Background: ANGPTL3 stimulates lipolysis in adipocytes, but the underlying molecular mechanism is yet unknown. The C-terminal fibrinogen-like domain of ANGPTL3 (ANGPTL3-Fld) activates the AKT pathway in endothelial cells. Hence, we evaluated whether ANGPTL3-Fld stimulates lipolysis in adipocytes through the MAPK kinase pathway. Materials and Methods: 3T3-L1 adipocytes were treated with isoproterenol (ISO), ANGPTL3-Fld, or both. Lipolysis was evaluated through the release of free fatty acids (FFAs) in the culture medium. The activation status of intracellular kinases was evaluated with and without the inhibition of the BRAF–ERK arm of the MAPK pathway. Results: ANGPTL3-Fld alone was not able to activate lipolysis, while the combination of ANGPTL3-Fld and ISO determined a 10-fold enrichment of the FFA concentration in the culture medium with an incremental effect (twofold) when compared with ISO alone. ANGPTL3-Fld alone inhibited hormone-sensitive lipase (HSL), whereas the treatment with ISO induced the activation of HSL. The net balance of ANGPTL3-Fld and ISO cotreatment resulted in HSL activation. The results indicate that ANGPTL3-Fld generated an intracellular activation signal involving the MAPK–ERK pathway, possibly through the PDGFRβ—PLCγ-AMPK axis. Conclusion: ANGPTL3-Fld appears to act as a facilitator of lipolysis in adipocytes, and this effect was driven by a signal mediated by a pathway that is different from the canonical β-adrenergic stimulus.

Cancer cachexia displays a complex nature in which systemic inflammation, impaired energy metabolism, loss of muscle and adipose tissues result in unintentional body weight loss. Cachectic patients have a poor prognosis and the presence of cachexia reduces the tolerability of chemo/radio-therapy treatments and it is frequently the primary cause of death in advanced cancer patients. Early detection of this condition could make treatments more effective. However, early diagnostic biomarkers of cachexia are currently lacking. In recent years, although solid biopsy still remains the “gold standard” for diagnosis of cancer, liquid biopsy is gaining increasing interest as a source of easily accessible potential biomarkers. Moreover, the growing interest in circulating microRNAs (miRNAs), has made these molecules attractive for the diagnosis of several diseases, including cancer. Some muscle-derived circulating miRNA might play a pivotal role in the onset/progression of cancer cachexia. This topic is of great interest since circulating miRNAs might be easily detectable by means of liquid biopsies and might allow an early diagnosis of this syndrome. We here summarize the current knowledge on circulating muscular miRNAs involved in muscle atrophy, since they might represent easily accessible and promising biomarkers of cachexia.

We assessed the molecular phenotype of the browning of white adipose tissue in newly diagnosed cancer patients and controls undergoing surgery for gastrointestinal tumors and for non-malignant diseases, respectively. We collected subcutaneous adipose tissue (SAT) samples and using RT-PCR, we analyzed the expression of markers of browning and using Western blot the protein levels of UCP1 and PGC1α. The Ucp1 mRNA levels were lower in cancer patients vs. controls (p = 0.01), whereas Cidea and Tmem26 mRNA levels were higher in cancer patients. We found higher PGC1α protein levels in patients vs. controls, while no differences were seen for UCP1. The Ucp1 expression was lower in cachectic and non-cachectic patients vs. controls, whereas Cidea expression was higher in cachectic and non-cachectic patients vs. controls. Pgc1α mRNA levels were higher in cachectic vs. non-cachectic patients (p = 0.03) vs. controls (p = 0.016). According to type of tumors, we did not observe differences in Cidea expression, whereas Pgc1α was higher in pancreatic cancer vs. colorectal and vs. controls. We observed the lower expression of Ucp1 in pancreatic and colorectal cancer vs. controls. We documented higher UCP1 protein levels in pancreatic cancer patients vs. colorectal (p = 0.002) and vs. controls (p = 0.031). PGC1α protein levels were higher in pancreatic cancer patients vs. controls. Different markers of the browning of SAT are modulated, and pancreatic cancer showed changes in UCP1 and PGC1α; PGC1α was highly expressed in cachectic patients, with clinical implications that should be further clarified.

MicroRNAs (miRNAs) are small, non-coding RNAs involved in post-transcriptional gene regulation in both animal and plant. miRNAs derived from edible plants, referred to as xenomiRs, are proposed to cross kingdom barriers and to modulate mammalian gene expression. However, this dietary xenomiR hypothesis remains controversial, given numerous inconsistencies and conflicting evidence regarding stability, bioavailability, and functionality of xenomiRs in mammals. Despite promising findings, including reports of plant-derived miRNAs influencing mammalian gene expression in vitro and in animal models, evidence remains inconclusive in humans. Several independent investigations have reported contradictory findings, emphasizing reproducibility lack in identifying and validating the transfer of xenomiRs from plants to mammals, which has raised concerns about the robustness, reliability, and biological significance of some results. Additionally, no direct molecular evidence currently demonstrates that plant xenomiRs bind to mammalian silencing machinery. While the concept of plant-derived xenomiRs holds significant potential, future research must address unresolved technical and biological limitations. If validated, this hypothesis may represent a novel avenue for epigenetic modulation through dietary intervention in precision medicine and personalized nutrition. This comprehensive narrative review critically provides an overview of the dietary xenomiR hypothesis, specifically focusing on those derived from edible plants. We summarize the current evidence regarding xenomiR cross-kingdom communication potential, and we discuss technical and biological challenges that impede their validation. We also explore the speculative yet plausible scenario that dietary miRNAs may act locally on the microbiota rather than systemically. STATEMENT OF SIGNIFICANCE: This review provides a timely and critical synthesis of the dietary xenomiR hypothesis, addressing supporting data and interpretations related to cross-kingdom communication, the ongoing controversy surrounding the phenomenon, and the lack of mechanistic insight into how these exogenous miRNAs might influence human health and disease. It highlights unresolved methodological challenges and offers clear directions for future mechanistic research to advance this controversial field.

Purpose of review: Systemic inflammation represents a complex, widespread physiological response initiated by the body in response to various noxious stressors, including infections, trauma, surgery, and chronic diseases. The assessment of systemic inflammation relies on a spectrum of measurable biological indicators. This review evaluates the current evidence on several systemic inflammation biomarkers, including the traditional Glasgow Prognostic Score (GPS) and other emerging indices such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI). Recent findings: Several simple biomarkers can assess systemic inflammation, each with specific strengths and limitations. The GPS is a well validated index in oncology and is increasingly being used in cardiovascular disease, integrating inflammatory and nutritional status. Blood count-derived ratios such as NLR, PLR, LMR, SII, and SIRI are widely available and have shown prognostic value across different clinical conditions. Current evidence supports their use in risk stratification and clinical decision-making, though interpretation should always consider the overall clinical picture. Summary: Inflammation biomarkers like GPS, NLR, PLR, LMR, SII, and SIRI offer accessible tools for risk stratification, with clinical utility varying by context and requiring further standardization.