Comparative Study of the Potential Cell-Penetrating Peptide ∆M4 on Apoptosis Cell Signaling in A375 and A431 Cancer Cell Lines.

In recent yearsjajajj, peptide-based therapeutics have attracted increasing interest as a potential approach to cancer treatment. Peptides are characterized by high specificity and low cytotoxicity, but they cannot be considered universal drugs for all types of cancer. Of the numerous anticancer-reported peptides, both natural and synthetic, only a few have reached clinical applications. However, in most cases, the mechanism behind the anticancer activity of the peptide is not fully understood. For this reason, in this work, we investigated the effect of the novel peptide ∆M4, which has documented anticancer activity, on two human skin cancer cell lines. A novel approach to studying the potential induction of apoptosis by anticancer peptides is the use of protein microarrays. The results of the apoptosis protein study demonstrated that both cell types, skin malignant melanoma (A375) and epidermoid carcinoma (A431), exhibited markers associated with apoptosis and cellular response to oxidative stress. Additionally, ∆M4 induced concentration- and time-dependent moderate ROS production, triggering a defensive response from the cells, which showed decreased activation of cytoplasmic superoxide dismutase. However, the studied cells exhibited a differential response in catalase activity, with A375 cells showing greater resistance to the peptide action, possibly mediated by the Nrf2 pathway. Nevertheless, both cell types showed moderate activity of caspases 3/7, suggesting that they may undergo partial apoptosis, although another pathway of programmed death cannot be excluded. Extended analysis of the mechanisms of action of anticancer peptides may help determine their effectiveness in overcoming chemoresistance in cancerous cells.

Study of the Membrane Activity of the Synthetic Peptide ∆M3 Against Extended-Spectrum ß-lactamase Escherichia coli Isolates.

Escherichia coli is the most common microorganism causing nosocomial or community-acquired bacteremia, and extended-spectrum ß-lactamase-producing Escherichia coli isolates are identified worldwide with increasing frequency. For this reason, it is necessary to evaluate potential new molecules like antimicrobial peptides. They are recognized for their biological potential which makes them promising candidates in the fight against infections. The goal of this research was to evaluate the potential of the synthetic peptide ΔM3 on several extended-spectrum ß-lactamase producing E. coli isolates. The antimicrobial and cytotoxic activity of the peptide was spectrophotometrically determined. Additionally, the capacity of the peptide to interact with the bacterial membrane was monitored by fluorescence microscopy and infrared spectroscopy. The results demonstrated that the synthetic peptide is active against Escherichia coli isolates at concentrations similar to Meropenem. On the other hand, no cytotoxic effect was observed in HaCaT keratinocyte cells even at 10 times the minimal inhibitory concentration. Microscopy results showed a permeabilizing effect of the peptide on the bacteria. The infrared results showed that ΔM3 showed affinity for the lipids of the microorganism's membrane. The results suggest that the ∆M3 interacts with the negatively charged lipids from the E. coli by a disturbing effect on membrane. Finally, the secondary structure experiments of the peptide showed a random structure in solution that did not change during the interaction with the membranes.

Evidence of Ongoing Transmission of Zika Virus in Mérida, Mexico.

Since the Zika virus (ZIKV) pandemic in 2015-2017, there has been a near absence of reported cases in the Americas outside of Brazil. However, the conditions for Aedes-borne transmission persist in Latin America, and the threat of ZIKV transmission is increasing as population immunity wanes. Mexico has reported only 70 cases of laboratory-confirmed ZIKV infection since 2020, with no cases recorded in the Yucatán peninsula. Here, we provide evidence of active ZIKV transmission, despite the absence of official case reports, in the city of Mérida, Mexico, the capital of the state of Yucatán. Capitalizing on an existing cohort, we detected cases in participants with symptoms consistent with flavivirus infection from 2021 to 2022. Serum samples from suspected cases were tested for ZIKV RNA by polymerase chain reaction or ZIKV-reactive IgM by ELISA. To provide more specific evidence of exposure, focus reduction neutralization tests were performed on ELISA-positive samples. Overall, we observed 25 suspected ZIKV infections for an estimated incidence of 2.8 symptomatic cases per 1,000 persons per year. Our findings emphasize the continuing threat of ZIKV transmission in the setting of decreased surveillance and reporting.

Perinatal depression and implementation of the "Thinking Healthy program" support intervention in an impoverished setting of Lima, Peru: Assessment before and during the COVID-19 pandemic.

Socios En Salud (SES) implemented the Thinking Healthy program (THP) to support women with perinatal depression before and during the COVID-19 pandemic in Lima Norte. We carried out an analysis of the in-person (5 modules) and remote (1 module) THP intervention. Depression was detected using PHQ-9, and THP sessions were delivered in women with a score (PHQ-9 ≥ 5). Depression was reassessed and pre- and post-scores were compared. In the pre-pandemic cohort, perinatal depression was 25.4% (47/185), 47 women received THP and 27 were reassessed (57.4%), and the PHQ-9 score median decreased from 8 to 2, p < 0.001. In the pandemic cohort, perinatal depression was 47.5% (117/247), 117 women received THP and 89 were reassessed (76.1%), and the PHQ-9 score median decreased from 7 to 2, p < 0.001. THP's modalities helped to reduce perinatal depression. Pregnant women who received a module remotely also reduced depression.

A mixed methods evaluation of a World Health Organization competency-based training package for foundational helping skills among pre-service and in-service health workers in Nepal, Peru and Uganda.

Health systems globally demand more competent workers but lack competency-based training programs to reach their goals. This study evaluates the effectiveness of a competency-based curriculum (EQUIP-FHS) for trainers and supervisors to teach foundational helping knowledge, attitudes and skills, guided by the WHO/UNICEF EQUIP platform, to improve the competency of in-service and pre-service workers from various health and other service sectors. A mixed-methods, uncontrolled before-and-after trial was conducted in Nepal, Peru, and Uganda from 2020 to 2021. Trainees' (N = 150) competency data were collected during 13 FHS trainings. Paired t-tests assessed pre- to post-change in ENACT competency measures (e.g., harmful, helpful). Qualitative data was analyzed using thematic analysis. EQUIP-FHS trainings, on average, were 20 h in duration. Harmful behaviors significantly decreased, and helpful behaviors significantly increased, across and within sites from pre-to post-training. Qualitatively, trainees and trainers promoted the training and highlighted difficult competencies and areas for scaling the training. A brief competency-based curriculum on foundational helping delivered through pre-service or in-service training can reduce the risk that healthcare workers and other service providers display harmful behaviors. We recommend governmental and nongovernmental organizations implement competency-based approaches to enhance the quality of their existing workforce programming and be one step closer to achieving the goal of quality healthcare around the globe.

Mutations Linked to Insecticide Resistance Not Detected in the Ace-1 or VGSC Genes in Nyssorhynchus darlingi from Multiple Localities in Amazonian Brazil and Peru.

Indoor residual spray (IRS), mainly employing pyrethroid insecticides, is the most common intervention for preventing malaria transmission in many regions of Latin America; the use of long-lasting insecticidal nets (LLINs) has been more limited. Knockdown resistance (kdr) is a well-characterized target-site resistance mechanism associated with pyrethroid and DDT resistance. Most mutations detected in acetylcholinesterase-1 (Ace-1) and voltage-gated sodium channel (VGSC) genes are non-synonymous, resulting in a change in amino acid, leading to the non-binding of the insecticide. In the present study, we analyzed target-site resistance in Nyssorhynchus darlingi, the primary malaria vector in the Amazon, in multiple malaria endemic localities. We screened 988 wild-caught specimens of Ny. darlingi from three localities in Amazonian Peru and four in Amazonian Brazil. Collections were conducted between 2014 and 2021. The criteria were Amazonian localities with a recent history as malaria hotspots, primary transmission by Ny. darlingi, and the use of both IRS and LLINs as interventions. Fragments of Ace-1 (456 bp) and VGSC (228 bp) were amplified, sequenced, and aligned with Ny. darlingi sequences available in GenBank. We detected only synonymous mutations in the frequently reported Ace-1 codon 280 known to confer resistance to organophosphates and carbamates, but detected three non-synonymous mutations in other regions of the gene. Similarly, no mutations linked to insecticide resistance were detected in the frequently reported codon (995) at the S6 segment of domain II of VGSC. The lack of genotypic detection of insecticide resistance mutations by sequencing the Ace-1 and VGSC genes from multiple Ny. darlingi populations in Brazil and Peru could be associated with low-intensity resistance, or possibly the main resistance mechanism is metabolic.

Data on the cytotoxicity of chlorogenic acid in 3D cultures of HT-29 cells.

Functional foods, beyond basic nutrition, offer health benefits to consumers thanks to the presence of bioactive compounds such as some phytochemicals [1,2]. Today, these foods are of particular interest in biomedical research due to their chemopreventive potential, as they have been shown to induce various biological effects on tumor cells, including the ability to inhibit cell proliferation, induce apoptosis, arrest cell cycle progression, and increase reactive oxygen species [3,4]. Multiple studies have confirmed the relationship between diet and the onset and progression of colorectal cancer (CRC), a malignant neoplasm that arises in the lining of the colon and/or rectum. Therefore, finding foods that can intervene in the carcinogenesis process is an important avenue of research [5,6]. Chlorogenic acid (CGA) is one of the most abundant phenolic compounds in coffee and is also found in fruits and vegetables. Scientific evidence suggests that CGA has chemopreventive potential on CRC cells [7], [8], [9]. For example, in previous studies conducted by our research group, green and roasted coffee extracts were characterized, and this compound was identified as the most abundant [7]. In addition, it was found to significantly decrease cell viability, reduce migration capacity, cause DNA fragmentation, and induce the production of reactive oxygen species in colorectal adenocarcinoma cells cultured in monolayer and treated with different doses of CGA. Furthermore, the mechanism underlying this biological activity has been related to CGA's ability to modulate the Wnt- /ß-catenin pathway, which is implicated in the development and progression of CRC [7,10,11]. This paper presents data on the cytotoxic response of CGA treatments on HT-29 cells cultured in a 3D model. To this end, morphological changes in cell spheroids, propidium iodide and DiOC6 uptake, quantification of reactive oxygen species (ROS) production, phosphatidylserine exposure, and cell cycle progression were evaluated by flow cytometry.

Characterization of airborne particulate matter and its toxic and proarrhythmic effects: A case study in Aburrá Valley, Colombia.

Particle matter (PM) is a complex mixture of particles suspended in the air, mainly caused by fuel combustion from vehicles and industry, and has been related to pulmonary and cardiovascular diseases. The Metropolitan Area of Aburrá Valley in Colombia is the second most populous urban agglomeration in the country and the third densest in the world, composed of ten municipalities. Examining the physicochemical properties of PM is crucial in comprehending its composition and its effects on human health, as it varies based on the socioeconomic dynamics specific to each city. This study characterized the PM collected from the north, south, and central zones to evaluate its chemical composition and morphology. Different elements such as silicon, carbon, aluminum, potassium, calcium, sodium, iron, magnesium, and copper and the presence of unburned fuel, motor oil, and silicon fibers were identified. In vitro and in silico studies were conducted to evaluate the toxicity of the PM, and it was found that the PM collected from the central zone had the greatest impact on cell viability and caused DNA damage. The in silico study demonstrated that PM has concentration-dependent proarrhythmic effects, reflected in an action potential duration shortening and an increased number of reentries, which may contribute to the development of cardiac arrhythmias. Overall, the results suggest that the size and chemical composition of ambient PM can induce toxicity and play an important role in the generation of arrhythmias.

Adhesion factors and antimicrobial resistance of Escherichia coli strains associated with colibacillosis in piglets in Colombia.

Background and Aims: The pathogenicity of Escherichia coli is determined by the presence of genes that mediate virulence factors such as adherence capacity and toxin production. This research aimed to identify the adhesion factors and antibiotic resistance capacity of E. coli strains associated with diarrhea in piglets in Colombia. Materials and Methods: Presumptive E. coli strains were isolated from the rectal swabs of piglets in swine farms between 4 and 40 days of age with evidence of diarrhea. Presumptive E. coli strains were tested for antibiotic resistance. The hemolytic capacity of presumptive E. coli strains was measured and molecularly identified. Strains confirmed as hemolytic E. coli was evaluated for the presence of five adhesion factors (F4, F5, F6, F18, and F41) and resistance to 11 antibiotics. Results: Fifty-two putative E. coli strains were isolated, six of which showed a hemolytic capacity. The hemolytic strains were molecularly identified as E. coli. Adhesive fimbriae were found in five of six ß-hemolytic E. coli isolates. Combinations of the adhesion factors F6-F18 and F6-F41 were linked to antibiotic resistance capacity. Conclusion: The phenomenon of E. coli strains resistant to multiple antibiotics on pig farms represents a constant risk factor for public health and pig production.

ΔM4: Membrane-Active Peptide with Antitumoral Potential against Human Skin Cancer Cells.

Peptides have become attractive potential agents due to their affinity to cancer cells. In this work, the biological activity of the peptide ΔM4 against melanoma cancer cell line A375, epidermoid carcinoma cell line A431, and non-tumoral HaCaT cells was evaluated. The cytotoxic MTT assay demonstrates that ΔM4 show five times more activity against cancer than non-cancer cells. The potential membrane effect of ΔM4 was evaluated through lactate dehydrogenase release and Sytox uptake experiments. The results show a higher membrane activity of ΔM4 against A431 in comparison with the A375 cell line at a level of 12.5 µM. The Sytox experiments show that ΔM4 has a direct effect on the permeability of cancer cells in comparison with control cells. Infrared spectroscopy was used to study the affinity of the peptide to membranes resembling the composition of tumoral and non-tumoral cells. The results show that ΔM4 induces a fluidization effect on the tumoral lipid system over 5% molar concentration. Finally, to determine the appearance of phosphatidylserine on the surface of the cell, flow cytometry analyses were performed employing an annexin V-PE conjugate. The results suggest that 12.5 µM of ΔM4 induces phosphatidylserine translocation in A375 and A431 cancer cells. The findings of this study support the potential of ΔM4 as a selective agent for targeting cancer cells. Its mechanism of action demonstrated selectivity, membrane-disrupting effects, and induction of phosphatidylserine translocation.

Natural Infection of Nyssorhynchus darlingi and Nyssorhynchus benarrochi B with Plasmodium during the Dry Season in the Understudied Low-Transmission Setting of Datem del Marañon Province, Amazonian Peru.

The persistence of malaria hotspots in Datem del Marañon Province, Peru, prompted vector control units at the Ministry of Health, Loreto Department, to collaborate with the Amazonian International Center of Excellence for Malaria Research to identify the main vectors in several riverine villages that had annual parasite indices > 15 in 2018-2019. Anophelinae were collected indoors and outdoors for two 12-hour nights/community during the dry season in 2019 using human landing catch. We identified four species: Nyssorhynchus benarrochi B, Nyssorhynchus darlingi, Nyssorhynchus triannulatus, and Anopheles mattogrossensis. The most abundant, Ny. benarrochi B, accounted for 96.3% of the total (7,550/7,844), of which 61.5% were captured outdoors (4,641/7,550). Six mosquitoes, one Ny. benarrochi B and five Ny. darlingi, were infected by Plasmodium falciparum or Plasmodium vivax. Human biting rates ranged from 0.5 to 592.8 bites per person per hour for Ny. benarrochi B and from 0.5 to 32.0 for Ny. darlingi, with entomological inoculation rates as high as 0.50 infective bites per night for Ny. darlingi and 0.25 for Ny. benarrochi B. These data demonstrate the risk of malaria transmission by both species even during the dry season in villages in multiple watersheds in Datem del Marañon province.

In Vitro and In Silico Study on the Impact of Chlorogenic Acid in Colorectal Cancer Cells: Proliferation, Apoptosis, and Interaction with ß-Catenin and LRP6.

Colorectal cancer mortality rate and highly altered proteins from the Wnt/ß-catenin pathway increase the scientific community's interest in finding alternatives for prevention and treatment. This study aims to determine the biological effect of chlorogenic acid (CGA) on two colorectal cancer cell lines, HT-29 and SW480, and its interactions with ß-catenin and LRP6 to elucidate a possible modulatory mechanism on the Wnt/ß-catenin pathway. These effects were determined by propidium iodide and DiOC6 for mitochondrial membrane permeability, MitoTracker Red for mitochondrial ROS production, DNA content for cell distribution on cell cycle phases, and molecular docking for protein-ligand interactions and binding affinity. Here, it was found that CGA at 2000 µM significantly affects cell viability and causes DNA fragmentation in SW480 cells rather than in HT-29 cells, but in both cell lines, it induces ROS production. Additionally, CGA has similar affinity and interactions for LRP6 as niclosamide but has a higher affinity for both ß-catenin sites than C2 and iCRT14. These results suggest a possible modulatory role of CGA over the Wnt/ß-catenin pathway in colorectal cancer.

Antioxidant capacity and cytotoxic effect of an optimized extract of isabella grape (Vitis labrusca) on breast cancer cells.

The phenolic profile of Isabella grape (Vitis labrusca) offers beneficial properties to human health and makes it a functional food product. In order to better understand the phenolic compounds found in this grape variety and the biological effect they induce on breast cancer cells, an ultrasound-assisted extraction was carried out. During the extraction of polyphenols from Isabella grapes organically grown in Antioquia (Colombia), parameters such as frequency (33 kHz and 40 kHz), time and solvent were optimized to finally obtain a crude extract with antioxidant properties (Oxygen Radical Absorbance Capacity, ORAC: 293.22 ± 34.73 µmol of Trolox/g of sample), associated with a total polyphenol content (TPC) of 43.14 ± 5.00 mg GAE/g sample and a total anthocyanin content composed of 17.69 ± 2.59 mg of malvidin-3-glucoside/100 g of sample. MCF-7 breast cancer cells were treated with different concentrations of the optimized extract, and results show a decrease in cell viability related to mitochondrial membrane depolarization, ROS increase, and chromatin condensation. To determine the possible death induction mechanism, molecular docking was simulated to predict the molecular interactions between the most abundant phenolic compounds in Isabella grape and the main apoptosis-related proteins. The results obtained from in silico and in vitro experiments were consistent with each other, suggesting that the phenolic compounds found in Isabella grape can be considered potential adjuvant chemopreventive agents for the treatment of breast cancer.

Practitioners' perspectives on preparing for and delivering remote psychological support in Nepal, Perú and the United States during COVID-19.

INTRODUCTION: The COVID-19 pandemic has propelled a global paradigm shift in how psychological support is delivered. Remote delivery, through phone and video calls, is now commonplace around the world. However, most adoption of remote delivery methods is occurring without any formal training to ensure safe and effective care. OBJECTIVE: The purpose of this applied qualitative study was to determine practitioners' experiences of rapidly adapting to deliver psychological support remotely during COVID-19. DESIGN: We used a pragmatic paradigm and applied approach to gain perspectives related to the feasibility and perceived usefulness of synchronous remote psychological support, including views on how practitioners can be prepared. METHODS: Key informant interviews were conducted remotely with 27 specialist and non-specialist practitioners in Nepal, Perú and the USA. Interviewees were identified through purposeful sampling. Data were analysed using framework analysis. RESULTS: Respondents revealed three key themes: (i) Remote delivery of psychological support raises unique safety concerns and interference with care, (ii) Remote delivery enhances skills and expands opportunities for delivery of psychological support to new populations, and (iii) New training approaches are needed to prepare specialist and non-specialist practitioners to deliver psychological support remotely. CONCLUSIONS: Remote psychological support is feasible and useful for practitioners, including non-specialists, in diverse global settings. Simulated remote role plays may be a scalable method for ensuring competency in safe and effective remotely-delivered care.

Histopathological, ultrastructural, and biochemical traits of apoptosis induced by peroxisomicine A1 (toxin T-514) from Karwinskia parvifolia in kidney and lung.

Peroxisomicine A1 (PA1) is a toxin isolated from the Karwinskia genus plants whose target organs are the liver, kidney, and lung. In vitro studies demonstrated the induction of apoptosis by PA1 in cancer cell lines, and in vivo in the liver. Apoptosis has a wide range of morphological features such as cell shrinkage, plasma membrane blistering, loss of microvilli, cytoplasm, and chromatin condensation, internucleosomal DNA fragmentation, and formation of apoptotic bodies that are phagocytized by resident macrophages or nearby cells. Early stages of apoptosis can be detected by mitochondrial alterations. We investigated the presence of apoptosis in vivo at the morphological, ultrastructural, and biochemical levels in two target organs of PA1: kidney and lung. Sixty CD-1 mice were divided into three groups (n = 20): untreated control (ST), vehicle control (VH), and PA1 intoxicated group (2LD50). Five animals of each group were sacrificed at 4, 8, 12, and 24 h post-intoxication. Kidney and lung were examined by morphometry, histopathology, ultrastructural, and DNA fragmentation analysis. Pre-apoptotic mitochondrial alterations were present at 4 h. Apoptotic bodies were observed at 8 h and increased over time. TUNEL positive cells were detected as early as 4 h, and the DNA ladder pattern was observed at 12 h and 24 h. The liver showed the highest value of fragmented DNA, followed by the kidney and the lung. We demonstrated the induction of apoptosis by a toxic dose of PA1 in the kidney and lung in vivo. These results could be useful in understanding the mechanism of action of this compound at toxic doses in vivo.

Brainstem auditory-evoked responses among children afflicted by severely hypoxic CHD.

MAIN AIM: To electrophysiologically determine the impact of moderate to severe chronic hypoxia (H) resulting from a wide array of CHD (HCHD) conditions on the integrity of brainstem function. MATERIALS AND METHODS: Applying brainstem auditory-evoked response methodology, 30 chronically afflicted HCHD patients, who already had undergone heart surgery, were compared to 28 healthy control children (1-15 yo) matched by age, gender and socioeconomic condition. Blood oxygen saturation was clinically determined and again immediately before brainstem auditory-evoked response testing. RESULTS: Among HCHD children, auditory wave latencies (I, III and V) were significantly longer (medians: I, 2.02 ms; III, 4.12 ms, and; V, 6.30 ms) compared to control (medians: I, 1.67ms; III, 3.72 ms, and; V, 5.65 ms), as well as interpeak intervals (HCHD medians: I-V, 4.25 ms, and; III-V, 2.25ms; control medians: I-V, 3.90 ms and, III-V, 1.80 ms) without significant differences in wave amplitudes between groups. A statistically significant and inverse correlation between average blood oxygen saturation of each group (control, 94%; HCHD, 78%) and their respective wave latencies and interpeak intervals was found. CONCLUSIONS: As determined by brainstem auditory-evoked responses, young HCHD patients manifestly show severely altered neuronal conductivity in the auditory pathway strongly correlated with their hypoxic condition. These observations are strongly supported by different brainstem neurological and image studies showing that alterations, either in microstructure or function, result from the condition of chronic hypoxia in CHD. The non-altered wave amplitudes are indicative of relatively well-preserved neuronal relay nuclei.

COMET Assay for Detection of DNA Damage During Axolotl Tail Regeneration.

The purpose of this chapter is to evaluate DNA damage during axolotl tail regeneration using an alkaline comet assay. Our method details the isolation of cells from regenerating and non-regenerating tissues and the isolation of peripheral blood for single-cell gel electrophoresis. Also, we detail each of the steps for the development of the comet assay technique which includes mounting the isolated cells on an agarose matrix, alkaline electrophoresis, and DNA damage detection.

Modulatory Effect of Chlorogenic Acid and Coffee Extracts on Wnt/ß-Catenin Pathway in Colorectal Cancer Cells.

The Wnt/ß-Catenin pathway alterations present in colorectal cancer (CRC) are of special interest in the development of new therapeutic strategies to impact carcinogenesis and the progression of CRC. In this context, different polyphenols present in natural products have been reported to have modulatory effects against the Wnt pathway in CRC. In this study, we evaluate the effect of two polyphenol-rich coffee extracts and chlorogenic acid (CGA) against SW480 and HT-29 CRC cells. This involved the use of MTT and SRB techniques for cell viability; wound healing and invasion assay for the evaluation of the migration and invasion process; T cell factor (TCF) reporter plasmid for the evaluation of transciption factor (TCF) transcriptional activity; polymerase chain reaction (PCR) of target genes and confocal fluorescence microscopy for ß-Catenin and E-Cadherin protein fluorescence levels; and subcellular localization. Our results showed a potential modulatory effect of the Wnt pathway on CRC cells, and we observed a reduction in the transcriptional activity of ß-catenin. All the results were prominent in SW480 cells, where the Wnt pathway deregulation has more relevance and implies a constitutive activation of the signaling pathway. These results establish a starting point for the discovery of a mechanism of action associated with these effects and corroborate the anticancer potential of polyphenols present in coffee, which could be explored as chemopreventive molecules or as adjunctive therapy in CRC.

Prodromes and biological markers in schizophrenia: Importance for the dopamine, glutamate, and neurodevelopmental hypothesis / Pródromos e indicadores biológicos en la esquizofrenia: Importancia para la hipótesis dopaminérgica, glutamatérgica y del neurodesarrollo

Abstract Background Since schizophrenia is a multifactorial mental illness, a basic understanding of its etiological components improves its understanding, diagnosis, and the selection of therapeutic targets. Objective To identify the prodromes and biological markers in schizophrenic or ultra-high risk (UHR) patients and elucidate their specificity. Method Narrative review of relevant sources in English and Spanish in the Medline-PubMed database on minor physical abnormalities, cognitive abnormalities, neuroanatomical, and synaptic and cell changes present in schizophrenic patients and/or subjects with a high risk of developing schizophrenia Results Patients with SZ and, to a lesser extent, UHR subjects present phenotypic and behavioral manifestations that correlate with underlying cell processes. The study of the latter makes it possible to characterize diagnostic biomarkers. At present, its clinical application is limited by factors such as poorly understood pathophysiology, lack of study models, homology with other psychiatric disorders, and the dearth of clinical trials conducted. Discussion and conclusion Schizophrenia is the final manifestation of damage to prenatal and post-natal neurodevelopment and is reflected during the prodromal stage in early biological markers with clinical relevance. It is necessary to establish new study models that will increase knowledge to offer specific biomarkers for use in early clinical diagnosis.

Resumen Antecedentes La esquizofrenia es una enfermedad mental multifactorial. Una comprensión básica de sus componentes etiológicos mejora su entendimiento, su diagnóstico y la selección de posibles blancos terapéuticos. Objetivo Reportar los pródromos e indicadores biológicos en pacientes esquizofrénicos o de ultra-alto riesgo (UHR) y dilucidar su especificidad. Método Revisión narrativa de fuentes relevantes en inglés y español en la base de datos Medline-PubMed sobre las anomalías física menores, anomalías cognitivas, cambios neuroanatómicos, sinápticos y celulares presentes en pacientes esquizofrénicos y/o en sujetos de UHR. Resultados Los pacientes con EZ y, de manera menos predominante, los sujetos de UHR presentan manifestaciones fenotípicas y conductuales que se correlacionan con los procesos celulares subyacentes. El estudio de éstos permite caracterizar diferentes biomarcadores diagnósticos. En la actualidad, su aplicación en la clínica es limitada por distintos factores como son la fisiopatología poco comprendida, la falta de modelos de estudio, la homología con otros trastornos psiquiátricos y los escasos ensayos clínicos realizados. Discusión y conclusión La esquizofrenia es la manifestación final de daños en el neurodesarrollo prenatal y post-natal, y se refleja durante la etapa prodrómica en indicadores biológicos tempranos con relevancia clínica. Se requiere establecer nuevos modelos de estudio que permitan ampliar el conocimiento para ofrecer biomarcadores específicos para ser usados en el diagnóstico clínico temprano.

Antidepressant Low Doses of Ketamine and Melatonin in Combination Produce Additive Neurogenesis in Human Olfactory Neuronal Precursors.

Melatonin (MEL), an indolamine with diverse functions in the brain, has been shown to produce antidepressant-like effects, presumably through stimulating neurogenesis. We recently showed that the combination of MEL with ketamine (KET), an NMDA receptor antagonist, has robust antidepressant-like effects in mice, at doses that, by themselves, are non-effective and have no adverse effects. Here, we show that the KET/MEL combination increases neurogenesis in a clone derived from human olfactory neuronal precursors, a translational pre-clinical model for effects in the human CNS. Neurogenesis was assessed by the formation of cell clusters > 50 µm in diameter, positively stained for nestin, doublecortin, BrdU and Ki67, markers of progenitor cells, neurogenesis, and proliferation. FGF, EGF and BDNF growth factors increased the number of cell clusters in cultured, cloned ONPs. Similarly, KET or MEL increased the number of clusters in a dose-dependent manner. The KET/MEL combination further increased the formation of clusters, with a maximal effect obtained after a triple administration schedule. Our results show that the combination of KET/MEL, at subeffective doses that do not produce adverse effects, stimulate neurogenesis in human neuronal precursors. Moreover, the mechanism by which the combination elicits neurogenesis is meditated by melatonin receptors, CaM Kinase II and CaM antagonism. This could have clinical advantages for the fast treatment of depression.