Diffuse alveolar hemorrhage in patients with systemic lupus erythematosus: data from the Spanish society of rheumathology Lupus Register (RELESSER).

INTRODUCTION:  Diffuse alveolar hemorrhage (DAH) is a rare complication with high mortality in patients with systemic lupus erythematosus (SLE). Early diagnosis and treatment are essential to improve patient prognosis. To determine the characteristics of patients with DAH and their mortality in a Spanish cohort of patients with SLE. METHODS:  Patients from the RELESSER (Spanish Society of Rheumatology Lupus Register) who had had at least one confirmed episode of DAH were included. Epidemiological, clinical, and laboratory characteristics were analyzed. RESULTS:  4024 patients were included in the RELESSER register, 37 (0.9%), had at least one recorded episode of DAH. Only further data for 14 patients could be analyzed. In total, 92.9% were women, and for 4 (28.6%) DAH coincided with the debut of SLE. More than 80% of patients had renal involvement and thrombocytopenia. The most frequent manifestations were dyspnea (85.7%) and hypoxemia (100%), with the classic triad of hemoptysis, anemia and pulmonary infiltrates, appearing in 6 (46.2%) patients. The most frequently used treatments were glucocorticoids (85.7%) and cyclophosphamide (69.2%); plasmapheresis was utilized in 5 patients (35.7%) and 8, (57.1%) received intravenous immunoglobulins; 12 (85.7%) patients required admission to the ICU and 5 (35.7%) died. Tobacco use, history of lupus nephritis (LN), concomitant infection, and treatment with cyclophosphamide were more frequent in patients who died. CONCLUSIONS:  DAH is rare in patients with SLE; in up to one-third of patients, it may appear at the onset of the disease. Some factors, such as smoking, a history of LN, treatment with cyclophosphamide, or concomitant infection, are more prevalent in patients with an unfavorable outcome.

Di- and Triselenoesters-Promising Drug Candidates for the Future Therapy of Triple-Negative Breast Cancer.

Breast cancer is a major malignancy among women, characterized by a high mortality rate. The available literature evidence indicates that selenium, as a trace element, has chemopreventive properties against many types of cancer; as such, compounds containing it in their structure may potentially exhibit anticancer activity. Accordingly, we have undertaken a study to evaluate the effects of novel selenoesters (EDAG-1, -7, -8, -10) on MCF-7 and MDA-MB-231 breast cancer cells. Our analysis included investigations of cell proliferation and viability as well as cytometric determinations of apoptosis/autophagy induction, changes in mitochondrial membrane polarity (ΔΨm), caspase 3/7, 8, and 9 activities, and Bax, Bcl-2, p53, Akt, AMPK, and LC3A/B proteins. The obtained data revealed that the tested derivatives are highly cytotoxic and inhibit cell proliferation even at nanomolar doses (0.41-0.79 µM). Importantly, their strong proapoptotic properties (↑ caspase 3/7) are attributable to the effects on both the extrinsic (↑ caspase 8) and intrinsic (↓ ΔΨm and Bcl-2, ↑ Bax, p53, and caspase 9) pathways of apoptosis. Moreover, the tested compounds are autophagy activators (↓ Akt, ↑ autophagosomes and autolysosomes, AMPK, LC3A/B). In summary, the potent anticancer activity suggests that the tested compounds may be promising drug candidates for future breast cancer therapy.

JAKinhibs in Psoriatic Disease: Analysis of the Efficacy/Safety Profile in Daily Clinical Practice.

Psoriatic disease (PsD) affects multiple clinical domains and causes a significant inflammatory burden in patients, requiring comprehensive evaluation and treatment. In recent years, new molecules such as JAK inhibitors (JAKinhibs) have been developed. These have very clear advantages: they act quickly, have a beneficial effect on pain, are well tolerated and the administration route is oral. Despite all this, there is still little scientific evidence in daily clinical practice. This observational, retrospective, single-center study was carried out in patients diagnosed with PsA in the last two years, who started treatment with Tofacitinib or Upadacitinib due to failure of a DMARD. The data of 32 patients were analyzed, and the majority of them (75%) started treatment with Tofacitinib. Most had moderate arthritis activity and mild psoriasis involvement according to activity indices. Both Tofacitinib and Upadacitinib demonstrated significant efficacy, with rapid and statistically significant improvement in joint and skin activity indices, C-reactive protein reduction, and objective measures of disease activity such as the number of painful and inflamed joints. Although there was some difference in the baseline characteristics of the cohort, treatment responses were comparable or even superior to those in the pivotal clinical trials. In addition, there was a low frequency of mild adverse events leading to treatment discontinuation and no serious adverse events. These findings emphasize the strong efficacy and tolerability of JAKinhibs in daily clinical practice, supporting their role as effective therapeutic options for patients with PsD.

Products of Selenite/Thiols Interaction Have Reducing Properties, Cleave Plasmid DNA and Decrease Rat Blood Pressure and Tension of Rat Mesenteric Artery.

Selenium compounds exert their antioxidant activity mostly when the selenium atom is incorporated into selenoproteins. In our work, we tested the possibility that selenite itself interacts with thiols to form active species that have reducing properties. Therefore, we studied the reduction of 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazol-1-yloxy-3-oxide radical (•cPTIO), damage of plasmid DNA (pDNA), modulation of rat hemodynamic parameters and tension of isolated arteries induced by products of interaction of selenite with thiols. We found that the products of selenite interaction with thiols had significant reducing properties that could be attributed mainly to the selenide and that selenite had catalytic properties in the access of thiols. The potency of thiols to reduce •cPTIO in the interaction with selenite was cysteine > homocysteine > glutathione reduced > N-acetylcysteine. Thiol/selenite products cleaved pDNA, with superoxide dismutase enhancing these effects suggesting a positive involvement of superoxide anion in the process. The observed •cPTIO reduction and pDNA cleavage were significantly lower when selenomethionine was used instead of selenite. The products of glutathione/selenite interaction affected several hemodynamic parameters including rat blood pressure decrease. Notably, the products relaxed isolated mesenteric artery, which may explain the observed decrease in rat blood pressure. In conclusion, we found that the thiol/selenite interaction products exhibited significant reducing properties which can be used in further studies of the treatment of pathological conditions caused by oxidative stress. The results of decreased rat blood pressure and the tension of mesenteric artery may be perspective in studies focused on cardiovascular disease and their prevention.

Tumor-Infiltrating Lymphocytes Refine Outcomes in Triple-Negative Breast Cancer Treated with Anthracycline-Free Neoadjuvant Chemotherapy.

PURPOSE: Stromal tumor-infiltrating lymphocytes (sTIL) are associated with pathologic complete response (pCR) and long-term outcomes for triple-negative breast cancer (TNBC) in the setting of anthracycline-based chemotherapy. The impact of sTILs on refining outcomes beyond prognostic information provided by pCR in anthracycline-free neoadjuvant chemotherapy (NAC) is not known. EXPERIMENTAL DESIGN: This is a pooled analysis of two studies where patients with stage I (T>1 cm)-III TNBC received carboplatin (AUC 6) plus docetaxel (75 mg/m2; CbD) NAC. sTILs were evaluated centrally on pre-treatment hematoxylin and eosin slides using standard criteria. Cox regression analysis was used to examine the effect of variables on event-free survival (EFS) and overall survival (OS). RESULTS: Among 474 patients, 44% had node-positive disease. Median sTILs were 5% (range, 1%-95%), and 32% of patients had ≥30% sTILs. pCR rate was 51%. On multivariable analysis, T stage (OR, 2.08; P = 0.007), nodal status (OR, 1.64; P = 0.035), and sTILs (OR, 1.10; P = 0.011) were associated with pCR. On multivariate analysis, nodal status (HR, 0.46; P = 0.008), pCR (HR, 0.20; P < 0.001), and sTILs (HR, 0.95; P = 0.049) were associated with OS. At 30% cut-point, sTILs stratified outcomes in stage III disease, with 5-year OS 86% versus 57% in ≥30% versus <30% sTILs (HR, 0.29; P = 0.014), and numeric trend in stage II, with 5-year OS 93% versus 89% in ≥30% versus <30% sTILs (HR, 0.55; P = 0.179). Among stage II-III patients with pCR, EFS was better in those with ≥30% sTILs (HR, 0.16; P, 0.047). CONCLUSIONS: sTILs density was an independent predictor of OS beyond clinicopathologic features and pathologic response in patients with TNBC treated with anthracycline-free CbD chemotherapy. Notably, sTILs density stratified outcomes beyond tumor-node-metastasis (TNM) stage and pathologic response. These findings highlight the role of sTILs in patient selection and stratification for neo/adjuvant escalation and de-escalation strategies.

Ameliorative effects of propolis and wheat germ oil on acute toxoplasmosis in experimentally infected mice are associated with reduction in parasite burden and restoration of histopathological changes in the brain, uterus, and kidney.

Toxoplasmosis continues to be a prevalent parasitic zoonosis with a global distribution. This disease is caused by an intracellular parasite known as Toxoplasma gondii, and the development of effective novel drug targets to combat it is imperative. There is limited information available on the potential advantages of wheat germ oil (WGO) and propolis, both individually and in combination, against the acute phase of toxoplasmosis. In this study, acute toxoplasmosis was induced in Swiss albino mice, followed by the treatment of infected animals with WGO and propolis, either separately or in combination. After 10 days of experimental infection and treatment, mice from all groups were sacrificed, and their brains, uteri, and kidneys were excised for histopathological assessment. Additionally, the average parasite load in the brain was determined through parasitological assessment, and quantification of the parasite was performed using Real-Time Polymerase Chain Reaction targeting gene amplification. Remarkably, the study found that treating infected animals with wheat germ oil and propolis significantly reduced the parasite load compared to the control group that was infected but not treated. Moreover, the group treated with a combination of wheat germ oil and propolis exhibited a markedly greater reduction in parasitic load compared to the other groups. Similarly, the combination treatment effectively restored the histopathological changes observed in the brain, uterus, and kidney, and the scoring of these reported lesions confirmed these findings. In summary, the present results reveal intriguing insights into the potential therapeutic benefits of wheat germ oil and propolis in the treatment of acute toxoplasmosis.

Unveiling the Multifaceted Roles of ISG15: From Immunomodulation to Therapeutic Frontiers.

The Interferon Stimulated Gene 15 (ISG15), a unique Ubiquitin-like (Ubl) modifier exclusive to vertebrates, plays a crucial role in the immune system. Primarily induced by interferon (IFN) type I, ISG15 functions through diverse mechanisms: (i) covalent protein modification (ISGylation); (ii) non-covalent intracellular action; and (iii) exerting extracellular cytokine activity. These various roles highlight its versatility in influencing numerous cellular pathways, encompassing DNA damage response, autophagy, antiviral response, and cancer-related processes, among others. The well-established antiviral effects of ISGylation contrast with its intriguing dual role in cancer, exhibiting both suppressive and promoting effects depending on the tumour type. The multifaceted functions of ISG15 extend beyond intracellular processes to extracellular cytokine signalling, influencing immune response, chemotaxis, and anti-tumour effects. Moreover, ISG15 emerges as a promising adjuvant in vaccine development, enhancing immune responses against viral antigens and demonstrating efficacy in cancer models. As a therapeutic target in cancer treatment, ISG15 exhibits a double-edged nature, promoting or suppressing oncogenesis depending on the tumour context. This review aims to contribute to future studies exploring the role of ISG15 in immune modulation and cancer therapy, potentially paving the way for the development of novel therapeutic interventions, vaccine development, and precision medicine.

Correlation between breast cancer subtypes determined by immunohistochemistry and n-COUNTER PAM50 assay: a real-world study.

PURPOSE: Molecular subtyping based on gene expression profiling (i.e., PAM50 assay) aids in determining the prognosis and treatment of breast cancer (BC), particularly in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative tumors, where luminal A and B subtypes have different prognoses and treatments. Several surrogate classifications have been proposed for distinguishing between the luminal A and B subtypes. This study determines the accuracy of local immunohistochemistry (IHC) techniques for classifying HR-positive/HER2-negative (HR+/HER2-) tumors according to intrinsic subtypes using the nCOUNTER PAM50 assay as reference and the HR status definition according the ASCO/CAP recommendations. METHODS: Molecular subtypes resulting from nCOUNTER PAM50 performed in our laboratory between 2014 and 2020 were correlated with three different proxy surrogates proposed in the literature based on ER, PR, HER2, and Ki67 expression with different cut-off values. Concordance was measured using the level of agreement and kappa statistics. RESULTS: From 1049 samples with the nCOUNTER test, 679 and 350 were luminal A and B subtypes, respectively. Only a poor-to-fair correlation was observed between the three proxy surrogates and real genomic subtypes as determined by nCOUNTER PAM50. Moreover, 5-11% and 18-36% of the nCOUNTER PAM50 luminal B and A tumors were classified as luminal A and B, respectively, by these surrogates. CONCLUSION: The concordance between luminal subtypes determined by three different IHC-based classifiers and the nCOUNTER PAM50 assay was suboptimal. Thus, a significant proportion of luminal A and B tumors as determined by the surrogate classifiers could be undertreated or over-treated.

Antitumor Activity of Symmetrical Selenoesters in Doxorubicin Resistant Breast Cancer.

BACKGROUND/AIM: Previously, selenocompounds (Se-compounds) and in particular selenoesters have shown promising anticancer activities. Since molecular symmetry can enhance the anticancer activity, nine symmetrical selenoesters (Se-esters) have been designed as novel, potentially active anticancer agents against doxorubicin resistant breast cancer cells. MATERIALS AND METHODS: To assess the biological effects of the symmetrical Se-esters, the antiproliferative activity was determined on sensitive MCF-7 and doxorubicin resistant KCR breast cancer cell lines. The interaction of the derivatives with doxorubicin was evaluated by checkerboard combination assay on KCR cells. Furthermore, apoptosis induction and ATPase activity in the presence of Se-esters were also determined on KCR cells. RESULTS: The symmetrical derivatives showed a noteworthy antiproliferative activity, with two of them showing IC50 values in submicromolar concentration on MCF-7 cells. In addition, some derivatives showed selectivity towards the resistant KCR cells. The combination of most of them with doxorubicin resulted in synergistic interaction, and all Se-esters could induce early and late apoptosis in KCR cells. Finally, the compounds affected the ATPase activity of ABCB1 (P-gp). CONCLUSION: The symmetrical Se-esters showed potent anticancer activity, according to in vitro tests. Further research needs to be performed to obtain similar derivatives with a better activity and selectivity, and to ascertain the potential application of these Se-containing compounds using in vivo systems.

Effects of Cymatocarpus solearis (Trematoda: Brachycoeliidae) on its second intermediate host, the Caribbean spiny lobster Panulirus argus.

Many digenean trematodes require three hosts to complete their life cycle. For Cymatocarpus solearis (Brachycoeliidae), the first intermediate host is unknown; the Caribbean spiny lobster Panulirus argus is a second intermediate host, and the loggerhead turtle Caretta caretta, a lobster predator, is the definitive host. Trophically-transmitted parasites may alter the behavior or general condition of intermediate hosts in ways that increase the hosts' rates of consumption by definitive hosts. Here, we examined the effects of infection by C. solearis on P. argus by comparing several physiological and behavioral variables among uninfected lobsters (0 cysts) and lobsters with light (1-10 cysts), moderate (11-30 cysts), and heavy (>30 cysts) infections. Physiological variables were hepatosomatic index, growth rate, hemocyte count, concentration in hemolymph of cholesterol, protein, albumin, glucose, dopamine (DA) and serotonin (5-HT). Behavioral variables included seven components of the escape response (delay to escape, duration of swimming bout, distance traveled in a swimming bout, swim velocity, acceleration, force exerted, and work performed while swimming). There was no relationship between lobster size or sex and number of cysts. Significant differences among the four lobster groups occurred only in concentration of glucose (lower in heavily infected lobsters) and 5-HT (higher in heavily and moderately infected lobsters) in plasma. As changes in 5-HT concentration can modify the host's activity patterns or choice of microhabitat, our results suggest that infection with C. solearis may alter the behavior of spiny lobsters, potentially increasing the likelihood of trophic transmission of the parasite to the definitive host.

Tobacco Knowledge, Attitudes, and Services Among Latino/a Community Health Workers.

BACKGROUND: Tobacco-related illnesses are among the leading preventable causes of death for Latinos/as in the United States. Latino/a groups are less likely to receive advice to quit from health professionals or use tobacco cessation strategies. The position of community health workers (CHWs) warrants further attention to address tobacco-related disparities in Latino/a communities. The objective of this study was to describe CHWs' roles to inform future smoking cessation training to ensure relevance and accessibility. METHODS: A needs assessment survey, including a 10-item tobacco knowledge questionnaire, was conducted with 29 Latino/a CHWs serving Latino/a communities in a metropolitan area to assess their roles, tobacco related services, attitudes, and knowledge. RESULTS: All CHWs were Spanish-speaking and mainly employed part time (55%) in community organizations (67%). They offered various services, primarily health education. Most of the CHWs (58.6%) assessed and discussed tobacco use, yet half (51.7%) reported low confidence in this area. Some CHWs (41%) expressed that their clients/patients would use evidence-based nicotine replacement therapies as a smoking cessation treatment if offered and identified "Financial Cost" (31%) as a deterrent of use. CHWs' score on a tobacco knowledge questionnaire indicated low knowledge in areas related to tobacco (4.03 out of 10; SD = 1.92). CONCLUSIONS: CHWs reported low tobacco related knowledge and confidence, and would benefit from tailored tobacco cessation training to decrease tobacco cessation disparities.

Multiple sclerosis plasma IgG aggregates induce complement-dependent neuronal apoptosis.

Grey matter pathology is central to the progression of multiple sclerosis (MS). We discovered that MS plasma immunoglobulin G (IgG) antibodies, mainly IgG1, form large aggregates (>100 nm) which are retained in the flow-through after binding to Protein A. Utilizing an annexin V live-cell apoptosis detection assay, we demonstrated six times higher levels of neuronal apoptosis induced by MS plasma IgG aggregates (n = 190, from two cohorts) compared to other neurological disorders (n = 116) and healthy donors (n = 44). MS IgG aggregate-mediated, complement-dependent neuronal apoptosis was evaluated in multiple model systems including primary human neurons, primary human astrocytes, neuroblastoma SH-SY5Y cells, and newborn mouse brain slices. Immunocytochemistry revealed the co-deposition of IgG, early and late complement activation products (C1q, C3b, and membrane attack complex C5b9), as well as active caspase 3 in treated neuronal cells. Furthermore, we found that MS plasma cytotoxic antibodies are not present in Protein G flow-through, nor in the paired plasma. The neuronal apoptosis can be inhibited by IgG depletion, disruption of IgG aggregates, pan-caspase inhibitor, and is completely abolished by digestion with IgG-cleaving enzyme IdeS. Transmission electron microscopy and nanoparticle tracking analysis revealed the sizes of MS IgG aggregates are greater than 100 nm. Our data support the pathological role of MS IgG antibodies and corroborate their connection to complement activation and axonal damage, suggesting that apoptosis may be a mechanism of neurodegeneration in MS.

Complete revascularization with PCI in STEMI patients with multivessel disease, when is the appropriate time? / Revascularización completa mediante ICP en pacientes con STEMI y enfermedad coronaria multivaso, ¿cuál es el momento adecuado?

Abstract Objective: The purpose was to compare the outcomes of patients with ST-elevation myocardial infarction and multivessel coronary artery disease undergoing one-time multivessel revascularization (OTMVR) versus in-hospital staged complete revascularization with percutaneous coronary intervention. Methods: This was a single-center, retrospective, observational, and cohort study, including data from January 2013 to April 2019. A total of 634 patients were included in the study. Comparisons were made between patients who underwent in-hospital staged complete revascularization versus OTMVR. The primary endpoint was all-cause in-hospital mortality, secondary endpoints included cardiovascular complications, all-cause new hospitalization, and mortality evaluated at 30 days and 1 year. In addition, we constructed a logistic regression model for determining the risk factors that predicted mortality. Results: Of the 634 patients, 328 were treated with staged revascularization and 306 with OTMVR. About 76.7% were men, with a mean age of 63.3 years. Less complex coronary lesions and a higher proportion of the left anterior descending artery as the culprit vessel were found in the OTMVR group. Compared with staged revascularization, the primary and secondary endpoints occurred less frequently with OTMVR strategy. Conclusions: OTMVR did not generate more complications and demonstrate better clinical outcomes than in-hospital staged revascularization.

Resumen Objetivo: El propósito fue comparar resultados de pacientes con infarto agudo de miocardio con elevación del segmento ST y enfermedad coronaria multivaso sometidos a revascularización completa de un solo momento frente a revascularización completa por etapas mediante intervención coronaria percutánea. Métodos: Estudio cohorte observacional, retrospectivo, unicéntrico, con datos de enero de 2013 a abril de 2019, incluyendo 634 pacientes. Se compararon resultados entre pacientes sometidos a revascularización completa por etapas frente a revascularización completa en un solo momento. El objetivo primario fue valorar mortalidad intrahospitalaria por cualquier causa y como objetivos secundarios se evaluaron a 30 días y 1 año las complicaciones cardiovasculares, hospitalizaciones y mortalidad. Se construyó un modelo de regresión logística para determinar los factores de riesgo que predijeron mortalidad. Resultados: De 634 pacientes, 328 fueron tratados con revascularización por etapas y 306 con revascularización en una intervención. El 76.7% fueron hombres, con una media de edad de 63.3 años. En el grupo de revascularización de un solo tiempo se encontraron lesiones coronarias menos complejas y una mayor proporción de la arteria descendente anterior como vaso culpable. Comparado con el grupo de revascularización por etapas, los objetivos primarios y secundarios ocurrieron con menos frecuencia en el grupo de revascularización en un solo tiempo. Conclusiones: Comparada con la revascularización intrahospitalaria por etapas, la revascularización en una intervención lleva a mejores desenlaces clínicos sin generar más complicaciones.

Reversal of Multidrug Resistance by Symmetrical Selenoesters in Colon Adenocarcinoma Cells.

Recently, selenium containing derivatives have attracted more attention in medicinal chemistry. In the present work, the anticancer activity of symmetrical selenoesters was investigated by studying the reversal of efflux pump-related and apoptosis resistance in sensitive and resistant human colon adenocarcinoma cells expressing the ABCB1 protein. The combined effect of the compounds with doxorubicin was demonstrated with a checkerboard assay. The ABCB1 inhibitory and the apoptosis-inducing effects of the derivatives were measured with flow cytometry. Whole transcriptome sequencing was carried out on Illumina platform upon the treatment of resistant cells with the most potent derivatives. One ketone and three methyl ester selenoesters showed synergistic or weak synergistic interaction with doxorubicin, respectively. Ketone selenoesters were the most potent ABCB1 inhibitors and apoptosis inducers. Nitrile selenoesters could induce moderate early and late apoptotic processes that could be explained by their ABCB1 modulating properties. The transcriptome analysis revealed that symmetrical selenoesters may influence the redox state of the cells and interfere with metastasis formation. It can be assumed that these symmetrical selenocompounds possess toxic, DNA-damaging effects due to the presence of two selenium atoms in the molecule, which may be augmented by the presence of symmetrical groups.

Aproximación hacia la evaluación de la aptitud clínica en residentes de cardiología. Diseño multicéntrico / Approach to cardiology residents clinical aptitude evaluation. Multicenter design

Resumen Introducción: Hasta donde se tiene conocimiento, la investigación que se presenta constituye el primer trabajo multicéntrico en México que estudia el desarrollo de la aptitud clínica en unidades formadoras de cardiólogos. Objetivo: Determinar el grado de desarrollo de la aptitud clínica en residentes de cardiología en tres unidades médicas de alta especialidad. Métodos: Diseño transversal multicéntrico. Se analizaron todos los estudiantes del ciclo académico 2019-2020. Se construyó un instrumento que evaluó la aptitud clínica a partir de ocho indicadores y 170 ítems; la validez conceptual/de contenido y la confiabilidad fueron valoradas por cinco cardiólogos con experiencia docente y en investigación educativa. Resultados: Por indicador y año de residencia se observaron diferencias estadísticas significativas en la sede CMN20Nov; en HCSXXI e INCICh se observaron diferencias estadísticamente significativas en uno de ocho indicadores. Se estimaron diferencias entre residentes R1 (n = 41) de las tres sedes por indicador, con significación estadística en tres de ocho indicadores. El resultado fue semejante al comparar R2 (n = 35) y R3 (n = 43). Conclusiones: El grado de desarrollo de la aptitud clínica se puede considerar medio en las tres sedes académicas, probablemente debido a que el instrumento exploró situaciones clínicas problematizadas que exigieron del residente la reflexión crítica de su experiencia clínica.

Abstract Introduction: To the best of our knowledge, the research herein presented is the first multicenter study in Mexico to analyze the development of clinical aptitude in medical units that train cardiologists. Objective: To determine the degree of development of clinical aptitude in cardiology residents at three High Specialty Medical Units. Methods: Multicenter, cross-sectional design. All students of the 2019-2020 academic year were included in the study. An instrument was constructed that evaluated clinical aptitude based on eight indicators and 170 items; conceptual/content validity and reliability were assessed by five cardiologists with teaching and educational research experience. Results: By indicator and year of residence, significant statistical differences were observed in the CMN20Nov academic site. At HCSXXI and INCICh, statistically significant differences were observed in one of eight indicators. Differences between R1 residents (n = 41) of all three academic sites were estimated by indicator, with statistical significance being recorded in three of eight indicators. Between R2 (n = 35) and between R3 residents (n = 43), the result was similar. Conclusions: The degree of clinical aptitude development can be considered intermediate in all three academic sites, probably because the instrument explored problematized clinical situations that required the residents to critically reflect on their clinical experience.

Novel Selenoesters as a Potential Tool in Triple-Negative Breast Cancer Treatment.

Disturbing cancer statistics, especially for breast cancer, are becoming a rationale for the development of new anticancer therapies. For the past several years, studies have been proving a greater role of selenium in the chemoprevention of many cancers than previously considered; hence, a trend to develop compounds containing this element as potential agents with anticancer activity has been set for some time. Therefore, our study aimed to evaluate the anticancer activity of novel selenoesters (EDA-71, E-NS-4) in MCF-7 and MDA-MB-231 human breast cancer cells. The assays evaluating proliferation and cell viability, and flow cytometer analysis of apoptosis/autophagy induction, changes in mitochondrial membrane potential, disruption of cell cycle phases, and protein activity of mTOR, NF-κB, cyclin E1/A2, and caspases 3/7, 8, 9, 10 were performed. The obtained results indicate that the tested selenoesters are highly cytotoxic and exhibit antiproliferative activity at low micromolar doses (<5 µM) compared with cisplatin. The most active compound­EDA-71­highly induces apoptosis, which proceeds via both pathways, as evidenced by the activation of all tested caspases. Furthermore, we observed the occurrence of autophagy (↓ mTOR levels) and cell cycle arrest in the S or G2/M phase (↓ cyclin E1, ↑ cyclin A2).

Selenium and tellurium in the development of novel small molecules and nanoparticles as cancer multidrug resistance reversal agents.

Selenium is an essential trace element that is crucial for cellular antioxidant defense against reactive oxygen species (ROS). Recently, many selenium-containing compounds have exhibited a wide spectrum of biological activities that make them promising scaffolds in Medicinal Chemistry, and, in particular, in the search for novel compounds with anticancer activity. Similarly, certain tellurium-containing compounds have also exhibited substantial biological activities. Here we provide an overview of the biological activities of seleno- and tellurocompounds including chemopreventive activity, antioxidant or pro-oxidant activity, modulation of the inflammatory processes, induction of apoptosis, modulation of autophagy, inhibition of multidrug efflux pumps such as P-gp, inhibition of cancer metastasis, selective targeting of tumors and enhancement of the cytotoxic activity of chemotherapeutic drugs, as well as overcoming tumor drug resistance. A review of the chemistry of the most relevant seleno- or tellurocompounds with activity against resistant cancers is also presented, paying attention to the synthesis of these compounds and to the preparation of bioactive selenium or tellurium nanoparticles. Based on these data, the use of these seleno- and tellurocompounds is a promising approach in the development of strategies that can drive forward the search for novel therapies or adjuvants of current therapies against drug-resistant cancers.

Ketone-selenoesters as potential anticancer and multidrug resistance modulation agents in 2D and 3D ovarian and breast cancer in vitro models.

Long-term treatment of cancer with chemotherapeutics leads to the development of resistant forms that reduce treatment options. The main associated mechanism is the overexpression of transport proteins, particularly P-glycoprotein (P-gp, ABCB1). In this study, we have tested the anticancer and multidrug resistance (MDR) modulation activity of 15 selenocompounds. Out of the tested compounds, K3, K4, and K7 achieved the highest sensitization rate in ovarian carcinoma cells (HOC/ADR) that are resistant to the action of the Adriamycin. These compounds induced oxidation stress, inhibited P-gp transport activity and altered ABC gene expression. To verify the effect of compounds, 3D cell models were used to better mimic in vivo conditions. K4 and K7 triggered the most significant ROS release. All selected selenoesters inhibited P-gp efflux in a dose-dependent manner while simultaneously altering the expression of the ABC genes, especially P-gp in paclitaxel-resistant breast carcinoma cells (MCF-7/PAX). K4, and K7 demonstrated sensitization potential in resistant ovarian spheroids. Additionally, all selected selenoesters achieved a high cytotoxic effect in 3D breast and ovarian models, which was comparable to that in 2D cultures. K7 was the only non-competitive P-gp inhibitor, and therefore appears to have considerable potential for the treatment of drug-resistant cancer.