Throughout the 20th and 21st centuries, the incidence of non-communicable diseases (NCDs), also known as chronic diseases, has been increasing worldwide. Changes in dietary and physical activity patterns, along with genetic conditions, are the main factors that modulate the metabolism of individuals, leading to the development of NCDs. Obesity, diabetes, metabolic associated fatty liver disease (MAFLD), and cardiovascular diseases (CVDs) are classified in this group of chronic diseases. Therefore, understanding the underlying molecular mechanisms of these diseases leads us to develop more accurate and effective treatments to reduce or mitigate their prevalence in the population. Given the global relevance of NCDs and ongoing research progress, this article reviews the current understanding about NCDs and their related risk factors, with a focus on obesity, diabetes, MAFLD, and CVDs, summarizing the knowledge about their pathophysiology and highlighting the currently available and emerging therapeutic strategies, especially pharmacological interventions. All of these diseases play an important role in the contamination by the SARS-CoV-2 virus, as well as in the progression and severity of the symptoms of the coronavirus disease 2019 (COVID-19). Therefore, we briefly explore the relationship between NCDs and COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as Coronavirus Disease 2019 (COVID-19). SARS-CoV-2 infects mainly lungs and may cause several immune-related complications, such as lymphocytopenia and cytokine storm, which are associated with the severity of the disease and predict mortality. The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is still not fully understood. Here, we show that SARS-CoV-2 infects human CD4⁺ T helper cells, but not CD8⁺ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells. This leads to impaired CD4 T cell function and may cause cell death. SARS-CoV-2-infected T helper cells express higher levels of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may contribute to a poor immune response in COVID-19 patients.

The nuclear receptor PPARγ is a promising target for treating type 2 diabetes mellitus. It regulates gene expression related to insulin and lipid metabolism. The obesity-linked phosphorylation of PPARγ S273 disrupts the expression of a specific subset of PPARγ-controlled genes linked to insulin metabolism, such as adiponectin. Previous research has demonstrated that this post-translational modification alters interactions with several coregulators, thereby influencing the expression of upstream genes. However, the effects of phosphorylation on the structural dynamics of PPARγ have not yet been fully understood. In this study, we applied atomistic and coarse-grained molecular dynamics simulations to examine the structural and dynamic changes induced by S273 phosphorylation. We observed that the phosphorylation impacts the dynamics of adjacent residues and influences more distantly located structural regions. Furthermore, S273 phosphorylation alters the flexibility of H12, the region responsible for canonical interaction with coregulators, potentially accounting for the previously observed differential interactions. These findings provide new insights into the mechanisms of gene expression regulation and may expand the avenues into diabetes therapy studies through PPARγ modulation. Moreover, they highlight the potential of combined atomistic and coarse-grained simulations to elucidate modifications of structural dynamics in proteins upon post-translational modification.

The intricate involvement of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in glucose homeostasis and adipogenesis is well-established. However, its role in cancer, particularly luminal bladder cancer, remains debated. The overexpression and activation of PPARγ are implicated in tumorigenesis. Specific gain-of-function mutations (M280I, I290M, and T475M) within the ligand-binding domain of PPARγ are associated with bladder cancer and receptor activation. The underlying molecular pathways prompted by these mutations remain unclear. We employed a dual-basin structure-based model (db-SBM) to explore the conformational dynamics between the inactive and active states of PPARγ and examined the effects of the M280I, I290M, and T475M mutations. Our findings, consistent with the existing literature, reveal heightened ligand-independent transcriptional activity in the I290M and T475M mutants. Both mutants showed enhanced stabilization of the active state compared to the wild-type receptor, with the I290M mutation promoting a specific transition route, making it a prime candidate for further study. Electrostatic analysis identified residues K303 and E488 as pivotal in the I290M activation cascade. Biophysical assays confirmed that disrupting the K303–E488 interaction reduced the thermal stabilization characteristic of the I290M mutation. Our study demonstrates the predictive capabilities of combining simulation and cheminformatics methods, validated by biochemical experiments, to gain insights into molecular activation mechanisms and identify target residues for protein modulation.

Growth differentiation factor 15 (GDF15) has emerged as a stress-responsive cytokine with systemic metabolic effects, yet its role in skeletal muscle remains poorly defined. Here, we show that GDF15 modulates mitochondrial phenotype and transcriptional programs in myotubes, linking stress signaling to muscle energy regulation. These findings identify skeletal muscle both as a source and a target of GDF15, revealing a novel mechanism by which muscle stress pathways influence whole body metabolic homeostasis.