Genetics, Pathophysiology, and Current Challenges in Von Hippel-Lindau Disease Therapeutics.

This review article focuses on von Hippel-Lindau (VHL) disease, a rare genetic disorder characterized by the development of tumors and cysts throughout the body. It discusses the following aspects of the disease. GENETICS: VHL disease is caused by mutations in the VHL tumor suppressor gene located on chromosome 3. These mutations can be inherited or occur spontaneously. This article details the different types of mutations and their associated clinical features. PATHOPHYSIOLOGY: The underlying cause of VHL disease is the loss of function of the VHL protein (pVHL). This protein normally regulates hypoxia-inducible factors (HIFs), which are involved in cell growth and survival. When pVHL is dysfunctional, HIF levels become elevated, leading to uncontrolled cell growth and tumor formation. CLINICAL MANIFESTATIONS: VHL disease can affect various organs, including the brain, spinal cord, retina, kidneys, pancreas, and adrenal glands. Symptoms depend on the location and size of the tumors. DIAGNOSIS: Diagnosis of VHL disease involves a combination of clinical criteria, imaging studies, and genetic testing. TREATMENT: Treatment options for VHL disease depend on the type and location of the tumors. Surgery is the mainstay of treatment, but other options like radiation therapy may also be used. CHALLENGES: This article highlights the challenges in VHL disease management, including the lack of effective therapies for some tumor types and the need for better methods to monitor disease progression. In conclusion, we emphasize the importance of ongoing research to develop new and improved treatments for VHL disease.

Etiology, risk factors, treatments and current status of Alzheimer's disease in Mexico.

Alzheimer's disease is a neurodegenerative disorder whose etiology continues to be discussed, to the point that there are different hypotheses that seek to clarify it, in addition to the fact that, given its multifactorial nature, there are different risk factors associated with its development. As regards diagnosis, advances in molecule detection techniques at femtomolar scales have allowed to distinguish between healthy and diseased subjects at relatively early stages, although there is still much to be done. Aducanumab is a monoclonal antibody targeted against Aß, whose marketing approval by the Food and Drug Administration has been questioned by the international medical community, given the controversial results in clinical trials. Approval of this antibody as a disease-modifying treatment for Alzheimer's disease opens the door to continue using this type of treatments, but with different therapeutic targets, such as, for example, tau protein. Finally, given the population tendency towards longevity, conditions such as Alzheimer's disease are gaining epidemiological importance, which is why it is imperative to analyze and link what is being done in the social, familiar, clinical and research fields and, most importantly, to find those areas of opportunity for the benefit of the patient.

La enfermedad de Alzheimer es un desorden neurodegenerativo cuya etiología aún se discute, al punto de que existen diferentes hipótesis que pretenden esclarecerla; además, dada su naturaleza multifactorial, existen diferentes factores de riesgo asociados a su desarrollo. Respecto al diagnóstico, los avances en las técnicas de detección de moléculas a escalas femtomolares han permitido discernir entre sujetos sanos y enfermos en estadios relativamente tempranos, aunque todavía hay mucho por hacer. Aducanumab es un anticuerpo monoclonal dirigido contra Aß, cuya aprobación por parte de la Food and Drug Administration para comercializarse ha sido cuestionada por la comunidad médica internacional, dados los resultados controversiales en los ensayos clínicos. La aprobación de este anticuerpo como tratamiento modificador de la enfermedad de Alzheimer abre la puerta para seguir utilizando este tipo de tratamientos, pero con blancos terapéuticos diferentes, como, por ejemplo, la proteína tau. Finalmente, dada la tendencia de la población hacia la longevidad, padecimientos como la enfermedad de Alzheimer están tomando importancia epidemiológica, por lo que resulta imperativo analizar y vincular lo que se está haciendo en los ámbitos social, familiar, clínico y de investigación y, sobre todo, encontrar esas áreas de oportunidad en beneficio del paciente.

Etiología, factores de riesgo, tratamientos y situación actual de la enfermedad de Alzheimer en México / Etiology, risk factors, treatments and current status of Alzheimer's disease in Mexico

Resumen La enfermedad de Alzheimer es un desorden neurodegenerativo cuya etiología aún se discute, al punto de que existen diferentes hipótesis que pretenden esclarecerla; además, dada su naturaleza multifactorial, existen diferentes factores de riesgo asociados a su desarrollo. Respecto al diagnóstico, los avances en las técnicas de detección de moléculas a escalas femtomolares han permitido discernir entre sujetos sanos y enfermos en estadios relativamente tempranos, aunque todavía hay mucho por hacer. Aducanumab es un anticuerpo monoclonal dirigido contra Aβ, cuya aprobación por parte de la Food and Drug Administration para comercializarse ha sido cuestionada por la comunidad médica internacional, dados los resultados controversiales en los ensayos clínicos. La aprobación de este anticuerpo como tratamiento modificador de la enfermedad de Alzheimer abre la puerta para seguir utilizando este tipo de tratamientos, pero con blancos terapéuticos diferentes, como, por ejemplo, la proteína tau. Finalmente, dada la tendencia de la población hacia la longevidad, padecimientos como la enfermedad de Alzheimer están tomando importancia epidemiológica, por lo que resulta imperativo analizar y vincular lo que se está haciendo en los ámbitos social, familiar, clínico y de investigación y, sobre todo, encontrar esas áreas de oportunidad en beneficio del paciente.

Abstract Alzheimer's disease is a neurodegenerative disorder whose etiology continues to be discussed, to the point that there are different hypotheses that seek to clarify it, in addition to the fact that, given its multifactorial nature, there are different risk factors associated with its development. As regards diagnosis, advances in molecule detection techniques at femtomolar scales have allowed to distinguish between healthy and diseased subjects at relatively early stages, although there is still much to be done. Aducanumab is a monoclonal antibody targeted against Aβ, whose marketing approval by the Food and Drug Administration has been questioned by the international medical community, given the controversial results in clinical trials. Approval of this antibody as a disease-modifying treatment for Alzheimer's disease opens the door to continue using this type of treatments, but with different therapeutic targets, such as, for example, tau protein. Finally, given the population tendency towards longevity, conditions such as Alzheimer's disease are gaining epidemiological importance, which is why it is imperative to analyze and link what is being done in the social, familiar, clinical and research fields and, most importantly, to find those areas of opportunity for the benefit of the patient.

Autophagy: A Key Regulator of Homeostasis and Disease: An Overview of Molecular Mechanisms and Modulators.

Autophagy is a highly conserved lysosomal degradation pathway active at basal levels in all cells. However, under stress conditions, such as a lack of nutrients or trophic factors, it works as a survival mechanism that allows the generation of metabolic precursors for the proper functioning of the cells until the nutrients are available. Neurons, as post-mitotic cells, depend largely on autophagy to maintain cell homeostasis to get rid of damaged and/or old organelles and misfolded or aggregated proteins. Therefore, the dysfunction of this process contributes to the pathologies of many human diseases. Furthermore, autophagy is highly active during differentiation and development. In this review, we describe the current knowledge of the different pathways, molecular mechanisms, factors that induce it, and the regulation of mammalian autophagy. We also discuss its relevant role in development and disease. Finally, here we summarize several investigations demonstrating that autophagic abnormalities have been considered the underlying reasons for many human diseases, including liver disease, cardiovascular, cerebrovascular diseases, neurodegenerative diseases, neoplastic diseases, cancers, and, more recently, infectious diseases, such as SARS-CoV-2 caused COVID-19 disease.

Biomarker Candidates for Alzheimer's Disease Unraveled through In Silico Differential Gene Expression Analysis.

Alzheimer's disease (AD) is neurodegeneration that accounts for 60-70% of dementia cases. Symptoms begin with mild memory difficulties and evolve towards cognitive impairment. The underlying risk factors remain primarily unclear for this heterogeneous disorder. Bioinformatics is a relevant research tool that allows for identifying several pathways related to AD. Open-access databases of RNA microarrays from the peripheral blood and brain of AD patients were analyzed after background correction and data normalization; the Limma package was used for differential expression analysis (DEA) through statistical R programming language. Data were corrected with the Benjamini and Hochberg approach, and genes with p-values equal to or less than 0.05 were considered to be significant. The direction of the change in gene expression was determined by its variation in the log2-fold change between healthy controls and patients. We performed the functional enrichment analysis of GO using goana and topGO-Limma. The functional enrichment analysis of DEGs showed upregulated (UR) pathways: behavior, nervous systems process, postsynapses, enzyme binding; downregulated (DR) were cellular component organization, RNA metabolic process, and signal transduction. Lastly, the intersection of DEGs in the three databases showed eight shared genes between brain and blood, with potential use as AD biomarkers for blood tests.

Analyzing Olfactory Neuron Precursors Non-Invasively Isolated through NADH FLIM as a Potential Tool to Study Oxidative Stress in Alzheimer's Disease.

Among all the proposed pathogenic mechanisms to understand the etiology of Alzheimer's disease (AD), increased oxidative stress seems to be a robust and early disease feature where many of those hypotheses converge. However, despite the significant lines of evidence accumulated, an effective diagnosis and treatment of AD are not yet available. This limitation might be partially explained by the use of cellular and animal models that recapitulate partial aspects of the disease and do not account for the particular biology of patients. As such, cultures of patient-derived cells of peripheral origin may provide a convenient solution for this problem. Peripheral cells of neuronal lineage such as olfactory neuronal precursors (ONPs) can be easily cultured through non-invasive isolation, reproducing AD-related oxidative stress. Interestingly, the autofluorescence of key metabolic cofactors such as reduced nicotinamide adenine dinucleotide (NADH) can be highly correlated with the oxidative state and antioxidant capacity of cells in a non-destructive and label-free manner. In particular, imaging NADH through fluorescence lifetime imaging microscopy (FLIM) has greatly improved the sensitivity in detecting oxidative shifts with minimal intervention to cell physiology. Here, we discuss the translational potential of analyzing patient-derived ONPs non-invasively isolated through NADH FLIM to reveal AD-related oxidative stress. We believe this approach may potentially accelerate the discovery of effective antioxidant therapies and contribute to early diagnosis and personalized monitoring of this devastating disease.

The KISS1 gene overexpression as a potential molecular marker for cervical cancer cells.

BACKGROUND: Similarities between the pathologic progression of cancer and the physiologic process of placentation have been recognized for many years proposing that both present similar mechanisms and processes. Cervical cancer (CC) is one of the most frequent neoplasia among Mexican women turning it into an important health problem. OBJECTIVE: The aim of this study was to determine the degree of the involvement of pregnancy related genes and in cancer progression by in-silico analysis and validated in CC samples. RESULTS: The data mining analysis resulted in the identification of genes expressed in term placenta, first trimester placenta and normal cervical tissues. Finally, we selected KISS1 for the involvement of pregnancy related gene and also in cancer process. In order to explore KISS1 in CC, we analyzed Copy Number Variation (CNV) and gene expression using microarray experiments. KISS1 showed 20% genomic gain in 1q32.1 on CC samples. Furthermore, microarray analysis showed KISS1 as up-regulated genes. Results were validated showing an overexpression of 85% of KISS1 in CC samples. CONCLUSIONS: Data suggest KISS1 as a great candidate for CC molecular markers or as a therapeutic target for CC. Also, HPV presence does not seem to alter the KISS1 expression in CC.

Krüppel-Like Factor 10 participates in cervical cancer immunoediting through transcriptional regulation of Pregnancy-Specific Beta-1 Glycoproteins.

Cervical cancer (CC) is associated with alterations in immune system balance, which is primarily due to a shift from Th1 to Th2 and the unbalance of Th17/Treg cells. Using in silico DNA copy number analysis, we have demonstrated that ~20% of CC samples exhibit gain of 8q22.3 and 19q13.31; the regions of the genome that encodes the KLF10 and PSG genes, respectively. Gene expression studies demonstrated that there were no alterations in KLF10 mRNA expression, whilst the PSG2 and -5 genes were up-regulated by 1.76 and 3.97-fold respectively in CC compared to normal tissue controls. siRNA and ChIP experiments in SiHa cells have demonstrated that KLF10 participates in immune response through regulation of IL6, IL25 and PSG2 and PSG5 genes. Using cervical tissues from KLF10-/- mice, we have identified down-regulation of PSG17, -21 and -23 and IL11. These results suggest that KLF10 may regulate immune system response genes in cervical cancer among other functions. KLF10 and PSG copy number variations and alterations in mRNA expression levels could represent novel molecular markers in CC.

Soluble Factors from Human Olfactory Neural Stem/Progenitor Cells Influence the Fate Decisions of Hippocampal Neural Precursor Cells.

Neurogenesis plays a significant role during adulthood, and the observation that neural stem cells reside in the central nervous system and the olfactory epithelium has attracted attention due to their importance in neuronal regeneration. In addition, soluble factors (SFs) release by neural stem cells may modulate the neurogenic process. Thus, in this study, we identified the SFs released by olfactory human neural stem/progenitor cells (hNS/PCs-OE). These cells express Ki67, nestin, and ßIII-tubulin, indicating their neural lineage. The hNS/PCs-OE also express PSD95 and tau proteins during proliferation, but increased levels are observed after differentiation. Thus, we evaluated the effects of SFs from hNS/PCs-OE on the viability, proliferation, and differentiation potential of adult murine hippocampal neural precursor cells (AHPCs). SFs from hNS/PCs-OE maintain cells in the precursor and proliferative stages and mainly promote the astrocytic differentiation of AHPCs. These effects involved the activation, as measured by phosphorylation, of several proteins (Erk1/2; Akt/PRAS40/GSK3ß and JAK/STAT) involved in key events of the neurogenic process. Moreover, according to the results from the antibody-based microarray approach, among the soluble factors, hNS/PCs-OE produce interleukin-6 (IL-6) and neurotrophin 4 (NT4). However, residual epidermal growth factor (EGF) was also detected. These proteins partially reproduced the effects of SFs from hNS/PCs-OE on AHPCs, and the mechanism underlying these effects is mediated by Src proteins, which have been implicated in EGF-induced transactivation of TrkB receptor. The results of the present study suggest the potential use of SFs from hNS/PCs-OE in controlling the differentiation potential of AHPCs. Thus, the potential clinical relevance of hNS/PCs-OE is worth pursuing.

Las zonas neurogénicas en el adulto y su relación con las enfermedades neuropsiquiátricas / Neurogenic regions in the adult: Relationship with the neuropsychiatric disorders

Neuropsychiatric diseases (NPD) are characterized by changes in brain plasticity involving alterations in the morphology and functionality of neurons. However, affectations of the neuronal development (neurogenesis) in the adult brain are also shown. The neurogenic process is widely regulated by different factors such as genes, microenvironment, hormones, neurotransmitters, environmental cues and, also, nutrition. Thus, alterations in these factors negatively impact the neuronal development. Several studies performed in humans have revealed alterations of neurogenesis in NPD. However, most of the knowledge derives from studies done in animal models of NPD. The evidences from animal models are controversial, thus the use of human-induced pluripotent stem cells as a model of NPD has marked a way to study alterations in the neuronal development. Recently, the use of another cellular model for studying NPD has been proposed. Multipotent stem cells derived from olfactory epithelium (MOESCs) are a good candidate. However, evidences are scarce and deeper studies are necessary to know if there is or not a correlation of alterations in neuronal development in the OE with the changes observed in the brain; or if the MOESCs can mimic alterations shown in NPD that could let to get more knowledge about the factors promoting these diseases. Thus, in this review we discuss basic information about adult neurogenesis under physiological and non-physiological conditions in the hippocampus, olfactory bulb and olfactory epithelium.

Las enfermedades neuropsiquiátricas (ENP) se caracterizan por cambios en la plasticidad cerebral que incluyen la pérdida neuronal en regiones específicas en el encéfalo, cambios en la transmisión sináptica originada por alteraciones en los contactos sinápticos y también por la expresión de genes. Además, otro proceso que forma parte de la plasticidad cerebral y que también se encuentra afectado en las ENP es la generación de nuevas neuronas (neurogénesis). El proceso neurogénico en el adulto es regulado de manera fina por diversos factores como los aspectos genéticos, celulares, el microambiente, los elementos neuroquímicos, los ambientales y los nutricionales. Las alteraciones de estos factores impactan en el desarrollo y en la función de las nuevas neuronas. Algunos estudios realizados en humanos han revelado las alteraciones en la neurogénesis en algunos ENP. Sin embargo los mayores avances logrados han utilizado modelos animales de ENP. En algunos casos estas evidencias son controvertidas y recientemente se han tratado de aclarar utilizando cultivos de células madre pluripotenciales-inducibles humanas como modelos de ENP. Otro modelo que se ha propuesto para estudiar las alteraciones en el desarrollo neuronal en las ENP son las células madre multipotenciales del epitelio olfatorio (CMPEO). Sin embargo las evidencias obtenidas con las CMPEO son escasas y resulta necesario demostrar si existe o no un correlato con las alteraciones que ocurren en el desarrollo neuronal a nivel central en las ENP, o bien si las CMPEO pueden mostrar las alteraciones observadas en las ENP que permitan obtener información acerca de los factores que promueven estas enfermedades. Por lo tanto en esta revisión se incluyen aspectos básicos de la neurogénesis e información relevante de las alteraciones de este proceso en las tres regiones neurogénicas en el adulto: el hipocampo, el bulbo olfatorio y el epitelio olfatorio.