Intestinal ABC transporters: Influence on the metronomic cyclophosphamide-induced toxic effect in an obese mouse mammary cancer model.

Metronomic chemotherapy (MCT) is a cancer therapeutic approach characterized by low dose drug chronic administration and limited or null toxicity. Obesity-induced metabolic alterations worsen cancer prognosis and influence the intestinal biochemical barrier, altering the Multidrug resistance-associated protein 2 (Mrp2) and Multidrug resistance protein-1 (Mdr-1), efflux pumps that transport chemotherapeutic drugs. Obesity and cancer are frequent co-morbidities; thus, our aim was to evaluate the effectiveness and toxicity of MCT with cyclophosphamide (Cy) in obese mice with metabolic alterations bearing a mammary adenocarcinoma. Simultaneously, the expression and activities of intestinal Mrp2 and Mdr-1 were assessed. CBi male mice, were fed with chow diet (C) or diet with 40 % of fat (HFD). After 16 weeks, metabolic alterations were confirmed by biochemical and morphological parameters. At that time-point, HFD group showed decreased expressions of Mrp2 mRNA (53 %) as well as Mdr-1a and Mdr-1b (42 % and 59 %, respectively), compared to C (P < 0.05). This result correlated with decreased intestinal Mrp2 and Mdr-1 efflux activities (64 % and 45 %, respectively), compared to C (P < 0.05). Ultimately, mice were challenged with M-406 mammary adenocarcinoma; when the tumor was palpable, mice were distributed into 4 groups. The % inhibition of tumor growth with Cy (30 mg/kg/day) in C + Cy was higher than that of HFD + Cy (P = 0.052). Besides, it was observed a 21 % diminution in body weight and leukopenia in the HFD + Cy group. Conclusion: Obesity-induced metabolic alterations impair intestinal Mrp2 and Mdr-1 functions, bringing about increments in Cy absorption, leading to toxicity; in addition, the antitumor effectiveness of MCT decreased in obese animals.

IL-12 drives the differentiation of human T follicular regulatory cells.

T follicular regulatory (Tfr) cells can counteract the B cell helper activity of T follicular helper (Tfh) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (Treg) cells into Tfr cells is still missing. Herein, we report that low doses of the pro-Tfh cytokine interleukin-12 (IL-12) drive the induction of a Tfr cell program on activated human Treg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12-driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating Tfr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of Tfr cell differentiation in vivo and provides an approach for the in vitro generation of human Tfr-like cells.

Fibroblast growth factor 21 is a hepatokine involved in MASLD progression.

AIM: We aimed to assess the role of FGF21 in metabolic dysfunction-associated steatotic liver disease (MASLD) at a multi-scale level. METHODS: We used human MASLD pathology samples for FGF21 gene expression analyses (qPCR and RNAseq), serum to measure circulating FGF21 levels and DNA for genotyping the FGF21 rs838133 variant in both estimation and validation cohorts. A hepatocyte-derived cell line was exposed to free fatty acids at different timepoints. Finally, C57BL/6J mice were fed a high-fat and choline-deficient diet (CDA-HFD) for 16 weeks to assess hepatic FGF21 protein expression and FGF21 levels by ELISA. RESULTS: A significant upregulation in FGF21 mRNA expression was observed in the liver analysed by both qPCR (fold change 5.32 ± 5.25 vs. 0.59 ± 0.66; p = 0.017) and RNA-Seq (3.5 fold; FDR: 0.006; p < 0.0001) in MASLD patients vs. controls. Circulating levels of FGF21 were increased in patients with steatohepatitis vs. bland steatosis (386.6 ± 328.9 vs. 297.9 ± 231.5 pg/mL; p = 0.009). Besides, sex, age, A-allele from FGF21, GG genotype from PNPLA3, ALT, type 2 diabetes mellitus and BMI were independently associated with MASH and significant fibrosis in both estimation and validation cohorts. In vitro exposure of Huh7.5 cells to high concentrations of free fatty acids (FFAs) resulted in overexpression of FGF21 (p < 0.001). Finally, Circulating FGF21 levels and hepatic FGF21 expression were found to be significantly increased (p < 0.001) in animals under CDA-HFD. CONCLUSIONS: Hepatic and circulating FGF21 expression was increased in MASH patients, in Huh7.5 cells under FFAs and in CDA-HFD animals. The A-allele from the rs838133 variant was also associated with an increased risk of steatohepatitis and significant and advanced fibrosis in MASLD patients.

Increased Osteoblastic and Osteocytic in Vitro Cell Viability by Yerba Mate (Ilex paraguariensis).

BACKGROUND: Yerba mate (YM, Ilex paraguariensis) consumption beneficially affects the bones. However, whether YM components exert their effect on bone cells directly remains elusive. METHODS: We evaluated how main YM components affect osteoblastic (MC3T3-E1) and osteocytic (MLO-Y4) cells in vitro when administered separately or in an aqueous extract. MC3T3-E1 and MLO-Y4 cells were exposed to three different experimental conditions: (1) Caffeine, chlorogenic acid, and their combinations; (2) Caffeine, rutin, and their combinations; (3) Aqueous YM extract. RESULTS: All polyphenol and caffeine concentrations as well as that of their tested combinations significantly increased MC3T3-E1 cell viability from 16.6% to 34.8% compared to the control. In MLO-Y4 cells, the lowest rutin and the two highest caffeine concentrations significantly increased cell viability by 11.9, 14.9, and 13.7%, respectively. While rutin and caffeine combinations tended to increase MLO-Y4 cell viability, different chlorogenic acid and caffeine combinations did not affect it. Finally, the aqueous YM extract significantly increased MLO-Y4, MC3T3-E1, and differentiated MC3T3-E1 cell viability compared to the control without treatment. CONCLUSIONS: YM components (rutin, chlorogenic acid, and caffeine) positively affected bone cells, mainly pre-osteoblast cells. Moreover, the aqueous YM extract significantly increased MLO-Y4, MC3T3-E1, and differentiated MC3T3-E1 cell viabilities indicating an additional relevant nutritional property of YM infusion. Further studies would be required to elucidate the underlying effector mechanism of YM on the bones and its relationship with previously described in vivo positive effects.

Metabolic and Low-Grade Inflammation Risk in Young Adults with a History of Extrauterine Growth Restriction.

Children with a history of extrauterine growth restriction (EUGR), later at prepubertal age, exhibit an increased metabolic risk including risen insulin resistance and low-grade inflammation. However, the progression of such metabolic changes after puberty and the lasting health implications have not yet been investigated. The objective of this study was to ascertain whether young adults with a history of EUGR faced increased vulnerability to metabolic disorders. A study was conducted comparing a group of adults with a history of EUGR with a healthy reference group. A total of 110 young adults (36 from the EUGR group and 74 from the control group) were included. Anthropometric variables, blood pressure (BP), general biochemical parameters, plasma inflammatory biomarkers, and adipokines were assessed. Compared to the reference group, the EUGR group had a shorter height and body weight with higher lean mass and waist circumference, as well as a greater percentage of individuals with high BP. In addition, EUGR patients had higher values of insulin, HOMA-IR, nerve growth factor, and leptin, and lower levels of adiponectin and resistin. The present study suggests that young adults with a history of EUGR present increased metabolic risk factors therefore, clinical follow-up should be considered.

Self-illuminated third-harmonic image upconversion.

We demonstrate third-harmonic upconversion imaging to visualize real time infrared images in the visible with standard CCD or CMOS silicon-based cameras operating at room temperature. Different from the usual sum-frequency mixing image upconversion, our third-harmonic image upconversion approach does not require an auxiliary IR source to illuminate a target. The upconversion system uses a passively Q-switched Nd3+:YVO4 laser operating at 1342 nm with two intracavity KTP crystals, obtaining a 447 nm upconverted image by a cascaded process where an upconverted image at 671 nm is also obtained as an intermediate step.

The Temporary Incapacity (TI) register as a complementary system to traditional epidemiological surveillance during the COVID-19 pandemic in Spain.

INTRODUCTION: During the COVID-19 pandemic, a set of social measures were adopted for the preservation of business activity and the protection of workers. One of these measures was issuing the Temporary Disability (TD) for COVID-19 cases, close contacts, and especially vulnerable workers. OBJETIVE: This study analyzes whether the TD registry could be used as a complementary source to traditional epidemiological surveillance. METHODS: A longitudinal study of time series was carried out with a cross-correlation analysis of TD and COVID-19 cases reported to the National Epidemiological Surveillance Network (RENAVE). The analysis included six pandemic waves between 10/03/2020 and 31/12/2021 in Spain. Cross-correlation coefficients (r) were calculated using a time lag of -14 days. RESULTS: During the study period, 2,253,573 TD processes were recorded in Spain and 4,894,802 COVID-19 cases were reported to RENAVE. Significant positive correlations were observed at time lags of -7, -10, and -14, indicating that TD notification preceded RENAVE notification. In the first and sixth pandemic waves, TD notification preceded RENAVE by 12 and 7 days, respectively. Negative correlations between the two series were observed in the second and fourth waves, coinciding with a lower number of reported cases. In the third and fifth waves, TD notification also preceded RENAVE (lags -1, -5 and -14, -7, respectively). CONCLUSIONS: The results confirm the usefulness of TD registry as a complementary system to traditional epidemiological surveillance in Spain, by detecting COVID-19 cases in the 7, 10, and 14 days prior. A better positive correlation is observed in waves where more cases were reported.

Remarkable enhancement of cinnamaldehyde antimicrobial activity encapsulated in capped mesoporous nanoparticles: A new "nanokiller" approach in the era of antimicrobial resistance.

Combating antimicrobial resistance is one of the biggest health challenges because of the ineffectiveness of standard biocide treatments. This challenge could be approached using natural products, which have demonstrated powerful therapeutics against multidrug-resistant microbes. In the present work, a nanodevice consisting of mesoporous silica nanoparticles loaded with an essential oil component (cinnamaldehyde) and functionalized with the polypeptide ε-poly-l-lysine is developed and used as an antimicrobial agent. In the presence of the corresponding stimuli (i.e., exogenous proteolytic enzymes from bacteria or fungi), the polypeptide is hydrolyzed, and the cinnamaldehyde delivery is enhanced. The nanodevice's release mechanism and efficacy are evaluated in vitro against the pathogenic microorganisms Escherichia coli, Staphylococcus aureus, and Candida albicans. The results demonstrate that the new device increases the delivery of the cinnamaldehyde via a biocontrolled uncapping mechanism triggered by proteolytic enzymes. Moreover, the nanodevice notably improves the antimicrobial efficacy of cinnamaldehyde when compared to the free compound, ca. 52-fold for E. coli, ca. 60-fold for S. aureus, and ca. 7-fold for C. albicans. The enhancement of the antimicrobial activity of the essential oil component is attributed to the decrease of its volatility due to its encapsulation in the porous silica matrix and the increase of its local concentration when released due to the presence of microorganisms.

Monkeypox virus genomic accordion strategies.

The 2023 monkeypox (mpox) epidemic was caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage traced back to Nigeria in 1971. Person-to-person transmission appears higher than for clade I or subclade IIa MPXV, possibly caused by genomic changes in subclade IIb MPXV. Key genomic changes could occur in the genome's low-complexity regions (LCRs), which are challenging to sequence and are often dismissed as uninformative. Here, using a combination of highly sensitive techniques, we determine a high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This reveals significant variation in short tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of single-nucleotide polymorphisms (SNPs) and that LCRs are not randomly distributed. In silico analyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs), including OPG153, OPG204, and OPG208, could be affected in a manner consistent with the established "genomic accordion" evolutionary strategies of orthopoxviruses. We posit that genomic studies focusing on phenotypic MPXV differences should consider LCR variability.

Role of psychopathology on children credibility of sexual abuse testimony.

When an alleged victim has a pre-existing psychopathological diagnosis, this can affect the rating of their version of the abuse in terms of credibility. The objective of this work is to analyze the relationship between the assessment of the credibility of the testimony of a CSA victim, the psychological problems that the child may have presented prior to sexual abuse and the possible psychological sequelae that she may present as a result of the abuse. 109 cases were selected in which the credibility of the testimony could be determined. Through forensic interviews and the study of the corresponding professional reports, the following were obtained: sociodemographic data, data on their previous psychological state and data on their psychological state after the reported events. The psychological state of the child after the reported events shows no relation to the forensic evaluation of the credibility of her testimony. The existence of a relationship between the absence of previous psychopathology and the fact that the victim's testimony is valued as a credible account is confirmed. This study reveals that children who presented psychological manifestations prior to their experience of abuse receive a lower credibility rating than those without previous psychopathological symptoms or diagnoses.

Cold exposure modulates potential brown adipokines in humans, but only FGF21 is associated with brown adipose tissue volume.

OBJECTIVE: The study objective was to investigate the effect of cold exposure on the plasma levels of five potential human brown adipokines (chemokine ligand 14 [CXCL14], growth differentiation factor 15 [GDF15], fibroblast growth factor 21 [FGF21], interleukin 6 [IL6], and bone morphogenic protein 8b [BMP8b]) and to study whether such cold-induced effects are related to brown adipose tissue (BAT) volume, activity, or radiodensity in young humans. METHODS: Plasma levels of brown adipokines were measured before and 1 h and 2 h after starting an individualized cold exposure in 30 young adults (60% women, 21.9 ± 2.3 y; 24.9 ± 5.1 kg/m2 ). BAT volume, 18 F-fluorodeoxyglucose uptake, and radiodensity were assessed by a static positron emission tomography-computerized tomography scan after cold exposure. RESULTS: Cold exposure increased the concentration of CXCL14 (Δ2h = 0.58 ± 0.98 ng/mL; p = 0.007), GDF15 (Δ2h = 19.63 ± 46.2 pg/mL; p = 0.013), FGF21 (Δ2h = 33.72 ± 55.13 pg/mL; p = 0.003), and IL6 (Δ1h = 1.98 ± 3.56 pg/mL; p = 0.048) and reduced BMP8b (Δ2h = -37.12 ± 83.53 pg/mL; p = 0.022). The cold-induced increase in plasma FGF21 was positively associated with BAT volume (Δ2h: ß = 0.456; R2 = 0.307; p = 0.001), but not with 18 F-fluorodeoxyglucose uptake or radiodensity. None of the changes in the other studied brown adipokines was related to BAT volume, activity, or radiodensity. CONCLUSIONS: Cold exposure modulates plasma levels of several potential brown adipokines in humans, whereas only cold-induced changes in FGF21 levels are associated with BAT volume. These findings suggest that human BAT might contribute to the circulatory pool of FGF21.

Development of Antibacterial Thermoplastic Starch with Natural Oils and Extracts: Structural, Mechanical and Thermal Properties.

In this study, the influence of the incorporation of eucalyptus (EO), tea tree (TT) and rosemary (RO) essential oils and Chiriyuyo extract (CE) on the structure and properties of thermoplastic starch (TPS) obtained from potato starch, glycerin and water was evaluated. All oils and the extract were used at a concentration of 0.5 g/100 g of TPS, while for TT, the effect of the concentration was also studied. The mixtures obtained were processed by extrusion and thermocompression molding. The sheets were characterized by XRD, FTIR, TGA, SEM and analyses of their mechanical properties, antimicrobial characteristics and biodegradability. The results show that the use of small concentrations of the oils in 70TPS does not induce changes in the TPS structure according to the results of XRD, FTIR and TGA, with each essential oil and CE affecting the mechanical properties unevenly, although in all cases, antimicrobial activity was obtained, and the biodegradability of TPS in soil was not modified. An increase in the concentration of TT in 60TPS causes marked changes in the crystallinity of TPS, providing a greater modulus with a higher concentration of TT. Regardless of the amount of TT, all sheets maintain antimicrobial characteristics, and their biodegradation in soil is delayed with a higher oil content.

Decreased Cognitive Function in Danish Children with Epilepsy.

OBJECTIVE: Children with epilepsy have a significantly increased risk of cognitive impairment. EpiTrack Junior is a screening tool developed for fast assessment of cognitive function in children with epilepsy. The tool is validated for German children. This cohort study aims to investigate the differences in cognitive function between healthy Danish children and Danish children diagnosed with epilepsy METHODS: The cognitive function of 204 healthy controls and 90 children and adolescents diagnosed with epilepsy was examined using EpiTrack Junior. The participants of the control group were aged 6 to 16 years. The patients were aged 6 to 20 years. Statistical analyses were performed with the use of SPSS Statistics. RESULTS: The control group showed significantly higher scores than the patient group in three of six subtests and total test scores (p-values ranging from 0.033 to <0.001). When grouped according to the EpiTrack Junior guidelines, more patients showed scores "below average" or "poor" compared to the control group. The age-corrected total score was not associated with antiepileptic drug treatment (p-value of 0.732) nor with a history of focal seizures (p-value of 0.215). A history of generalized tonic-clonic seizures (GTCS) was associated with a higher EpiTrack Junior score (p-value of 0.035). CONCLUSION: The patient group showed statistically significant lower test scores compared to the control group confirming the relationship between impaired cognitive function and childhood epilepsy. Furthermore, a correlation between a higher EpiTrack Junior score and the presence of GTCS was found. Focal seizures and antiepileptic drug treatment were not associated with the EpiTrack Junior score.