In recent years, gut–brain axis signaling has been recognized as an essential factor modifying behavior, mood, cognition, and cellular viability under physiological and pathological conditions. Consequently, the intestinal microbiome has become a potential therapeutic target in neurological and psychiatric disorders. The microbiota-derived metabolite of tryptophan (Trp), indole-3-propionic acid (IPA), was discovered to target a number of molecular processes and to impact brain function. In this review, we outline the key mechanisms by which IPA may affect neuronal activity and survival and provide an update on the evidence supporting the neuroprotective action of the compound in various experimental paradigms. Accumulating data indicates that IPA is a free radical scavenger, a ligand of aryl hydrocarbon receptors (AhR) and pregnane X receptors (PXR), and an anti-inflammatory molecule. IPA decreases the synthesis of the proinflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-α (TNF-α), and other cytokines, reduces the generation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, and enhances the synthesis of neurotrophic factors. Furthermore, produced in the gut, or administered orally, IPA boosts the central levels of kynurenic acid (KYNA), a neuroprotective metabolite of Trp. IPA reduces the release of proinflammatory molecules in the gut, breaking the gut–inflammation–brain vicious cycle, which otherwise leads to neuronal loss. Moreover, as a molecule that easily enters central compartment, IPA may directly impact brain function and cellular survival. Overall, the gathered data confirms neuroprotective features of IPA, and supports its potential use in high-risk populations, in order to delay the onset and ameliorate the course of neurodegenerative disorders and cognitive impairment. Clinical trials evaluating IPA as a promising therapeutic add-on, able to slow down the progress of neurodegenerative disorders such as Alzheimer’s or Parkinson’s disease and to limit the morphological and behavioral consequences of ischemic stroke, are urgently needed.

Delivery by caesarean section (CS) is increasingly common worldwide and has been associated with altered health outcomes in offspring, which can be partially mitigated with breastfeeding. Interestingly, the mode of delivery itself may influence the composition of human milk. The aim of this narrative review was to comprehensively examine current evidence on the impact of CS on breast milk composition and to discuss its potential implications for neonatal and infant health. A literature search of the MEDLINE database was conducted in July 2025. It identified 1212 studies addressing associations between mode of delivery and human milk components, of which 54 were included in the qualitative synthesis. Available evidence suggests that CS is associated with transient, lactation stage-dependent alterations in breast milk composition, most pronounced in colostrum and transitional milk. Reported changes include differences in macronutrients, mineral content, immune-related molecules, hormones, antioxidants, microbiota, microRNA profiles, and other bioactive components. Findings related to mature milk are less consistent and often influenced by confounding factors. While some CS-associated alterations may slightly reduce the beneficial effect of breastfeeding, e.g., reducing certain antimicrobial or nutritional components, other changes seem to be potentially advantageous for the neonate/infant after CS, in particular in immune-related factors. Overall, the clinical significance of these compositional differences remains unclear, as no studies have directly linked CS-related changes in milk composition to long-term infant outcomes. Further well-designed longitudinal studies are needed to clarify these associations. Regardless of delivery mode, breastfeeding remains the optimal feeding strategy and a key intervention to support infant health after CS.

Background/Objectives: Pro-inflammatory, neurotrophic, and proapoptotic factors affect the course of schizophrenia; however, their impact on the clinical response during relapse is not well recognized. A member of TNF family, Fas ligand (FasL), participates in apoptosis, but its connection with treatment-resistant schizophrenia is unknown. Methods: For this preliminary exploratory study, 53 patients with schizophrenia relapse and 45 healthy subjects were enrolled. Pro-inflammatory interleukin IL-1β, brain-derived neurotrophic factor (BDNF), FasL levels, and clinical evaluations (PANSS, SANS, SAPS) were studied at admission, after a 4-week therapy, and at remission. Results: In the clozapine-treated therapy-resistant group, IL-1β correlated negatively with clinical improvement (admission, 4-week treatment). In patients not treated with clozapine, IL-1β correlated negatively with disease duration (admission). A negative correlation occurred between FasL and clinical improvement in general symptoms (admission, 4-week treatment), FasL and leukocyte count (admission), and IL-1β and BDNF levels (4-week treatment). In the clozapine-treated group, the negative correlation between FasL levels and the leukocyte count was absent. Conclusions: The severity of psychopathology in patients with schizophrenia seems to correlate with higher IL-1β and lower BDNF. The novelty of our findings is the observation that higher FasL is negatively associated with the degree of clinical improvement. Thus, a decline of FasL during treatment may be proposed as a predictor of clinical recovery. With caution, we suggest that clozapine use may be linked to a protective effect against FasL signaling and the alleviation of apoptotic processes.

Background: Doxorubicin, a widely used chemotherapeutic agent, has been shown to increase reactive oxygen species (ROS) levels, disrupting cellular homeostasis not only in cancer cells but also in healthy tissues, particularly in cardiomyocytes, which leads to chemotherapy-induced cardiotoxicity. Therefore, new strategies are continually being explored to mitigate these adverse effects. One such approach is the use of additional substances with cardioprotective properties during doxorubicin therapy. A promising candidate is elabela, a peptide of the apelinergic system, which may exert protective effects against doxorubicin-induced oxidative stress in cardiomyocytes. Objectives: This study aims to evaluate the modulatory effects of elabela on oxidative stress markers, malondialdehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the left ventricle of the myocardium following chronic doxorubicin administration in rats. Material and Methods: 32 male, 12-week-old Sprague-Dawley rats (SPRD) were randomly assigned to four experimental groups. For 28 days, all animals received continuous infusions (2.5 μL/h) via subcutaneously implanted osmotic pumps of 0.9% NaCl or elabela (40 μg/kg body weight/day or 200 μg/kg body weight/day). Simultaneously, animals were injected intraperitoneally 4 times at weekly intervals with 0.9% NaCl or DOX (3.5 mg/kg body weight). Next, the animals were sacrificed, and left ventricular (LV) cardiac tissue was collected for further analysis. MDA and 8-OHdG and elabela level in LV lysate were assessed by ELISA. The Ela expression in LV was quantified by Real-Time PCR. The TUNEL assay, labeled with a 5′-triphosphate strand, was used to assess the degree of apoptosis. Results: DOX treatment decreased both the Ela expression and elabela levels in the LV. Elabela administration at a dose of 200 µg/kg body weight/day significantly decreased ELA levels and Ela expression compared to the control group. The level of 8-OhdG was unexpectedly decreased in the DOX group compared to controls, while elabela treatment at both doses restored 8-OHdG levels observed in the control group. However, TUNEL staining demonstrated that elabela administration at 200 µg/kg body weight/day reduced the number of apoptotic cardiomyocytes compared to the DOX-only group, indicating a protective effect against DOX-induced apoptosis. The lower dose of 40 µg/kg body weight/day showed a moderate, non-significant attenuation of apoptosis. Conclusions: Elabela showed a protective effect against DOX-induced cardiomyocyte apoptosis in the LV by promoting processes that reduce oxidative stress in cardiac cells.

The mechanisms underlying doxorubicin (DOX) cardiotoxicity include activation of the renin–angiotensin–aldosterone system (RAAS), oxidative stress, mitochondrial dysfunction, calcium overload, and cardiomyocyte apoptosis. Cortisol plays a key role in regulating multiple metabolic, immunological, cardiovascular, and neuroendocrine processes and may additionally influence drug pharmacokinetics by modulating the activity of P-glycoprotein (P-gp). The peptide apelin, through its specific target, angiotensin II protein J receptor (APJ), exerts cardioprotective, antifibrotic, and anti-inflammatory effects. The available data demonstrate that apelin signaling protects against DOX-induced cardiotoxicity, impacts cortisol secretion, and inhibits RAAS. Short-term elevation in cortisol levels, caused by apelin, may reduce inflammation and thus have cardioprotective properties. However, through chronically elevated cortisol levels, apelin may indirectly contribute to peripheral resistance, cardiac remodeling, and myocardial damage, especially when cortisol metabolism by 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) is altered. This narrative review explores the potential molecular and cellular mechanisms shaping the outcome of apelin–cortisol interplay, offering a potential foundation for developing cardioprotective strategies during anticancer therapy. Future studies should be aimed at assessing the complex interactions between cortisol, apelin, and the RAAS regarding DOX-induced cardiotoxicity.

Background/Objectives: Endometriosis is a prevalent gynecological illness associated with chronic pain, inflammation, and infertility, as ectopic endometrial lesions are formed. No fully effective treatment is available, and the pathogenesis of this disease is unclear. The survival of ectopic endometrial cells is facilitated by their low susceptibility to apoptosis, an immunosuppressive environment, and local angiogenesis. Chromogranin A (CgA), a glycoprotein prohormone, modulates various processes including angiogenesis and innate immunity, and its higher levels are detected in neuroendocrine tumors and inflammatory disorders. Since endometriosis may be considered an autoinflammatory disorder, this study aimed to evaluate serum and peritoneal fluid concentrations of CgA and its derivatives, catestatin and pancreastatin, and to correlate these levels with disease severity. Methods: The study was conducted on samples of serum and peritoneal fluid (PF) obtained from 65 women diagnosed with endometriosis and from 60 control individuals who underwent surgery for other reasons. The concentrations of CgA, catestatin, and pancreastatin were assessed in the collected samples by specific enzyme-linked immunosorbent assays. Results: CgA, catestatin, and pancreastatin concentrations were significantly higher in the sera and PF of endometriosis patients compared to controls. There was a correlation between their serum and PF levels, and all tested factors were correlated with each other in both serum and PF. Serum concentrations of CgA, catestatin, and pancreastatin were also associated with disease progression. Receiver operating characteristic (ROC) analysis further confirmed that endometriosis is associated with increased circulating CgA, catestatin, and pancreastatin levels, suggesting that they may be considered markers of endometriosis. Conclusions: The upregulation of CgA and its derivatives in endometriosis may indicate their role in the disease pathogenesis and implicate them as potential diagnostic markers and/or therapeutic targets.