Nox4 is involved in acute kidney injury associated to intravascular hemolysis.

Massive intravascular hemolysis occurs not unfrequently in many clinical conditions. Breakdown of erythrocytes promotes the accumulation of heme-derivates in the kidney, increasing oxidative stress and cell death, thus promoting acute kidney injury (AKI). NADPH oxidase 4 (Nox4) is a major source of reactive oxygen species (ROS) in the kidney, however it is unknown the role of Nox4 in hemolysis and whether inhibition of this enzyme may protect from heme-mediated injury. To answer these questions, we elicited intravascular hemolysis in wild type and Nox4 knockout mice. We also evaluated whether nephrotoxic effects of heme may be reduced by using Nox4 siRNA and pharmacologic inhibition with GKT137831, a Nox4 inhibitor, both in vivo and in cultured renal cells. Our results showed that induction of massive hemolysis elicited AKI characterized by loss of renal function, morphological alterations of the tubular epithelium and podocytes, oxidative stress, inflammation, mitochondrial dysfunction, blockade of autophagy and cell death. These pathological effects were significantly prevented in Nox4-deficient mice and in animals treated with GKT137831. In vitro studies showed that Nox4 disruption by specific siRNAs or Nox4 inhibitors declined heme-mediated ROS production and cell death. Our data identify Nox4 as a key enzyme involved in intravascular hemolysis-induced AKI. Thus, Nox4 inhibition may be a potential therapeutic approach to prevent renal damage in patients with severe hemolytic crisis.

Impact of connective tissue diseases on complications following aesthetic surgery: A matched cohort study.

BACKGROUND: The association between connective tissue diseases (CTDs), including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and scleroderma, and complications following aesthetic surgery is under-investigated. We hypothesized that the risk of complications following aesthetic surgery was higher in patients with these connective tissue disorders compared to matched non-CTD patients. METHODS: All patients diagnosed with RA, SLE, and scleroderma who underwent aesthetic surgery at our institution from 2003-2022 were reviewed. Demographic data, comorbidities, medications, procedures, and postoperative complications were collected. Non-CTD controls were identified for each procedure and matched 1:1 based on propensity scores derived from race, sex, body mass index, smoking status, and comorbidities. RESULTS: Six hundred 38 patients were included, comprising 319 (50%) patients diagnosed with CTD and 319 (50%) controls. The average age at surgery was 56.3 years. There were 129 complications. There were no differences between the CTD and non-CTD patients in number of total complications (69 versus 60, p = 0.38), major complications (23 versus 16, p = 0.25), or minor complications (46 versus 44, p = 0.73). Complications were not significantly different between CTD patients and controls who underwent blepharoplasty (p = 0.38), breast reduction (p = 0.91), abdominoplasty (p = 0.46), or rhytidectomy (p = 0.50). CTD patients who underwent breast augmentation had significantly more complications than matched non-CTD patients in bivariate analysis (7 versus 0, p = 0.018*) and multivariable logistic regression (OR: 10.2, 95% CI: 1.21 to 93.3, p = 0.039*). CONCLUSIONS: Most aesthetic surgeries can safely be performed in patients with CTDs. Patients seeking breast augmentation should be counseled on a potentially increased risk of postoperative complications.

Quantitative evaluation of a theoretical-conceptual model based on affective and socio-behavioral dimensions to explain the academic performance of mathematics students.

Objective: There is evidence that suggests that affective dimensions, personality traits, as well as students' cooperative interpersonal interactions, are an important element in the students learning process. In this work we propose a theoretical model, based on evidence, that shows the direct and indirect relationships between these factors and academic performance in mathematics courses, in undergraduate and school students. Methods: To understand the type of relationships between these variables, the PANAS psychometric test of positive and negative affect, the BIG FIVE personality test and the economic decision game DUPLES GAME were applied. The study sample was 130 students between 17 and 22 years of age from undergraduate and school (M ± SD = 20.1 ± 3.99). Results: From a path analysis, statistically significant relationships were found, for example, a direct relationship between neuroticism and positive affect, which in turn is related to academic performance. We also found a direct relationship between neuroticism and negative affect, extraversion and positive affect. This allows us to propose that some of the independent variables of the model directly and indirectly influence the academic performance of students in the subject of mathematics. Conclusion: Positive affect and negative affect directly affect academic performance in mathematics, neuroticism has a direct impact on negative affect and extraversion direct impact on positive affect. Consequently, there are direct and indirect relationships between personality traits and affective dimensions, which affect the academic performance of mathematics students.

Prediction of Concomitant Nosocomial Infection in Patients Previously Colonized Colorectally by Multidrug-Resistant Bacteria in an SDD Setting.

BACKGROUND: Antibiotic resistance is a worldwide concern. This study retrospectively analyzed patients admitted to the ICU of a tertiary hospital over a period of 7 months who were rectally colonized by multidrug-resistant microorganisms. The incidence of concomitant nosocomial infections was estimated, thus providing the risk of a colonizing microorganism producing a nosocomial infection. METHODS: Infections with the same microorganism (concomitant) or different microorganisms (non-concomitant) were analyzed in order to adjust the empirical antibiotic treatment. Patients with rectal colonization by at least one multidrug-resistant bacterium (MDRB) on admission or after ICU admission were included. All patients had complete selective digestive decontamination (SDD) prophylaxis. For univariate analysis, categorical variables are expressed as frequencies and percentages and continuous variables as means and standard deviations, or as medians and interquartile ranges. For multivariate analysis, the model is summarized with p-values and hazard ratios with 95% confidence intervals. Survival analysis was conducted using the Kaplan-Meier method, which was performed to evaluate the time elapsed from colonization to infection by the same bacteria. Statistical significance was considered at p < 0.05. RESULTS: Of the 130 patients with MDRB bacterial colonization analyzed, 98 remained free of infection, while 22 developed non-concomitant infections and 10 had infections concomitant to rectal colonizing bacteria. OXA-48-producing bacteria and MDR-Pseudomonas spp. incidences were 18.9% (95% CI: 7.96-35.2) and 44.4% (CI: 13.7-78.8), respectively. CONCLUSIONS: OXA-48-producing bacteria and MDR-Pseudomonas spp. were the only bacteria associated with the development of infections concomitant to rectal colonization in an SDD setting. The incidence of MDRB infections was low.

Histological study of the development of the digestive system during larval feeding in the pike silverside Chirostoma estor.

Chirostoma estor (Jordan, 1879) is an endemic freshwater species with a high potential for aquaculture; however, as in many other fish, larviculture of this species is the most critical stage, in which the higher mortality rates. Therefore, it is necessary to fully describe the development of the digestive system to establish better feeding protocols in the larval culture of C. estor, both for aquaculture and restoration purposes. In the present study, larviculture was carried out from hatching to 20 days after hatching (DAH). The organisms were fed with the rotifer Brachionus plicatilis from 2 to 14 DAH, and nauplii of Artemia sp. from 15 to 20 DAH. A total of 12 organisms (0, 3, 5, 10, 15, and 20 DAH) were taken for size and weight growth and histological and histochemical analysis. The histological analysis indicated that after 3 DAH, the opening of the mouth and anus was observed, coinciding with the beginning of exogenous feeding. In addition, the digestive system developed, with differentiation of the oropharyngeal sections, esophagus, and intestine, folding of the intestinal mucosa, as well as associated organs (liver and pancreas) that reach their maximum development at 20 DAH. Thus, C. estor at this stage of development can digest and absorb nutrients despite being an agastric fish. The results obtained in this study will facilitate a better understanding of the ontogenetic morphophysiological development processes, associated with the transition of larvae to exogenous feeding, which ensures a higher percentage of survival during larval development and of course, adds to the diversity ontogenetics of teleostean.

Evidence on psychometric properties of self-report questionnaires in evaluating blended learning in health sciences university students: research protocol for systematic review and meta-analysis.

INTRODUCTION: Due to the COVID-19 outbreak, schools had to switch online. As universities ease face-to-face (F2F) schooling, blended teaching and learning (BTL) enables the continuous delivery of education. However, the sudden transition to BTL poses challenges for students and teachers, especially for health sciences programmes that require hands-on practical experience. Several studies have evaluated F2F teaching and learning contexts through student feedback and evaluations. However, there needs to be more reliable and valid self-report questionnaires that focus on the perceptions and experiences of students experiencing BTL. This study will critically appraise, compare and summarise the quality of self-report questionnaires evaluating BTL among health science university students based on their psychometric properties. METHODS AND ANALYSIS: A systematic review and meta-analysis design will be used. This review will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols and follow the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) standardised guidelines. 13 databases will be searched for studies reporting BTL self-report questionnaires as evaluation tools with their respective psychometric properties. Two independent reviewers will appraise the paper using the COSMIN risk of bias checklist and the quality of evidence of the psychometric properties of the relevant questionnaires will be assessed using the modified Grading of Recommendations Assessment, Development and Evaluation approach. Based on their psychometric properties, these assessments will comprehensively summarise and present the best recommendations for the most appropriate self-report questionnaires for BTL evaluation. ETHICS AND DISSEMINATION: The University of the Philippines' Research Grants Administration Office exempted this research protocol from ethics review evaluation (protocol number UPMREB 2022-0259-EX) since this study will not collect individual data. The research protocol was registered with PROSPERO. The results will be disseminated through peer-reviewed journals and conferences to aid researchers and professionals in the field of health education to prudently choose effective self-report questionnaires evaluating blended learning.CRD42022372362.

Comparative analysis of COVID-19-associated venous thromboembolism outcomes: evolution from 2020 to 2021-2022.

Patients with COVID-19 are at an increased risk for venous thromboembolism (VTE). With the advent of vaccinations and novel treatments from 2020 through 2022, the landscape of COVID-19 has evolved. Notably, the effects of such interventions on the outcomes of COVID-19-associated VTE have not been thoroughly examined. Data from the RIETE registry were analyzed to evaluate 90-day VTE-related outcomes (all-cause mortality, major bleeding, and VTE recurrences) in patients with COVID-19-associated VTE. We compared the periods before and after the widespread introduction of COVID-19 vaccines: March to December 2020 (pre-vaccine period) and March 2021 to December 2022 (post-vaccine period). Statistical analysis included mixed-effects parametric survival-time models. Among 1,620 patients with COVID-19-associated VTE, most (74.1%) were identified during 2020 period. The analysis revealed a more than two-fold increase in the risk of death within 90 days (adjusted hazard ratio [HR]: 2.27; 95% confidence interval, CI: 1.18-4.38) and major bleeding (adjusted HR: 2.91; 95%CI: 1.08-7.84) for patients from the 2020 period compared to those from the 2021-2022 period. Inpatient subgroup analysis confirmed the observed mortality differences. The frequency of recurrent VTE was low (1.1 vs. 0.7%, respectively), and did not show significant variation between the two periods. Our research provides a comparative perspective on the clinical outcomes of COVID-19-associated VTE before and after the introduction of vaccines. Our findings reveal a significant decrease in the incidence of 90-day mortality and major bleeding in patients with COVID-19-associated VTE in the 2021-2022 period.

CYB5R3 overexpression exhibits sexual dimorphism: Mitochondrial and metabolic adaptations in transgenic female mice during calorie restriction.

There is a pressing need to develop new strategies for enhancing health in the elderly and preventing the rise in age-related diseases. Calorie restriction without malnutrition (CR) stands among the different antiaging interventions. Lifelong CR leads to increased expression and activity of plasma membrane CYB5R3, and male mice overexpressing CYB5R3 exhibit some beneficial adaptations that are also seen with CR. However, the mechanisms involved in both interventions could be independent since key aspects of energy metabolism and tissue lipid profile do not coincide, and many of the changes induced by CR in mitochondrial abundance and dynamics in the liver and skeletal muscle could be counteracted by CYB5R3 overexpression. In this study, we sought to elucidate the impact of CR on key markers of metabolic status, mitochondrial function, and pro-oxidant/antioxidant balance in transgenic (TG) female mice overexpressing CYB5R3 compared to their WT littermates. In females fed ad libitum, CYB5R3 overexpression decreased fat mass, led to a preferred utilization of fatty acids as an energy source, upregulated key antioxidant enzymes, and boosted respiration both in skeletal muscle and liver mitochondria, supporting that CYB5R3 overexpression is phenotypic closer to CR in females than in males. Whereas some markers of mitochondrial biogenesis and dynamics were found decreased in TG females on CR, as also found for the levels of Estrogen Receptor α, mitochondrial abundance and activity were maintained both in skeletal muscle and in liver. Our results reveal overlapping metabolic adaptations resulting from the overexpression of CYB5R3 and CR in females, but a specific crosstalk occurs when both interventions are combined, differing from the adaptations observed in TG males.

SARS-CoV-2 E protein interacts with BRD2 and BRD4 SEED domains and alters transcription in a different way than BET inhibition.

Bromodomain and extra-terminal (BET) proteins are relevant chromatin adaptors involved in the transcriptional control of thousands of genes. Two tandem N-terminal bromodomains are essential for chromatin attachment through acetyl-histone recognition. Recently, the BET proteins members BRD2 and BRD4 were found to interact with the SARS-CoV-2 envelope (E) protein, raising the question of whether the interaction constitutes a virus hijacking mechanism for transcription alteration in the host cell. To shed light on this question, we have compared the transcriptome of cells overexpressing E with that of cells treated with the BET inhibitor JQ1. Notably, E overexpression leads to a strong upregulation of natural immunity- and interferon response-related genes. However, BET inhibition results in the downregulation of most of these genes, indicating that these two conditions, far from causing a significant overlap of the altered transcriptomes, course with quite different outputs. Concerning the interaction of E protein with BET members, and differing from previous reports indicating that it occurs through BET bromodomains, we find that it relies on SEED and SEED-like domains, BET regions rich in Ser, Asp, and Glu residues. By taking advantage of this specific interaction, we have been able to direct selective degradation of E protein through a PROTAC system involving a dTAG-SEED fusion, highlighting the possible therapeutic use of this peptide for targeted degradation of a viral essential protein.

Functional consequences of a p53-MDM2-p21 incoherent feedforward loop.

Genetically identical cells can respond heterogeneously to cancer therapy, with a subpopulation of cells often entering a temporarily arrested treatment-tolerant state before repopulating the tumor. To investigate how heterogeneity in the cell cycle arrest protein p21 arises, we imaged the dynamics of p21 transcription and protein expression along with those of p53, its transcriptional regulator, in single cells using live cell fluorescence microscopy. Surprisingly, we found that the rate of p21 transcription depends on the change in p53 rather than its absolute level. Through combined theoretical and experimental modeling, we determined that p21 transcription is governed by an incoherent feedforward loop mediated by MDM2. This network architecture facilitates rapid induction of p21 expression and variability in p21 transcription. Abrogating the feedforward loop overcomes rapid S-phase p21 degradation, with cells transitioning into a quiescent state that transcriptionally resembles a treatment-tolerant persister state. Our findings have important implications for therapeutic strategies based on activating p53.

Endogenous innate sensor NLRP3 is a key component in peritoneal macrophage dynamics required for cestode establishment.

The NLRP3 receptor can assemble inflammasome platforms to trigger inflammatory responses; however, accumulating evidence suggests that it can also display anti-inflammatory properties. Here, we explored the role of nucleotide-binding oligomerization domain pyrin-containing protein 3 (NLRP3) in Taenia crassiceps experimental infection, which requires immune polarization into a Th2-type profile and peritoneal influx of suppressive macrophages for successful colonization. NLRP3 deficient mice (NLRP3-/-) were highly resistant against T. crassiceps, relative to wild-type (WT) mice. Resistance in NLRP3-/- mice was associated with a diminished IL-4 output, high levels of IL-15, growth factor for both innate and adaptive lymphocytes, and a dramatic decrease in peritoneum-infiltrating suppressive macrophages. Also, a transcriptional analysis on bone marrow-derived macrophages exposed to Taenia-secreted antigens and IL-4 revealed that NLRP3-/- macrophages express reduced transcripts of relm-α and PD-1 ligands, markers of alternative activation and suppressive ability, respectively. Finally, we found that the resistance displayed by NLRP3-/- mice is transferred through intestinal microbiota exchange, since WT mice co-housed with NLRP3-/- mice were significantly more resistant than WT animals preserving their native microbiota. Altogether, these data demonstrate that NLRP3 is a component of innate immunity required for T. crassiceps to establish, most likely contributing to macrophage recruitment, and controlling lymphocyte-stimulating cytokines such as IL-15.

Impact of efavirenz on hormone-positive breast cancer survival in women living with HIV.

Women living with HIV and breast cancer have poorer survival than HIV-negative women. Efavirenz-estrogen interactions are documented; however, the survival impact is unknown. Survival between women with estrogen-receptor positive breast cancer taking efavirenz (n = 38) and nonefavirenz regimens (n = 51) were compared. The 5-year overall-survival was 48.9% [95% confidence interval (CI) 33.0-72.2 and 51.1% (95% CI 34.0-76.8)] in the efavirenz and nonefavirenz groups, respectively suggesting efavirenz is unlikely driving poorer survival in women living with HIV and estrogen-receptor positive breast cancer.

Angular momentum transfer from swift electrons to non-spherical nanoparticles within the dipolar approximation.

In this work, we study the angular momentum transfer from a single swift electron to non-spherical metallic nanoparticles, specifically investigating spheroidal and polyhedral (Platonic Solids) shapes. While previous research has predominantly focused on spherical nanoparticles, our work expands the knowledge by exploring various geometries. Employing classical electrodynamics and the small particle limit, we calculate the angular momentum transfer by integrating the spectral density, ensuring causality through Fourier-transform analysis. Our findings demonstrate that prolate spheroidal nanoparticles exhibit a single blueshifted plasmonic resonance, compared to spherical nanoparticles of equivalent volume, resulting in lower angular momentum transfer. Conversely, oblate nanoparticles display two resonances - one blueshifted and one redshifted - resulting in a higher angular momentum transfer than their spherical counterparts. Additionally, Platonic Solids with fewer faces exhibit significant redshifts in plasmonic resonances, leading to higher angular momentum transfer due to edge effects. We also observe resonances and angular momentum transfers with similar characteristics in specific pairs of Platonic Solids, known as duals. These results highlight promising applications, particularly in electron tweezers technology.

The effect of intergroup competition outcome on ingroup cooperation: insights from the male warrior hypothesis.

Introduction: The Male Warrior Hypothesis (MWH) proposes that sex-specific selective pressures have promoted male cooperation with the ingroup members to outcompete rival groups. However, intergroup conflicts do not occur in isolation and the outcomes of previous competitions may influence group cooperativeness. Since this phenomenon is not well understood, we aimed to shed light on the effect of previous competition outcome on later cooperative behavior under intergroup conflicts. Based on the MWH, we hypothesized that repeated contests between groups could enhance ingroup cooperation, regardless of the outcome of the previous contest because status is at risk, but when competition is not present, participants would move to the symmetric equilibria. Methods: To test this hypothesis, we recruited 246 individuals organized in groups of 6 and measured cooperation using a threshold public good game over two rounds, manipulating the outcome in the first round to create groups of winners and losers. Results: Our results show that intergroup conflict scenarios promoted cooperation in both victory and defeat conditions, whereas, in the control scenario only losers increased their cooperation. Discussion: We argue that winners under the presence of an external threat may enhance in-group cooperation in order to assure their status; whereas, losers may be attempting to regain it.

The prognostic value of blood cellular indices in pulmonary embolism.

Prognostication in acute pulmonary embolism (PE) requires reliable markers. While cellular indices such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) appear promising, their utility in PE prognostication needs further exploration. We utilized data from the RIETE registry and the Loyola University Medical Center (LUMC) to assess the prognostic value of NLR, PLR, and SII in acute PE, using logistic regression models. The primary outcome was 30-day all-cause mortality. We compared their prognostic value versus the simplified Pulmonary Embolism Severity Index (sPESI) alone. We included 10 085 patients from RIETE and 700 from the LUMC. Thirty-day mortality rates were 4.6% and 8.3%, respectively. On multivariable analysis, an elevated NLR (>7.0) was associated with increased mortality (adjusted odds ratio [aOR]: 3.46; 95% CI: 2.60-4.60), outperforming the PLR > 220 (aOR: 2.36; 95% CI: 1.77-3.13), and SII > 1600 (aOR: 2.52; 95% CI: 1.90-3.33). The c-statistic for NLR in patients with low-risk PE was 0.78 (95% CI: 0.69-0.86). Respective numbers were 0.66 (95% CI: 0.63-0.69) and 0.68 (95% CI: 0.59-0.76) for intermediate-risk and high-risk patients. These findings were mirrored in the LUMC cohort. Among 9810 normotensive patients in RIETE, those scoring 0 points in sPESI and with an NLR ≤ 7.0 (35% of the population) displayed superior sensitivity (97.1%; 95% CI: 95.5-98.7) and negative predictive value (99.7%; 95% CI: 99.5-99.8) than sPESI alone (87.1%; 95% CI: 83.9-90.3, and 98.7%; 95% CI: 98.4-99.1, respectively) for 30-day mortality. The NLR is a significant prognostic marker for 30-day mortality in PE patients, especially useful to identify patients with very low-risk PE.

Direct interaction between marine cyanobacteria mediated by nanotubes.

Microbial associations and interactions drive and regulate nutrient fluxes in the ocean. However, physical contact between cells of marine cyanobacteria has not been studied thus far. Here, we show a mechanism of direct interaction between the marine cyanobacteria Prochlorococcus and Synechococcus, the intercellular membrane nanotubes. We present evidence of inter- and intra-genus exchange of cytoplasmic material between neighboring and distant cells of cyanobacteria mediated by nanotubes. We visualized and measured these structures in xenic and axenic cultures and in natural samples. We show that nanotubes are produced between living cells, suggesting that this is a relevant system of exchange material in vivo. The discovery of nanotubes acting as exchange bridges in the most abundant photosynthetic organisms in the ocean may have important implications for their interactions with other organisms and their population dynamics.

[Economic burden assessment for the management of asthma patients at Mexico's National Institute for Respiratory Diseases]. / Evaluación de la carga económica para el tratamiento de pacientes con asma en el Instituto Nacional de Enfermedades Respiratorias de México.

OBJETIVO: Determinar la carga económica anual del asma, desde una perspectiva institucional y con base en la clasificación recomendada por GINA, en una cohorte retrospectiva de adultos atendidos en el Instituto Nacional de Enfermedades Respiratorias (INER) de México. MÉTODOS: Estudio observacional, longitudinal y retrospectivo, llevado a cabo a partir de la información recabada de 247 pacientes femeninas con asma. Se estimaron los costos directos anuales: visitas, pruebas de laboratorio, tratamiento farmacológico y de las crisis o exacerbaciones, para determinar la carga anual de la enfermedad desde una perspectiva institucional, y según la clasificación de la Iniciativa Global para el Asma. RESULTADOS: El costo promedio anual fue de $43,813,92, que aumentó en relación con la necesidad de aumento de dosis de corticoides inhalados y beta-agonistas de acción prolongada. El costo promedio de la consulta médica fue de $2004.57, $982.82 por gestión de crisis y $2645.95 por pruebas de laboratorio. El tratamiento farmacológico representó la principal carga económica, con un costo promedio anual de $38,180.58. CONCLUSIONES: Los resultados resaltan una carga económica del asma estimada en un costo anual por paciente de $43,813.92 MXN (DE=93,348.85), en el contexto del tercer nivel de atención en el sistema de salud público mexicano. La gravedad del asma, los tratamientos y los biológicos fueron los principales factores que aumentaron los costos directos de la atención.

OBJECTIVE: Determine the annual economic burden of the disease from an institutional perspective and based on GINA's recommended classification in a retrospective cohort of adults treated at Instituto Nacional de Enfermedades Respiratorias (INER) of Mexico City. METHODS: A retrospective, longitudinal observational study comprised by data from 247 female asthma patients, annual direct costs were estimated including: visits, laboratory tests, pharmacological treatment and management of crisis or exacerbations, to determine the annual burden of the disease from an institutional perspective and according to Global Initiative for Asthma classification. RESULTS: The average annual cost was $43,813.92, which increased in relation to the need of inhaled corticosteroids and long-acting beta agonists dosage increase. The average doctor's appointment cost was $2,004.57, $982.82 for crisis management and $2,645.95 for laboratory testing. Pharmacological treatment represented the main economic burden with an annual average cost of $38,180.58. CONCLUSIONS: The results highlight an economic burden of asthma estimated at an annual cost per patient of $43,813.92 MXN (SD=93,348.85) in the context of the third level of care in the Mexican public health system. The asthma severity and treatments such as biologics were the main factors that increased direct costs of care.

Helminth-derived molecules improve 5-fluorouracil treatment on experimental colon tumorigenesis.

Colorectal cancer (CRC) is one of the most prevalent fatal neoplasias worldwide. Despite efforts to improve the early diagnosis of CRC, the mortality rate of patients is still nearly 50%. The primary treatment strategy for CRC is surgery, which may be accompanied by chemotherapy and radiotherapy. The conventional and first-line chemotherapeutic agent utilized is 5-fluorouracil (5FU). However, it has low efficiency. Combination treatment with leucovorin and oxaliplatin or irinotecan improves the effectiveness of 5FU therapy. Unfortunately, most patients develop drug resistance, leading to disease progression. Here, we evaluated the effect of a potential alternative adjuvant treatment for 5FU, helminth-derived Taenia crassiceps (TcES) molecules, on treating advanced colitis-associated colon cancer. The use of TcES enhanced the effects of 5FU on established colonic tumors by downregulating the expression of the immunoregulatory cytokines, Il-10 and Tgf-ß, and proinflammatory cytokines, Tnf-α and Il-17a, and reducing the levels of molecular markers associated with malignancy, cyclin D1, and Ki67, both involved in apoptosis inhibition and the signaling pathway of ß-catenin. TcES+5FU therapy promoted NK cell recruitment and the release of Granzyme B1 at the tumor site, consequently inducing tumor cell death. Additionally, it restored P53 activity which relates to decreased Mdm2 expression. In vitro assays with human colon cancer cell lines showed that therapy with TcES+5FU significantly reduced cell proliferation and migration by modulating the P53 and P21 signaling pathways. Our findings demonstrate, for the first time in vivo, that helminth-derived excreted/secreted products may potentiate the effect of 5FU on established colon tumors.

Somatostatin: a possible mediator of the long-term effects of experimental vertical gastrectomy on glucose metabolism in rats?

BACKGROUND: Sleeve gastrectomy (SG) is one of the most commonly performed bariatric surgeries. SG treats type 2 diabetes mellitus better than several drugs. The mechanisms that underlie this phenomenon are not clear. This study proposed that somatostatin (SST) isoforms SST-14 and SST-28 are key in the carbohydrate after SG. METHODS: Surgeries were performed on 3 groups of Wistar rats: the fasting, surgery control, and SG groups. Plasma levels of glucose, insulin, SST-14, and SST-28 were measured at 2 survival periods after surgery. Islet SST receptor (SSTR) and cell populations were studied. We performed a pasireotide (SST-28 analogue) infusion assay in another group of rats to confirm the influence of SST-28 plasma levels on the delta-cell population. RESULTS: This study found an elevation in the insulin response after SG in animals but a decrease in the insulin response over the long term with a loss of beta-cell mass. An increase in duodenal SST-28-producing cells in the duodenum and a loss of pancreatic SST-14-producing cells were observed after SG in animals but not in controls. The expression of SSTR type 5 in delta-cell populations from each group and the ability of the pasireotide infusion assay to decrease the delta-cell population indicated the effect of SST-28 plasma levels on delta-cell maintenance. CONCLUSION: After SG initiates a compensatory response in the duodenum, beta-cell mass is depleted after loss of the brake that regulates SST-14 at the paracrine level in a nonobese, normoglycemic rat model. This was an experimental model, with no clinical translation to the human clinic, with a preliminary importance regarding new pathophysiologic perspectives or pathways.