Despite the multiple identified common genetic, molecular, and cellular processes connecting pulmonary fibrosis (PF) and lung cancer (LC), there is still no clear answer about the contribution of each of them to the development of pathology. It is known that most cell populations involved in the development of PF are involved in LC. At the same time, there are differences that can be explained by the specificity of PF development or changes specific to LC. We evaluated the changes in the lung and blood at the modeling of PF, LC, PF+LC. To induce PF in male C57BL6 mice, we used bleomycin; on the 15th day after bleomycin administration, we modeled non-small cell LC by introducing Lewis lung carcinoma (LLC) cells. The material for this study was collected on the 28th day of the experiment and was analyzed by histology and cytometry. In the lung tissue of mice, against the background of PF and LC modeling, an increase in pathological changes in the lungs was observed compared to each pathological situation separately. Disorders of the lungs in the group of animals with PF and LC were based on increased migration from the blood to the lungs of populations of CD309+ endothelial cells, an increase in atypical/hybrid cells (CD45+CD326+), and cancer stem cell markers CD90, CD117, CD274, CD276, and EGFR in various combinations in the lung tissue. Biomarkers confirming tumor development against the background of pulmonary fibrosis are populations of cancer stem cells, atypical/hybrid cells, endothelial cells, hematopoietic stem cells, myeloid fibrocytes, and changes in the composition of CD4+ T-cells. Further clinical and experimental studies are needed to determine the role of these changes and to find biomarkers that predict the progression of pulmonary fibrosis and the risk of developing lung cancer.

Over the past decade, it has been shown that transcutaneous vagus nerve stimulation (tVNS) has a cardioprotective effect both in chronic heart failure and in coronary heart disease, preventing reperfusion injury and weakening myocardial remodeling.

The purpose of this study was to evaluate the prognostic effect of tVNS on hospital and long-term clinical outcomes in patients with STEMI.

Methods. A randomized, placebo-controlled trial. tVNS was performed on a group of patients who were eligible for the study according to the inclusion/exclusion criteria. tVNS was performed from the moment of admission to the PCI, during the PCI, and for the next 30 minutes after it. This clinical trial is registered with ClinicalTrials database under a unique identifier: NCT05992259.

Results. A total of 109 patients were included: 54 - Active tVNS, 55 - Sham tVNS. At the hospital stage, the levels of myocardial damage markers (troponin, CPKMB, NTproBNP) in dynamics (after 6, 72, and 96 hours) were significantly lower (p < 0.001) in the Active tVNS group. In this group, there was a lower incidence of cardiac arrhythmias (p < 0.001), cardiogenic shock (p = 0.044), and a better survival rate in the Active tVNS compared to the Sham tVNS (p=0.024). After 12 months, in the long term, trends towards differences in groups were found, without statistical significance. When comparing patient groups for survival by Kaplan–Meier, we obtained statistically insignificant log-rank tests in terms of total mortality (p = 0.618), in terms of the frequency of recurrent MI (p = 0.161), in terms of the frequency of hospitalization (p = 0.391), and in terms of the frequency of stroke (p = 0.490).

Conclusion. The use of tVNS in STEMI patients reduces myocardial damage, thereby reducing the incidence of hospital complications and hospital mortality. In the long term, there were trends towards differences in the groups in the frequency of MACE.

Introduction: Immunotherapy improves cancer outcomes but can cause myocarditis, with high mortality risk. Immune checkpoint inhibitor-induced myocarditis (ICI-M) involves T cell and macrophage infiltration in the myocardium, leading to tissue necrosis. The NLRP3 inflammasome pathway, triggered by IFN-γ, is overexpressed in ICI-M patients.

Objective: To study ICI-M pathophysiology using a preclinical model to investigate electrophysiological disorders linked to myocardial immune infiltration, and to explore molecular mechanisms in an IPSC cellular model from ICI-M patients.

Method: The preclinical ICI-M model was performed by injecting murine melanocytic cells into BALB/c mice, treated with anti-PD1/anti-CTLA-4 therapy. IPSC-derived cardiomyocytes (CM) and endothelial cells (EC) from ICI-M patients and healthy donors were exposed to IFN-γ.

Results: A decrease in tumour volume (p<0.01) was observed in mice with ECG disturbances, showing reduced QRS (p<0.01) and T wave (p<0.01) amplitude, as well as shorter repolarisation time (p<0.05). Impaired cardiac function correlated with increased CD3 transcript (p<0.01) and PD-L1 overexpression in the myocardium. In hiPSC-derived CM and EC, IFN-γ (10 ng/ml, 72 h) upregulated immune-response genes (PD-L1, MHC-II, p<0.001) and NLRP3 inflammasome genes (GBP5, GBP6, NLRC5, p<0.0001). More dysregulated genes were found in EC (FDR 0%, 2,210 vs. 789 in CM) after treatment. These genes are linked to immune response, apoptosis, and inflammasome activation. HiPSC-ECs showed a decreased expression of cell communication genes and an increased expression of JAK-STAT/MAP Kinases, NF-κB, and cytokine production genes. The inflammasome activated by IFN-γ differed between cell types, with NLRP3 in CM and AIM2 in EC. HiPSC-ECs from ICI-M patients showed specific immune-response regulations, including PD-L2, TLR2 overexpression, and pro-inflammatory cytokines (CCL2, CCL5, IL-1β), linked to NLRP3 inflammasome activation.

Conclusion: Mice treated with ICI show ECG disturbances linked to myocardial inflammation. Our model highlights the key role of endothelial cells in the IFN-γ response and NLRP3 inflammasome regulation in ICI-M patient cells.

Neurodegenerative diseases such as Alzheimer's and Parkinson's are characterized by cholinergic dysfunction and oxidative stress, leading to progressive cognitive decline. The lack of effective treatments for these disorders makes the search for naturally derived neuroprotective agents increasingly important. Various Camellia species have demonstrated neuroprotective effects, primarily attributed to their rich phytochemical composition. However, no previous study has investigated the neuroprotective properties of Camellia japonica, particularly the Hagoromo cultivar. This study evaluates the neuroprotective potential of C. japonica var. Hagoromo flower extract by evaluating its inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes using previously established methods. The extract showed a dose-dependent increase in AChE inhibition, with 1 mg/mL achieving 7% inhibition and 2 mg/mL reaching 22%. For BuChE inhibition, the extract showed its highest activity at 1 mg/mL, reaching 37% inhibition. These findings indicate potential neuroprotective properties, although the observed inhibition levels were lower than the levels of well-known neuroprotective compounds such as fucoxanthin and polyphenols found in seaweeds (Pruccoli et al., 2024; Dhami et al., 2021). However, this study was conducted using unpurified extracts, which may limit the accuracy of the observed effects. Therefore, further studies should focus on purifying and isolating the bioactive compounds present in the sample to provide a more precise assessment of their neuroprotective potential. Previous studies suggest that catechins, quercetin, kaempferol, and their derivatives are the primary neuroprotective phytochemicals in Camellia. These compounds exert their effects by synergistically enhancing endogenous antioxidant defenses, regulating neurotrophic signaling pathways, and reducing neuroinflammation (An et al., 2020). Future research should optimize extraction parameters, identify key active compounds, and conduct in vivo evaluations to further validate the therapeutic potential of C. japonica in neurodegenerative disorders.

Introduction: Inflammatory cytokines, particularly IFN-γ, are highly elevated in biopsies and the peripheral blood of patients with ICI-induced myocarditis (ICI-M). While the NLRP3 inflammasome has been implicated in ICI-M pathophysiology, its underlying mechanisms remain poorly understood.

Objective: This study investigates the transcriptional effects of inflammatory cytokines associated with ICI-M on endothelial cells (hiPSC-EC) and cardiomyocytes (hiPSC-CM) derived from a healthy individual’s hiPSC clone.

Method: The transcriptional profiles of both the hiPSC-derived endothelial cells (hiPSC-EC) and cardiomyocytes (hiPSC-CM) were analyzed following the IFN-γ treatment. Inflammatory responses, cell mortality, and apoptosis were assessed after stimulation with pro-inflammatory molecules, either through individual IFN-γ exposure or a combined cytokine cocktail (CCL5, GZMB, IL-1β, IL-2, IL-6, IFN-γ, and TNF-α), to characterize their effects on cellular function and viability better.

Results: Our findings reveal that hiPSC-ECs are highly sensitive to cytokine treatment, exhibiting significant mortality and marked transcriptomic changes in immunity- and inflammation-related pathways. In contrast, hiPSC-CMs show lower transcriptomic alterations, reduced mortality, and less apoptosis. In both cell types, cytokine treatment upregulates key components of the NLRP3 inflammasome pathway, including regulators (GBP5, GBP6, P2X7, NLRC5), a core component (AIM2), and an effector (GSDMD). Notably, cytokine treatment increases the GBP5 protein expression and CASP-1 cleavage in hiPSC-CMs, mirroring observations in endomyocardial biopsies from ICI-M patients.

Conclusion: This cellular model provides valuable insights into endocardial and microvascular dysfunctions in inflammatory conditions and their impact on cardiomyocytes. These findings establish a robust experimental model for investigating the response of hiPSC-derived cardiac cells to inflammatory cytokines implicated in immuno-mediated myocarditis. Moreover, they provide essential reference values for comparative studies using hiPSC clones derived from affected patients, thereby facilitating a deeper understanding of the disease mechanisms.

Introduction: Antibiotic-resistant bacterial infections pose a growing global health threat and are projected to become the leading cause of mortality by 2050. Staphylococcus aureus (S. aureus), a common antibiotic-resistant pathogen, colonizes approximately two billion people, with 53 million carrying methicillin-resistant S. aureus (MRSA). The increasing prevalence of MRSA presents treatment challenges, particularly in resource-limited settings. In Mongolia, antibiotic consumption reached 40.48 defined daily doses (DDDs) per 1000 inhabitants per day in 2020, underscoring the need for alternative therapies. This study aimed to encapsulate doxycycline in liposomes and evaluate its antibacterial efficacy against S. aureus and MRSA.

Methods: Phospholipids were extracted from egg yolk and analyzed by thin-layer chromatography (TLC). Liposomes were prepared using the thin-film hydration technique with freeze–thaw cycles. Atomic force microscopy (AFM) characterized liposome morphology and size, while high-performance liquid chromatography (HPLC) quantified doxycycline content. The minimum inhibitory concentration (MIC) of liposome-encapsulated doxycycline was determined via broth microdilution assays against S. aureus and MRSA.

Results: Phospholipid extraction yielded 32%, with TLC confirming phosphatidylcholine presence. AFM revealed an average liposome height of 41.15 nm (±4.9 nm) and a diameter of 153.07 nm (±70.48 nm), with a polydispersity index of 0.212. HPLC showed a retention time of 5.843 minutes, confirming high doxycycline purity (981 ppm). MIC values for free doxycycline against S. aureus and MRSA were 8 μg/mL and 32 μg/mL, respectively, whereas liposome-encapsulated doxycycline reduced MIC to 4 μg/mL (S. aureus) and 16 μg/mL (MRSA).

Conclusion: Liposomes with an average diameter of 153 nm were successfully produced. Encapsulated doxycycline demonstrated enhanced antibacterial activity, reducing MIC values by 50% for both S. aureus and MRSA compared to free doxycycline. These findings highlight liposomal drug delivery as a promising approach for combating antibiotic-resistant infections.

Introduction: Maternal metabolic syndrome (MetS) can profoundly impact offspring development. This study aimed to evaluate the effects of maternal MetS on somatic growth, developmental milestones, neurochemical and metabolic alterations, and behavior using an animal model.

Methods: Female Wistar rats were given 20% fructose in drinking water before and during pregnancy to induce MetS, while the control group consumed only water. Offspring were assessed for biochemical markers in whole-brain tissue at postnatal day (PN) 1 and for somatic development and developmental milestones from birth to PN21. Behavioral tests evaluating anxiety-like behavior, cognition, nociception, and social interactions were conducted in adolescence and early adulthood. Metabolic status was assessed at PN100.

Results: At PN1, female MetS offspring exhibited increased lipid peroxidation (TBARS levels), heightened antioxidant enzyme activity (catalase) and expression (superoxide dismutase), and elevated pro-inflammatory COX-2 expression in whole-brain tissue. Neurodevelopmental delays were observed in females (delayed grasp reflexes, cliff aversion, plantar reflex, and righting reflex) and males (delayed forelimb grasp and plantar reflex). Behaviorally, female MetS offspring displayed increased anxiety-like behavior, impaired social interactions, heightened neophobia, and altered nociception, while males exhibited cognitive deficits and social interaction impairments. Additionally, female MetS offspring showed prolonged latency in the nocifensive tail flick response to thermal stimuli, indicating altered pain sensitivity. At PN100, female MetS offspring exhibited increased visceral fat accumulation and elevated triglyceride levels, suggesting long-term metabolic disturbances.

Conclusion: Maternal MetS disrupts offspring development, leading to early biochemical imbalances, neurodevelopmental delays, and long-term metabolic dysfunction. These effects were sex-dependent, with females showing greater oxidative stress, inflammation, anxiety, and metabolic alterations, while males exhibited milder but significant neurodevelopmental and cognitive impairments. These findings underscore the long-lasting impact of maternal MetS on offspring health and highlight the need for early interventions to mitigate neurodevelopmental and metabolic risks.

Introduction: Women are underrepresented in both clinical studies and drug development. However, significant sex differences exist in the occurrence and progression of diseases, which are predominantly attributed to hormonal influences. This also applies to cardiovascular diseases. Failure to consider the sex of cells in basic research can lead to erroneous results and false conclusions. Therefore, in this project, we aimed to investigate hormone-independent sex differences at the cellular level using a cell model of atherosclerosis.

Methods: Male and female human umbilical vein endothelial cells (HUVECs) from twin pairs were treated with either TNF-α (10 ng/ml) or with supernatants from pro-inflammatory stimulated male THP-1 and female HL-60 monocyte-like cells. The expression of the focal adhesion proteins paxillin, vinculin, talin, and tensin and the cell adhesion molecules VCAM1 and ICAM-1 was assessed using quantitative real-time PCR or Western blot analysis. In addition, the levels of secreted cytokines and chemokines were measured in the HUVEC cell culture supernatants via a Cytokine Multiplex Assay.

Results: Female HUVECs exhibited increased levels of the secreted proinflammatory cytokines IL-17a and IL-22, the anti-inflammatory cytokine IL13, the pro-angiogenic cytokine TGF-α, and the chemoattractant protein Eotaxin in the supernatant after treatment with TNF-α or with supernatants from pro-inflammatory stimulated monocyte-like cells compared to the controls (p<0,05). Conversely, male supernatants exhibited increased levels of IL17f and RANTES. Moreover, the cell adhesion proteins VCAM-1 and ICAM-1, the chemokine MDC, and the cytokine MIP-1α showed opposite directions of regulation between female and male cells after both stimulations. The gene and protein expressions of the focal adhesion proteins paxillin, vinculin, talin, and tensin showed no significant differences.

Conclusion: These results provide evidence for the differential regulation of adhesion proteins and cytokines in female and male cells. Hormone-independent sex differences in endothelial cell signaling within a pro-inflammatory environment may be of relevance for the development of atherosclerosis.

Withaferin A, a bioactive steroidal lactone derived from Withania somnifera (Ashwagandha), has gained attention for its potent immunomodulatory and anti-inflammatory properties. Cancer immunotherapy, particularly immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 antibodies, has revolutionized cancer treatment but is frequently associated with immune-related adverse effects (irAEs) [1], including systemic inflammation and autoimmune-like responses. Recent studies suggest that Withaferin A can regulate immune pathways by inhibiting NF-κB activation [2], suppressing pro-inflammatory cytokines (e.g., IL-6, TNF-α) [3], and restoring immune homeostasis. These mechanisms make Withaferin A a promising candidate for mitigating irAEs without compromising the anti-tumor efficacy of ICIs. Preclinical studies further highlight its ability to modulate T-cell responses and macrophage polarization, both critical in the pathogenesis of immunotherapy-induced toxicities. This review synthesizes current evidence on Withaferin A’s immunomodulatory mechanisms and discusses its potential integration as an adjunct therapy to reduce adverse effects in cancer immunotherapy. While promising, further in vivo studies and clinical trials are essential to confirm its safety, optimal dosage, and long-term impact on patient outcomes. This work underscores the importance of exploring plant-derived bioactive molecules as complementary strategies to improve the tolerability and effectiveness of cancer treatment.

References:
[1] Ramos-Casals, M., et al. (2020). Immune-related adverse events of checkpoint inhibitors. Nature Reviews Disease Primers, 6, 1-21. https://doi.org/10.1038/s41572-020-0160-6.
[2] Heyninck, K., et al. (2014). Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKKβ.. Biochemical pharmacology, 91 4, 501-9 . https://doi.org/10.1016/j.bcp.2014.08.004.
[3] Alnuqaydan, A., et al. (2022). Evaluation of the Cytotoxic, Anti-Inflammatory, and Immunomodulatory Effects of Withaferin A (WA) against Lipopolysaccharide (LPS)-Induced Inflammation in Immune Cells Derived from BALB/c Mice. Pharmaceutics, 14. https://doi.org/10.3390/pharmaceutics14061256.

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that results in the deterioration of neuromuscular connections, with no effective treatment currently available. The present study aimed to synthesize clinical trial data regarding pharmacological approaches in amyotrophic lateral sclerosis, focusing on the impact of various drugs on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), patient survival, and safety profiles. A systematic review was conducted following the PRISMA 2020 guidelines (PROSPERO ID: CRD42023373675). The inclusion criteria consisted of clinical trials published in Portuguese, Spanish, or English, with participants diagnosed solely with amyotrophic lateral sclerosis and no other comorbidities. The exclusion criteria were systematic reviews, meta-analyses, and studies involving patients with additional health conditions. A total of 616 articles were identified through databases such as PubMed®, Cochrane Library®, ScienceDirect®, and Clinical Trials®. After applying selection filters, 37 articles met the inclusion criteria. Data from these studies were extracted into a table, detailing authors, publication year, sample size, clinical trial phase, and endpoints, including ALSFRS-R scores, survival rates, and adverse events. Regarding survival, Edaravone demonstrated a significant survival benefit, with active treatment groups living longer than placebo groups. Other promising treatments, such as Sodium Phenylbutyrate and Taurursodiol, reduced mortality and hospitalizations, offering hope for improving patient outcomes. Tofersen also showed a survival increase, indicating substantial clinical potential. Safety profiles revealed common adverse effects, including headaches, dizziness, gastrointestinal issues, and increased fall risks, primarily affecting the nervous and digestive systems. These findings highlight the importance of careful risk–benefit evaluation in ALS treatment. Although the results indicate positive therapeutic developments, further trials are essential to confirm the long-term safety and efficacy of these treatments.