Osteoarthritis (OA) is a painful and disabling disease that affects millions of patients. Its etiology is largely unknown, but it is most likely multifactorial. OA pathogenesis involves the catabolism of the cartilage extracellular matrix and is supported by inflammatory and oxidative signaling pathways and marked epigenetic changes. To delay OA progression, a wide range of exercise programs and naturally derived compounds have been suggested. This literature review aims to analyze the main signaling pathways and the evidence about the synergistic effects of these two interventions to counter OA. The converging nutrigenomic and physiogenomic intervention could slow down and reduce the complex pathological features of OA. This review provides a comprehensive picture of a possible signaling approach for targeting OA molecular pathways, initiation, and progression.

Transcranial direct current stimulation (tDCS) has emerged as an appealing rehabilitative approach to improve brain function, with promising data on gait and balance in people with multiple sclerosis (MS). However, single variable weights have not yet been adequately assessed. Hence, the aim of this pilot randomized controlled trial was to evaluate the tDCS effects on balance and gait in patients with MS through a machine learning approach. In this pilot randomized controlled trial (RCT), we included people with relapsing–remitting MS and an Expanded Disability Status Scale >1 and <5 that were randomly allocated to two groups—a study group, undergoing a 10-session anodal motor cortex tDCS, and a control group, undergoing a sham treatment. Both groups underwent a specific balance and gait rehabilitative program. We assessed as outcome measures the Berg Balance Scale (BBS), Fall Risk Index and timed up-and-go and 6-min-walking tests at baseline (T0), the end of intervention (T1) and 4 (T2) and 6 weeks after the intervention (T3) with an inertial motion unit. At each time point, we performed a multiple factor analysis through a machine learning approach to allow the analysis of the influence of the balance and gait variables, grouping the participants based on the results. Seventeen MS patients (aged 40.6 ± 14.4 years), 9 in the study group and 8 in the sham group, were included. We reported a significant repeated measures difference between groups for distances covered (6MWT (meters), p < 0.03). At T1, we showed a significant increase in distance (m) with a mean difference (MD) of 37.0 [−59.0, 17.0] (p = 0.003), and in BBS with a MD of 2.0 [−4.0, 3.0] (p = 0.03). At T2, these improvements did not seem to be significantly maintained; however, considering the machine learning analysis, the Silhouette Index of 0.34, with a low cluster overlap trend, confirmed the possible short-term effects (T2), even at 6 weeks. Therefore, this pilot RCT showed that tDCS may provide non-sustained improvements in gait and balance in MS patients. In this scenario, machine learning could suggest evidence of prolonged beneficial effects.

The canonical Wnt/Wingless pathway is implicated in regulating cell proliferation and cell differentiation of neural stem/progenitor cells. Depending on the context, β-Catenin, a key mediator of the Wnt signaling pathway, may regulate either cell proliferation or differentiation. Here, we show that β-Catenin signaling regulates the differentiation of neural stem/progenitor cells in the presence of the β-Catenin interactor Homeodomain interacting protein kinase-1 gene (Hipk1). On one hand, Hipk1 is expressed at low levels during the entire embryonic forebrain development, allowing β-Catenin to foster proliferation and to inhibit differentiation of neural stem/progenitor cells. On the other hand, Hipk1 expression dramatically increases in neural stem/progenitor cells, residing within the subventricular zone (SVZ), at the time when the canonical Wnt signaling induces cell differentiation. Analysis of mouse brains electroporated with Hipk1, and the active form of β-Catenin reveals that coexpression of both genes induces proliferating neural stem/progenitor cells to escape the cell cycle. Moreover, in SVZ derive neurospheres cultures, the overexpression of both genes increases the expression of the cell-cycle inhibitor P16Ink4. Therefore, our data confirm that the β-Catenin signaling plays a dual role in controlling cell proliferation/differentiation in the brain and indicate that Hipk1 is the crucial interactor able to revert the outcome of β-Catenin signaling in neural stem/progenitor cells of adult germinal niches.