L-carvone is a ketone monoterpene best known as the characteristic scent of spearmint, produced by plants of the Mentha genus. It exists as two mirror-image forms, or optical isomers, with the (R)-(−) form, known as L-carvone, and the (S)-(+) form, known as D-carvone, displaying distinct biological profiles. Previous research has attributed a remarkable range of activities to carvone, including antibacterial, antifungal, antioxidant, anti-neurodegenerative, vasorelaxant, and anticancer effects. Studies have also linked the compound to cardiovascular protection and atheroprotection through mechanisms such as reducing foam cell formation, modulating macrophage balance, and lowering oxidative stress. The new study, led by Guilherme Miniskiskosky and senior author Andréa Emilia Marques Stinghen at the Federal University of Paraná in Curitiba, is the first to test whether these properties extend to the specific inflammatory storm that uremia unleashes on blood vessel walls.

To create a realistic model of the uremic environment, the researchers recruited 14 patients with stable end-stage kidney disease undergoing hemodialysis at a single dialysis unit in Curitiba, Brazil. Participants had been on dialysis for at least three months, and the team carefully excluded anyone with active infection, cancer, autoimmune disease, liver dysfunction, severe mineral disturbances, or use of drugs such as glucocorticoids and immunosuppressants that could confound inflammatory measurements. Serum collected from all patients was pooled in equal amounts to create an averaged uremic milieu, minimizing the influence of any single patient’s biochemistry. The study was approved by the Ethics Committee of Pontifícia Universidade Católica do Paraná, and all patients provided signed informed consent.

The experimental system centered on EA.hy926 cells, a well-established human endothelial cell line, grown under standard conditions and exposed for 24 hours to one of three treatments: a 10 percent uremic serum pool, L-carvone at 100 micromolar, or the two combined. The carvone dose was chosen after a careful dose-response screen. At concentrations of 200 micromolar and above, the compound significantly reduced endothelial cell viability, but at 100 micromolar it left viability untouched, whether applied alone or alongside uremic serum. This established a safe working concentration for probing anti-inflammatory effects without cytotoxic confounders. The 24-hour exposure window was selected to allow sufficient time for transcriptional and inflammatory responses to unfold.

The results were striking. Uremic serum, as expected, drove up gene expression of the pro-inflammatory interleukins IL-6, IL-8, and IL-1β in the endothelial cells. When L-carvone was added, it significantly reduced IL-1β gene expression compared with uremic serum alone, a finding of particular importance because IL-1β sits near the top of the inflammatory cascade, amplifying vascular damage through activation of the nuclear factor kappa-B (NF-κB) pathway and contributing to arterial calcification. At the protein level, the effects broadened considerably. Carvone treatment significantly lowered production of IL-6, IL-8, and IL-1β, as well as tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor A (VEGF-A), and serum amyloid A (SAA), an acute-phase protein secreted by the liver that promotes pro-inflammatory and pro-thrombotic activity on vascular endothelial cells. Levels of the adhesion molecule ICAM-1 also fell substantially, from about 12.05 picograms per milliliter in uremic serum-treated cells to 6.25 picograms per milliliter when carvone was present.

Beyond quieting inflammatory signaling, the compound appeared to interfere with one of the most consequential steps in atherosclerosis: the recruitment of monocytes to the vessel wall. Endothelial cells exposed to uremic serum produce monocyte chemoattractant protein 1 (MCP-1), a chemical beacon that draws circulating monocytes toward the endothelium, where they can invade the vessel wall and seed atherosclerotic plaques. In the study, carvone significantly reduced MCP-1 production under uremic conditions. To test the functional consequence, the team used modified Boyden chambers, placing treated endothelial cell supernatant in the lower compartment and U-937 monocyte-like cells above a porous membrane. Supernatant from uremic serum-treated endothelial cells significantly increased monocyte migration, but supernatant from cells co-treated with carvone significantly reduced it, demonstrating that the anti-inflammatory effect translates into reduced leukocyte recruitment.

Perhaps the most visually compelling evidence came from scanning electron microscopy. Untreated control cells displayed the classic architecture of intact endothelium, spread flat across the substrate in a confluent monolayer. Cells exposed to uremic serum showed the hallmarks of uremic injury: an abundance of filopodia, loss of intercellular adhesions, rounded cell bodies, perforations in the plasma membrane, and scattered cellular debris. These morphological changes matter because uremic toxins are known to disrupt adherens and occluding junctions between endothelial cells, increasing vascular permeability and accelerating vascular damage. Remarkably, cells treated with uremic serum plus carvone largely reverted to a control-like pattern, remaining adhered and spread across the substrate. Carvone also promoted endothelial cell proliferation, which the authors suggest could support regeneration of an endothelial barrier damaged by toxin accumulation, although they caution that increased proliferation alone does not prove restored barrier function.

The authors are careful to frame these findings as mechanistic observations rather than a prescription. The 100 micromolar concentration used in vitro may exceed the circulating levels achievable in humans, since pharmacokinetic studies indicate that carvone is rapidly metabolized and cleared, and quantitative data on attainable plasma or tissue concentrations remain limited. Previous human studies have documented systemic exposure to carvone after oral intake of peppermint and caraway oil preparations and after topical exposure, but these do not establish clinical efficacy or safety of isolated carvone in CKD patients. The researchers also acknowledge that they did not directly measure NF-κB activation or antioxidant pathways, so the precise molecular mechanism behind the observed effects remains speculative, even though other experimental models have linked carvone’s anti-inflammatory actions to NF-κB inhibition.

Additional limitations shape how the results should be interpreted. The EA.hy926 cell line, while a standard tool, may not fully reproduce the behavior of primary human endothelial cells, and validation in primary cells is needed. The pooled serum from 14 patients smooths away inter-individual variability, so studies using serum from larger numbers of individual patients will be important to confirm that the effects hold across different clinical profiles. The authors also note that future work should explore carvone’s effects in other relevant cell types, such as vascular smooth muscle cells and renal tissue, and that in vivo studies will be essential to understand how the compound behaves in complex biological systems.

Even with those caveats, the study represents a genuine first. The researchers demonstrated for the first time that the dysfunctional, inflammatory profile that uremia imposes on endothelial cells can be attenuated by L-carvone treatment in vitro, with reductions in inflammatory biomarkers, reduced leukocyte recruitment, and reversal of uremia-induced structural damage. Because elevated levels of molecules like IL-6, TNF-α, and MCP-1 are linked to poorer cardiovascular prognosis, blunting their production could, in principle, translate into meaningful vascular protection for the CKD population. The work opens a new avenue for investigating how natural monoterpenes might be harnessed against uremic inflammation, and it provides a foundation for the animal studies and, eventually, clinical trials that would determine whether the spearmint molecule can move from the culture dish to the dialysis clinic.

Subject of Research: Anti-inflammatory effects of L-carvone on uremia-induced endothelial dysfunction in chronic kidney disease

Article Title: Potential anti-inflammatory effect of L-carvone in endothelial dysfunction triggered by uremia related to chronic kidney disease

Article References: Miniskiskosky, G., da Cunha, R. S., Gregório, P. C., Azevedo, C. A. B., Pereira, V. C., de Souza Ramos, E. A., & Stinghen, A. E. M. (2026). Potential anti-inflammatory effect of L-carvone in endothelial dysfunction triggered by uremia related to chronic kidney disease. Molecular Biology Reports, 53(1), Article 1651. https://doi.org/10.1007/s11033-026-12806-7

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12806-7

Keywords: chronic kidney disease, L-carvone, endothelial dysfunction, uremic toxins, inflammation, hemodialysis, monoterpene, cardiovascular disease, IL-1β, MCP-1, monocyte recruitment, natural compounds

Multiple myeloma remains incurable, accounting for roughly 1.8 percent of all cancers and between 10 and 18 percent of hematological malignancies. The disease begins as a clonal expansion of plasma cells tucked into specialized niches of the bone marrow, evolving slowly through precursor states such as monoclonal gammopathy of undetermined significance and smoldering myeloma. In some patients, however, malignant plasma cells eventually break their dependence on the marrow and disseminate to soft tissues and organs, a phenomenon known as extramedullary disease. This high-risk variant carries a grim prognosis, with median survival measured in little more than a year, and its biology remains incompletely understood despite rapid advances in myeloma therapy.

The Hungarian team, led by Tünde Tóth and Andrea Tamás, set out to test whether the inflammatory milieu of the blood could serve as a window onto these microenvironmental changes. They enrolled 48 patients with multiple myeloma, including 15 with extramedullary involvement, along with 10 healthy controls of comparable age. Using an enzyme-linked immunosorbent assay for PACAP-38 and a high-sensitivity Luminex multiplex platform for 13 cytokines and chemokines, including interferon-gamma, interleukin-1 beta, IL-2, IL-3, IL-6, IL-8, IL-9, IL-10, IL-17A, MCP-1, MIP-1 alpha, TGF-alpha and TNF-alpha, they quantified each molecule in plasma and then asked how the resulting profiles related to disease activity, extramedullary spread and progression-free survival.

The results reveal a distinctive inflammatory signature in myeloma. Compared with healthy controls, patients showed significantly elevated levels of interferon-gamma, the immunosuppressive cytokine IL-10 and the monocyte-recruiting chemokine MCP-1, alongside reduced levels of IL-17A and TGF-alpha. When the investigators applied a stringent correction for multiple testing, only IL-10, IL-17A and MCP-1 retained statistical significance, marking them as the most robust biomarker candidates to emerge from the comparison. Receiver operating characteristic analysis indicated that IL-10, IL-17A and MCP-1 offered excellent discrimination between patients and controls, while TGF-alpha performed acceptably, suggesting these molecules could potentially serve as accessible diagnostic indicators of myeloma biology.

Disease activity left an even clearer fingerprint. Patients with active myeloma, whether newly diagnosed, relapsed or refractory, had markedly higher IL-10 and TNF-alpha than patients in remission, and their interferon-gamma, IL-10 and MCP-1 levels were all significantly elevated relative to controls. After multiple-testing correction, IL-10 alone remained significant, but its consistency across every comparison in the study impressed the authors. IL-10 is a paradoxical cytokine in cancer: it dampens antigen presentation, fosters regulatory T cell expansion and supports angiogenesis, collectively helping malignant cells escape immune surveillance. Its co-elevation with interferon-gamma, normally an antitumor cytokine, points to a dysfunctional immune state in which chronic stimulation paradoxically drives immune exhaustion rather than tumor rejection.

The extramedullary subgroup told an even more striking story. Patients whose myeloma had escaped the bone marrow showed sharply increased interferon-gamma, IL-10, MCP-1 and, unexpectedly, PACAP-38, together with a pronounced drop in TGF-alpha. Only IL-10 survived correction for multiple testing in this comparison, but the overall pattern suggests that extramedullary disease represents a genuinely distinct inflammatory phenotype rather than simply a more advanced version of marrow-bound myeloma. Mechanistically, this fits with what is known about how myeloma cells disseminate: hypoxia stabilizes HIF-1 alpha, upregulating the chemokine receptor CXCR4 and promoting an epithelial-mesenchymal transition-like program that loosens the cells’ adhesion to the marrow and licenses migration to distant sites.

The behavior of PACAP-38, an anti-inflammatory and cytoprotective neuropeptide, added a further layer of complexity. Previous work by the same group had shown that PACAP-38 levels are lower in myeloma patients than in healthy individuals, with reductions linked to poorer prognosis, particularly in older patients. In the new cohort, however, PACAP-38 was paradoxically elevated in patients with extramedullary disease. The authors propose that this rise may represent a compensatory response to extreme systemic stress, since hypoxia and oxidative stress are known inducers of PACAP expression, though they are careful to frame this as a hypothesis-generating interpretation rather than a demonstrated mechanism. Notably, PACAP-38 correlated positively with IL-10 and negatively with the pro-inflammatory chemokines MCP-1 and MIP-1 alpha, consistent with a role in counter-regulating inflammation and protecting the marrow microenvironment.

Survival analyses reinforced the prognostic relevance of the cytokine network. Progression-free survival correlated negatively with IL-6, IL-10 and TGF-alpha across the myeloma cohort, and in the extramedullary subgroup with IL-6 and IL-9, while IL-17A showed a positive association with survival. Exploratory Kaplan-Meier analyses, splitting patients at the median concentration of each cytokine, confirmed that IL-6, IL-9 and IL-10 distinguished patients with different progression-free survival, although the small number of progression events meant that multivariable adjustment was not feasible. After correction for multiple testing, IL-9 was the only survival-associated variable to remain significant, underscoring the exploratory nature of these findings and the need for larger validation cohorts.

The study arrives at a moment when myeloma treatment is being transformed by chimeric antigen receptor T cell therapy, bispecific antibodies and increasingly sensitive monitoring technologies, yet current staging systems still lean heavily on tumor burden and cytogenetic risk while largely ignoring the inflammatory microenvironment. The Hungarian authors argue that biomarkers such as IL-10 could complement, rather than replace, existing frameworks by capturing biological features that clinical variables miss, from identifying biologically aggressive disease to flagging patients at risk of extramedullary progression or relapse. They also suggest that inflammatory pathways, including IL-6 and MCP-1 signaling, warrant attention as therapeutic targets, and that restoring PACAP-38-mediated neuroimmune regulation might one day offer a complementary strategy, potentially in combination with immune-based therapies.

The researchers are candid about their study’s limitations. It was a single-center investigation with a modest sample size, particularly in the control and extramedullary subgroups, and cytokines were measured in peripheral blood rather than bone marrow, which may not fully reflect the local milieu. Treatment effects, detectable only for IL-10 in this cohort, cannot be entirely excluded, and the cross-sectional design precludes causal inference. Several cytokines, including IL-1 beta, IL-2 and IL-3, fell below detection limits in many samples. Even so, the strengths are real: a simultaneous assessment of a broad cytokine panel together with PACAP-38, careful characterization of extramedullary patients, and rigorous false-discovery-rate correction that sharpened rather than diluted the central message. What emerges is a coherent picture of multiple myeloma as an inflammation-driven malignancy in which IL-10 stands out as the most promising blood-based biomarker, and in which the ebb and flow of a protective neuropeptide may help explain why some patients’ disease stays confined while others break free. Larger, multicenter, longitudinal studies will now be needed to determine whether these inflammatory fingerprints can earn a place in the clinic.

Subject of Research: Inflammatory cytokine and PACAP-38 alterations and their prognostic value in multiple myeloma

Article Title: The relationship between inflammation and multiple myeloma: insights into alterations and prognostic value

Article References: Tóth, T., Alizadeh, H., Polgár, B., Csalódi, R., Kemény, Á., Reglődi, D., Faludi, P., Pethő, B., & Tamás, A. (2026). The relationship between inflammation and multiple myeloma: insights into alterations and prognostic value. GeroScience. https://doi.org/10.1007/s11357-026-02494-3

Image Credits: AI Generated

DOI: 10.1007/s11357-026-02494-3

Keywords: multiple myeloma, extramedullary disease, cytokines, IL-10, PACAP-38, inflammation, bone marrow microenvironment, prognosis, biomarkers, MCP-1, interferon-gamma, GeroScience