Hyperhomocysteinemia: related genetic diseases and congenital defects, abnormal DNA methylation and newborn screening issues

Homocysteine, a sulfur-containing amino acid derived from the methionine metabolism, is located at the branch point of two pathways of the methionine cycle, i.e. remethylation and transsulfuration. Gene abnormalities in the enzymes catalyzing reactions in both pathways lead to hyperhomocysteinemia. Hyperhomocysteinemia is associated with increased risk for congenital disorders, including neural tube closure defects, heart defects, cleft lip/palate, Down syndrome, and multi-system abnormalities in adults. Since hyperhomocysteinemia is known to affect the extent of DNA methylation, it is likely that abnormal DNA methylation during embryogenesis, may be a pathogenic factor for these congenital disorders. In this review we highlight the importance of homocysteinemia by describing the genes encoding for enzymes of homocysteine metabolism relevant to the clinical practice, especially cystathionine-β-synthase and methylenetetrahydrofolate reductase mutations, and the impairment of related metabolites levels. Moreover, a possible correlation between hyperhomocysteine and congenital disorders through the involvement of abnormal DNA methylation during embryogenesis is discussed. Finally, the relevance of present and future diagnostic tools such as tandem mass spectrometry and next generation sequencing in newborn screening is highlighted

Heat shock affects mitotic segregation of human chromosomes bound to stress-induced satellite III RNAs

Heat shock activates the transcription of arrays of Satellite III (SatIII) DNA repeats in the pericentromeric heterochromatic domains of specific human chromosomes, the longest of which is on chromosome 9. Long non-coding SatIII RNAs remain associated with transcription sites where they form nuclear stress bodies or nSBs. The biology of SatIII RNAs is still poorly understood. Here, we show that SatIII RNAs and nSBs are detectable up to four days after thermal stress and are linked to defects in chromosome behavior during mitosis. Heat shock perturbs the execution of mitosis. Cells reaching mitosis during the first 3 h of recovery accumulate in pro-metaphase. During the ensuing 48 h, this block is no longer detectable; however, a significant fraction of mitoses shows chromosome segregation defects. Notably, most of lagging chromosomes and chromosomal bridges are bound to nSBs and contain arrays of SatIII DNA. Disappearance of mitotic defects at the end of day 2 coincides with the processing of long non-coding SatIII RNAs into a ladder of small RNAs associated with chromatin and ranging in size from 25 to 75 nt. The production of these molecules does not rely on DICER and Argonaute 2 components of the RNA interference apparatus. Thus, massive transcription of SatIII DNA may contribute to chromosomal instability

The suggested structure of final demand shock for sectoral labour digital skills

International data seem to confirm that countries with a relative abundancy of highly-skilled labour with digital competences grow faster than others. For this reason, digital competences and skills in general are progressively assuming a central role in labour market policies. In this article, we show the potential of the disaggregated multisectoral analysis with the macro multipliers approach as a tool of economic policy. Such analyses allow identifying a set of endogenous policies in which specific objectives do not clash with growth objectives. The identification and the quantification of the macro multipliers is based on an extended multi-industry, multi-factor and multi-sector model, which accounts for the representation of the income circular flow as in the social accounting matrix (SAM). The SAM constructed for this exercise allows for a proper disaggregation of the labour factor by formal educational attainment, digital competences and gender for the case of Italy

Transcription of the mitochondrial citrate carrier gene: identification of a silencer and its binding protein ZNF224

In the last few years, we have been functionally characterizing the promoter of the human mitochondrial citrate carrier (CIC). In this study we show that CIC silencer activity extends over 26 bp (-595/-569), which specifically bind a protein present in HepG2 cell nuclear extracts. This transcription factor was purified by DNA affinity and identified as ZNF224. Overexpression of ZNF224 decreases LUC transgene activity in cells transfected with a construct containing the CIC silencer region, whereas ZNF224 silencing activates reporter transcription in cells transfected with the same construct. Moreover, overexpression and silencing of ZNF224 diminishes and enhances, respectively, CIC transcript and protein levels. Finally, ZNF224 is abundantly expressed in fetal tissues contrary to CIC. It is suggested that CIC transcriptional repression by ZNF224 explains, at least in part, the low expression of CIC in fetal tissues in which fatty acid synthesis is low

Is a combination of melatonin and amino acids useful to sarcopenic elderly patients? A randomized trial

This study evaluated the effectiveness of a 4-week intervention of melatonin and essential aminoacid supplementation on body composition, protein metabolism, strength and inflammation in 159 elderly sarcopenic patients (42/117, men/women), assigned to four groups: isocaloric placebo (P, n = 44), melatonin (M, 1 mg/daily, n = 42), essential amino acids (eAA 4 g/daily, n = 40) or eAA plus melatonin (eAAM, 4 g eAA and 1 mg melatonin/daily, n = 30). Data from body composition (dual X-ray absortiometry (DXA)), strength (handgrip test) and biochemical parameters for the assessment of protein metabolism (albumin) and inflammation (CRP) were collected at baseline and after the 4-week intervention. Compared with P and M, supplementation with eAA plus M increased total fat-free mass (vs. P: +2190 g; p < 0.01; vs. M: +2107 g; p < 0.05). M alone lowered albumin levels (vs. P: -0.39 g; p < 0.01; vs. eAA: -0.47 g; p < 0.01). This data on albumin was confirmed by within-group analysis (M -0.44g; p < 0.001; eAAM: -0.34 p < 0.05). M and eAA seemed to lower the percentage of gynoid fat (p < 0.05) and android fat (p < 0.01). No significant changes in inflammation or strength were reported. A 4-week intervention with eAA plus M together may be effective in enhancing fat-free-mass compared to M and P but not versus eAA. M alone demonstrates a negative effect on albumin level

Impairment of methyl cycle affects mitochondrial methyl availability and glutathione level in Down's Sindrome

In Down's syndrome there is evidence that increased gene expression coding for specific cystathionine beta-synthase translates directly into biochemical aberrations, which result in a biochemical and metabolic imbalance of the methyl status. This event is destined to impact mitochondrial function since methylation is a necessary event in mitochondria and relies on the availability and uptake of the methyl donor S-adenosylmethionine. Indeed mitochondrial dysfunctions have been widely described in Down's syndrome, but they have never been correlated to a possible mitochondrial methyl unbalance. In the present study we find that the mitochondrial levels of S-adenosylmethionine are reduced in Down's syndrome compared to control cells demonstrating the effect of the methyl unbalance on mitochondria. The possible role of methylation in mitochondria is discussed and some preliminary results on a possible methylation target are presented

Impairment of methyl cycle affects mitochondrial methyl availability and glutathione level in Down's Sindrome

In Down's syndrome there is evidence that increased gene expression coding for specific cystathionine beta-synthase translates directly into biochemical aberrations, which result in a biochemical and metabolic imbalance of the methyl status. This event is destined to impact mitochondrial function since methylation is a necessary event in mitochondria and relies on the availability and uptake of the methyl donor S-adenosylmethionine. Indeed mitochondrial dysfunctions have been widely described in Down's syndrome, but they have never been correlated to a possible mitochondrial methyl unbalance. In the present study we find that the mitochondrial levels of S-adenosylmethionine are reduced in Down's syndrome compared to control cells demonstrating the effect of the methyl unbalance on mitochondria. The possible role of methylation in mitochondria is discussed and some preliminary results on a possible methylation target are presented

Are we ready for genetic testing in metabolic dysfunction-associated steatotic liver disease?

Metabolic dysfunction-associated steatotic liver disease (MASLD), with its steadily increasing prevalence, represents now a major problem in public health. A proper referral could benefit from tools allowing more precise risk stratification. To this end, in recent decades, several genetic variants that may help predict and refine the risk of development and progression of MASLD have been investigated. In this review, we aim to discuss the role genetics in MASLD plays in everyday clinical practice. We performed a comprehensive literature search of PubMed for relevant publications. Available evidence highlights the emergence of genetic-based noninvasive algorithms for diagnosing fatty liver, metabolic dysfunction-associated steatohepatitis, fibrosis progression and occurrence of liver-related outcomes including hepatocellular carcinoma. Nevertheless, their accuracy is not optimal and application in everyday clinical practice remains challenging. Furthermore, susceptible genetic markers have recently become subjects of great scientific interest as therapeutic targets in precision medicine. In conclusion, decisional algorithms based on genetic testing in MASLD to facilitate the clinician decisions on management and treatment are under growing investigation and could benefit from artificial intelligence methodology

Pivotal role of boron supplementation on bone health: A narrative review

Background: Boron is a trace element that plays an important role in numerous biological functions, including calcium metabolism, growth and maintenance of bone tissue. However, there are still no precise indications regarding a possible role of boron supplementation, and its amount of supplementation, to maintain bone health. So the aim of this narrative review was to consider the state of the art on the effectiveness of boron supplementation (alone or with other micronutrients) on growth and maintenance of bone in humans through control of calcium, vitamin D and sex steroid hormone metabolism in order to suggest a daily dosage of boron supplementation. Main findings: This review included 11 eligible studies: 7 regarding the supplementation with boron alone and 4 regarding supplementation with boron and other nutrients. Despite the number of studies considered being low, the number of subjects studied is high (594) and the results are interesting. Conclusions: The studies considered in this narrative review have evaluated the positive effectiveness on bone, in humans, through control of calcium, vitamin D and sex steroid hormone metabolism, considering a dietary supplementation of 3 mg/day of boron (alone or with other nutrients); this supplementation is demonstrably useful to support bone health (in order to prevent and maintain adequate bone mineral density), also considering the daily dose of 3 mg is much lower than the Upper Level indicated by EFSA in the daily dose of 10 mg