Branka Djordjevic

Background/Objectives: Quiescent leukemia stem cells (LSCs) are self-renewing, pluripotent cells that present a major obstacle to the successful curative treatment of chronic myeloid leukemia (CML). LSCs function independently of BCR::ABL1 signaling and persist following tyrosine kinase inhibitor treatment. The mechanisms enabling LSC survival are a central focus of current CML research. This review details the complex relationship between signaling pathways and discusses recent advancements in energy metabolism research within the pathogenesis of CML. Discussion: Energy metabolism is critical to the biology of CML LSCs. These cells depend on oxidative phosphorylation (OXPHOS) and mitochondrial homeostasis, utilizing fatty acid oxidation as their primary ATP source. Research highlights significant alterations in signaling networks, marked by a dynamic interplay among dominant pathways within the CML clone. While TGF-β-FOXO signaling maintains the self-renewal capacity of quiescent LSCs, proliferating mature CML cells rely heavily on glycolysis and the PI3K/Akt pathway. Furthermore, unique metabolic traits of LSCs underscore the impact of leukemic cell–microenvironment interactions in fostering a permissive niche. Conclusions: Fatty acid oxidation is critical to the survival and self-renewal of CML LSCs. This adaptation of mitochondrial function is closely linked to signaling alterations and entails an adjustment of mitochondrial respiration alongside stimulated OXPHOS. Emerging research unveils many potential targets within metabolic signaling that can be exploited to overcome these survival mechanisms, highlighting the disruption of mitochondrial energy support as a promising strategy to selectively eradicate CML LSCs.

Dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) is considered a marker of vitamin K status and vascular calcification risk in chronic kidney disease. This study assessed the association of serum dp-ucMGP, alone and combined with albumin, with all-cause and cardiovascular mortality in maintenance hemodialysis patients. This single-center observational cohort study included 133 maintenance hemodialysis patients with a two-year survival follow-up. Analyses involving dp-ucMGP and albumin were performed in 113 patients with complete biomarker data. Baseline serum dp-ucMGP, albumin, inflammatory markers, and routine laboratory parameters were measured. Associations with all-cause and cardiovascular mortality were evaluated using group comparisons, ROC curve analysis, Kaplan–Meier analysis, and Cox regression. Patients who died had significantly lower dp-ucMGP and albumin levels and higher inflammatory and hematological indices than survivors, with similar findings for cardiovascular mortality. The combined dp-ucMGP–albumin model showed higher apparent discriminatory performance than either marker alone for all-cause mortality (AUC 0.793, 95% CI 0.708–0.878, p < 0.001) and cardiovascular mortality (AUC 0.778, 95% CI 0.687–0.868, p < 0.001). Lower dp-ucMGP levels were associated with worse survival. In multivariable Cox regression, higher dp-ucMGP and albumin were independently associated with lower mortality. Combined dp-ucMGP and albumin assessment may provide complementary prognostic information in hemodialysis patients but requires validation in larger cohorts.

Background/Objectives: Quiescent leukemia stem cells (LSCs) are self-renewing, pluripotent cells that represent a major obstacle to successful curative treatment of chronic myeloid leukemia (CML). LSCs are independent of BCR-ABL1 signaling and persist following tyrosine-kinase inhibitor treatment. The mechanisms that enable LSCs' survival are currently the focus of CML research. The review examines the complex relationship between signaling pathways and discusses recent advancements in research on energy metabolism in the pathogenesis of CML. Methods: This comprehensive narrative review used a systematic approach to selecting studies published in peer-reviewed journals, without year or publication-type limits. Results: Energy metabolism assumes a critical role in the biology of CML LSCs. These cells show dependency on oxidative phosphorylation (OXPHOS) and mitochondrial homeostasis, with fatty acid oxidation as the primary source of ATP. Studies highlight significant alterations in signaling networks with a dynamic interplay among dominant pathways in the CML clone. TGF-β-FOXO signaling is proposed to be crucial for maintaining the self-renewal capacity of quiescent LSCs, unlike the majority of proliferating mature CML cells that exhibit strong activation of the PI3K/AKT pathway and glycolysis. Additionally, unique aspects of LSCs' metabolism underline the contribution of leukemic cell interactions, including the induction of a more permissive microenvironment. Conclusion: Fatty acid oxidation appears critical to the survival and self-renewal of CML LSCs. Adaptation of mitochondrial function is concordant with signaling changes and presumes adjustment of mitochondrial respiration with stimulated OXPHOS. Research findings unveil many potential targets to consider to overcoming survival mechanisms, with disrupting the mitochondrial support as a promising strategy to selectively eradicate CML LSCs.

Intense physical activity imposes substantial oxidative, metabolic, and immunological stress on the human body. It is often accompanied by reductions in plasma glutamine levels, making this amino acid conditionally essential. Glutamine plays a vital role in energy production, nitrogen transport, acid–base balance, antioxidant defense, and immune function. It is required in the biosynthesis of neurotransmitters, nucleotides, nicotinamide-derived coenzymes, glutathione, and hexosamines, making it a candidate for supporting exercise recovery. In addition, glutamine may support key mechanisms involved in muscle adaptation and recovery during exercise-induced stress by contributing to redox balance, energy sensing, anabolic signaling, intestinal barrier integrity, and immune function. This narrative review aims to synthesize biochemical mechanisms underlying glutamine effects relevant to exercise and evaluate preclinical and clinical findings on supplementation outcomes, with emphasis on timing strategies. Preclinical findings demonstrate that glutamine can modulate protein synthesis, reduce oxidative stress, improve intestinal integrity, and attenuate immune and inflammatory disturbances. Limited preclinical data suggest that post-exercise supplementation may better resolve muscle and organ damage. Clinical trials, however, report heterogeneous outcomes: several studies show improvements in markers of intestinal permeability and intestinal epithelial damage, oxidative stress, muscle damage, and inflammation, whereas others report minimal or no effect, including limited influence on performance outcomes. Variability in timing protocols, participant characteristics, and measured endpoints contributes to inconsistent findings. Overall, glutamine demonstrates several biologically plausible mechanisms that could support recovery and overall health in active individuals, athletes, and specific clinical populations. However, current evidence remains insufficient to determine clear supplementation benefits or define an optimal timing strategy. Future research using standardized protocols and integrated biochemical and functional endpoints is needed to clarify timing effects. Until such evidence emerges, recommendations should remain individualized, considering athlete-specific needs.

Colorectal cancer (CRC) is characterized by complex interactions between inflammation, oxidative stress, and extracellular matrix remodeling. Recent studies have highlighted the significance of the reactive oxygen species (ROS)–nuclear factor kappa B (NF-κB)–matrix metalloproteinase-9 (MMP-9) axis in promoting tumor invasion and metastasis in CRC, linking oxidative stress with inflammatory signaling and extracellular matrix degradation. In this study, we analyzed the concentration of advanced oxidation protein products (AOPPs), expression of NF-κB, and the activity of MMP-9 in tumor tissue, adjacent tissue, and healthy control colon tissue. Tissue specimens were collected from 50 patients with primary CRC following surgical resection. The analyses were performed using appropriate and validated biochemical methods, including ELISA, spectrophotometry, and indirect immunofluorescence. Significantly higher levels of all three markers were observed in tumor tissue compared to controls. Additionally, adjacent tissue exhibited elevated NF-κB expression and MMP-9 activity when compared to healthy colon tissue. AOPP levels correlated strongly with MMP-9 activity, highlighting the role of oxidative stress in the activation of MMP-9. MMP-9 demonstrated the highest predictive value for CRC, emphasizing its potential as a diagnostic and theranostic marker. Our findings support the hypothesis that the ROS–NF-κB–MMP-9 axis plays an important role in CRC progression, particularly during stages T2 and T3. Targeting this pathway may offer new therapeutic strategies for limiting tumor invasion and recurrence. Moreover, ensuring adequate surgical resection margins is crucial to optimizing treatment outcomes.

The treatment approach to RA has changed over time, but the main goal of treatment has remained the same, that is, achieving disease remission. Given the lack of RA disease activity tools and biomarkers that can reliably predict RA drug effectiveness not just on joints but also on extra-articular manifestations. The involvement of galectins, especially Galectin-1 (Gal1) in the regulation of immune regulation makes them potential good candidate non-specific biomarkers of autoimmune diseases like RA. Examining the possibility of applying Gal1 as a potential biomarker for evaluating the effectiveness of therapy. A quasi-experimental study was conducted to assess changes in serum Gal1 concentrations in patients with RA, compared with a healthy control group. The study included a total of 88 participants, consisting of 48 patients diagnosed with RA and 40 healthy voluntary blood donors. Patients were enrolled in the study based on a selective recruitment process, provided they met the criteria outlined in the Inclusion Criteria section. The diagnosis of RA was established by physicians in accordance with the ACR/EULAR2010 classification criteria. The collected samples were subjected to concentration determination using a commercial ELISA kit for human Gal1. The serum Gal1 concentration of the examined groups differed significantly ( P < 0.0001). There was a significant difference in serum concentration of Gal1 between first and second measurement (pre- and post-intervention) ( P = 0.015). The obtained values of post-intervention Gal1 did not show a positive correlation with the values of DAS28-ESR, HAQ-DI, and CDAI. The conducted study showed a pronounced statistical significance in the values of Gal1 concentrations in RA patients (in both time points) compared to the group of healthy subjects, suggesting that lower levels of this marker may be associated with the degree of inflammation characteristic of RA. No significant correlation was observed between Gal1 levels and clinical disease activity indices, limiting conclusions.

Background: A dysregulated proinflammatory microenvironment is considered one of the reasons why current therapies of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKI) do not secure disease control. Therefore, the development of BCR-ABL1-independent therapies is encouraged. Renalase (RNLS) is a multifunctional protein that exhibits both enzymatic and non-enzymatic cytokine-like properties, along with potent anti-inflammatory and anti-apoptotic effects. It is expressed in various tissues, including tumors. Methods: We investigated the levels of RNLS in the blood of CML patients in the chronic phase, treatment naïve patients, and those in remission under TKI treatment (either imatinib or nilotinib) and compared them to healthy individuals. Results: Renalase concentration was markedly decreased in treatment-naive CML patients compared to other groups (p = 0.000), while lower levels in the TKI group were not statistically significant compared to controls. The levels correlated negatively with the total leukocyte and neutrophil count (p < 0.05), while a positive correlation was present with CRP levels in treatment naïve patients. Conclusions: Dynamic regulation of RNLS expression and activity is coupled with transcription factors NF-κB and STAT3. Interpretation of our results might rely on differential requirements of activated STATs (STAT3/5) during CML clone development and maintenance, including the observation of RNLS rise upon TKI introduction. Overall, our research provides new insights into the field of hematological malignancies. Unlike other malignancies studied, RNLS plasma levels are significantly decreased in CML. In future perspectives, RNLS could potentially serve as a diagnostic, prognostic, or therapeutic option for these patients.

This study investigated the diagnostic accuracy of plasma biomarkers—specifically, matrix metalloproteinase (MMP-9), tissue inhibitor of metalloproteinase (TIMP-1), CD147, and the MMP-/TIMP-1 ratio in patients with Alzheimer’s disease (AD) dementia. The research cohort comprised patients diagnosed with probable AD dementia and a control group of cognitively unimpaired (CU) individuals. Neuroradiological assessments included brain magnetic resonance imaging (MRI) following dementia protocols, with subsequent volumetric analysis. Additionally, cerebrospinal fluid (CSF) AD biomarkers were classified using the A/T/N system, and apolipoprotein E (APOE) ε4 carrier status was determined. Findings revealed elevated plasma levels of MMP-9 and TIMP-1 in AD dementia patients compared to CU individuals. Receiver operating characteristic (ROC) curve analysis demonstrated significant differences in the areas under the curve (AUC) for MMP-9 (p < 0.001) and TIMP-1 (p < 0.001). Notably, plasma TIMP-1 levels were significantly lower in APOE ε4+ patients than in APOE ε4− patients (p = 0.041). Furthermore, APOE ε4+ patients exhibited reduced hippocampal volume, particularly in total, right, and left hippocampal measurements. TIMP-1 levels exhibited a positive correlation, while the MMP-9/TIMP-1 ratio showed a negative correlation with hippocampal volume parameters. This study sheds light on the potential use of TIMP-1 as a diagnostic marker and its association with hippocampal changes in AD.

Advanced age is a well-established risk factor for severe coronavirus disease 2019 (COVID-19). Exacerbated inflammation affects multiple organs, among which hematopoiesis responds by increased output of various cells. We aimed to determine the association between COVID-19 progression and large immature cell (LIC) counts, changes in erythrocyte and platelet distribution widths (RDW, PDW) with reference to patients' age. A total of 755 patients with complete blood cell (CBC) analysis in the first 24 h of hospitalization were enrolled. Patients were divided into two groups: under and above 65 years of age. The LIC counts were different in both groups (p < 0.003). However, only the senior patients had markedly different values of RDW and PDW (p < 0.001). The receiver operating characteristic (ROC) curve analysis provided increased LIC (AUC = 0.600), RDW (AUC = 0.609), PDW (AUC = 0.556), and platelet to LIC ratio (AUC = 0.634) as significant in discriminating outcome in the older group. Importantly, these results were not repeated in the younger patients. In the elderly, the progression was predicted with LIC cut-off at ≥ 0.305 × 109/L (OR = 3.166) and RDW over 12.15% (OR = 2.081). Aging is characterized by a decline in immunological competence with a compromised control of inflammation leading to a proinflammatory state. This background together with the actions of pathogens may lead to emergency myelopoiesis. Our results point to the important differences between age groups regarding CBC-related parameters of stress hematopoiesis during severe infection. Higher LIC, RDW and PDW levels were reliable in the early identification of COVID-19 progression only in the elderly.