MicroRNA-204 Regulates Angiogenesis and Vasculogenic Mimicry in CD44+/CD24- Breast Cancer Stem-like Cells.

Tumors have high requirements in terms of nutrients and oxygen. Angiogenesis is the classical mechanism for vessel formation. Tumoral vascularization has the function of nourishing the cancer cells to support tumor growth. Vasculogenic mimicry, a novel intratumoral microcirculation system, alludes to the ability of cancer cells to organize in three-dimensional (3D) channel-like architectures. It also supplies the tumors with nutrients and oxygen. Both mechanisms operate in a coordinated way; however, their functions in breast cancer stem-like cells and their regulation by microRNAs remain elusive. In the present study, we investigated the functional role of microRNA-204 (miR-204) on angiogenesis and vasculogenic mimicry in breast cancer stem-like cells. Using flow cytometry assays, we found that 86.1% of MDA-MB-231 and 92% of Hs-578t breast cancer cells showed the CD44+/CD24- immunophenotype representative of cancer stem-like cells (CSCs). The MDA-MB-231 subpopulation of CSCs exhibited the ability to form mammospheres, as expected. Interestingly, we found that the restoration of miR-204 expression in CSCs significantly inhibited the number and size of the mammospheres. Moreover, we found that MDA-MB-231 and Hs-578t CSCs efficiently undergo angiogenesis and hypoxia-induced vasculogenic mimicry in vitro. The transfection of precursor miR-204 in both CSCs was able to impair the angiogenesis in the HUVEC cell model, which was observed as a diminution in the number of polygons and sprouting cells. Remarkably, miR-204 mimics also resulted in the inhibition of vasculogenic mimicry formation in MDA-MB-231 and Hs-578t CSCs, with a significant reduction in the number of channel-like structures and branch points. Mechanistically, the effects of miR-204 were associated with a diminution of pro-angiogenic VEGFA and ß-catenin protein levels. In conclusion, our findings indicated that miR-204 abrogates the angiogenesis and vasculogenic mimicry development in breast cancer stem-like cells, suggesting that it could be a potential tool for breast cancer intervention based on microRNA replacement therapies.

Temporal variation in tree diversity effects on birds and its implications for top-down control of insect herbivores in a tropical system.

Tree diversity promotes predator abundance and diversity, but evidence linking these effects to increased predation pressure on herbivores remains limited. In addition, tree diversity effects on predators can vary temporally as a function of environmental variation, or due to contrasting responses by different predator types. In a multi-year study, we assessed temporal variation in tree diversity effects on bird community abundance, diversity, and predation rates as a whole and by functional group based on feeding guild (omnivores vs. insectivores) and migratory status (migrant vs. resident). To this end, we conducted bird point counts in tree monocultures and polycultures and assessed attacks on clay caterpillars four times over a 2-year period in a tree diversity experiment in Yucatan, Mexico. Tree diversity effects on the bird community varied across surveys, with positive effects on bird abundance and diversity in most but not all surveys. Tree diversity had stronger and more consistent effects on omnivorous and resident birds than on insectivorous and migratory species. Tree diversity effects on attack rates also varied temporally but patterns did not align with variation in bird abundance or diversity. Thus, while we found support for predicted increases in bird abundance, diversity, and predation pressure with tree diversity, these responses exhibited substantial variation over time and the former two were uncoupled from patterns of predation pressure, as well as contingent on bird functional traits. These results underscore the need for long-term studies measuring responses by different predator functional groups to better understand tree diversity effects on top-down control.

Determining Structural Changes for Ligand Recognition between Human and Rat Phosphorylated BACE1 in Silico and Its Phosphorylation by GSK3ß at Thr252 by in Vitro Studies.

Alzheimer's disease (AD) is a neurodegenerative disease affecting older adults. AD pathogenesis involves the production of the highly neurotoxic amyloid-ß peptide 1-42 (Aß1-42) from ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). The phosphorylation of BACE1 at Thr252 increases its enzymatic activity. This study examined the phosphorylation of BACE1 from human and rat BACE1 in silico through phosphorylation predictors. Besides, we explored how phosphorylation at various sites affected the BACE1 structure and its affinity with amyloid precursor protein (APP) and six BACE1 inhibitors. Additionally, we evaluated the phosphorylation of Thr252-BACE1 by glycogen synthase kinase 3 ß (GSK3ß) in vitro. The phosphorylation predictors showed that Thr252, Ser59, Tyr76, Ser71, and Ser83 could be phosphorylated. Also, Ser127 in rat BACE1 can be phosphorylated, but human BACE1 has a Gly at this position. Molecular dynamics simulations showed that Ser127 plays an important role in the open and closed BACE1 conformational structures. Docking studies and the molecular mechanics generalized Born surface area (MMGBSA) approach showed that human BACE1 phosphorylated at Thr252 and rat BACE1 phosphorylated at Ser71 have the best binding and free energy with APP, forming hydrogen bonds with Asp672. Importantly, inhibitors have a higher affinity for the phosphorylated rat BACE1 than for its human counterpart, which could explain their failure during clinical trials. Finally, in vitro experiments showed that GSK3ß could phosphorylate BACE1. In conclusion, BACE1 phosphorylation influences the BACE1 conformation and its recognition of ligands and substrates. Thus, these features should be carefully considered in the design of BACE1 inhibitors.

Differential efficacy of two small molecule PHLPP inhibitors to promote nucleus Pulposus cell health.

Background: Intervertebral disc (IVD) degeneration is associated with chronic back pain. We previously demonstrated that the phosphatase pleckstrin homology domain and leucine-rich repeat protein phosphatase (PHLPP) 1 was positively correlated with IVD degeneration and its deficiency decelerated IVD degeneration in both mouse IVDs and human nucleus pulposus (NP) cells. Small molecule PHLPP inhibitors may offer a translatable method to alleviate IVD degeneration. In this study, we tested the effectiveness of the two PHLPP inhibitors NSC117079 and NSC45586 in promoting a healthy NP phenotype. Methods: Tail IVDs of 5-month-old wildtype mice were collected and treated with NSC117079 or NSC45586 under low serum conditions ex vivo. Hematoxylin & eosin staining was performed to examine IVD structure and NP cell morphology. The expression of KRT19 was analyzed through immunohistochemistry. Cell apoptosis was assessed by TUNEL assay. Human NP cells were obtained from patients with IVD degeneration. The gene expression of KRT19, ACAN, SOX9, and MMP13 was analyzed via real time qPCR, and AKT phosphorylation and the protein expression of FOXO1 was analyzed via immunoblot. Results: In a mouse IVD organ culture model, NSC45586, but not NSC117079, preserved vacuolated notochordal cell morphology and KRT19 expression while suppressing cell apoptosis, counteracting the degenerative changes induced by serum deprivation, especially in males. Likewise, in degenerated human NP cells, NSC45586 increased cell viability and the expression of KRT19, ACAN, and SOX9 and reducing the expression of MMP13, while NSC117079 treatment only increased KRT19 expression. Mechanistically, NSC45586 treatment increased FOXO1 protein expression in NP cells, and inhibiting FOXO1 offset NSC45586-induced regenerative potential, especially in males. Conclusions: Our study indicates that NSC45586 was effective in promoting NP cell health, especially in males, suggesting that PHLPP plays a key role in NP cell homeostasis and that NSC45586 might be a potential drug candidate in treating IVD degeneration.

Differences in the Evolution of Clinical, Biochemical, and Hematological Indicators in Hospitalized Patients with COVID-19 According to Their Vaccination Scheme: A Cohort Study in One of the World's Highest Hospital Mortality Populations.

COVID-19 vaccines primarily prevent severe illnesses or hospitalization, but there is limited data on their impact during hospitalization for seriously ill patients. In a Mexican cohort with high COVID-19 mortality, a study assessed vaccination's effects. From 2021 to 2022, 462 patients with 4455 hospital days were analyzed. The generalized multivariate linear mixed model (GENLINMIXED) with binary logistic regression link, survival analysis and ROC curves were used to identify risk factors for death. The results showed that the vaccinated individuals were almost half as likely to die (adRR = 0.54, 95% CI = 0.30-0.97, p = 0.041). When stratifying by vaccine, the Pfizer group (BNT162b2) had a 2.4-times lower risk of death (adRR = 0.41, 95% CI = 0.2-0.8, p = 0.008), while the AstraZeneca group (ChAdOx1-S) group did not significantly differ from the non-vaccinated (adRR = 1.04, 95% CI = 0.5-2.3, p = 0.915). The Pfizer group exhibited a higher survival, the unvaccinated showed increasing mortality, and the AstraZeneca group remained intermediate (p = 0.003, multigroup log-rank test). Additionally, BNT162b2-vaccinated individuals had lower values for markers, such as ferritin and D-dimer. Biochemical and hematological indicators suggested a protective effect of both types of vaccines, possibly linked to higher lymphocyte counts and lower platelet-to-lymphocyte ratio (PLR). It is imperative to highlight that these results reinforce the efficacy of COVID-19 vaccines. However, further studies are warranted for a comprehensive understanding of these findings.

pH-sensing G protein-coupled orphan receptor GPR68 is expressed in human cartilage and correlates with degradation of extracellular matrix during OA progression.

Background: Osteoarthritis (OA) is a debilitating joints disease affecting millions of people worldwide. As OA progresses, chondrocytes experience heightened catabolic activity, often accompanied by alterations in the extracellular environment's osmolarity and acidity. Nevertheless, the precise mechanism by which chondrocytes perceive and respond to acidic stress remains unknown. Recently, there has been growing interest in pH-sensing G protein-coupled receptors (GPCRs), such as GPR68, within musculoskeletal tissues. However, function of GPR68 in cartilage during OA progression remains unknown. This study aims to identify the role of GPR68 in regulation of catabolic gene expression utilizing an in vitro model that simulates catabolic processes in OA. Methods: We examined the expression of GPCR by analyzing high throughput RNA-Seq data in human cartilage isolated from healthy donors and OA patients. De-identified and discarded OA cartilage was obtained from joint arthroplasty and chondrocytes were prepared by enzymatic digestion. Chondrocytes were treated with GPR68 agonist, Ogerin and then stimulated IL1ß and RNA isolation was performed using Trizol method. Reverse transcription was done using the cDNA synthesis kit and the expression of GPR68 and OA related catabolic genes was quantified using SYBR® green assays. Results: The transcriptome analysis revealed that pH sensing GPCR were expressed in human cartilage with a notable increase in the expression of GPR68 in OA cartilage which suggest a potential role for GPR68 in the pathogenesis of OA. Immunohistochemical (IHC) and qPCR analyses in human cartilage representing various stages of OA indicated a progressive increase in GPR68 expression in cartilage associated with higher OA grades, underscoring a correlation between GPR68 expression and the severity of OA. Furthermore, IHC analysis of Gpr68 in murine cartilage subjected to surgically induced OA demonstrated elevated levels of GPR68 in knee cartilage and meniscus. Using IL1ß stimulated in vitro model of OA catabolism, our qPCR analysis unveiled a time-dependent increase in GPR68 expression in response to IL1ß stimulation, which correlates with the expression of matrix degrading proteases suggesting the role of GPR68 in chondrocytes catabolism and matrix degeneration. Using pharmacological activator of GPR68, our results further showed that GPR68 activation repressed the expression of MMPs in human chondrocytes. Conclusions: Our results demonstrated that GPR68 was robustly expressed in human cartilage and mice and its expression correlates with matrix degeneration and severity of OA progression in human and surgical model. GPR68 activation in human chondrocytes further repressed the expression of MMPs under OA pathological condition. These results identify GPR68 as a possible therapeutic target in the regulation of matrix degradation during OA.

Differentiation of Human Induced Pluripotent Stem Cells (iPSCs)-derived Mesenchymal Progenitors into Chondrocytes.

Induced pluripotent stem cells (iPSCs) generated from human sources are valuable tools for studying skeletal development and diseases, as well as for potential use in regenerative medicine for skeletal tissues such as articular cartilage. To successfully differentiate human iPSCs into functional chondrocytes, it is essential to establish efficient and reproducible strategies that closely mimic the physiological chondrogenic differentiation process. Here, we describe a simple and efficient protocol for differentiation of human iPSCs into chondrocytes via generation of an intermediate population of mesenchymal progenitors. These methodologies include step-by-step procedures for mesenchymal derivation, induction of chondrogenic differentiation, and evaluation of the chondrogenic marker gene expression. In this protocol, we describe the detailed procedure for successful derivation of mesenchymal progenitor population from human iPSCs, which are then differentiated into chondrocytes using high-density culture conditions by stimulating with bone morphogenetic protein-2 (BMP-2) or transforming growth factor beta-3 (TGFß-3). The differentiated iPSCs exhibit temporal expression of cartilage genes and accumulation of a cartilaginous extracellular matrix in vitro, indicating successful chondrogenic differentiation. These detailed methodologies help effective differentiation of human iPSCs into the chondrogenic lineage to obtain functional chondrocytes, which hold great promise for modeling skeletal development and disease, as well as for potential use in regenerative medicine for cell-based therapy for cartilage regeneration. Key features • Differentiation of human iPSCs into chondrocytes using 3D culture methods. • Uses mesenchymal progenitors as an intermediate for differentiation into chondrocytes.

Efficient Differentiation of Human Induced Pluripotent Stem Cell (hiPSC)-Derived Mesenchymal Progenitors Into Adipocytes and Osteoblasts.

Human induced pluripotent stem cells (hiPSCs) hold immense promise in regenerative medicine as they can differentiate into various cell lineages, including adipocytes, osteoblasts, and chondrocytes. Precisely guiding hiPSC-derived mesenchymal progenitor cells (iMSCs) towards specific differentiation pathways is crucial for harnessing their therapeutic potential in tissue engineering, disease modeling, and regenerative therapies. To achieve this, we present a comprehensive and reproducible protocol for effectively differentiating iMSCs into adipocytes and osteoblasts. The differentiation process entails culturing iMSCs in tailored media supplemented with specific growth factors, which act as cues to initiate adipogenic or osteogenic commitment. Our protocol provides step-by-step guidelines for achieving adipocyte and osteoblast differentiation, ensuring the generation of mature and functional cells. To validate the success of differentiation, key assessment criteria are employed. For adipogenesis, the presence of characteristic lipid droplets within the iMSC-derived cells is considered indicative of successful differentiation. Meanwhile, Alizarin Red staining serves as a marker for the osteogenic differentiation, confirming the formation of mineralized nodules. Importantly, the described method stands out due to its simplicity, eliminating the need for specialized equipment, expensive materials, or complex reagents. Its ease of implementation offers an attractive advantage for researchers seeking robust and cost-effective approaches to derive adipocytes and osteoblasts from iMSCs. Overall, this protocol establishes a foundation for exploring the therapeutic potential of hiPSC-derived cells and advancing the field of regenerative medicine. Key features • iMSC derivation in this protocol uses embryonic body formation technique. • Adipogenesis and osteogenesis protocols were optimized for human iPSC-derived iMSCs. • Derivation of iMSC from hiPSC was developed in a feeder-free culture condition. • This protocol does not include human iPSC reprogramming strategies.

Untargeted LC-MS/MS Metabolomics Study of HO-AAVPA and VPA on Breast Cancer Cell Lines.

Breast cancer (BC) is one of the biggest health problems worldwide, characterized by intricate metabolic and biochemical complexities stemming from pronounced variations across dysregulated molecular pathways. If BC is not diagnosed early, complications may lead to death. Thus, the pursuit of novel therapeutic avenues persists, notably focusing on epigenetic pathways such as histone deacetylases (HDACs). The compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA), a derivative of valproic acid (VPA), has emerged as a promising candidate warranting pre-clinical investigation. HO-AAVPA is an HDAC inhibitor with antiproliferative effects on BC, but its molecular mechanism has yet to be deciphered. Furthermore, in the present study, we determined the metabolomic effects of HO-AAVPA and VPA on cells of luminal breast cancer (MCF-7) and triple-negative breast cancer (MDA-MB-231) subtypes. The LC-MS untargeted metabolomic study allowed for the simultaneous measurement of multiple metabolites and pathways, identifying that both compounds affect glycerophospholipid and sphingolipid metabolism in the MCF-7 and MDA-MB-231 cell lines, suggesting that other biological targets were different from HDACs. In addition, there are different dysregulate metabolites, possibly due to the physicochemical differences between HO-AAVPA and VPA.

LDH-A Promotes Metabolic Rewiring in Leucocytes from the Intestine of Rats Treated with TNBS.

Although the aetiology of inflammatory bowel diseases (IBDs) is still unknown, one of their main characteristics is that the immune system chronically affects the permeability of the intestinal lamina propria, in turn altering the composition of the microbiota. In this study, the TNBS rat model of colitis was used because it contains a complex inflammatory milieu of polymorphonuclear cells (PMN) and lymphocytes infiltrating the lamina propria. The aim of the present study was to investigate six dehydrogenases and their respective adaptations in the tissue microenvironment by quantifying enzymatic activities measured under substrate saturation conditions in epithelial cells and leukocytes from the lamina propria of rats exposed to TNBS. Our results show that in the TNBS group, an increased DAI score was observed due to the presence of haemorrhagic and necrotic areas in the colon. In addition, the activities of G6PDH and GADH enzymes were significantly decreased in the epithelium in contrast to the increased activity of these enzymes and increased lactate mediated by the LDH-A enzyme in leukocytes in the lamina propria of the colon. Over the past years, evidence has emerged illustrating how metabolism supports aspect of cellular function and how a metabolic reprogramming can drive cell differentiation and fate. Our findings show a metabolic reprogramming in colonic lamina propria leukocytes that could be supported by increased superoxide anion.

LC-MS metabolomic evidence metabolites from Oenothera rosea L´ Hér. ex Ait with antiproliferative properties on DU145 human prostate cancer cell line.

Prostate cancer remains one of the leading health issues without a fully effective treatment. Medicinal plants are one of the primary sources of compounds for treating numerous ailments. In this sense, the Oenothera genus contains metabolites with antiproliferative activity on cancer cells. For this, the study aimed to explore the antiproliferative activity of its extracts against prostate cancer and identify its metabolites (under metabolomics analyses) associated with anticancer and/or antiproliferative properties. For this reason, a LC-MS/MS-based metabolomic analysis was performed to demonstrate the possible metabolites present in O. rosea. In addition, the antiproliferative activity of different extracts in the human prostate cancer cell line DU145 was evaluated. All extracts have antiproliferative effects on DU145 cells at 72 h, with moderate activity being the best ethanolic either 48 or 72 h. Finally, by LC-MS/MS-based metabolomics, 307 compounds from aqueous, methanolic, ethanolic, and ethyl acetate extracts from which 40 putative metabolites identified were organized as anti-inflammatory, anticancer, and/or antiproliferative activities according to previously reported. These results provide evidence that O. rosea could be used as an antiproliferative agent due to its chemical contents used as polypharmacy with low concentration levels.

Design, Synthesis and Biological Activities of (Thio)Urea Benzothiazole Derivatives.

(Thio)ureas ((T)Us) and benzothiazoles (BTs) each have demonstrated to have a great variety of biological activities. When these groups come together, the 2-(thio)ureabenzothizoles [(T)UBTs] are formed, improving the physicochemical as well as the biological properties, making these compounds very interesting in medicinal chemistry. Frentizole, bentaluron and methabenzthiazuron are examples of UBTs used for treatment of rheumatoid arthritis and as wood preservatives and herbicides in winter corn crops, respectively. With this antecedent, we recently reported a bibliographic review about the synthesis of this class of compounds, from the reaction of substituted 2-aminobenzothiazoles (ABTs) with iso(thio)cyanates, (thio)phosgenes, (thio)carbamoyl chlorides, 1,1'-(thio)carbonyldiimidazoles, and carbon disulfide. Herein, we prepared a bibliographic review about those features of design, chemical synthesis, and biological activities relating to (T)UBTs as potential therapeutic agents. This review is about synthetic methodologies generated from 1968 to the present day, highlighting the focus to transform (T)UBTs to compounds containing a range substituents, as illustrated with 37 schemes and 11 figures and concluded with 148 references. In this topic, the scientists dedicated to medicinal chemistry and pharmaceutical industry will find useful information for the design and synthesis of this interesting group of compounds with the aim of repurposing these compounds.

Immigration Status, Legal Vulnerability, and Suicidal/Self-harm Ideation Disparities Among Immigrant-Origin Latinx Young Adults in the U.S.

Theories of suicidality typically center intrapersonal processes, with limited attention to social determinants of mental health disparities. Using a legal vulnerability framework, we examined the association between self/parental immigration status and suicidal and self-harm ideation (SI) disparities in three groups of immigrant-origin Latinx young adults attending college in the USA: undocumented students (n = 564), US citizens with undocumented parents (n = 605), and US citizens with lawfully present parents (n = 596). We also evaluated whether self/parental immigration status differences in SI could be accounted for by six dimensions of legal vulnerability and, based on prominent theories of suicidality, explored the role of campus belongingness as a protective factor. Participants completed self-report measures, and SI was assessed using one item from the Patient Health Questionnaire-9, a screening tool that assesses the severity of depression symptomatology. Rates of SI were significantly higher among undocumented students (23.1%) and US citizens with undocumented parents (24.3%) compared to US citizens with lawfully present parents (17.8%). Immigration policy-related social exclusion and discrimination-mediated self/parental immigration status differences in SI. Although food insecurity did not differ by self/parental immigration status, greater food insecurity was associated with higher likelihood of SI. Greater campus belongingness was associated with a lower likelihood of endorsing SI for all students regardless of immigration status or legal vulnerability factors. Findings underscore the importance of examining self and parental immigration status as a social determinant of SI and the value of investigating aspects of legal vulnerability as explanatory factors.

Individual variability in diving behavior of the Black-vented Shearwater in an ever-changing habitat.

Oceanic mesoscale systems are characterized by inherent variability. Climatic change adds entropy to this system, making it a highly variable environment in which marine species live. Being at the higher levels of the food chain, predators maximize their performance through plastic foraging strategies. Individual variability within a population and the possible repeatability across time and space may provide stability in a population facing environmental changes. Therefore, variability and repeatability of behaviors, particularly diving behavior, could play an important role in understanding the adaptation pathway of a species. This study focuses on characterizing the frequency and timing of different dives (termed simple and complex) and how these are influenced by individual and environmental characteristics (sea surface temperature, chlorophyll a concentration, bathymetry, salinity, and Ekman transport). This study is based on GPS and accelerometer-recorded information from a breeding group of 59 Black-vented Shearwater and examine consistency in diving behavior at both individual and sex levels across four different breeding seasons. The species was found to be the best performing free diver in the Puffinus genus with a maximum dive duration of 88 s. Among the environmental variables assessed, a relationship was found with active upwelling conditions enhancing low energetic cost diving, on the contrary, reduced upwelling and warmer superficial waters induce more energetically demanding diving affecting diving performance and ultimately body conditions. The body conditions of Black-vented Shearwaters in 2016 were worse than in subsequent years, in 2016, deepest and longest complex dives were recorded, while simple dives were longer in 2017-2019. Nevertheless, the species' plasticity allows at least part of the population to breed and feed during warmer events. While carry-over effects have already been reported, the effect of more frequent warm events is still unknown.

Potassium permanganate use in the management of a wound induced by contact with Paederus: A case report.

Pederin is a vesicant toxic amide, found in the hemolymph of the beetle genus, Paederus. Physical contact with these insects produces a type of irritant dermatitis with variable clinical symptoms. It has been identified that Pederin (a vesicant toxic amide responsible for the ulcerative lesion) is produced by Gram-negative endosymbiotic bacteria of the Pseudomonas genus. The present study describes the case of a patient who had come into contact with the insect Paederus sp. and developed an ulcerative lesion. He was first treated with topical steroids, as part of the conventional management, and following no response to treatment, he was treated locally with a 5% potassium permanganate solution, in conjunction with systemic antibiotic therapy, obtaining a good response in the healing process. On the whole, the present study demonstrates that potassium permanganate solutions, in conjunction with antibiotics and anti-inflammatories, may be beneficial in the treatment of dermatitis or ulcerative lesions caused by insects of the Paederus genus. However, further research is required to fully determine the complete benefits and any side-effects.

Doxycycline Prevents Preclinical Atherosclerosis, Pancreatic Islet Loss and Improves Insulin Secretion after Glycemic Stimulation: Preclinical Study in Individuals with a High-Fat Diet.

Doxycycline (Doxy) is an antibiotic, which has exhibited anti-inflammatory activity and glucose metabolism improvement. The present study was proposed to evaluate its effects on glucose metabolism and other associated processes, such as lipemia and adipogenesis, as well as, to evaluate its effects on the liver, pancreas, and aorta in subjects fed with an occidental high-fat diet (HFD). The trial followed three groups of BALB/c mice for 6 months: (1) Standard diet (SD); (2) HFD-placebo (saline solution); and (3) HFD-Doxy (10 mg/kg/day). Intrahepatic fat accumulation (steatohepatosis) and the epididymal fat pad, as well as the hepatic inflammatory infiltrate and ALT serum levels were higher in both groups with the HFD (with/without doxycycline) in comparison with the SD group. The thickness of the aorta (preclinic atherosclerosis) was significantly elevated in the HFD group with respect to the HFD + Doxy and SD group, these two being similar groups to each other. The HFD-Doxy group had pancreatic morphological parameters very similar to those of the SD group; on the contrary, the HFD group reduced the number of pancreatic islets and the number of ß cells per mm2, in addition to losing large islets. The index of ß cell function (∆Insulin0-30/∆Glucose0-30 ratio) was significantly higher in the HFD + Doxy group, compared to the rest of the groups.

PAMAM-G4 protect the N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) and maintain its antiproliferative effects on MCF-7.

Our work group designed and synthesized a promissory compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA). The HO-AAVPA is a HDAC1 inhibitor and antiproliferative in cancer cell lines. However, HO-AAVPA is poor water solubility and enzymatically metabolized. In this work, the fourth-generation poly(amidoamine) dendrimer (PAMAM-G4) was used as a drug deliver carrier of HO-AAVPA. Moreover, HO-AAVPA and HO-AAVPA-PAMAM complex were submitted to forced degradation studies (heat, acid, base, oxidation and sunlight). Also, the HO-AAVPA-PAMAM-G4 complex was assayed as antiproliferative in a breast cancer cell line (MCF-7). The HO-AAVPA-PAMAM-G4 complex was obtained by docking and experimentally using three pH conditions: acid (pH = 3.0), neutral (pH = 7.0) and basic (pH = 9.0) showing that PAMAM-G4 captureand protect the HO-AAVPA from forced degradation, it is due to sunlight yielded a by-product from HO-AAVPA. In addition, the PAMAM-G4 favored the HO-AAVPA water solubility under basic and neutral pH conditions with significant difference (F(2,18) = 259.9, p < 0.001) between the slopes of the three conditions being the basic condition which solubilizes the greatest amount of HO-AAVPA. Finally, the HO-AAVPA-PAMAM-G4 complex showed better antiproliferative effects on MCF-7 (IC50 = 75.3 µM) than HO-AAVPA (IC50 = 192 µM). These results evidence that PAMAM-G4 complex improve the biological effects of HO-AAVPA.

A novel multifamily treatment targeting symptoms related to Latinx caregiver deportation.

OBJECTIVE: Latinx youth who have experienced caregiver deportation show higher rates of posttraumatic stress disorder (PTSD) and internalizing symptoms compared to Latinx youth who have not. Thus, there is a need for culturally and linguistically appropriate therapeutic approaches to address psychiatric needs related to caregiver deportation. Positive Adaptations for Trauma and Healing (PATH) is a manualized 10-week group therapy for Latinx youth and their caregivers that integrates trauma-informed interventions with positive psychology and resilience interventions. The present study examined PATH for reducing trauma symptomatology for Latinx youth who endured at least three traumatic experiences in their caregiving system as well as differences for Latinx youth who experienced their caregiver's deportation. METHOD: Self-identified Latinx youth (N = 31) and their Spanish-speaking caregivers were recruited from two urban hospitals. All youth experienced three or more traumatic events. Pre- to postintervention mean change was measured with t tests; mixed-effects analysis of variance assessed whether the program was feasible for youth who had experienced a caregiver deportation versus Latinx youth who did not. RESULTS: Assessment with the Trauma Symptom Checklist and the UCLA PTSD Index for Youth showed statistically significant reductions on Anxiety, Depression, Anger, and PTSD subscales. Latinx youth who experienced a caregiver's deportation exhibited larger reductions in anger symptoms and PTSD symptoms. CONCLUSION: Study results suggest that the novel group therapy intervention was feasible and acceptable for Latinx youth and their caregivers. Despite a small sample size, the intervention proved feasible for Latinx youth who experienced caregiver deportation. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Clinical Characteristics in the Acute Phase of COVID-19 That Predict Long COVID: Tachycardia, Myalgias, Severity, and Use of Antibiotics as Main Risk Factors, While Education and Blood Group B Are Protective.

BACKGROUND: Risk factors for developing long COVID are not clearly established. The present study was designed to determine if any sign, symptom, or treatment of the acute phase, or personal characteristics of the patient, is associated with the development of long COVID. METHODS: A cohort study was carried out, randomly selecting symptomatic COVID-19 patients and not vaccinated. The severity of the acute illness was assessed through the number of compatible COVID-19 symptoms, hospitalizations, and the symptom severity score using a 10-point visual analog scale. RESULTS: After multivariate analysis, a severity score ≥8 (RR 2.0, 95%CI 1.1-3.5, p = 0.022), hospitalization (RR 2.1, 95%CI 1.0-4.4, p = 0.039), myalgia (RR 1.9, 95%CI 1.08-3.6, p = 0.027), tachycardia (RR 10.4, 95%CI 2.2-47.7, p = 0.003), and use of antibiotics (RR 2.0, 95%CI 1.1-3.5, p = 0.022), was positively associated with the risk of having long COVID. Higher levels of education (RR 0.6, 95%CI 0.4-0.9, p = 0.029) and type positive B blood group (B + AB, RR 0.44, 95%CI 0.2-0.9, p = 0.044) were protective factors. The most important population attributable fractions (PAFs) for long COVID were myalgia (37%), severity score ≥8 (31%), and use of antibiotics (27%). CONCLUSIONS: Further studies in diverse populations over time are needed to expand the knowledge that could lead us to prevent and/or treat long COVID.

Cytotoxic evaluation of YSL-109 in a triple negative breast cancer cell line and toxicological evaluations.

Breast cancer (BC) is the leading cause of cancer-related death in women worldwide. Triple negative breast cancer (TNBC) is the most aggressive form of BC being with the worst prognosis and the worst survival rates. There is no specific pharmacological target for the treatment of TNBC; conventional therapy includes the use of non-specific chemotherapy that generally has a poor prognosis. Therefore, the search of effective therapies against to TNBC continues at both preclinical and clinical level. In this sense, the exploration of different pharmacological targets is a continue task that pave the way to epigenetic modulation using novel small molecules. Lately, the inhibition of histone deacetylases (HDACs) has been explored to treat different BC, including TNBC. HDACs remove the acetyl groups from the ɛ-amino lysine resides on histone and non-histone proteins. In particular, the inhibition of HDAC6 has been suggested to be useful for the treatment of TNBC due to it is overexpressed in TNBC. Therefore, in this work, an HDAC6 selective inhibitor, the (S)-4-butyl-N-(1-(hydroxyamino)-3-(naphthalen-1-yl)-1-oxopropan-2-yl) benzamide (YSL-109), was assayed on TNBC cell line (MDA-MB231) showing an antiproliferative activity (IC50 = 50.34 ± 1.11 µM), whereas on fibroblast, it was lesser toxic. After corroborating the in vitro antiproliferative activity of YSL-109 in TNBC, the toxicological profile was explored using combined approach with in silico tools and experimental assays. YSL-109 shows moderate mutagenic activity on TA-98 strain at 30 and 100 µM in the Ames test, whereas YSL-109 did not show in vivo genotoxicity and its oral acute toxicity (LD50) in CD-1 female mice was higher than 2000 mg/kg, which is in agreement with our in silico predictions. According to these results, YSL-109 represents an interesting compound to be explored for the treatment of TNBC under preclinical in vivo models.