Parkinson’s disease (PD) is not only characterized by motor disturbances but also, by cognitive, sensory, psychiatric and autonomic dysfunction. It has been proposed that some of these symptoms might be related to the widespread pathology of α-synuclein (α-syn) aggregation in different nuclei of the central and peripheral nervous system. However, the pathogenic formation of α-syn aggregates in different brain areas of PD patients is poorly understood. Most experimental models of PD are valuable to assess specific aspects of its pathogenesis, such as toxin-induced dopaminergic neurodegeneration. However, new models are required that reflect the widespread and progressive formation of α-syn aggregates in different brain areas. Such α-syn aggregation is induced in only a few animal models, for example perikaryon inclusions are found in rats administered rotenone, aggregates with a neuritic morphology develop in mice overexpressing either mutated or wild-type α-syn, and in Smad3 deficient mice, aggregates form extensively in the perikaryon and neurites of specific brain nuclei. In this review we focus on α-syn aggregation in the human disorder, its genetics and the availability of experimental models. Indeed, evidences show that dopamine (DA) metabolism may be related to α-syn and its conformational plasticity, suggesting an interesting link between the two pathological hallmarks of PD: dopaminergic neurodegeneration and Lewy body (LB) formation.

Impaired adipose tissue (AT) lipid handling and inflammation is associated with obesity-related metabolic diseases. Circulating lipopolysaccharides (LPSs) from gut microbiota (metabolic endotoxemia), proposed as a triggering factor for the low-grade inflammation in obesity, might also be responsible for AT dysfunction. Nevertheless, this hypothesis has not been explored in human obesity. To analyze the relationship between metabolic endotoxemia and AT markers for lipogenesis, lipid handling, and inflammation in human obesity, 33 patients with obesity scheduled for surgery were recruited and classified according to their LPS levels. Visceral and subcutaneous AT gene and protein expression were analyzed and adipocyte and AT in vitro assays performed. Subjects with obesity with a high degree of metabolic endotoxemia had lower expression of key genes for AT function and lipogenesis ( SREBP1, FABP4, FASN, and LEP) but higher expression of inflammatory genes in visceral and subcutaneous AT than subjects with low LPS levels. In vitro experiments corroborated that LPS are responsible for adipocyte and AT inflammation and downregulation of PPARG, SCD, FABP4, and LEP expression and LEP secretion. Thus, metabolic endotoxemia influences AT physiology in human obesity by decreasing the expression of factors involved in AT lipid handling and function as well as by increasing inflammation.

Background: Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra (SN). Transforming growth factor-β1 (TGF-β1) levels increase in patients with PD, although the effects of this increment remain unclear. We have examined the mesostriatal system in adult mice deficient in Smad3, a molecule involved in the intracellular TGF-β1 signalling cascade.Results: Striatal monoamine oxidase (MAO)-mediated dopamine (DA) catabolism to 3,4-dihydroxyphenylacetic acid (DOPAC) is strongly increased, promoting oxidative stress that is reflected by an increase in glutathione levels. Fewer astrocytes are detected in the ventral midbrain (VM) and striatal matrix, suggesting decreased trophic support to dopaminergic neurons. The SN of these mice has dopaminergic neuronal degeneration in its rostral portion, and the pro-survival Erk1/2 signalling is diminished in nigra dopaminergic neurons, not associated with alterations to p-JNK or p-p38. Furthermore, inclusions of α-synuclein are evident in selected brain areas, both in the perikaryon (SN and paralemniscal nucleus) or neurites (motor and cingulate cortices, striatum and spinal cord). Interestingly, these α-synuclein deposits are detected with ubiquitin and P^S129-α-synuclein in a core/halo cellular distribution, which resemble those observed in human Lewy bodies (LB).Conclusions: Smad3 deficiency promotes strong catabolism of DA in the striatum (ST), decrease trophic and astrocytic support to dopaminergic neurons and may induce α-synuclein aggregation, which may be related to early parkinsonism. These data underline a role for Smad3 in α-synuclein and DA homeostasis, and suggest that modulatory molecules of this signalling pathway should be evaluated as possible neuroprotective agents.

A rare germline duplication upstream of the bone morphogenetic protein antagonist GREM1 causes a Mendelian-dominant predisposition to colorectal cancer (CRC). The underlying disease mechanism is strong, ectopic GREM1 overexpression in the intestinal epithelium. Here, we confirm that a common GREM1 polymorphism, rs16969681, is also associated with CRC susceptibility, conferring ∼20% differential risk in the general population. We hypothesized the underlying cause to be moderate differences in GREM1 expression. We showed that rs16969681 lies in a region of active chromatin with allele- and tissue-specific enhancer activity. The CRC high-risk allele was associated with stronger gene expression, and higher Grem1 mRNA levels increased the intestinal tumor burden in Apc(Min) mice. The intestine-specific transcription factor CDX2 and Wnt effector TCF7L2 bound near rs16969681, with significantly higher affinity for the risk allele, and CDX2 overexpression in CDX2/GREM1-negative cells caused re-expression of GREM1. rs16969681 influences CRC risk through effects on Wnt-driven GREM1 expression in colorectal tumors.

Compacted Au@16-mph-16/DNA-AMOX (NSi) nanosystems were prepared from amoxicillin (AMOX) and precursor Au@16-mph-16 gold nanoparticles (Ni) using a Deoxyribonucleic acid (DNA) biopolymer as a glue. The synthesized nanocarrier was tested on different bacterial strains of Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae to evaluate its effectiveness as an antibiotic as well as its internalization. Synthesis of the nanosystems required previous structural and thermodynamic studies using circular dichroism (CD) and UV-visible techniques to guarantee optimal complex formation and maximal DNA compaction, characteristics which facilitate the correct uptake of the nanocarrier. Two nanocomplexes with different compositions and structures, denoted NS₁ and NS₂, were prepared, the first involving external Au@16-mph-16 binding and the second partial intercalation. The Ni and NSi nanosystems obtained were characterized via transmission electron microscopy (TEM), zeta potential, and dynamic light scattering (DLS) techniques to measure their charge, aggregation state and hydrodynamic size, and to verify their presence inside the bacteria. From these studies, it was concluded that the zeta potential values for gold nanoparticles, NS₁, and NS₂ nanosystems were 67.8, −36.7, and −45.1 mV. Moreover, the particle size distribution of the Au@16-mph-16 gold nanoparticles and NS₂ nanoformulation was found to be 2.6 nm and 69.0 nm, respectively. However, for NS₁ nanoformulation, a bimodal size distribution of 44 nm (95.5%) and 205 nm (4.5%) was found. Minimal inhibitory concentration (MIC) values were determined for the bacteria studied using a microdilution plates assay. The effect on Escherichia coli bacteria was notable, with MIC values of 17 µM for both the NS₁ and NS₂ nanosystems. The Staphylococcus aureus chart shows a greater inhibition effect of NS₂ and NP₂ in non-diluted wells, and clearly reveals a great effect on Streptococcus pneumoniae, reaching MIC values of 0.53 µM in more diluted wells. These results are in good agreement with TEM internalization studies of bacteria that reveal significant internalization and damage in Streptococcus pneumoniae. In all the treatments carried out, the antibiotic capacity of gold nanosystems as enhancers of amoxicillin was demonstrated, causing both the precursors and the nanosystems to act very quickly, and thus favoring microbial death with a small amount of antibiotic. Therefore, these gold nanosystems may constitute an effective therapy to combat resistance to antibiotics, in addition to avoiding the secondary effects derived from the administration of high doses of antibiotics.