NFE2L1/Nrf1 serves as a potential therapeutical target for neurodegenerative diseases.

The failure of the proper protein turnover in the nervous system is mainly linked to a variety of neurodegenerative disorders. Therefore, a better understanding of key protein degradation through the ubiquitin-proteasome system is critical for effective prevention and treatment of those disorders. The proteasome expression is tightly regulated by a CNC (cap'n'collar) family of transcription factors, amongst which the nuclear factor-erythroid 2-like bZIP factor 1 (NFE2L1, also known as Nrf1, with its long isoform TCF11 and short isoform LCR-F1) has been identified as an indispensable regulator of the transcriptional expression of the ubiquitin-proteasome system. However, much less is known about how the pivotal role of NFE2L1/Nrf1, as compared to its homologous NFE2L2 (also called Nrf2), is translated to its physiological and pathophysiological functions in the nervous system insomuch as to yield its proper cytoprotective effects against neurodegenerative diseases. The potential of NFE2L1 to fulfill its unique neuronal function to serve as a novel therapeutic target for neurodegenerative diseases is explored by evaluating the hitherto established preclinical and clinical studies of Alzheimer's and Parkinson's diseases. In this review, we have also showcased a group of currently available activators of NFE2L1, along with an additional putative requirement of this CNC-bZIP factor for healthy longevity based on the experimental evidence obtained from its orthologous SKN1-A in Caenorhabditis elegans.

The Structure of Temperament in Caregivers of Patients with Schizophrenia.

The onset of schizophrenia symptoms usually occurs in early youth. As a result, the parents of these patients usually become their caregivers. The role of a caregiver for a person with schizophrenia is a considerable mental and physical burden. Therefore, an interesting issue is what motivates these people to take up this challenge. It is probable that, apart from the moral imperative or kinship, the factor determining this decision is the personality structure of the caregiver. The aim of our study was to compare the structure of temperament (according to the model of temperament as formal characteristics of behavior developed by Jan Strelau) in caregivers of young adults (age 18-25 years) with schizophrenia with the structure of temperament of parents of healthy young adults still living in the family home under their care. The study group consisted of 64 people (51 women), who were taking care of young adults (aged 18-25 years) with schizophrenia, while the control group (53 people, 42 women) consisted of parents of healthy adults still living in the family home. Both groups were asked to complete a questionnaire of the authors' own design on their demographic data as well as The Formal Characteristics of Behavior-Temperament Inventory to assess the temperament traits. The results were given in the number of points obtained on average in each dimension. Both groups did not differ in terms of size and age, with women predominating. Caregivers of young adults with schizophrenia had higher values of briskness (43.22 ± 4.45 vs. 42.90 ± 3.98, p = 0.032), emotional reactivity (46.02 ± 4.39 vs. 41.01 ± 3.12, p = 0.012) and activity level (44.01.89 ± 4.15 vs. 37.59 ± 4.77, p = 0.022) compared to the control group. The remaining dimensions of temperament: perseverance, sensory sensitivity, rhythmicity, and endurance did not differentiate between the two groups. The temperament structure of caregivers of young people with schizophrenia differs from the temperament structure of caregivers of healthy adults. Caregivers of sick people have higher values of briskness, emotional reactivity, and activity level compared to the control group.

Being an adult sibling of an individual with autism spectrum disorder may be a predictor of loneliness and depression - Preliminary findings from a cross-sectional study.

Background: The aim of this study is to compare depression and loneliness among adult siblings of people on the autism spectrum, adult siblings of normotypic individuals, and adults raised alone (only child). In recent years, an increasing interest in the perspective of siblings of children diagnosed with autism has been observed, with studies among this population particularly concerned with the developmental trajectories of children and adolescents at "high risk" for ASD, rarely focusing on their mental well-being. Methods: The respondents filled out: the survey on sociodemographic data designed by the authors, Beck Depression Inventory II (BDI, measure of depression), and De Jong Gierveld Loneliness Scale (DJGLS, assessment of loneliness). Results: A rise in BDI and an increase in the DJGLS score were predicted by having a sibling diagnosed with ASD. Those effects were independent of subjects' sex, educational status, place of residence, or a number of siblings. Conclusion: The results underline a fundamental need for the development of mental hygiene programs for families where children with autism spectrum are accompanied by healthy siblings.

Disruption of Tumor Suppressors HNF4α/HNF1α Causes Tumorigenesis in Liver.

The hepatocyte nuclear factor-4α (HNF4α) and hepatocyte nuclear factor-1α (HNF1α) are transcription factors that influence the development and maintenance of homeostasis in a variety of tissues, including the liver. As such, disruptions in their transcriptional networks can herald a number of pathologies, such as tumorigenesis. Largely considered tumor suppressants in liver cancer, these transcription factors regulate key events of inflammation, epithelial-mesenchymal transition, metabolic reprogramming, and the differentiation status of the cell. High-throughput analysis of cancer cell genomes has identified a number of hotspot mutations in HNF1α and HNF4α in liver cancer. Such results also showcase HNF1α and HNF4α as important therapeutic targets helping us step into the era of personalized medicine. In this review, we update current findings on the roles of HNF1α and HNF4α in liver cancer development and progression. It covers the molecular mechanisms of HNF1α and HNF4α dysregulation and also highlights the potential of HNF4α as a therapeutic target in liver cancer.

NRF2 DLG Domain Mutations Identified in Japanese Liver Cancer Patients Affect the Transcriptional Activity in HCC Cell Lines.

Geographically, East Asia had the highest liver cancer burden in 2017. Besides this, liver cancer-related deaths were high in Japan, accounting for 3.90% of total deaths. The development of liver cancer is influenced by several factors, and genetic alteration is one of the critical factors among them. Therefore, the detailed mechanism driving the oncogenic transformation of liver cells needs to be elucidated. Recently, many researchers have focused on investigating the liver cancer genome and identified somatic mutations (MTs) of several transcription factors. In this line, next-generation sequencing of the cancer genome identified that oxidative stress-related transcription factor NRF2 (NFE2L2) is mutated in different cancers, including hepatocellular carcinoma (HCC). Here, we demonstrated that NRF2 DLG motif mutations (NRF2 D29A and L30F), found in Japanese liver cancer patients, upregulate the transcriptional activity of NRF2 in HCC cell lines. Moreover, the transcriptional activity of NRF2 mutations is not suppressed by KEAP1, presumably because NRF2 MTs disturb proper NRF2-KEAP1 binding and block KEAP1-mediated degradation of NRF2. Additionally, we showed that both MTs upregulate the transcriptional activity of NRF2 on the MMP9 promoter in Hepa1-6 and Huh7 cells, suggesting that MT derived gain-of-function of NRF2 may be important for liver tumor progression. We also found that ectopic overexpression of oncogenic BRAF WT and V600E increases the transcriptional activity of NRF2 WT on both the 3xARE reporter and MMP9 promoter. Interestingly, NRF2 D29A and L30F MTs with oncogenic BRAF V600E MT synergistically upregulate the transcription activity of NRF2 on the 3xARE reporter and MMP9 promoter in Hepa1-6 and Huh7 cells. In summary, our findings suggest that MTs in NRF2 have pathogenic effects, and that NRF2 MTs together with oncogenic BRAF V600E MT synergistically cause more aberrant transcriptional activity. The high activity of NRF2 MTs in HCC with BRAF MT warrants further exploration of the potential diagnostic, prognostic, and therapeutic utility of this pathway in HCC.