RESUMEN
Apolipoprotein C-III (ApoC-III) amyloidosis in humans is a hereditary amyloidosis caused by a D25V mutation in the APOC3 gene. This condition has only been reported in a French family and not in animals. We analyzed a 19-year-old white lion (Panthera leo) that died in a Japanese safari park and found renal amyloidosis characterized by severe deposition confined to the renal corticomedullary border zone. Mass spectrometry-based proteomic analysis identified ApoC-III as a major component of renal amyloid deposits. Amyloid deposits were also positive for ApoC-III by immunohistochemistry. Based on these results, this case was diagnosed as ApoC-III amyloidosis for the first time in nonhuman animals. Five additional white lions were also tested for amyloid deposition retrospectively. ApoC-III amyloid deposition was detected in 3 white lions aged 19 to 21 years but not in 2 cases aged 0.5 and 10 years. Genetic analysis of white and regular-colored lions revealed that the APOC3 sequences of the lions were identical, regardless of amyloid deposition. These results suggest that ApoC-III amyloidosis in lions, unlike in humans, may not be a hereditary condition but an age-related condition. Interestingly, lion ApoC-III has a Val30 substitution compared with other species of Panthera that have Met30. Structural predictions suggest that the conformation of ApoC-III with Met30 and ApoC-III with Val30 are almost identical, but this substitution may alter the ability to bind to lipids. As with the D25V mutation in human ApoC-III, the Val30 substitution in lions may increase the proportion of free ApoC-III, leading to amyloid formation.
Asunto(s)
Amiloidosis , Apolipoproteína C-III , Leones , Animales , Amiloidosis/veterinaria , Amiloidosis/patología , Amiloidosis/metabolismo , Apolipoproteína C-III/genética , Apolipoproteína C-III/metabolismo , Masculino , Femenino , Riñón/patología , Secuencia de Aminoácidos , Amiloide/metabolismo , Enfermedades Renales/veterinaria , Enfermedades Renales/patología , Inmunohistoquímica/veterinariaRESUMEN
Plasmalogens are a special class of polar glycerolipids containing a vinyl-ether bond and an ester bond at sn-1 and sn-2 positions of the glycerol backbone, respectively. In animals, impaired biosynthesis and regulation of plasmalogens may lead to certain neurological and metabolic diseases. Plasmalogens deficiency was proposed to be strongly associated with neurodegenerative and metabolic diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), and appropriate supplement of plasmalogens could help to prevent and possibly provide therapy of these diseases. Plasmalogens evolved first in anaerobic bacteria with an anaerobic biosynthetic pathway. Later, an oxygen-dependent biosynthesis of plasmalogens appeared in animal cells. This review summarizes and updates current knowledge of anaerobic and aerobic pathways of plasmalogens biosynthesis, including the enzymes involved, steps and aspects of the regulation of these processes. Strategies for increasing the expression of plasmalogen synthetic genes using synthetic biology techniques under specific conditions are discussed. Deep understanding of plasmalogens biosynthesis will provide the bases for the use of plasmalogens and their precursors as potential therapeutic regimens for age-related degenerative and metabolic diseases.
RESUMEN
In pace with the development of gene sequencing technology and transcriptome research, it has been found that 70 to 90% of the human genome is transcribed into RNAs, while only 2% of RNAs encode proteins. This implies that non-coding RNAs (ncRNAs) may exert vital biological functions and a full analysis of non-coding transcriptomes is needed. Over the past decade, the advance in high-throughput sequencing and transcriptome profiling has enabled the identification of circular RNAs (circRNAs) involved in many biological processes and the occurrence and development of diseases. Accumulating evidence has revealed that circRNAs may serve as new biomarkers for diagnosis as well as provide promising therapeutic approaches and novel drug screening strategies for leukemia. A comprehensive understanding of circRNAs in leukemia is a prerequisite for the development of clinical translational research. In this review, we will discuss the general information of circRNAs and focus on the current advances in understanding the association between dysregulated circRNAs and leukemia.
Asunto(s)
Leucemia/genética , ARN Circular/genética , Humanos , Leucemia/patologíaRESUMEN
Sirtuin 1 (SIRT1) enzyme regulates major cell activities, and its activation offers lucrative therapeutic potentials for aging diseases including Alzheimer's disease (AD). Regarding the global aging society, continual attention has been given to various chemical scaffolds as a source for the discovery of novel SIRT1 activators since the discovery of the pioneer activator, resveratrol. Understanding structure-activity relationship (SAR) is essential for screening, designing as well as improving the properties of drugs. In this study, an in silico approach based on quantitative structure-activity relationship (QSAR) modeling, was employed for understanding the SAR of currently available SIRT1 fused-aromatic activators (i.e., imidazothiazole, oxazolopyridine, and azabenzimidazole analogs). Three QSAR models constructed using multiple linear regression (MLR) provided good predictive performance (R 2 LOOCV = 0.729 - 0.863 and RMSE LOOCV = 0.165 - 0.325). An additional novel set of 181 structurally modified compounds were rationally designed according to key descriptors deduced from the QSAR findings and their SIRT1 activities were predicted using the constructed models. In overview, the study provides insightful SAR findings of currently available SIRT1 activators that would be useful for guiding the rational design, screening, and development of further potent SIRT1 activators for managing age-related clinical conditions. A series of promising compounds as well as important scaffolds and molecular properties for potent SIRT1 activator were highlighted. This study demonstrated the efficacious role of QSAR-driven structural modification for the rational design of novel leads.
RESUMEN
Calcification of the human lens has been described in senile cataracts and in young patients with congenital cataract or chronic uveitis. Lens calcification is also a major complication of cataract surgery and plays a role in the opacification of intraocular lenses. A cell-mediated process has been suggested in the background of lens calcification, but so far the exact mechanism remained unexplored. Lens calcification shares remarkable similarities with vascular calcification; in both pathological processes hydroxyapatite accumulates in the soft tissue. Vascular calcification is a regulated, cell-mediated process in which vascular cells undergo osteogenic differentiation. Our objective was to investigate whether human lens epithelial cells (HuLECs) can undergo osteogenic transition in vitro, and whether this process contributes to lens calcification. We used inorganic phosphate (Pi) and Ca to stimulate osteogenic differentiation of HuLECs. Osteogenic stimuli (2.5mmol/L Pi and 1.2mmol/L Ca) induced extracellular matrix mineralization and Ca deposition in HuLECs with the critical involvement of active Pi uptake. Osteogenic stimuli almost doubled mRNA expressions of osteo-/chondrogenic transcription factors Runx2 and Sox9, which was accompanied by a 1.9-fold increase in Runx2 and a 5.5-fold increase in Sox9 protein expressions. Osteogenic stimuli induced mRNA and protein expressions of alkaline phosphatase and osteocalcin in HuLEC. Ca content was higher in human cataractous lenses, compared to non-cataractous controls (n=10). Osteocalcin, an osteoblast-specific protein, was expressed in 2 out of 10 cataractous lenses. We conclude that osteogenic stimuli induce osteogenic differentiation of HuLECs and propose that this mechanism might play a role in lens calcification.
Asunto(s)
Calcinosis/patología , Cristalino/patología , Anciano , Anciano de 80 o más Años , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Calcinosis/etiología , Calcinosis/metabolismo , Calcio/metabolismo , Catarata/etiología , Catarata/metabolismo , Catarata/patología , Diferenciación Celular , Células Cultivadas , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Transición Epitelial-Mesenquimal , Matriz Extracelular/metabolismo , Femenino , Humanos , Cristalino/metabolismo , Masculino , Osteocalcina/genética , Osteocalcina/metabolismo , Osteogénesis , Fosfatos/metabolismo , Factor de Transcripción SOX9/genética , Factor de Transcripción SOX9/metabolismo , Regulación hacia ArribaRESUMEN
PURPOSE: To compare the safety and efficacy of PAE for the treatment of benign prostatic hyperplasia (BPH) in men ≥75 years, who we defined as elderly, to those <75 years. METHODS: A total of 157 patients diagnosed with lower urinary tract symptoms (LUTS) due to BPH underwent PAE. Group A (n = 52) included patients ≥75 years, and group B (n = 105) included patients <75 years. Follow-up was performed using the International Prostate Symptoms Score (IPSS), quality of life (QoL), peak urinary flow rate (Q max), post-void residual volume (PVR), the International Index of Erectile Function short form (IIEF-5), prostatic-specific antigen (PSA), and prostate volume (PV), at 1, 3, 6, and every 6 months thereafter. RESULTS: More coexistent systemic diseases were identified in group A than in group B (P < 0.05). Technical success rate of PAE was 90.4 % in group A and 95.2 % in group B (P = 0.06). A total of 147 patients had completed the follow-up with a mean of 20 months. Compared with the baseline, there were significant improvements in IPSS, QoL, Q max, PV, PVR, and PSA in both groups after PAE. There were no significant differences in the changes of IPSS, Q max, PVR, PSA, and IIEF-5 between groups after PAE. No major complications were noted. CONCLUSION: PAE could be used as an effective, safe, and well tolerable method in the treatment of elderly symptomatic BPH patients, similarly to younger patients, and it may play an important role in patients in whom medical therapy has failed, who are at high surgical and anesthetic risk or who refuse the standard surgical therapy.