Correction: Garza-Morales et al. Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy In Vitro. Cancers 2018, 10, 144.

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Metformin and Trehalose-Modulated Autophagy Exerts a Neurotherapeutic Effect on Parkinson's Disease.

Since the number of aged people will increase in the next years, neurodegenerative diseases, including Parkinson's Disease (PD), will also rise. Recently, we demonstrated that autophagy stimulation with rapamycin decreases dopaminergic neuronal death mediated by oxidative stress in the paraquat (PQ)-induced PD model. Assessing the neurotherapeutic efficacy of autophagy-inducing molecules is critical for preventing or delaying neurodegeneration. Therefore, we evaluated the autophagy inducers metformin and trehalose effect in a PD model. Autophagy induced by both molecules was confirmed in the SH-SY5Y dopaminergic cells by detecting increased LC3-II marker and autophagosome number compared to the control by western blot and transmission electron microscopy. Both autophagy inducers showed an antioxidant effect, improved mitochondrial activity, and decreased dopaminergic cell death induced by PQ. Next, we evaluated the effect of both inducers in vivo. C57BL6 mice were pretreated with metformin or trehalose before PQ administration. Cognitive and motor deteriorated functions in the PD model were evaluated through the nest building and the gait tests and were prevented by metformin and trehalose. Both autophagy inducers significantly reduced the dopaminergic neuronal loss, astrocytosis, and microgliosis induced by PQ. Also, cell death mediated by PQ was prevented by metformin and trehalose, assessed by TUNEL assay. Metformin and trehalose induced autophagy through AMPK phosphorylation and decreased α-synuclein accumulation. Therefore, metformin and trehalose are promising neurotherapeutic autophagy inducers with great potential for treating neurodegenerative diseases such as PD.

A neuroprotective dose of trehalose is harmless to metabolic organs: comprehensive histopathological analysis of liver, pancreas, and kidney.

BACKGROUND: Trehalose is a non-reducing disaccharide synthesized by lower organisms. It has recently received special attention because of its neuroprotective properties by stimulating autophagy in Parkinson's disease (PD) models. Therefore, evaluating whether trehalose affects metabolic organs is vital to determine its neurotherapeutic safety. METHODS: We validated the trehalose neuroprotective dosage in a PD model induced with intraperitoneal paraquat administration twice weekly for 7 weeks. One week before paraquat administration, mice were treated with trehalose in the drinking water and continued along with paraquat treatment. Histological and morphometrical analyses were conducted on the organs involved in trehalose metabolism, including the liver, pancreas, and kidney. RESULTS: Paraquat-induced dopaminergic neuronal loss was significantly decreased by trehalose. After trehalose treatment, the liver morphology, the mononucleated/binucleated hepatocytes percentage, and sinusoidal diameter remained unchanged in each liver lobes. Endocrine and exocrine pancreas's histology was not affected, nor was any fibrotic process observed. The islet of Langerhans's structure was preserved when analyzing the area, the largest and smallest diameter, and circularity. Renal morphology remained undamaged, and no changes were identified within the glomerular basement membrane. The renal corpuscle structure did not suffer alterations in the Bowman's space, area, diameter, circularity, perimeter, and cellularity. Besides, the renal tubular structures's luminal area and internal and external diameter were preserved. CONCLUSION: Our study demonstrates that systemic trehalose administration preserved the typical histological architecture of the organs involved in its metabolism, supporting its safety as a potential neuroprotective agent.

Peroxiredoxin 5 overexpression decreases oxidative stress and dopaminergic cell death mediated by paraquat.

Peroxiredoxins (Prdxs) are thiol-dependent enzymes that scavenge peroxides. Previously, we found that Prdxs were hyperoxidized in a Parkinson's disease model induced by paraquat (PQ), which led to their inactivation, perpetuating reactive oxygen species (ROS) formation. Herein, we evaluated the redox state of the typical 2-Cys-Prx subgroup. We found that PQ induces ROS compartmentalization in different organelles, reflected by the 2-Cys-Prdx hyperoxidation pattern detected by redox eastern blotting. 2-Cys Prdxs are most vulnerable to hyperoxidation, while atypical 2-Cys Peroxiredoxin 5 (Prdx5) is resistant and is expressed in multiple organelles, such as mitochondria, peroxisomes, and cytoplasm. Therefore, we overexpressed human Prdx5 in the dopaminergic SHSY-5Y cell line using the adenoviral vector Ad-hPrdx5. Prdx5 overexpression was confirmed by western blotting and immunofluorescence (IF) and effectively decreased PQ-mediated mitochondrial and cytoplasmic ROS assessed with a mitochondrial superoxide indicator and DHE through IF or flow cytometry. Decreased ROS mediated by Prdx5 in the main subcellular compartments led to overall cell protection against PQ-induced cell death, which was demonstrated by flow cytometry using Annexin V labeling and 7-AAD. Therefore, Prdx5 is an attractive therapeutic target for PD, as its overexpression protects dopaminergic cells from ROS and death, which warrants further experimental animal studies for its subsequent application in clinical trials.

Neuroimmunomodulation of adrenoblockers during liver cirrhosis: modulation of hepatic stellate cell activity.

The sympathetic nervous system and the immune system are responsible for producing neurotransmitters and cytokines that interact by binding to receptors; due to this, there is communication between these systems. Liver immune cells and nerve fibres are systematically distributed in the liver, and the partial overlap of both patterns may favour interactions between certain elements. Dendritic cells are attached to fibroblasts, and nerve fibres are connected via the dendritic cell-fibroblast complex. Receptors for most neuroactive substances, such as catecholamines, have been discovered on dendritic cells. The sympathetic nervous system regulates hepatic fibrosis through sympathetic fibres and adrenaline from the adrenal glands through the blood. When there is liver damage, the sympathetic nervous system is activated locally and systemically through proinflammatory cytokines that induce the production of epinephrine and norepinephrine. These neurotransmitters bind to cells through α-adrenergic receptors, triggering a cellular response that secretes inflammatory factors that stimulate and activate hepatic stellate cells. Hepatic stellate cells are key in the fibrotic process. They initiate the overproduction of extracellular matrix components in an active state that progresses from fibrosis to liver cirrhosis. It has also been shown that they can be directly activated by norepinephrine. Alpha and beta adrenoblockers, such as carvedilol, prazosin, and doxazosin, have recently been used to reverse CCl4-induced liver cirrhosis in rodent and murine models.KEY MESSAGESNeurotransmitters from the sympathetic nervous system activate and increase the proliferation of hepatic stellate cells.Hepatic fibrosis and cirrhosis treatment might depend on neurotransmitter and hepatic nervous system regulation.Strategies to reduce hepatic stellate cell activation and fibrosis are based on experimentation with α-adrenoblockers.

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.

In Vivo Models for the Study of Hyaluronic Acid Fillers: A Review.

BACKGROUND: Hyaluronic acid (HA) filler application is one of the most frequent minimally invasive aesthetic procedures used worldwide. Its properties and characterization, performance, effects in other tissues, and response to complication treatments have been studied in several animal models. This review aims to categorize animal models considering the advantages and disadvantages regarding the purpose of the study. METHODS: Literature research was made using MEDLINE via PubMed by two reviewers using keywords "hyaluronic acid" "filler" and "animal model". Full-text articles published in English and with an in vivo animal model were included for data extraction. RESULTS: The rat model was the most common animal used to evaluate properties or characteristics and degradation of HA fillers. Rabbits were preferred for evaluating HA embolism treatments; however, anatomical names of the arteries differ in some studies. Mice and rats used as vascular occlusion model are challenging due to the size of the vessels and viscosity of the filler. CONCLUSION: There is a wide variability of options of in vivo animal models to evaluate HA fillers. The animal characteristics, laboratory resources, and HA properties should be considered in accordance with the objective of the study, when choosing the ideal model. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Enhanced antitumor activity induced by a DNA vaccine encoding E7 antigen fused to an ERAD-targeting sequence.

The endoplasmic reticulum (ER) is a key organelle in cell homeostasis and cell health through antigen presentation to immune cells. Thus, the ER has become a therapeutic target to induce cellular immune responses. We previously reported the antitumor effect of a DNA vaccine that expresses the E7 antigen fused to the cyclooxygenase-2 (COX-2) protein. This inflammation-related enzyme contains a degradation cassette associated with the endoplasmic reticulum-associated degradation (ERAD) pathway. To avoid the use of full-length COX-2 and any risk of adverse effects due to the activity of its catalytic site, we designed new versions of the fusion protein. These new constructs encode the E7 antigen fused to the signal peptide and the ERAD sequence of COX-2 with or without the membrane-binding domain (MBD) as well as deletion of the catalytic site. We evaluated the antigen-specific antitumor effect of these DNA constructs in murine prophylactic and therapeutic cancer models. These assays showed that the ERAD cassette is the minimum sequence in the COX-2 protein that induces an antitumor effect when fused to the E7 antigen with the advantage of eliminating any potential adverse effects from the use of full-length COX-2.

Chronic diseases: Origin and cell mechanisms involved.

Chronic diseases are a worldwide health problem directly related to society, lifestyle, and the development of unhealthy habits over time. Cardiovascular disease, cancer, chronic respiratory disease, and diabetes are the main causes of death. Environmental factors, such as air pollutants, poor diet, genetic predisposition, or a combination of these, are related to the development of these diseases. These factors activate cell mechanisms, such as DNA damage, oxidative stress, endoplasmic reticulum stress, autophagy, inflammation, and cell death. Depending on the dose and duration of exposure to causative agents, this cell damage can be acute or chronic. Activating these cell mechanisms can rescue normal cell function and cause permanent damage, unleashing the degeneration of tissues and organs over time. A wide variety of treatments help control chronic diseases; however, they cannot be cured completely. This fact leads to complications, dysfunctions, and disabilities. Herein, we discuss some of the principal mechanisms involved and how cellular stress can lead to these diseases when they persist for a long time.

Cerebrolysin induces hair repigmentation associated to MART-1/Melan-A reactivation.

Hair graying, a prototypical sign of human aging, is a progressive loss of pigmentation from growing hair shafts caused by disease and as a side effect of medications. Cerebrolysin is a neuropeptide preparation that mimics the effect of endogenous neurotrophic factors. Cerebrolysin has been widely used in neurologic conditions, such as cerebral stroke, Alzheimer's disease, and dementia, among others. Cerebrolysin treatment has achieved to regain or maintain the cognitive ability of affected patients; however, up to date, there are no reports about the reactivation of hair pigmentation. We describe a previously not described effect occurring on patients receiving Cerebrolysin treatment for neurologic diseases and whether this effect is associated in reactivation of melanocytes and melanin expression. Here, we report five patients (mean age, 70.6 years), who also had age-related hair graying and scalp hair repigmentation during Cerebrolysin treatment. Macroscopic analysis revealed hair repigmentation consisted in diffuse darkening of the scalp hair. Impregnation and immunostaining analysis were performed on scalp biopsies taken before and after Cerebrolysin treatment; the results showed greater melanin and melanocyte marker MART-1/Melan-A staining following Cerebrolysin treatment. We present, to our knowledge, the first report on hair repigmentation is a previously not described effect occurring following Cerebrolysin treatment.

Plasmid DNA for Therapeutic Applications in Cancer.

Recently, the interest in using nucleic acids for therapeutic applications has been increasing. DNA molecules can be manipulated to express a gene of interest for gene therapy applications or vaccine development. Plasmid DNA can be developed to treat different diseases, such as infections and cancer. In most cancers, the immune system is limited or suppressed, allowing cancer cells to grow. DNA vaccination has demonstrated its capacity to stimulate the immune system to fight against cancer cells. Furthermore, plasmids for cancer gene therapy can direct the expression of proteins with different functions, such as enzymes, toxins, and cytotoxic or proapoptotic proteins, to directly kill cancer cells. The progress and promising results reported in animal models in recent years have led to interesting clinical results. These DNA strategies are expected to be approved for cancer treatment in the near future. This review discusses the main strategies, challenges, and future perspectives of using plasmid DNA for cancer treatment.

Peripheral tissular analysis of rapamycin's effect as a neuroprotective agent in vivo.

Rapamycin is the best-characterized autophagy inducer, which is related to its antiaging and neuroprotective effects. Although rapamycin is an FDA-approved drug for human use in organ transplantation and cancer therapy, its administration as an antiaging and neuroprotective agent is still controversial because of its immunosuppressive and reported side effects. Therefore, it is critical to determine whether the dose that exerts a neuroprotective effect, 35 times lower than that used as an immunosuppressant agent, harms peripheral organs. We validated the rapamycin neuroprotective dosage in a Parkinson's disease (PD) model induced with paraquat. C57BL/6 J mice were treated with intraperitoneal (IP) rapamycin (1 mg/kg) three times per week, followed by paraquat (10 mg/kg) twice per week for 6 weeks, along with rapamycin on alternate days. Rapamycin significantly decreased dopaminergic neuronal loss induced by paraquat. Since rapamycin's neuroprotective effect in a PD model was observed at 7 weeks of treatment; we evaluated its effect on the liver, kidney, pancreas, and spleen. In addition, we prolonged treatment with rapamycin for 14 weeks. Tissue sections were subjected to histochemical, immunodetection, and morphometric analysis. Chronic rapamycin administration does not affect bodyweight, survival, and liver or kidney morphology. Although the pancreas tissular architecture and cellular distribution in Langerhans islets are modified, they may be reversible. The spleen B lymphocyte and macrophage populations were decreased. Notably, the lymphocyte T population was not affected. Therefore, chronic administration of a rapamycin neuroprotective dose does not produce significant tissular alterations. Our findings support the therapeutic potential of rapamycin as a neuroprotective agent.

A combined antitumor strategy of separately transduced mesenchymal stem cells with soluble TRAIL and IFNß produces a synergistic activity in the reduction of lymphoma and mice survival enlargement.

As the understanding of cancer grows, new therapies have been proposed to improve the well-known limitations of current therapies, whose efficiency relies mostly on early detection, surgery and chemotherapy. Mesenchymal stem cells (MSCs) have been introduced as a promissory and effective therapy. This fact is due to several useful features of MSCs, such as their accessibility and easy culture and expansion in vitro, and their remarkable ability for 'homing' towards tumors, allowing MSCs to exert their anticancer effects directly into tumors. Additionally, MSCs offer the practicability of being genetically engineered to carry anticancer genes, increasing their specificity and efficacy for fighting tumors. In the present study, the antitumoral efficacy and post-implant survival of mice bearing lymphomas implanted intratumorally were determined using mouse bone marrow-derived (BM)-MSCs transduced with soluble TRAIL (sTRAIL), full length TRAIL (flTRAIL), or interferon ß (IFNß), naïve BM-MSCs, or combinations of these. The percentage of surviving mice was determined once all not-implanted mice succumbed. It was found that the percentage of surviving mice implanted with the combination of MSCs-sTRAIL and MSCs-IFN-ß was 62.5%. Lymphoma model achieved 100% fatality in the non-treated group by day 41. On the other hand, the percentage of surviving mice implanted with MSCs-sTRAIL was 50% and with MSCs-INFß 25%. All the aforementioned differences were statistically significant (P<0.05). In conclusion, all implants exhibited tumor size reduction, growth delay, or apparent tumor clearance. MSCs proved to be effective anti-lymphoma agents; additionally, the combination of soluble TRAIL and IFN-ß resulted in the most effective antitumor and life enlarging treatment, showing an additive antitumoral effect compared with individual treatments.

Effect of exogenous lipase on subcutaneous adipose tissue in a porcine animal model.

BACKGROUND: Topical exogenous lipase has been approved for cosmetic use and has been used to mobilize fat from adipocytes. The objective of this study was to determine the effects of exogenous lipase in the subcutaneous adipose tissue. METHODS: Three different concentrations of exogenous lipase 1× (2 Units per ml), 5× (10 units per ml), and 10× (20 units per ml) were applied in a porcine model. Normal saline (NS) solution (as negative control) and phosphatidylcholine (as positive control) were also injected. Skin and subcutaneous tissue biopsies, up to the fascia, were obtained from each injection site on the 3rd day after injection. The number of cells per 20× field was counted as an indirect measurement of the size of the adipocytes. RESULTS: For 1× lipase, the number of cells per field was 47.80 (±7.63) versus 27.26 (±4.93), and 34.66 (±6.84) for NS, and phosphatidylcholine, respectively. For 5× lipase, the count was 36.06 (±4.74) versus 24.13 (±5.18), and 33.2 (±9.34). For 10× lipase, it was 40.06 (±4.35) versus 29.26 (±2.34) and 32.66 (±6.30) (p < .05 for all groups). CONCLUSIONS: A higher number of cells per field were observed in the lipase samples, inferring a decreased volume of adipocytes. No inflammation and/or loss of cell architecture were evidenced in the exogenous lipase groups.

Repair of ovine peripheral nerve injuries with xenogeneic human acellular sciatic nerves prerecellularized with allogeneic Schwann-like cells-an innovative and promising approach.

INTRODUCTION: The iatrogenic effects of repairing peripheral nerve injuries (PNIs) with autografts (AGTs) encouraged the present study to involve a new approach consisting of grafting xenogeneic prerecellularized allogeneic cells instead of AGTs. METHODS: We compared sheep's AGT regenerative and functional capacity with decellularized human nerves prerecellularized with allogeneic Schwann-like cell xenografts (onwards called xenografts). Mesenchymal stem cells were isolated from ovine adipose tissue and induced in vitro to differentiate into Schwann-like cells (SLCs). Xenografts were grafted in ovine sciatic nerves. Left sciatic nerves (20 mm) were excised from 10 sheep. Then, five sheep were grafted with 20 mm xenografts, and five were reimplanted with their nerve segment rotated 180° (AGT). RESULTS: All sheep treated with xenografts or AGT progressively recovered the strength, movement, and coordination of their intervened limb, which was still partial when the study was finished at sixth month postsurgery. At this time, numerous intrafascicular axons were observed in the distal and proximal graft extremes of both xenografts or AGTs, and submaximal nerve electrical conduction was observed. The xenografts and AGT-affected muscles appeared partially stunted. CONCLUSIONS: Xenografts and AGT were equally efficacious in starting PNI repair and justified further studies using longer observation times. The hallmarks from this study are that human xenogeneic acellular scaffolds were recellularized with allogenic SCL and were not rejected by the nonhuman receptors but were also as functional as AGT within a relatively short time postsurgery. Thus, this innovative approach promises to be more practical and accessible than AGT or allogenic allografts and safer than AGT for PNI repair.

Severe COVID-19 patients have severe vitamin D deficiency in Northeast Mexico.

Introduction: Objective: the association between vitamin D and COVID-19 severity is not consistent. We compared prevalences and analyzed the association between vitamin D deficiency and COVID-19 severity in Northeast Mexico. Methods: this was a cross-sectional study with individuals consecutively included at a referral diagnostic center during March-September 2020 (n = 181). Concurrently, every patient admitted to intensive care was also consecutively included (n = 116). Serum 25(OH)D < 20 ng/mL was considered vitamin D deficiency. Descriptive, ANOVA, and multivariate ordinal regression analyses were performed. Results: vitamin D deficiency prevalence was 63.8 % (95 % CI, 54.7, 72.0) in severe COVID-19; 25.6 % (95 % CI, 17.4, 36.0) in mild COVID-19; and 42.4 % (95 % CI, 33.2, 52.3) in non-diseased individuals. Vitamin D deficiency increased 5 times the odds of severe COVID-19 (95 % CI, 1.1, 24.3), independently of sex, age, body mass index, and inflammatory markers. Conclusions: this study is the first report of vitamin D deficiency in Northeast Mexico. Vitamin D deficiency was associated with COVID-19 severity.

Introducción: Objetivo: la asociación entre la vitamina D y la gravedad de la COVID-19 no es consistente. Se comparó la prevalencia y se analizó la asociación de la deficiencia de vitamina D con la gravedad de los pacientes con COVID-19 en el noreste de México. Métodos: este fue un estudio transversal. Se incluyó consecutivamente a individuos de un centro de diagnóstico de referencia durante marzo-septiembre de 2020 (n = 181). Paralelamente, se reclutó a todos los pacientes que ingresaron a cuidados intensivos en ese mismo periodo (n = 116). Se consideró que había deficiencia de vitamina D ante cifras de 25(OH)D sérica < 20 ng/ml. Se realizaron un análisis descriptivo, un ANOVA y una regresión ordinal multivariante. Resultados: la prevalencia de la deficiencia de vitamina D fue del 63,8 % (IC del 95 %: 54,7; 72,0) en la COVID-19 grave, del 25,6 % (IC del 95 %: 17,4; 36,0) en la COVID-19 leve y del 42,4 % (IC del 95 %: 33,2; 52,3) sin COVID-19. La deficiencia aumentó 5 veces las probabilidades de una COVID-19 grave (IC del 95 %: 1,1; 23,9) independientemente del sexo, la edad, el índice de masa corporal y los marcadores inflamatorios. Conclusiones: este estudio es el primer informe de la deficiencia de vitamina D en el noreste de México. La deficiencia de vitamina D se asoció con la gravedad de la COVID-19.

Copper induces damage, oxidative stress and cell death in endothelium of chronic intoxicated Wistar rats / El cobre induce daño, estrés oxidativo y muerte celular en el endotelio de ratas Wistar intoxicadas

SUMMARY: Reactive Oxygen Species (ROS) are part of the functional balance of various systems, they can generate cellular damage by oxidative stress associated with disease processes such as atherosclerosis, cardiovascular disease, diabetes, and aging. Some studies report that copper induces damage to the endothelium, which could be associated with cardiovascular pathologies. This study was an experimental comparative, prospective, longitudinal, and controlled clinical trial in a murine animal model. Twenty-four male Wistar rats were included, the distribution of the groups was time-depending chronic exposition to copper, and a control group. Results show gradual alterations in the groups treated with copper: areas with loss of the endothelium, signs of disorganization of smooth muscle fibers in the tunica media, as well as areas with the fragmentation of the elastic sheets. A significant statistical difference was observed in the active- Caspase-3 analysis expression in the aortic endothelium and endothelium of the capillaries and arterioles of the lung between the control group vs 300 ppm of copper. Expression of eNOS was detected in the endothelium of the aorta and vessels of the lung. Our study shows histological changes in the walls of the great vessels of intoxicated rats with copper, and the increment of inflammatory cells in the alveoli of the study model, mainly at a high dose of copper exposition. These results will be useful to understand more about the mediators involved in the effect of copper over endothelium and cardiovascular diseases in chronic intoxication in humans.

RESUMEN: Las Especies Reactivas de Oxígeno (ROS) son parte del equilibrio funcional de varios sistemas, pueden generar daño celular por estrés oxidativo asociado a procesos patológicos como aterosclerosis, enfermedades cardiovasculares, diabetes y envejecimiento. Algunos estudios informan que el cobre induce daños en el endotelio, lo que podría estar asociado a patologías cardiovasculares. Este estudio fue un ensayo clínico experimental comparativo, prospectivo, longitudinal y controlado en un modelo animal murino. Se incluyeron veinticuatro ratas Wistar macho, la distribución de los grupos fue la exposición crónica al cobre en función del tiempo y un grupo de control. Los resultados muestran alteraciones graduales en los grupos tratados con cobre: áreas con pérdida del endotelio, signos de desorganización de las fibras musculares lisas en la túnica media, así como áreas con la fragmentación de las láminas elásticas. Se observó una diferencia estadística significativa en la expresión del análisis de caspasa-3 activa en el endotelio aórtico y el endotelio de los capilares y arteriolas del pulmón entre el grupo de control frente a 300 ppm de cobre. Se detectó expresión de eNOS en el endotelio de la aorta y los vasos del pulmón. Nuestro estudio muestra cambios histológicos en las paredes de los grandes vasos de ratas intoxicadas con cobre, y el incremento de células inflamatorias en los alvéolos del modelo de estudio, principalmente a una alta dosis de exposición de cobre. Estos resultados serán útiles para comprender más sobre los mediadores involucrados en el efecto del cobre sobre el endotelio y las enfermedades cardiovasculares en la intoxicación crónica en humanos.

Cytotoxic Effect In Vitro of Acalypha monostachya Extracts over Human Tumor Cell Lines.

Acalypha monostachya (A. monostachya) is a plant that is used in traditional medicine as a cancer treatment; however, its effect has not been validated. In this study, the potential cytotoxic effects and morphological changes of A. monostachya were evaluated in human tumor cell lines. The aqueous (AE), methanolic (ME), and hexane (HE) extracts were obtained, and flavonoid-type phenolic compounds were detected, which indicates an antineoplastic effect. We observed a time-dependent and concentration-selective toxicity in human tumor cells. Additionally, the ME and HE showed the greatest cytotoxic effect at minimum concentrations compared to the AE, which showed this effect at the highest concentrations. All extracts induced significant morphological changes in tumor cells. The HeLa (cervix carcinoma) cells were more sensitive compared to the MDA-MB-231 (triple-negative breast cancer) cells. In conclusion, we demonstrated a cytotoxic in vitro effect of A. monostachya extracts in tumoral human cell lines. These results show the potential antineoplastic effects of A. monostachya in vitro. Hereafter, our lab team will continue working to usefully isolate and obtain the specific compounds of A. monostachya extracts with cytotoxic effects on tumor cells to find more alternatives for cancer treatment.

Neuropathic or systemic chronic intoxication with Karwinskia humboldtiana (Buckthorn) fruit? Histopathological effect in myocardial and skeletal muscle.

In accidental intoxicated animals and humans, Karwinskia humboldtiana (Kh) causes lesions in the central and peripheral nervous system and organs like the kidney, liver, and lung. The objective was to evaluate the histology of myocardium and skeletal muscle after experimental chronic intoxication with mature fruit of Kh in Wistar rat. Twenty-five rats were used and divided into five groups (n = 5): four intoxicated and one control. Kh fruit was ground, dried, sieved, and administered by an orogastric tube. Intoxicated rats received 3.5 g/kg body weight fractionated in 5 doses. Control rats received only water. Animals were euthanized at 24, 48, 58, and 112 days, respectively. Samples of the myocardium and skeletal muscle were obtained and processed for light microscopy evaluation. Morphological analyses were performed, including a microdensitometric analysis. Results showed areas of necrosis in the muscle fibers, fibers with vacuolated cytoplasm, and disorganization of myofilaments, as well as staining variations in both myocardium and skeletal muscle time-depending. Zones with loss of continuity of the external lamina were identified with PAS with the diastase histochemical method. Immunolabeling with specific antibodies demonstrated diminution of actin and desmin myofilaments. The microdensitometric analysis showed a statistically significant difference between the intoxicated vs control group. These findings demonstrate that chronic intoxication of Kh fruit also causes damage in myocardial and skeletal muscle, these alterations will be useful to understand that the toxic effects of Kh fruit in accidently intoxicated humans are systemic, and not only over the nervous system.

Pursuing Multiple Biomarkers for Early Idiopathic Parkinson's Disease Diagnosis.

Parkinson's disease (PD) ranks first in the world as a neurodegenerative movement disorder and occurs most commonly in an idiopathic form. PD patients may have motor symptoms, non-motor symptoms, including cognitive and behavioral changes, and symptoms related to autonomic nervous system (ANS) failures, such as gastrointestinal, urinary, and cardiovascular symptoms. Unfortunately, the diagnostic accuracy of PD by general neurologists is relatively low. Currently, there is no objective molecular or biochemical test for PD; its diagnosis is based on clinical criteria, mainly by cardinal motor symptoms, which manifest when patients have lost about 60-80% of dopaminergic neurons. Therefore, it is urgent to establish a panel of biomarkers for the early and accurate diagnosis of PD. Once the disease is accurately diagnosed, it may be easier to unravel idiopathic PD's pathogenesis, and ultimately, finding a cure. This review discusses several biomarkers' potential to set a panel for early idiopathic PD diagnosis and future directions.