Toxicity of Synthetic Cannabinoids in K2/Spice: A Systematic Review.

(1) Background: Synthetic cannabinoids (SCs) are emerging drugs of abuse sold as 'K2', 'K9' or 'Spice'. Evidence shows that using SCs products leads to greater health risks than cannabis. They have been associated with greater toxicity and higher addiction potential unrelated to the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). Moreover, early cases of intoxication and death related to SCs highlight the inherent danger that may accompany the use of these substances. However, there is limited knowledge of the toxicology of Spice ingredients. This systematic review intends to analyze the toxicity of SCs compounds in Spice/K2 drugs. (2) Methods: Studies analyzing synthetic cannabinoid toxicity and dependence were included in the present review. We searched the PubMed database of the US National Library of Medicine, Google Scholar, CompTox Chemicals, and Web of Science up to May 2022. (3) Results: Sixty-four articles reporting the effects of synthetic cannabinoids in humans were included in our review. Ten original papers and fifty-four case studies were also included. Fourteen studies reported death associated with synthetic cannabinoid use, with AB-CHMINACA and MDMB-CHMICA being the main reported SCs. Tachycardia and seizures were the most common toxicity symptoms. The prevalence of neuropsychiatric symptoms was higher in third-generation SCs. (4) Conclusion: SCs may exhibit higher toxicity than THC and longer-lasting effects. Their use may be harmful, especially in people with epilepsy and schizophrenia, because of the increased risk of the precipitation of psychiatric and neurologic disorders. Compared to other drugs, SCs have a higher potential to trigger a convulsive crisis, a decline in consciousness, and hemodynamic changes. Therefore, it is crucial to clarify their potential harms and increase the availability of toxicology data in both clinical and research settings.

The Antioxidant N-Acetyl-L-Cysteine Restores the Behavioral Deficits in a Neurodevelopmental Model of Schizophrenia Through a Mechanism That Involves Nitric Oxide.

The disruption of neurodevelopment is a hypothesis for the emergence of schizophrenia. Some evidence supports the hypothesis that a redox imbalance could account for the developmental impairments associated with schizophrenia. Additionally, there is a deficit in glutathione (GSH), a main antioxidant, in this disorder. The injection of metilazoximetanol acetate (MAM) on the 17th day of gestation in Wistar rats recapitulates the neurodevelopmental and oxidative stress hypothesis of schizophrenia. The offspring of rats exposed to MAM treatment present in early adulthood behavioral and neurochemical deficits consistent with those seen in schizophrenia. The present study investigated if the acute and chronic (250 mg/kg) treatment during adulthood with N-acetyl-L-cysteine (NAC), a GSH precursor, can revert the behavioral deficits [hyperlocomotion, prepulse inhibition (PPI), and social interaction (SI)] in MAM rats and if the NAC-chronic-effects could be canceled by L-arginine (250 mg/kg, i.p, for 5 days), nitric oxide precursor. Analyses of markers involved in the inflammatory response, such as astrocytes (glial fibrillary acid protein, GFAP) and microglia (binding adapter molecule 1, Iba1), and parvalbumin (PV) positive GABAergic, were conducted in the prefrontal cortex [PFC, medial orbital cortex (MO) and prelimbic cortex (PrL)] and dorsal and ventral hippocampus [CA1, CA2, CA3, and dentate gyrus (DG)] in rats under chronic treatment with NAC. MAM rats showed decreased time of SI and increased locomotion, and both acute and chronic NAC treatments were able to recover these behavioral deficits. L-arginine blocked NAC behavioral effects. MAM rats presented increases in GFAP density at PFC and Iba1 at PFC and CA1. NAC increased the density of Iba1 cells at PFC and of PV cells at MO and CA1 of the ventral hippocampus. The results indicate that NAC recovered the behavioral deficits observed in MAM rats through a mechanism involving nitric oxide. Our data suggest an ongoing inflammatory process in MAM rats and support a potential antipsychotic effect of NAC.

Mitochondria-ER Tethering in Neurodegenerative Diseases.

Organelles juxtaposition has been detected for decades, although only recently gained importance due to a pivotal role in the regulation of cellular processes dependent on membrane contact sites. Endoplasmic reticulum (ER) and mitochondria interaction is a prime example of organelles contact sites. Mitochondria-associated membranes (MAM) are proposed to harbor ER-mitochondria tether complexes, mainly when these organelles are less than 30 nm apart. Dysfunctions of proteins located at the MAM are associated with neurodegenerative diseases such as Parkinson's, Alzheimer's and amyotrophic lateral sclerosis, as well as neurodevelopmental disorders; hence any malfunction in MAM can potentially trigger cell death. This review will focus on the role of ER-mitochondria contact sites, regarding calcium homeostasis, lipid metabolism, autophagy, morphology and dynamics of mitochondria, mainly in the context of neurodegenerative diseases. Approaches that have been employed so far to study organelles contact sites, as well as methods that were not used in neurosciences yet, but are promising and accurate ways to unveil the functions of MAM during neurodegeneration, is also discussed in the present review.

Lesiones papilares de mama: estudio clínico-patológico y sobre pronóstico en 144 casos de Medellín, Colombia / Breast papillary lesions: Clinical, pathological, and prognostic study in 144 cases in Medellin, Colombia / Lesões papilares mamárias: estudo clínico-patológico e prognóstico em 144 casos de Medellín, Colômbia

Objetivo: describir los datos sociodemográficos, las manifestaciones clínicas, los paraclínicos, el tratamiento y la recurrencia, en un grupo de pacientes con lesiones papilares. Metodología: estudio analítico de cohorte retrospectiva con fuentes secundarias de información, historias clínicas. Se incluyeron pacientes evaluados entre el 1º enero de 2016 y el 31 de diciembre de 2019. Se recopilaron datos demográficos, clínicos y paraclínicos, que fueron analizados con estadística descriptiva. Resultados: la prevalencia en la muestra fue de 4.7%; todos los casos fueron en mujeres, la media de edad fue 55,5 años; el motivo de consulta más frecuente fue alteración en la imagen de mama (n=79, 54.9%), el tamaño medio de la lesión fue 1,9 cm (rango 0,1-20). Se encontró discordancia entre el diagnóstico por biopsia cortante y el espécimen de patología en 70 (48.6%) casos, en estos se encontró infraestimación de lesiones con mayor riesgo en el 36,1% (n=52). Según la clasificación histológica, el tipo más frecuente de lesión fue el papiloma intraductal 34.7% (n=50), seguido por el carcinoma papilar en 11,8% (n=17). El tipo de cirugía más efectuado fue la cuadrantectomía, con un 68.7% (n=99). La media de seguimiento fue de 28.5 meses y se encontró recaída en siete casos (4.9%). Conclusión: las lesiones papilares comprenden un grupo heterogéneo, que incluye desde las benignas hasta aquellas con potencial maligno. Afectan a las mujeres en la quinta década de la vida, se presentan como una masa, pequeña, unilateral, sin predominio de lateralidad, de crecimiento lento. El tratamiento óptimo para las lesiones de riesgo y con atipias es la cirugía con márgenes negativos, el riesgo de recurrencia es clínicamente relevante.

Objective: to describe the sociodemographic data, the clinical and paraclinical ma-nifestations, the treatment and the recurrence, in a group of patients diagnosed with papillary lesions.Methodology:analytical study of a retrospective cohort with secondary sources of information from users' medical records in the period of January 1, 2016 to December 31, 2019. The demographic, clinical and paraclinical data collected were analyzed using descriptive statistics.Results:the prevalence in the sample was 4.7%; all cases were women, the mean age was 55.5 years; the most frequent reason for consultation was abnormal breast imaging examination (n=79, 54.9 %), the mean size was 1.9 cm (range 0,1-20). Disagreement was found between the diagnosis by sharp biopsy and the pathology specimen in 48.6% of cases (n=70); lesion underestimation with higher risk was found in 36.1% of them (n=52). According to the histological classification, the most frequent was intraductal papilloma in 34.7% (n=50), followed by papillary carcinoma in 11.8% (n=17). The type of surgery most performed was quadrantectomy, 68.7% (n=99). The mean follow-up was 28.5 months and relapse was found in 4.9% (n=7).Conclusion:papillary lesions comprise a heterogeneous group, with a spectrum that includes both benign lesions and those with malignant potential. The lesions affect women in their fifties. They become apparent as a small, unilateral mass, without a pre-dominance of laterality, and of slow growth. The optimal treatment in risk lesions and with atypia is surgery with negative margins. The risk of recurrence is clinically important.

Objetivo: descrever os dados sociodemográficos, manifestações clínicas e paraclínicas, tratamento e recorrência, em um grupo de pacientes com lesões papilares.Metodologia: estudo analítico de coorte retrospectivo com fontes secundárias de informação, prontuários. Foram incluídos os pacientes avaliados entre 1º de janeiro de 2016 e 31 de dezembro de 2019. Foram coletados dados demográficos, clínicos e paraclínicos, os quais foram analisados com estatística descritiva.Resultados: a prevalência na amostra foi de 4,7%; todos os casos eram em mulheres, a média de idade foi de 55,5 anos; o motivo de consulta mais frequente foi a alteração da imagem da mama (n = 79, 54,9%), o tamanho médio da lesão foi de 1,9 cm (variação de 0,1-20). Houve discordância entre o diagnóstico por biópsia cortante e o espécime anatomopatológico em 70 (48,6%) casos, nestes casos subestimação das lesões de maior risco em 36,1% (n = 52). De acordo com a classificação histológica, o tipo de lesão mais frequente foi o papiloma intraductal em 34,7% (n = 50), seguido do carcinoma papilífero em 11,8% (n = 17). O tipo de cirurgia mais realizada foi a quadrantectomia, com 68,7% (n = 99). O seguimento médio foi de 28,5 meses e recidiva foi encontrada em sete casos (4,9%).Conclusão: as lesões papilares constituem um grupo heterogêneo, que inclui desde as benignas até as com potencial maligno. Atingem mulheres na quinta década de vida, aparecem como uma massa, pequena, unilateral, sem predomínio da lateralidade, de crescimento lento. O tratamento ideal para lesões de risco e com atipia é a cirurgia com margens negativas, o risco de recorrência é clinicamente relevante.

The prefrontal cortex as a target for atypical antipsychotics in schizophrenia, lessons of neurodevelopmental animal models.

Prefrontal cortex (PFC) inflammatory imbalance, oxidative/nitrosative stress (O/NS) and impaired neuroplasticity in schizophrenia are thought to have neurodevelopmental origins. Animal models are not only useful to test this hypothesis, they are also effective to establish a relationship among brain disturbances and behavior with the atypical antipsychotics (AAPs) effects. Here we review data of PFC post-mortem and in vivo neuroimaging, human induced pluripotent stem cells (hiPSC), and peripheral blood studies of inflammatory, O/NS, and neuroplasticity alterations in the disease as well as about their modulation by AAPs. Moreover, we reviewed the PFC alterations and the AAP mechanisms beyond their canonical antipsychotic action in four neurodevelopmental animal models relevant to the study of schizophrenia with a distinct approach in the generation of schizophrenia-like phenotypes, but all converge in O/NS and altered neuroplasticity in the PFC. These animal models not only reinforce the neurodevelopmental risk factor model of schizophrenia but also arouse some novel potential therapeutic targets for the disease including the reestablishment of the antioxidant response by the perineuronal nets (PNNs) and the nuclear factor erythroid 2-related factor (Nrf2) pathway, as well as the dendritic spine dynamics in the PFC pyramidal cells.

Relevance of endoplasmic reticulum and mitochondria interactions in age-associated diseases.

Although the elixir of youth remains in the darkness, medical and scientific advances have succeeded in increasing human longevity; however, the predisposition to disease and its high economic cost are raising. Different strategies (e.g., antioxidants) and signaling pathways (e.g., Nrf2) have been identified to help regulate disease progression, nevertheless, there are still missing links that we need to understand. Contact sites called mitochondria-associated membranes (MAM) allow bi-directional communication between organelles as part of the essential functions in the cell to maintain its homeostasis. Different groups have deeply studied the role of MAM in aging; however, it's necessary to analyze their involvement in the progression of age-related diseases. In this review, we highlight the role of contact sites in these conditions, as well as the morphological and functional changes of mitochondria and ER in aging. We emphasize the intimate relationship between both organelles as a reflection of the biological processes that take place in the cell to try to regulate the deterioration characteristic of the aging process; proposing MAM as a potential target to help limit the disease progression with age.

Combined genomic and structural analyses of a cultured magnetotactic bacterium reveals its niche adaptation to a dynamic environment.

BACKGROUND: Magnetotactic bacteria (MTB) are a unique group of prokaryotes that have a potentially high impact on global geochemical cycling of significant primary elements because of their metabolic plasticity and the ability to biomineralize iron-rich magnetic particles called magnetosomes. Understanding the genetic composition of the few cultivated MTB along with the unique morphological features of this group of bacteria may provide an important framework for discerning their potential biogeochemical roles in natural environments. RESULTS: Genomic and ultrastructural analyses were combined to characterize the cultivated magnetotactic coccus Magnetofaba australis strain IT-1. Cells of this species synthesize a single chain of elongated, cuboctahedral magnetite (Fe3O4) magnetosomes that cause them to align along magnetic field lines while they swim being propelled by two bundles of flagella at velocities up to 300 µm s-1. High-speed microscopy imaging showed the cells move in a straight line rather than in the helical trajectory described for other magnetotactic cocci. Specific genes within the genome of Mf. australis strain IT-1 suggest the strain is capable of nitrogen fixation, sulfur reduction and oxidation, synthesis of intracellular polyphosphate granules and transporting iron with low and high affinity. Mf. australis strain IT-1 and Magnetococcus marinus strain MC-1 are closely related phylogenetically although similarity values between their homologous proteins are not very high. CONCLUSION: Mf. australis strain IT-1 inhabits a constantly changing environment and its complete genome sequence reveals a great metabolic plasticity to deal with these changes. Aside from its chemoautotrophic and chemoheterotrophic metabolism, genomic data indicate the cells are capable of nitrogen fixation, possess high and low affinity iron transporters, and might be capable of reducing and oxidizing a number of sulfur compounds. The relatively large number of genes encoding transporters as well as chemotaxis receptors in the genome of Mf. australis strain IT-1 combined with its rapid swimming velocities, indicate that cells respond rapidly to environmental changes.