Apolipoprotein A-II (apoA-II) is the second most abundant apolipoprotein in high-density lipoprotein (HDL) particles, playing an important role in lipid metabolism. Human and murine apoA-II proteins have dissimilar properties, partially because human apoA-II is dimeric whereas the murine homolog is a monomer, suggesting that the role of apoA-II may be quite different in humans and mice. As a component of HDL, apoA-II influences lipid metabolism, being directly or indirectly involved in vascular diseases. Clinical and epidemiological studies resulted in conflicting findings regarding the proatherogenic or atheroprotective role of apoA-II. Human apoA-II deficiency has little influence on lipoprotein levels with no obvious clinical consequences, while murine apoA-II deficiency causes HDL deficit in mice. In humans, an increased plasma apoA-II concentration causes hypertriglyceridemia and lowers HDL levels. This dyslipidemia leads to glucose intolerance, and the ensuing high blood glucose enhances apoA-II transcription, generating a vicious circle that may cause type 2 diabetes (T2D). ApoA-II is also used as a biomarker in various diseases, such as pancreatic cancer. Herein, we provide a review of the most recent findings regarding the roles of apoA-II and its functions in various physiological processes and disease states, such as cardiovascular disease, cancer, amyloidosis, hepatitis, insulin resistance, obesity, and T2D.

Mesenchymal stromal cells (MSC) display several mechanisms of action that may be harnessed for therapeutic purposes. One of their most attractive features is their immunomodulatory activity that has been extensively characterized both in vitro and in vivo. While this activity has proven to be very efficient, it is transient. We aimed to enhance it by transforming MSC to overexpress a first apoptosis signal (Fas) ligand (FasL). In this study, our goal was to induce FasL overexpression through adenoviral transduction in MSC to improve their immunomodulatory activity. We characterized the impact of FasL overexpression on the morphology, proliferation, viability, phenotype, multilineage differentiation potential and immunomodulation of MSC. Moreover, we determined their suppressive properties in mixed reactions with A20 cells, as well as with stimulated splenocytes. Our findings demonstrate that FasL-overexpressing MSC exhibit improved immunosuppressive properties, while maintaining their MSC-characteristic features. In conclusion, we establish, in a proof-of-concept set-up, that FasL-overexpressing MSC represent good candidates for therapeutic intervention targeted at autoimmune disorders.

Adenoviral vectors are important vehicles for delivering therapeutic genes into mammalian cells. However, the yield of the adenoviral transduction of murine mesenchymal stromal cells (MSC) is low. Here, we aimed to improve the adenoviral transduction efficiency of bone marrow-derived MSC. Our data showed that among all the potential transduction boosters that we tested, the K2 Transfection System (K2TS) greatly increased the transduction efficiency. After optimization of both K2TS components, the yield of the adenoviral transduction increased from 18% to 96% for non-obese diabetic (NOD)-derived MSC, from 30% to 86% for C57BL/6-derived MSC, and from 0.6% to 63% for BALB/c-derived MSC, when 250 transduction units/cell were used. We found that MSC derived from these mouse strains expressed different levels of the coxsackievirus and adenovirus receptors (MSC from C57BL/6≥NOD>>>BALB/c). K2TS did not increase the level of the receptor expression, but desensitized the cells to foreign DNA and facilitated the virus entry into the cell. The expression of Stem cells antigen-1 (Sca-1) and 5′-nucleotidase (CD73) MSC markers, the adipogenic and osteogenic differentiation potential, and the immunosuppressive capacity were preserved after the adenoviral transduction of MSC in the presence of the K2TS. In conclusion, K2TS significantly enhanced the adenoviral transduction of MSC, without interfering with their main characteristics and properties.

Apolipoprotein E (APOE) plays a tissue-specific role in diet-induced obesity: brain-expressed APOE promotes obesity, while hepatic APOE appears protective. Physiological plasma APOE levels facilitate clearance of atherogenic lipoproteins; however, supraphysiological levels induce hypertriglyceridemia and impair cholesterol clearance. APOE-induced hypertriglyceridemia has been linked to its carboxyl-terminal region (amino acids 260-270), particularly residues L261, W264, F265, L268, and V269. A bioengineered APOE4 variant, APOE4mut1, where these residues are substituted with alanine, promotes cholesterol clearance without inducing hypertriglyceridemia at any level of expression. This study examined APOE4mut1 effects on adipose tissue metabolism in vivo. Wild-type (C57BL/6) and APOE4_knock-in mice were fed a western-type diet for varying periods and infected with adenoviruses expressing APOE4 (AdAPOE4), APOE4mut1 (AdAPOE4mut1), or only the green fluorescent protein (GFP) (AdGFP). AdAPOE4mut1 infection of C57BL/6 mice fed western-type diet for 8 or 24 weeks stimulated brown adipose tissue (BAT) metabolism by inducing non-shivering thermogenesis and oxidative phosphorylation. In contrast, AdAPOE4 suppressed thermogenesis in this tissue. In white adipose tissue (WAT) AdAPOE4mut1 was able to stimulate thermogenesis after 24 weeks of feeding. This stimulatory effect in WAT was dominant over wild type APOE4, since APOE4mut1 similarly enhanced mitochondrial activity in WAT of APOE4_knock-in mice. These findings suggest that amino acid residues 260-270 of APOE4 critically regulate adipose tissue metabolism, in addition to their previously reported role in APOE-induced hypertriglyceridemia. Targeted mutagenesis within this region offers a potential therapeutic strategy for addressing hypertriglyceridemia and obesity in metabolic syndrome.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively triggers apoptosis in malignant, infected, or stressed cells while sparing normal tissues, making it an attractive therapeutic candidate. However, many tumors exhibit intrinsic or acquired resistance to TRAIL, driven by reduced DR4/DR5 surface expression, elevated decoy receptor levels, dysregulated DISC assembly, overexpression of c-FLIP and anti-apoptotic Bcl-2 family proteins, or activation of survival pathways such as NF-κB, PI3K/Akt, and MAPK. Moreover, TRAIL receptors can initiate non-canonical signaling pathways that promote migration, invasion, and metastasis in specific oncogenic contexts, thereby further limiting therapeutic efficacy. We aimed to integrate mechanistic insights into TRAIL biology with current therapeutic advances, providing a comprehensive framework for understanding resistance and for designing rational TRAIL-based combination strategies. We summarized the structural and signaling features of TRAIL receptors, outlined the major determinants of TRAIL sensitivity, and evaluated predictive biomarkers that may guide patient selection. In addition, we examined next-generation TRAIL agonists and targeted delivery systems developed to enhance receptor clustering, pharmacokinetics, and tumor specificity. Together, these insights highlight the therapeutic promise of mechanistically informed TRAIL combinations. A deeper understanding of resistance pathways and biomarker-guided stratification will be essential for restoring apoptotic competence and improving clinical outcomes.