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Sabatini, S.

Publications and source records attributed to Sabatini, S..

9 recordsLinked to original sources

Beige/brown fat-mediated cardiac protection from high-fat diet is dependent on adipocyte beta3-adrenergic receptor

Cardiometabolic diseases associated with obesity are continuously increasing worldwide. Yet, current therapeutic strategies remain insufficient to improve patient outcomes. The beta3-adrenergic receptor ({beta}3AR) promotes lipolysis in adipose tissue (AT) and thermogenesis specifically in brown adipose tissue (BAT). In mice, BAT activation also improves systemic metabolism and limits cardiometabolic damage. While BAT is limited in humans (e.g., with ageing and obesity), {beta}3AR activation induces beige adipocytes within white adipose depots with similar thermogenic properties. To study the role of adipocyte {beta}3AR in the regulation of cardiac metabolism and remodeling, mice with/without adipocyte-specific {beta}3AR genetic deletion were fed a high-fat-sucrose (HF-S) diet and treated with the selective {beta}3AR agonist CL316,243 (CL). The metabolic and cardiac protection following {beta}3AR activation was abrogated upon {beta}3AR deletion in adipocytes, together with the beiging of the epididymal (visceral) AT, highlighting a critical role of adipose {beta}3AR signalling in mediating these benefits. Multi-omic analysis of AT and cardiac samples identified CL-induced secreted mediators of the crosstalk between AT and the heart. Therefore, adipocyte {beta}3AR is critical for the adipose-cardiac communication and supports the therapeutic potential of targeting {beta}3AR for the management of obesity-related cardiometabolic diseases.

systems biology↗

Storage protein biosynthesis is affected by ionome composition in soybean (Glycine max (L.) Merrill) seeds

Soybean seeds are a significant source of protein for human and animal nutrition, primarily due to seed storage proteins (SSPs) from the albumin and globulin families, which are predominantly located in protein storage vacuoles within cotyledon cells. This study characterised the dynamics of protein and mineral nutrient accumulation in four soybean genotypes with contrasting protein content--two transgenic (tg1 and tg2) and two conventional (ct1 and ct2)--from the beginning of seed filling (R5.5) through to maturity (R8) under field conditions. Profiles of globulin SSPs (glycinin and {beta}-conglycinin), as well as the protein and elemental distribution in mature seed cotyledons were examined. Results revealed that genotypes with higher protein content showed increased S and Zn concentrations and a higher glycinin:{beta}-conglycinin ratio. Subcellular analyses further indicated co-localisation of proteins and Zn within cotyledon cells. Our findings reveal a complex association between S and Zn accumulation and SSPs biosynthesis, indicating that their availability can limit the SSP content. HIGHLIGHTSoybean seed genotypes containing higher sulphur (S) and zinc (Zn) content in the cotyledonary cells exhibit a distinct storage proteins profile by increasing the abundance of sulphur-amino acids rich globulins.

plant biology↗

Ancient genomics support deep divergence between Eastern and Western Mediterranean Indo-European languages

The Indo-European languages are among the most widely spoken in the world, yet their early diversification remains contentious1-5. It is widely accepted that the spread of this language family across Europe from the 5th millennium BP correlates with the expansion and diversification of steppe-related genetic ancestry from the onset of the Bronze Age6,7. However, multiple steppe-derived populations co-existed in Europe during this period, and it remains unclear how these populations diverged and which provided the demographic channels for the ancestral forms of the Italic, Celtic, Greek, and Armenian languages8,9. To investigate the ancestral histories of Indo-European-speaking groups in Southern Europe, we sequenced genomes from 314 ancient individuals from the Mediterranean and surrounding regions, spanning from 5,200 BP to 2,100 BP, and co-analysed these with published genome data. We additionally conducted strontium isotope analyses on 224 of these individuals. We find a deep east-west divide of steppe ancestry in Southern Europe during the Bronze Age. Specifically, we show that the arrival of steppe ancestry in Spain, France, and Italy was mediated by Bell Beaker (BB) populations of Western Europe, likely contributing to the emergence of the Italic and Celtic languages. In contrast, Armenian and Greek populations acquired steppe ancestry directly from Yamnaya groups of Eastern Europe. These results are consistent with the linguistic Italo-Celtic10,11 and Graeco-Armenian1,12,13 hypotheses accounting for the origins of most Mediterranean Indo-European languages of Classical Antiquity. Our findings thus align with specific linguistic divergence models for the Indo-European language family while contradicting others. This underlines the power of ancient DNA in uncovering prehistoric diversifications of human populations and language communities.

genetics↗

Steppe Ancestry in western Eurasia and the spread of the Germanic Languages

Today, Germanic languages, including German, English, Frisian, Dutch and the Nordic languages, are widely spoken in northwest Europe. However, key aspects of the assumed arrival and diversification of this linguistic group remain contentious1-3. By adding 712 new ancient human genomes we find an archaeologically elusive population entering Sweden from the Baltic region by around 4000 BP. This population became widespread throughout Scandinavia by 3500 BP, matching the contemporaneous distribution of Palaeo-Germanic, the Bronze Age predecessor of Proto-Germanic4-6. These Baltic immigrants thus offer a new potential vector for the first Germanic speakers to arrive in Scandinavia, some 800 years later than traditionally assumed7-12. Following the disintegration of Proto-Germanic13-16, we find by 1650 BP a southward push from Southern Scandinavia into presumed Celtic-speaking areas, including Germany, Poland and the Netherlands. During the Migration Period (1575-1375 BP), we see this ancestry representing West Germanic Anglo-Saxons in Britain, and Langobards in southern Europe. We find a related large-scale northward migration into Denmark and South Sweden corresponding with historically attested Danes and the expansion of Old Norse. These movements have direct implications for multiple linguistic hypotheses. Our findings show the power of combining genomics with historical linguistics and archaeology in creating a unified, integrated model for the emergence, spread and diversification of a linguistic group.

genetics↗

microRNA165 and 166 modulate salt stress response of the Arabidopsis root.

In plants, developmental plasticity allows for the modulation of organ growth in response to environmental cues. Being in contact with soil, roots are the first organ responding to soil abiotic stresses such as high salt concentration. In the root, plasticity relies on changes in the activity of the apical meristem, the region at the tip of the root where a set of self-renewing undifferentiated stem cells sustains growth. We show that salt stress promotes root meristem cells differentiation via reducing the dosage of the microRNAs miR165 and 166. By means of genetic, molecular and computational analysis, we show that the levels of miR165 and 166 respond to high salt concentration, and that miR165 and 166-dependent PHB modulation is fundamental for the response of root growth to this stress. Salt dependent reductions of miR165 and 166 causes rapid increase of the Arabidopsis homeobox protein PHABULOSA (PHB) expression and production of the root meristem pro-differentiation hormone cytokinin. Our data provide direct evidence of how the miRNA-dependent modulation of transcription factors dosage mediates plastic development in plants. In plants, development must be both robust - to ensure appropriate growth - and plastic - to enable the adaptation to external cues. Plastic development largely depends on the modulation of gene expression, controlling the concentration of developmental factors, such as hormones, transcription factors (TFs) and signalling molecules (Garcia-Molina et al, 2013; Hofhuis & Heidstra, 2018; Lopez-Ruiz et al, 2020; Schroder et al, 2021). A classic example of plant developmental plasticity is the adaptation of plant growth to high salt conditions, a stress that inhibits shoot and root development (Flowers et al, 1997). Roots are the first organs sensing salt concentration in soil, where high salt reduces meristem activity and root growth (Dinneny et al, 2008; Geng et al, 2013; Jiang et al, 2016). It has been suggested that the regulation of several plant hormones and miRNAs mediate the plant response to salt stress (Dolata et al, 2016; Geng et al, 2013; Iglesias et al, 2014; Jiang et al, 2016; Nishiyama et al, 2011; Yan et al, 2016). However, the molecular interplays mediating the adaptation of plant roots to salt stress are still vague. Post-embryonic root growth is supported by the activity of the root meristem, a region located at the root tip where self-renewing stem cells divide asymmetrically in the stem cell niche (SCN), originating transit-amplifying daughter cells that divide in the division zone (DZ) (Di Mambro et al, 2018). Once these cells reach a developmental boundary denominated transition zone (TZ), they stop dividing and start to elongate in the so-called elongation/differentiation zone (EDZ) (Di Mambro et al, 2018). A dynamic balance between cell division and cell differentiation ensures continuous root growth, maintaining a fixed number of cells in the DZ. Alterations in this dynamic equilibrium promote or inhibit root growth (Di Mambro et al, 2018; Salvi et al, 2020). microRNA molecules (miRNA) play a key role in the control of root meristem development (Bertolotti et al, 2021a; Skopelitis et al, 2012). Maturation of plant miRNAs depends on the activity of a multiprotein complex comprising the DICER-LIKE1 (DCL1), HYPONASTIC LEAVES1 (HYL1) and SERRATE (SE) proteins that cut pre-miRNA transcripts into 21 nucleotides mature miRNA (Yan et al, 2016). Among miRNAs, miR165 and 166 have been shown to be main regulator of root development (Carlsbecker et al, 2010; Dello Ioio et al, 2012). miR165 and miR166 are pleiotropic regulators of plant developmental processes. miR165 and 166 family consists of nine independent loci (MIR165 A-B and MIR166 A-G) that drive expression of pre-miR165 and 166 in different tissues and at different developmental stages (Miyashima et al, 2011). miR165/166 activity is crucial in the control of robust development, restricting the expression of the HOMEODOMAIN LEUCINE ZIPPER III (HD-ZIPIII), including PHABULOSA (PHB) and PHAVOLUTA (PHV), which are involved in root and shoot development, vascular growth, and leaf and embryo polarity (Carlsbecker et al, 2010; Dello Ioio et al, 2012; Di Ruocco et al, 2017; Grigg et al, 2009; McConnell et al, 2001; Skopelitis et al, 2017; Williams et al, 2005). In the root, miR165/166 regulate meristem homeostasis and radial patterning (Carlsbecker et al, 2010; Dello Ioio et al, 2012); pre-miR165a, pre-miR166a and b transcription is promoted by the SCARECROW (SCR) and SHORTROOT (SHR) transcription factors (Carlsbecker et al, 2010) and, thanks to the cell-to-cell mobility, mature miR165 and 166 forms diffuse to patterns both the root vasculature and the ground tissue (Carlsbecker et al, 2010; Miyashima et al, 2011; Skopelitis et al, 2018; Vaten et al, 2011; Bertolotti et al, 2021b). In the root meristem the miR165-166-PHB module promotes the synthesis of the plant hormone cytokinin, an important player in root developmental plasticity regulating cell differentiation rate of meristematic cells via the activation of the ARABIDOPSIS HISTIDINE KINASE3 (AHK3)/ARABIDOPSIS RESPONSE REGULATOR 1/12 (ARR1/12) pathway (Dello Ioio et al, 2007,2008). Here, we show that in response to salt stress miR165 and 166 modulates PHB expression to adjust root meristem activity. Salt exposure results in changes in cytokinin biosynthesis, which further regulates the miR165/166-PHB module. Hence, in addition to the above-described miRNA activity in controlling root robust development, we provide clear evidence that, in response to environmental cues, miRNAs are crucial also in the control of root plastic development, modulating the dosage of transcription factors.

plant biology↗

Microprobe-XRF assessment of nutrient distribution in soybean, cowpea, and kidney bean seeds: a Fabaceae family case study

The present study explored the microprobe X-ray fluorescence spectroscopy ({micro}-XRF) for quantitative and space-resolved distribution of macro, i.e., K, P, S, and Ca, and micronutrients, i.e., Fe, Zn, and Mn elemental composition in the cross-sectioned seeds of cowpea (Vigna unguiculata L.), kidney bean (Phaseolus vulgaris L.), and soybean (Glycine max L.) seeds, important agricultural species within the Fabaceae family. It unveils that both macro and micronutrients were heterogeneously distributed across seed tissues. Most of the P and S, Fe, Zn, and Mn were mainly found at the embryo axis tissues in all three Fabaceae species, whereas K was spread along the cotyledon and Ca was mostly observed trapped at the seed coat region. Furthermore, the Pearson correlation coefficient revealed a strong spatial correlation between P and S, and K and S in cowpea and soybean seed tissues, whereas Zn and Mn association was also recorded. Therefore, the {micro}-XRF technique demonstrates to be an important tool for assessing seed nutrient distribution, thus subsidizing the understanding of the physiological role of nutrients in seeds and fostering innovative approaches for nutrient supply and biofortification.

biochemistry↗

Adipose tissue dysfunction and visceral fat are associated to hepatic insulin resistance and severity of NASH even in lean individuals

Background & AimsNonalcoholic fatty liver disease (NAFLD) is a heterogeneous disorder, but the factors that determine this heterogeneity remain poorly understood. Adipose tissue (AT) dysfunction is causally linked to NAFLD since it causes intrahepatic triglyceride (IHTG) accumulation through increased hepatic lipid flow, due to insulin resistance (IR) and pro-inflammatory adipokines release. While many studies in NAFLD have looked at total adiposity (that is mainly subcutaneous fat, SC-AT), it is still unclear the impact of visceral fat (VF). Thus, we investigated how VF vs. SC-AT were related to NAFLD in lean, overweight, and obese individuals compared to lean controls. MethodsThirty-four non-diabetic NAFLD with liver biopsy and eight lean control individuals (CT) were enrolled in this study. We measured fat distribution (VF, SC-AT and IHTG) by magnetic resonance imaging (MRI), adiponectin concentration, free fatty acids (FFAs) and triglyceride (TAG) concentration and composition by mass spectrometry (MS), lipolysis and IR by tracer infusion. ResultsIHTG was positively associated with lipolysis, adipose tissue IR, TG concentrations, and increased ratio of saturated/unsaturated fatty acids. VF was higher in NAFLD (including lean individuals) compared to controls, was increased with fibrosis stage and was associated with IR in liver, muscle and adipose tissue, increased lipolysis, and decreased adiponectin levels. Collectively, our results suggest that VF accumulation, given its location close to the liver, is one of the major risk factors for NAFLD. ConclusionsThese findings propose VF as an early indicator of NAFLD independently of BMI, which may allow for evidence-based prevention and intervention strategies.

physiology↗

TM6SF2/PNPLA3/MBOAT7 loss-of-function genetic variants impact on NAFLD development and progression both in patients and in in vitro models

Background and aimsThe I148M PNPLA3, the rs641738 in MBOAT7/TMC4 locus and the E167K TM6SF2 polymorphisms represent the main predisposing factors to non-alcoholic fatty liver disease (NAFLD) development and progression. We previously generated a full knockout of MBOAT7 in HepG2 cells (MBOAT7-/-), homozygous for the I148M PNPLA3. Therefore, we aimed to:1) investigate the synergic impact of the 3 at-risk variants on liver injury and hepatocellular carcinoma (HCC) in a large cohort of NAFLD patients;2) create in vitro models of genetic NAFLD by silencing TM6SF2 in both HepG2 and MBOAT7-/- cells. MethodsNAFLD patients (n=1380) of whom 121 had HCC were stratified with a semi-quantitative score ranging from 0 to 3 according to the number of PNPLA3, TM6SF2 and MBOAT7 at-risk variants. TM6SF2 was silenced in HepG2 (TM6SF2-/-) and MBOAT7-/- (MBOAT7-/-TM6SF2-/-) through CRISPR/Cas9. ResultsIn NAFLD patients, the additive weight of these mutations was associated with liver disease severity and increased risk to develop HCC. In HepG2 cells, TM6SF2 silencing altered lipid composition and induced the accumulation of micro-vesicular LDs, whereas the MBOAT7-/-TM6SF2-/- cells showed a mixed micro/macro pattern of LDs. TM6SF2 deletion strongly affected endoplasmic reticulum (ER) and mitochondria ultrastructures thus increasing ER/oxidative stress. Mitochondrial number raised in both TM6SF2-/- and MBOAT7-/-TM6SF2-/- models, suggesting an unbalancing in mitochondrial dynamics and the silencing of both MBOAT7 and TM6SF2 impaired mitochondrial activity with a shift towards anaerobic glycolysis. MBOAT7-/-TM6SF2-/- cells also showed the highest proliferation rate. ConclusionsThe co-presence of the 3 at-risk variants impacts on NAFLD course, in both patients and experimental models affecting LDs accumulation, mitochondrial functionality and metabolic reprogramming towards HCC.

genetics↗

Pleiotropic effect of Lactoferrin in the prevention and treatment of COVID-19 infection: in vivo, in silico and in vitro preliminary evidences

Lactoferrin, a multifunctional cationic glycoprotein, secreted by exocrine glands and neutrophils, possesses an antiviral activity extendable to SARS-CoV-2. We performed in vitro assays proving lactoferrin antiviral activity through direct attachment to both virus and cell surface components. This activity varied according to concentration (100/500g/ml), multiplicity of infection (0.1/0.01) and cell type (Vero E6/Caco-2 cells). Interestingly, the in silico results strongly supported the hypothesis of a direct recognition between the lactoferrin and the Spike S glycoprotein, thus hindering the viral entry into the cells. Hence, we conducted a clinical trial to investigate effect and tolerability of a liposomal lactoferrin formulation as a supplementary nutraceutical agent in mild-to-moderate and asymptomatic COVID-19 patients. A total of 92 mild-to-moderate (67/92) and asymptomatic (25/92) COVID-19 patients were recruited and divided in 3 groups according to the administered regimen. Thirty-two patients, 14 hospitalised and 18 in home-based insolation received oral and intranasal liposomal bovine lactoferrin (bLf), 32 hospitalised patients were treated with standard of care treatment (hydroxychloroquine, azitromicin and lopinavir/darunavir), and 28, in home-based isolation, did not take any medication. Furthermore, 32 COVID-19 negative, not-treated, healthy subjects were added as a control group for ancillary analysis. bLf-supplemented COVID-19 patients obtained an earlier and significant (p < 0,0001.) median rRT-PCR SARS-COV-2 RNA negative conversion than standard of care-treated and non-treated COVID-19 patients (14.25 vs 27.13 vs 32.61 days, respectively). In addition, bLf-supplemented COVID-19 patients showed significant fast clinical symptoms recovery than standard of care-treated and non-treated COVID-19 patients. Moreover, in bLf-supplemented patients, a significant decrease of either serum ferritin or IL-6 levels or host iron overload, all parameters characterizing inflammatory processes, were observed. Serum D-dimers was also found significantly decreased following bLf supplement. No adverse events were reported. These in vitro and in vivo observations led us to speculate a potential and safe supplementary role of Blf in the management of mild-to-moderate and asymptomatic COVID-19 patients.

microbiology↗