Re-thinking the Etiological Framework of Neurodegeneration

Neurodegenerative diseases are among the leading causes of disability and death worldwide. The disease-related socioeconomic burden is expected to increase with the steadily increasing life expectancy. In spite of decades of clinical and basic research, most strategies designed to manage degenerative brain diseases are palliative. This is not surprising as neurodegeneration progresses "silently" for decades before symptoms are noticed. Importantly, conceptual models with heuristic value used to study neurodegeneration have been constructed retrospectively, based on signs and symptoms already present in affected patients;a circumstance that may confound causes and consequences. Hence, innovative, paradigm-shifting views of the etiology of these diseases are necessary to enable their timely prevention and treatment. Here, we outline four alternative views, not mutually exclusive, on different etiological paths toward neurodegeneration. First, we propose neurodegeneration as being a secondary outcome of a primary cardiovascular cause with vascular pathology disrupting the vital homeostatic interactions between the vasculature and the brain, resulting in cognitive impairment, dementia, and cerebrovascular events such as stroke. Second, we suggest that the persistence of senescent cells in neuronal circuits may favor, together with systemic metabolic diseases, neurodegeneration to occur. Third, we argue that neurodegeneration may start in response to altered body and brain trophic interactions established via the hardwire that connects peripheral targets with central neuronal structures or by means of extracellular vesicle (E\-mediated communication. Lastly, we elaborate on how lifespan body dysbiosis may be linked to the origin of neurodegeneration. We highlight the existence of bacterial products that modulate the gut-brain axis causing neuroinflammation and neuronal dysfunction. As a concluding section, we end by recommending research avenues to investigate these etiological paths in the future. We think that this requires an integrated, interdisciplinary conceptual research approach based on the investigation of the multimodal aspects of physiology and pathophysiology. It involves utilizing proper conceptual models, experimental animal units, and identifying currently unused opportunities derived from human data. Overall, the proposed etiological paths and experimental recommendations will be important guidelines for future cross-discipline research to overcome the translational roadblock and to develop causative treatments for neurodegenerative diseases

Serum nucleosomes during neoadjuvant chemotherapy in patients with cervical cancer. Predictive and prognostic significance

BACKGROUND: It has been shown that free DNA circulates in serum plasma of patients with cancer and that at least part is present in the form of oligo- and monucleosomes, a marker of cell death. Preliminary data has shown a good correlation between decrease of nucleosomes with response and prognosis. Here, we performed pre- and post-chemotherapy determinations of serum nucleosomes with an enzyme-linked immunosorbent assay (ELISA) method in a group of patients with cervical cancer receiving neoadjuvant chemotherapy. METHODS: From December 2000 to June 2001, 41 patients with cervical cancer staged as FIGO stages IB2-IIIB received three 21-day courses of carboplatin and paclitaxel, both administered at day 1; then, patients underwent radical hysterectomy. Nucleosomes were measured the day before (baseline), at day seven of the first course and day seven of the third course of chemotherapy. Values of nucleosomes were analyzed with regard to pathologic response and to time to progression-free and overall survival. RESULTS: All patients completed chemotherapy, were evaluable for pathologic response, and had nucleosome levels determined. At a mean follow-up of 23 months (range, 7–26 months), projected progression time and overall survival were 80.3 and 80.4%, respectively. Mean differential values of nucleosomes were lower in the third course as compared with the first course (p >0.001). The decrease in the third course correlated with pathologic response (p = 0.041). Survival analysis showed a statistically significant, better progression-free and survival time in patients who showed lower levels at the third course (p = 0.0243 and p = 0.0260, respectively). Cox regression analysis demonstrated that nucleosome increase in the third course increased risk of death to 6.86 (95% confidence interval [CI 95%], 0.84–56.0). CONCLUSION: Serum nucleosomes may have a predictive role for response and prognostic significance in patients with cervical cancer patients treated with neoadjuvant chemotherapy

Sobre la historia de la arquitectura de los conventos del norte de la península de Yucatán: desde la llegada de los franciscanos a Campeche en 1544 hasta la construcción del convento de Santa Clara de Asís en 1567.

En 1524, con el arribo de los doce franciscanos dirigidos por fray Martín de Valencia, ini- ció la evangelización de la Nueva España. Los conocimientos y la experiencia del grupo no serían suficientes para el éxito de esta empresa; fue necesario también incorporar los hábitos esenciales de las culturas prehispánicas en ese proceso. El sincretismo derivado de ello generó resultados en todas las disciplinas humanas. Para la arquitectura, el más importante fue el convento novohispano del siglo XVI, que resignificó los espacios y fue un verdadero eje de la vida de las nacientes poblaciones. Este trabajo es un recuento del proceso de evangelización del norte de la península de Yucatán, a través de la presenta- ción y el análisis de la arquitectura de los conventos franciscanos

Caracterización molecular de la respuesta celular ante excitotoxicidad por ácido kaínico en el hipocampo durante la lactancia en Rattus norvegicus /

 tesis que para obtener el grado de Doctor en Ciencias Bioquímicas, presenta América Vanoye Carlo ; asesor Marco A. Cerbón Cervantes. IV, 76, [20] páginas : ilustraciones. Doctorado en Ciencias Bioquímicas UNAM, Facultad de Química, 200

Effect of Nicotine on CYP2B1 Expression in a Glioma Animal Model and Analysis of CYP2B6 Expression in Pediatric Gliomas

Cyclophosphamide (CPA) is a pro-drug commonly used in the chemotherapeutic schemes for glioma treatment but has high toxicity and the side effects include brain damage and even death. Since CPA is activated mainly by CY2B6, over-expression of the enzyme in the tumor cells has been proposed to enhance CPA activation. In this study, we explored the induction of the Cyp2b1 (homologous to CYP2B6) by nicotine in an animal rat model with glioma. Gene expression and protein levels were analyzed by RT-PCR and Western blot. Nicotine treatment increased CYP2B1 protein levels in the healthy animals’ brain tissue. In the brain tissue of animals with glioma, the CYP2B1 showed a high expression, even before nicotine treatment. Nicotine did not increase significantly the CYP2B1 protein expression in the tumor, but increased its expression in the tumor vicinity, especially around blood vessels in the cortex. We also explored CY2B6 expression in glioma samples derived from pediatric patients. Tumor tissue showed a variable expression of the enzyme, which could depend on the tumor malignancy grade. Induction of the CYP2B6 in pediatric gliomas with lower expression of the enzyme, could be an alternative to improve the antitumoral effect of CPA treatment

Use of Antioxidants for the Neuro-Therapeutic Management of COVID-19

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is an emergent infectious disease that has caused millions of deaths throughout the world. COVID-19 infection’s main symptoms are fever, cough, fatigue, and neurological manifestations such as headache, myalgias, anosmia, ageusia, impaired consciousness, seizures, and even neuromuscular junctions’ disorders. In addition, it is known that this disease causes a series of systemic complications such as adverse respiratory distress syndrome, cardiac injury, acute kidney injury, and liver dysfunction. Due to the neurological symptoms associated with COVID-19, damage in the central nervous system has been suggested as well as the neuroinvasive potential of SARS-CoV-2. It is known that CoV infections are associated with an inflammation process related to the imbalance of the antioxidant system; cellular changes caused by oxidative stress contribute to brain tissue damage. Although anti-COVID-19 vaccines are under development, there is no specific treatment for COVID-19 and its clinical manifestations and complications; only supportive treatments with immunomodulators, anti-vascular endothelial growth factors, modulating drugs, statins, or nutritional supplements have been used. In the present work, we analyzed the potential of antioxidants as adjuvants for the treatment of COVID-19 and specifically their possible role in preventing or decreasing the neurological manifestations and neurological complications present in the disease

Functional and Biochemical Analysis of Glucose-6-Phosphate Dehydrogenase (G6PD) Variants: Elucidating the Molecular Basis of G6PD Deficiency

G6PD deficiency is the most common enzymopathy, leading to alterations in the first step of the pentose phosphate pathway, which interferes with the protection of the erythrocyte against oxidative stress and causes a wide range of clinical symptoms of which hemolysis is one of the most severe. The G6PD deficiency causes several abnormalities that range from asymptomatic individuals to more severe manifestations that can lead to death. Nowadays, only 9.2% of all recognized variants have been related to clinical manifestations. It is important to understand the molecular basis of G6PD deficiency to understand how gene mutations can impact structure, stability, and enzymatic function. In this work, we reviewed and compared the functional and structural data generated through the characterization of 20 G6PD variants using different approaches. These studies showed that severe clinical manifestations of G6PD deficiency were related to mutations that affected the catalytic and structural nicotinamide adenine dinucleotide phosphate (NADPH) binding sites, and suggests that the misfolding or instability of the 3D structure of the protein could compromise the half-life of the protein in the erythrocyte and its activity

RNAi-Mediated Specific Gene Silencing as a Tool for the Discovery of New Drug Targets in Giardia lamblia; Evaluation Using the NADH Oxidase Gene

The microaerophilic protozoan Giardia lamblia is the agent causing giardiasis, an intestinal parasitosis of worldwide distribution. Different pharmacotherapies have been employed against giardiasis; however, side effects in the host and reports of drug resistant strains generate the need to develop new strategies that identify novel biological targets for drug design. To support this requirement, we have designed and evaluated a vector containing a cassette for the synthesis of double-stranded RNA (dsRNA), which can silence expression of a target gene through the RNA interference (RNAi) pathway. Small silencing RNAs were detected and quantified in transformants expressing dsRNA by a stem-loop RT-qPCR approach. The results showed that, in transformants expressing dsRNA of 100–200 base pairs, the level of NADHox mRNA was reduced by around 30%, concomitant with a decrease in enzyme activity and a reduction in the number of trophozoites with respect to the wild type strain, indicating that NADHox is indeed an important enzyme for Giardia viability. These results suggest that it is possible to induce the G. lamblia RNAi machinery for attenuating the expression of genes encoding proteins of interest. We propose that our silencing strategy can be used to identify new potential drug targets, knocking down genes encoding different structural proteins and enzymes from a wide variety of metabolic pathways