The investigators analyzed 2,533 eligible participants from three National Health and Nutrition Examination Survey cycles: 2013–2014, 2015–2016 and 2017–2018. The survey analysis included 1,252 participants classified as having substance use disorder and 1,281 healthy controls. Substance use disorder was diagnosed according to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders, using self-reported information on lifetime use of cannabis with or without other illicit drugs, and cocaine, heroin and/or methamphetamine.

Sleep disturbance was identified with a single yes-or-no question asking whether a doctor or other health professional had ever told participants that they had trouble sleeping. Because the data were cross-sectional, the findings show associations but cannot establish whether substance use, inflammation, impaired sleep or another factor preceded the others. SIRI was calculated by multiplying the monocyte count by the neutrophil count and dividing the result by the lymphocyte count.

The formula combines circulating measures associated with innate immune activity and adaptive immune function, allowing the researchers to assess systemic inflammatory balance using routine hematology measurements. Among participants with substance use disorder, those reporting sleep disturbance had a median SIRI of 1.217, compared with 1.043 among those without sleep disturbance. The difference was statistically significant, with a reported p-value below 0.001.

The clinical cohort also showed a difference in the same direction: mean SIRI was 0.93 in the opioid use disorder group and 0.74 in healthy controls. Adjusted survey analysis showed a graded relationship between SIRI and the odds of reporting sleep disturbance. The model accounted for age, sex, education, race, marital status, annual family income and body mass index.

The odds ratio was 1.29, with a 95% confidence interval of 1.19–1.39, for SIRI from 1.125 to 1.622 and 2.00, with a 95% confidence interval of 1.85–2.17, for SIRI above 1.622. These are cross-sectional odds ratios rather than estimates of future risk, and the categories were defined within the analyzed sample. The researchers also performed a mediation analysis across the full survey sample, treating substance use disorder status as the exposure, SIRI as the mediator and sleep disturbance as the outcome.

The estimated total effect was 0.168, with a 95% confidence interval of 0.120–0.216; the average direct effect was 0.128, with a 95% confidence interval of 0.080–0.173; and the average indirect effect through SIRI was 0.040, with a 95% confidence interval of 0.026–0.056. The estimated proportion of the association statistically mediated through SIRI was 23.9%, with a 95% confidence interval of 15.3%–35.1%. The remainder was described as direct or potentially mediated through unmeasured pathways.

The analysis supports a partial statistical relationship, but its cross-sectional design does not demonstrate causal mediation. The clinical dataset provided a focused test of the same pattern in opioid use disorder. Between January and December 2024, researchers recruited 44 people with opioid use disorder from Changsha, Hunan Province, and 44 healthy controls matched on age, education, sex, body mass index, smoking and drinking.

The opioid group had used opioids for a median of 18 years, and all reported hot smoking as their primary route of administration. Urine screening was positive for heroin, and participants met Diagnostic and Statistical Manual of Mental Disorders criteria for opioid use disorder. The groups did not differ significantly in most demographic characteristics, although marital status differed significantly.

Sleep quality in the clinical cohort was measured with the Chinese version of the Pittsburgh Sleep Quality Index, an 18-item questionnaire organized into seven domains and scored from 0 to 21, with higher scores indicating poorer sleep quality. The median score was 11 in the opioid use disorder group and 4.5 in healthy controls, a significant difference with a reported p-value below 0.001. Within the opioid group, SIRI was positively correlated with PSQI, with a partial correlation coefficient of 0.327 and a p-value of 0.037 after adjustment for age, sex, body mass index, education, Fagerstrom Test for Nicotine Dependence score, Alcohol Use Disorders Identification Test score and marital status.

The correlation was modest, and the sample was small and geographically narrow. Machine-learning analysis offered a second way of examining whether SIRI contributed information about sleep status within the survey population. Eleven algorithms were evaluated, including LASSO, CatBoost, gradient boosting, support vector machines, decision trees, LightGBM, neural networks, naive Bayes, XGBoost, random forest and logistic regression.

The data were divided into stratified training and test sets at a 70%–30% ratio, with ten-fold cross-validation used for training and hyperparameters selected according to mean cross-validated area under the receiver operating characteristic curve. Missing continuous variables were imputed with medians, categorical variables with modes, and variables with at least 10% missingness were excluded before modeling. CatBoost had the highest test-set area under the ROC curve at 0.880, followed by random forest at 0.846.

The other algorithms had test-set areas ranging from 0.500 to 0.688. In the training set, CatBoost and random forest achieved areas of 0.999 and 0.996, respectively, indicating a degree of overfitting. Test-set calibration and decision-curve analyses identified CatBoost as demonstrating optimal performance and the greatest net benefit.

The investigators used SHAP analysis to interpret model predictions. SIRI ranked first in both models. In CatBoost, the next leading features were race, body mass index, age and sex; in random forest, they were neutrophil count, body mass index, monocyte count and white blood cell count.

These results identify SIRI as an influential feature in the fitted models, not as a validated diagnostic test. Biologically, the findings were consistent with previous observations discussed by the investigators that substance use and withdrawal can be accompanied by systemic immune responses, while inflammatory signaling can influence the central nervous system through humoral mediators, neural pathways and transport across the blood-brain barrier. Neutrophils and monocytes participate in innate immune regulation and can generate pro-inflammatory factors including tumor necrosis factor-alpha and interleukin-6.

The paper also discusses possible immune effects of opioids, including signaling through toll-like receptor 4 on myeloid cells. The present study did not directly measure these proposed pathways, test anti-inflammatory treatments or demonstrate that inflammation caused sleep disruption. Its evidence is observational and cross-sectional.

Important limitations constrain the conclusions. Sleep was self-reported in both datasets, creating the possibility of recall and classification bias. The NHANES measure was a single question, whereas the clinical cohort used the multidimensional PSQI, so sleep estimates from the two populations were not directly equivalent.

Detailed route-of-use information was unavailable in the survey data, limiting comparisons between intravenous and other administration methods. The clinical cohort contained only 44 participants with opioid use disorder, excluded people with major psychiatric comorbidities, antidepressant use or anti-inflammatory treatment, and represented one Han Chinese community in Changsha. External validation, longitudinal follow-up and experimental work are therefore needed before the observed associations can establish temporal order, causation or clinical utility.

The evidence supports SIRI as a promising marker for further study alongside established sleep assessments, rather than as a standalone diagnostic or treatment-selection tool.

Subject of Research: Association of the systemic inflammatory response index with sleep disturbance in substance use disorders

Article Title: Systemic inflammatory response index: a potential mediator between substance use disorder and sleep disturbance

Article References: Yang, L., Tang, Y., Wang, X., Chen, X., Zou, Q., Zeng, Y., Chen, Q., & Liu, J. (2026). Systemic inflammatory response index: a potential mediator between substance use disorder and sleep disturbance. Frontiers in Pharmacology, 17, Article 1964417. https://doi.org/10.3389/fphar.2026.1964417

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1964417

Keywords: systemic inflammatory response index, substance use disorder, sleep disturbance, opioid use disorder, peripheral inflammation, NHANES, machine learning, cross-sectional study, Pittsburgh Sleep Quality Index, blood biomarkers, Systemic, inflammatory

Necroptosis is a lytic, caspase-independent form of regulated cell death that depends on RIPK3 and mixed lineage kinase domain-like pseudokinase (MLKL) and is initiated by RIPK1. Unlike apoptosis, necroptosis ruptures the plasma membrane, causing cellular swelling, fragmentation, and release of cytoplasmic contents including damage-associated molecular patterns such as high-mobility group box 1 (HMGB1). Once outside the cell, HMGB1 acts like a cytokine, fueling inflammatory diseases. The RIPK1/RIPK3/MLKL necrosome also activates transcription factors such as nuclear factor-κB (NF-κB), increasing production of pro-inflammatory and vasodilator mediators that contribute to cardiovascular, renal, hepatic, and neurodegenerative diseases.

Ischemia develops when blood flow to tissues is insufficient, leading to oxygen deficiency, irreversible damage, and cell death as duration increases. Reperfusion, while necessary to restore oxygen and nutrients, can paradoxically exacerbate existing cellular damage and cause new injury through formation of reactive nitrogen species, reactive oxygen species, and eicosanoids via enzymes such as xanthine oxidase, inducible nitric oxide synthase (iNOS), NADPH oxidase, and cyclooxygenase-2 (COX-2). These mediators circulate and injure distant organs, producing systemic inflammation, endothelial dysfunction, and ultimately multiple organ failure (MOF). Lower-extremity I/R, which occurs in peripheral arterial disease, traumatic arterial injury, and abdominal aortic aneurysm, can damage the heart, kidney, lung, liver, and brain.

To model this, researchers applied rubber tourniquets to both hind limbs of male Wistar rats at the level of the greater trochanter under ketamine and xylazine anesthesia, inducing 3 hours of ischemia followed by 24 hours of reperfusion. Nec-1s was injected intraperitoneally 1 hour before reperfusion at doses of 1, 2, or 3 mg/kg. Mean arterial pressure (MAP) and heart rate (HR) were recorded noninvasively using a volume-pressure tail-cuff method. After 24 hours, blood was drawn from the caudal vena cava and the heart, kidney, lung, liver, and brain were isolated for molecular and histopathological analysis.

The results showed that MAP values decreased by 25 and 22 mmHg at 3 hours after ischemia and 24 hours after reperfusion, respectively, while HR values increased by 116 and 74 beats per minute over the same intervals. Nec-1s at 1, 2, or 3 mg/kg reversed the drop in MAP, but only the 3 mg/kg dose prevented the I/R-induced rise in HR. Because 3 mg/kg was the lowest effective dose that prevented both hypotension and tachycardia without mortality, it was selected for ex vivo studies.

Immunoblotting revealed that I/R increased the expression and phosphorylation of RIPK1, RIPK3, and MLKL in all five tissues examined, indicating activation of the necroptotic necrosome. HMGB1 protein expression also rose in the heart, kidney, lung, liver, and brain after I/R. Nec-1s prevented these I/R-induced increases in necrosome components and HMGB1, consistent with its role as a selective RIPK1 inhibitor that suppresses necroptotic signaling and the release of pro-inflammatory alarmins.

The study further demonstrated that I/R activated the IKKα/β/γ/IκB-α/NF-κB pathway in all five tissues, increasing phosphorylated IKKα, IKKβ, IKKγ, IκB-α, and NF-κB p65 while decreasing unphosphorylated IκB-α. Downstream, iNOS and COX-2 expression increased, as did serum and tissue nitrite levels (an indicator of iNOS-mediated NO formation) and prostaglandin I2 (PGI2) levels (an indicator of COX-2-mediated vasodilatory prostaglandin formation). Interleukin-1β expression also rose. Nec-1s prevented all of these I/R-induced molecular changes, showing that RIPK1 inhibition suppresses the transcriptional programs that generate vasodilator and pro-inflammatory mediators.

Histopathological examination using hematoxylin and eosin staining revealed mild to moderate injury-related changes in all five tissues after I/R, including inflammatory cell infiltration, edema, congestion, hemorrhage, hyperemia, necrosis, and apoptosis. Nec-1s reduced the I/R-induced increase in histopathological scores in tissues other than the liver, but the effect was statistically significant only in the heart. This suggests that while Nec-1s broadly suppresses necroptotic and inflammatory signaling at the molecular level, its ability to reverse structural tissue damage varies by organ and may require longer treatment or different dosing strategies.

The findings indicate that Nec-1s, a systemically administered drug candidate, may be beneficial in managing diseases associated with hypotension, arrhythmia, inflammation, and necroptosis caused by increased production of vasodilator mediators such as NO and PGI2 and pro-inflammatory cytokines such as HMGB1 and IL-1β. Because lower-extremity I/R injury can lead to death through MOF, a selective RIPK1 inhibitor that prevents cardiovascular deterioration and inflammatory tissue damage could represent an important therapeutic advance for patients at risk of reperfusion-related systemic collapse.

Subject of Research: Effects of RIPK1 inhibitor necrostatin-1s on cardiovascular responses and inflammatory damage in a bilateral hind limb I/R injury model in rats

Article Title: Effects of RIPK1 inhibitor necrostatin-1s on cardiovascular responses and inflammatory damage in a bilateral hind limb I/R injury model in rats

Article References: Ikiz, E., Ahmed-Reda Elosman, M., Senol, S. P., Kara, T., & Tunctan, B. (2026). Effects of RIPK1 inhibitor necrostatin-1s on cardiovascular responses and inflammatory damage in a bilateral hind limb I/R injury model in rats. Pharmacia, 73, Article e206332. https://doi.org/10.3897/pharmacia.73.e206332

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e206332

Keywords: Effects, RIPK1, inhibitor, necrostatin-1s, cardiovascular, responses, inflammatory, damage, bilateral, hind, limb, injury

The research team hypothesized that β-estradiol and dihydrotestosterone (DHT), the most potent androgen, would differentially modulate inflammatory signaling and monocyte–endothelial interactions during SARS-CoV-2 exposure. To test this, they exposed HULEC-5a lung microvascular endothelial cells, THP-1 monocytic leukemia cells, and primary monocytes and neutrophils isolated from patients with confirmed COVID-19 to in vitro-amplified Wuhan-1 SARS-CoV-2 at a multiplicity of infection of 0.001 for 24 and 48 hours. All procedures involving live virus were conducted in a certified Biosafety Level 3 laboratory in accordance with institutional biosafety regulations and World Health Organization recommendations. Cells were treated with DHT, β-estradiol, or the androgen receptor antagonist flutamide at nanomolar to micromolar concentrations before viral exposure. Receptor gene expression was measured by RT-qPCR, inflammatory signaling by Western blot against phosphorylated and total NFκB, STAT3, and p38 MAPK proteins, and monocyte transendothelial migration by Boyden chamber assay. Patient samples were collected between June 2020 and April 2022 at the Clinic for Infectious and Tropical Diseases of the University Clinical Center of Serbia.

The first key finding concerns how SARS-CoV-2 itself reshapes the expression of sex steroid receptors in a cell-specific manner. The virus reduced expression of estrogen receptor 1 (ESR1) in endothelial cells after 24 hours (p<0.05), while simultaneously increasing ESR1 expression in neutrophils (p<0.05) and monocytes (p<0.01) from patients with COVID-19. Androgen receptor (AR) expression was inversely regulated in neutrophils and monocytes: the virus reduced AR in neutrophils after 24 hours (p<0.001) but increased it in monocytes (p<0.05). These differential patterns suggest that SARS-CoV-2 actively reprograms the hormonal responsiveness of both vascular and immune compartments. The authors propose that suppression of ESR1 in endothelial cells may contribute to endothelial dysfunction, vascular inflammation, and thrombotic complications of severe disease, whereas increased ESR1 in circulating innate immune cells may represent a compensatory immunoregulatory response to systemic inflammation.

In THP-1 monocytic cells, SARS-CoV-2 generally activated inflammatory signaling pathways including NFκB, STAT3, and p38 MAPK, with activation reaching up to 1.9-fold above baseline. The NFκB response was further augmented by DHT (44.6%) and attenuated by flutamide (44.1%), indicating that androgen receptor signaling amplifies a central mediator of virus-induced cytokine production. STAT3 signaling was also activated by the virus (p<0.01), and both AR activation and AR blockade were associated with sustained STAT3 phosphorylation at 48 hours, though with different temporal dynamics: the DHT-associated increase at 48 hours was 3.4-fold lower than at 24 hours, whereas the flutamide-associated level remained unchanged between the two time points. Prolonged p38 MAPK activation was maintained by a low dose of DHT (10 nM) and reduced by low-dose flutamide (100 nM), but not by higher flutamide concentrations, suggesting dose-dependent and pathway-specific modulation of inflammatory cascades by androgen-responsive mechanisms.

In HULEC-5a lung endothelial cells of human male origin, the picture was notably different. SARS-CoV-2 reduced STAT3 activation at 24 hours (p<0.05), an effect not further modified by DHT or flutamide. After 48 hours, DHT alone reduced STAT3 activation even in the absence of virus (p<0.01), indicating a direct effect of androgen signaling on baseline STAT3 activity in endothelial cells. In SARS-CoV-2-exposed cells, DHT twice reduced virus-induced activation of the p38 MAPK pathway (p<0.05). These results suggest that androgen signaling can partially suppress inflammatory signaling in endothelial cells both at baseline and during viral exposure, a finding that contrasts with the amplifying effects observed in monocytic cells and underscores the highly cell-specific nature of sex steroid immunoregulation during SARS-CoV-2 infection.

Primary immune cells from patients with COVID-19 revealed further complexity. In neutrophils, β-estradiol inhibited NFκB signaling 2.2-fold, whereas DHT stimulated it 4.9-fold. SARS-CoV-2 reduced NFκB activation in neutrophils from female patients after 24 hours (p<0.001), and β-estradiol further reduced NFκB activation in a dose-dependent manner irrespective of viral exposure (p<0.01). In contrast, DHT increased NFκB activation after 48 hours independently of SARS-CoV-2. Simultaneously, the virus strongly induced p38 MAPK activation in neutrophils (>10-fold) after 24 hours (p<0.001). The authors note that persistent p38 MAPK activation may sustain neutrophil activation despite partial NFκB inhibition, contributing to oxidative stress, neutrophil extracellular trap formation, and tissue damage associated with severe disease. They also highlight that G protein-coupled estrogen receptor 1 (GPER1), a membrane-associated estrogen receptor expressed in human monocytes and neutrophils, may regulate neutrophil inflammatory responses through cAMP/PKA/CREB and MAPK signaling pathways.

In monocytes from patients with COVID-19, DHT at 1 nM enhanced NFκB activation in the presence of SARS-CoV-2 after 24 hours (p<0.05), while β-estradiol at 100 nM increased p38 MAPK activation (p<0.01) and at the lowest concentration tested (1 nM) increased p38 MAPK activation irrespective of viral exposure (p<0.05). Comparison of exposure durations showed stronger SARS-CoV-2-induced activation of NFκB and p38 MAPK after 24 hours than after 48 hours (p<0.05), indicating a transient but pronounced activation of these pathways during early viral exposure. Notably, SARS-CoV-2 activation of inflammatory signaling deteriorates over time in monocytes from patients with COVID-19 (p<0.05), suggesting that androgen-mediated amplification of NFκB and MAPK cascades may contribute to exaggerated innate immune activation and heightened inflammatory responses in male patients with severe disease.

Perhaps the most functionally significant results emerged from the Boyden chamber migration assay. DHT significantly increased trans-endothelial migration of monocytes from patients with COVID-19 (p<0.001) and promoted detachment of SARS-CoV-2-exposed HULEC-5a endothelial cells (p<0.01). Monocyte migration through SARS-CoV-2-exposed endothelial layers was predominantly enhanced by DHT and, to a lesser extent, by β-estradiol and flutamide (p<0.001). After correction for endothelial background fluorescence and monocyte-only controls, increased migration remained evident, particularly in DHT-treated conditions. These findings suggest that androgen signaling promotes endothelial dysfunction and facilitates monocyte transmigration during SARS-CoV-2 infection, key events in COVID-19-associated immunothrombosis and vascular injury. Enhanced leukocyte trafficking across the endothelial barrier may promote tissue infiltration by inflammatory cells and aggravate local cytokine production.

The authors acknowledge limitations, including that sex-stratified analyses were not uniformly performed across all experiments involving primary immune cells because of limited availability of freshly isolated samples, and that the use of HULEC-5a cells derived from a single male donor restricts assessment of sex-dependent differences in endothelial responses. Nevertheless, the findings elucidate molecular mechanisms driving male-biased COVID-19 severity and underscore the potential of targeting androgen-responsive pathways as a therapeutic strategy to mitigate severe viral inflammation and endothelial dysfunction. Beyond SARS-CoV-2, the differential regulation of NFκB, STAT3, and p38 MAPK pathways observed here may reflect fundamental mechanisms of sex hormone-mediated immunoregulation that extend to other immune-mediated and vascular diseases in which sex steroids contribute to disease susceptibility and progression.

The study’s experimental design merits closer attention because it bridges two levels of analysis that are often treated separately in COVID-19 research: controlled cell-line experiments and primary cells drawn from acutely ill patients. By using the same Wuhan-1 viral stock, verified by sequencing and titrated by TCID50 and plaque assay, for every condition, the investigators minimized viral preparation as a confounding variable. The low multiplicity of infection of 0.001 is notable, as it means relatively few cells received productive viral input, yet robust signaling changes were still detectable. This suggests that even limited viral exposure can trigger substantial inflammatory pathway activation, consistent with the idea that a small number of infected cells can amplify responses through paracrine signaling, although the study did not directly test such amplification mechanisms.

The choice of signaling readouts also connects the findings to established COVID-19 biology. NFκB is the canonical transcription factor driving transcription of tumor necrosis factor, interleukin-6, and interleukin-1 family cytokines, all of which are elevated in severe disease and correlate with the testosterone deficits described in the clinical literature. STAT3 links cytokine signaling, particularly through the interleukin-6 receptor JAK-STAT axis, to cell survival and inflammatory differentiation programs in monocytes and neutrophils. p38 MAPK is a stress-activated kinase implicated in cytokine translation, oxidative burst, and neutrophil extracellular trap formation. The observation that SARS-CoV-2 activated all three pathways in monocytic cells, and that androgen receptor agonism and antagonism shifted the magnitude of these responses in opposite directions, provides a mechanistic scaffold for interpreting why male patients with lower testosterone might nonetheless experience androgen-driven hyperinflammation, since DHT effects were observed at concentrations within the physiological range.

The dose-dependence of the androgen effects deserves particular emphasis. In the THP-1 experiments, low-dose DHT at 10 nanomolar sustained p38 MAPK activation while low-dose flutamide at 100 nanomolar reduced it, but higher flutamide concentrations did not reproduce this effect. Such non-monotonic dose relationships are a recognized feature of sex steroid biology, where receptor occupancy, receptor isoform expression, and co-regulator availability can produce qualitatively different outcomes at different ligand concentrations. For translational purposes, this complexity cautions against simple assumptions that androgen blockade will uniformly suppress inflammatory signaling across all cell types and doses, and it highlights the need for careful pharmacological characterization before any therapeutic repurposing of androgen receptor antagonists in viral disease.

The cell-type specificity of the findings is equally important. DHT amplified NFκB signaling in monocytic cells and neutrophils, yet it twice reduced virus-induced p38 MAPK activation in endothelial cells and lowered baseline STAT3 activity after 48 hours. This divergence means that androgen signaling cannot be characterized as simply pro- or anti-inflammatory; rather, its net effect on systemic inflammation depends on the relative contribution of vascular versus immune compartments to a given clinical phenotype. In severe COVID-19, where both endothelial injury and myeloid cell hyperactivation drive pathology, the opposing effects could partially offset each other or, alternatively, the monocyte- and neutrophil-directed amplification may dominate because these cells produce the circulating cytokines and tissue-damaging mediators observed in patients.

The transendothelial migration results add a functional dimension that goes beyond signaling biochemistry. Monocyte recruitment across the endothelial barrier is a hallmark of vascular inflammation and contributes directly to immunothrombosis, the process by which leukocyte activation, tissue factor expression, and platelet engagement generate thrombi in the pulmonary and systemic microvasculature. The finding that DHT promoted monocyte migration with high statistical significance, and that it also induced detachment of virus-exposed endothelial cells, links androgen signaling to two mechanistically connected events: weakening of the endothelial monolayer and enhanced leukocyte trafficking through it. Detachment of endothelial cells, if it occurs in vivo, could expose subendothelial matrix and tissue factor, providing a procoagulant surface that complements the inflammatory effects of infiltrating monocytes.

The differential regulation of estrogen receptor expression by the virus itself adds another layer of interpretation. Reduced ESR1 in endothelial cells could diminish the protective, anti-inflammatory tone that estrogen signaling normally provides to the vasculature, including nitric oxide-mediated vasodilation and suppression of adhesion molecule expression. Increased ESR1 in neutrophils and monocytes, conversely, might represent a compensatory attempt by innate immune cells to enhance estrogen-dependent immunoregulation during systemic inflammation. Whether this compensatory upregulation is functionally effective in patients, or is overwhelmed by the concurrent androgen-driven amplification of NFκB and MAPK signaling, remains an open question that would require measuring receptor protein levels and downstream estrogen-responsive gene expression in patient cells.

The temporal dimension of the findings, with stronger pathway activation at 24 hours than at 48 hours in patient monocytes and progressive deterioration of inflammatory signaling over the course of disease, aligns with clinical observations that COVID-19 inflammation evolves in phases. Early innate immune activation, followed by sustained or dysregulated myeloid responses, characterizes progression toward severe disease. The observation that signaling responses in patient monocytes worsened over time suggests that longitudinal sampling, rather than single time-point measurements, may be necessary to capture the full trajectory of sex steroid modulation in COVID-19, and it raises the possibility that therapeutic timing, whether targeting androgen signaling early or late in disease, could substantially influence outcomes.

Finally, the study’s reliance on the Wuhan-1 variant, collected during the first years of the pandemic, invites consideration of how these mechanisms might apply to later variants with altered inflammatory profiles. The core signaling pathways investigated here, NFκB, STAT3, and p38 MAPK, are activated by multiple pattern recognition receptors and cytokine circuits, so the sex steroid modulation described is unlikely to be variant-specific in principle. However, the magnitude of viral replication, the efficiency of cell entry, and the specific cytokine milieu induced by different variants could shift the balance between androgen-amplified and estrogen-attenuated responses. Extending this experimental framework to contemporary variants, and to cells from vaccinated individuals with pre-existing adaptive immunity, would help determine whether the androgen-responsive mechanisms identified here remain relevant targets for mitigating severe viral inflammation and endothelial dysfunction in current clinical practice.

Subject of Research: Sex steroids differentially modulate SARS-CoV-2-induced inflammatory responses in endothelial and immune cells

Article Title: Sex steroids differentially modulate SARS-CoV-2-induced inflammatory responses in endothelial and immune cells

Article References: Bižić-Radulović, S., Subotički, T., Kovačević, A., Živković, E., Popović, O., Mitrović-Ajtić, O., Diklić, M., Jovanović, S., Čokić, V. P., & Beleslin-Čokić, B. (2026). Sex steroids differentially modulate SARS-CoV-2-induced inflammatory responses in endothelial and immune cells. Frontiers in Cellular and Infection Microbiology, 16, Article 1976945. https://doi.org/10.3389/fcimb.2026.1976945

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1976945

Keywords: steroids, differentially, modulate, SARS-CoV-2-induced, inflammatory, responses, endothelial, immune, cells, scientific research

The team used a technique called Mendelian randomization, which exploits the random allocation of genetic variants at conception as natural experiments. Because genes are inherited independently of lifestyle or environment, they can serve as proxies for biological exposures without the confounding that plagues ordinary observational studies. The researchers drew on genome-wide association data from hundreds of thousands of adults of European ancestry, selecting variants strongly linked to two markers: the triglyceride-glucose index, a widely used proxy for insulin resistance, and high-sensitivity C-reactive protein, a blood protein that rises with systemic inflammation.

Genetically predicted increases in both markers were associated with higher odds of major depressive disorder. Each standard deviation rise in the genetically proxied triglyceride-glucose index corresponded to an 8 percent increase in odds, while each standard deviation rise in genetically proxied C-reactive protein corresponded to an 11 percent increase. Reverse analyses, testing whether depression liability predicted the metabolic markers, showed no significant associations, suggesting the direction runs from metabolism and inflammation toward depression rather than the other way around.

Crucially, the association between insulin resistance and depression persisted even after the researchers adjusted for genetically proxied body mass index. This suggests that insulin resistance itself, rather than overall adiposity, may be the relevant exposure. The effect sizes are modest, and the authors caution that statistical significance at these odds ratios does not translate directly into clinical predictive or therapeutic value.

To corroborate the genetic findings, the team turned to real-world data. They analyzed 327 late adolescents aged 18 to 19 years from the National Health and Nutrition Examination Survey, pooling pre-pandemic cycles to obtain fasting blood measurements. In this nationally representative sample, each standard deviation increase in the triglyceride-glucose index was associated with 28 percent higher odds of moderate-to-severe depressive symptoms, defined as a score of 10 or higher on the nine-item Patient Health Questionnaire. Each standard deviation increase in log-transformed C-reactive protein was associated with 33 percent higher odds.

The researchers also examined a retrospective clinical cohort of 224 adolescents diagnosed with major depressive disorder and 200 age- and sex-matched controls without psychiatric diagnoses. Depressed adolescents showed markedly higher triglyceride-glucose indices and C-reactive protein levels than controls. After adjusting for age, sex, and body mass index, each unit increase in the triglyceride-glucose index corresponded to 35 percent higher odds of depression, and adolescents with C-reactive protein above 3.0 milligrams per liter had roughly two and a half times the odds compared with those below 1.0 milligrams per liter.

The biological mechanisms linking these pathways are likely multifactorial. Insulin receptors are distributed throughout the brain, and impaired insulin signaling can disrupt synaptic plasticity, neurotransmitter regulation, and neurogenesis. Insulin resistance may also exacerbate hypothalamic-pituitary-adrenal axis dysregulation, leading to chronically elevated cortisol. On the inflammatory side, pro-inflammatory cytokines can alter tryptophan metabolism, shunting it away from serotonin synthesis toward neurotoxic metabolites, and can reduce the availability of brain-derived neurotrophic factor, impairing neuronal survival and function.

The study’s triangulation design is a methodological strength, but the authors are careful about interpretation. The genetic analyses relied on adult or mixed-age genome-wide association studies, so the estimates reflect liability across the life course rather than effects specific to adolescence. The observational components are cross-sectional and cannot exclude reverse causation. The clinical cohort was retrospective and single-center, and unmeasured socioeconomic factors remain possible confounders. Depression phenotypes also differed across the three arms, from genome-wide defined disorder to self-reported symptoms to psychiatrist-assigned diagnosis.

Despite these limitations, the convergence of evidence from methodologically distinct designs strengthens the case that metabolic-inflammatory dysregulation is worth serious attention in adolescent depression research. The authors emphasize that their findings generate a rationale for prospective longitudinal studies and future intervention trials rather than supporting immediate changes to clinical practice. Replication in larger, more ancestrally diverse adolescent cohorts is needed before broader claims can be made, and whether modifying metabolic or inflammatory pathways can prevent or treat depression in teenagers remains an open question for the next generation of studies.

The triglyceride-glucose index deserves a brief explanation for readers unfamiliar with it. It is calculated from fasting triglyceride and fasting glucose values using a simple logarithmic formula, and it has gained popularity in recent years as an inexpensive surrogate for insulin resistance. Unlike the hyperinsulinemic-euglycemic clamp, which is considered the reference standard but is impractical outside specialized research settings, the triglyceride-glucose index requires only routine bloodwork. It has been validated against clamp-based measures in multiple populations and has been associated with cardiometabolic outcomes, type 2 diabetes, and, increasingly, with neuropsychiatric conditions. Its appeal in adolescent research lies partly in the fact that it avoids the pubertal and developmental complications that can affect insulin-based measures, although it remains an approximation rather than a direct assessment of insulin sensitivity.

High-sensitivity C-reactive protein, meanwhile, is produced primarily by the liver in response to interleukin-6 and other inflammatory signals. Values below 1.0 milligram per liter are generally considered low risk, values between 1.0 and 3.0 indicate average risk, and values above 3.0 signal elevated systemic inflammation. The clinical cohort’s finding that adolescents exceeding the 3.0 threshold had roughly two and a half times the odds of depression aligns with a substantial adult literature linking elevated C-reactive protein to depressive symptoms and diagnosis. Some researchers have proposed that a subgroup of depression, sometimes described as inflammatory or melancholic in character, may be particularly responsive to inflammatory signaling, which raises the possibility that metabolic and inflammatory markers could eventually help stratify patients into biologically distinct subtypes.

The bidirectional structure of the genetic analysis is worth emphasizing. In reverse Mendelian randomization, the authors tested whether genetic liability to major depressive disorder predicted the metabolic and inflammatory markers, and found no statistically significant associations. This asymmetry matters because observational studies in psychiatry have long struggled with the question of whether physical health problems cause depression or whether depression, through inactivity, poor diet, and disrupted sleep, degrades metabolic health. The genetic results do not settle this question definitively, since the instruments capture lifelong liability rather than adolescent-specific dynamics, but they tilt the interpretive balance toward metabolism and inflammation as upstream contributors.

The multivariable adjustment for genetically proxied body mass index also carries interpretive weight. Obesity and insulin resistance are tightly correlated, and adipose tissue is itself an endocrine organ that secretes pro-inflammatory cytokines. If the apparent effect of insulin resistance were entirely attributable to excess adiposity, adjusting for genetically predicted body mass index should have attenuated the estimate toward the null. The persistence of the association suggests a partially independent pathway, although residual correlation between the genetic instruments cannot be fully excluded, and the authors acknowledge this limitation.

The choice of the Patient Health Questionnaire-9 with a cutoff of 10 or higher in the NHANES sample is a standard approach for identifying moderate-to-severe depressive symptoms in population surveys, but it is a screening tool rather than a diagnostic instrument. This means the population-based arm captures symptomatic burden rather than clinically confirmed disorder, a distinction that matters when comparing effect sizes across the three study arms. The clinical cohort, by contrast, used psychiatrist-assigned diagnoses, which provides greater specificity but introduces referral and treatment-seeking biases that a representative survey avoids.

The multiple-imputation sensitivity analysis in the NHANES component addresses a common problem in survey-based research: missing exposure or outcome data. By retaining all 561 participants with complete exposure and outcome information under imputation assumptions, the researchers demonstrated that their complete-case estimates were not artifacts of selective attrition. Directional consistency across both analytical approaches strengthens confidence that the observed associations are not driven by the particular subset of adolescents who happened to have fasting blood measurements available.

It is also notable that the study deliberately restricted the observational analyses to pre-pandemic survey cycles. The COVID-19 pandemic substantially disrupted adolescent mental health and metabolic behaviors alike, and pooling post-pandemic data could have introduced period effects that confounded the associations. This design choice reflects growing awareness in the field that pandemic-era data require careful handling when studying developmental psychopathology.

Looking forward, the most informative next steps would be longitudinal cohorts that measure metabolic and inflammatory markers in early adolescence and track depressive outcomes over years, ideally with repeated sampling to capture developmental trajectories. Interventional studies, whether of lifestyle modification, insulin-sensitizing agents, or anti-inflammatory treatments, would provide the strongest test of causality, but such trials in adolescents raise ethical and practical complexities. In the interim, the convergence of genetic, population-based, and clinical evidence in this study offers a credible foundation for treating metabolic-inflammatory dysregulation as a serious candidate mechanism in adolescent depression, one that may eventually inform prevention strategies aimed at metabolic health during a developmental window when interventions could have lasting impact.

Subject of Research: Metabolic and inflammatory traits and depression: a Mendelian randomization study with late-adolescent population-based and clinical triangulation

Article Title: Metabolic and inflammatory traits and depression: a Mendelian randomization study with late-adolescent population-based and clinical triangulation

Article References: Wu, Y., Xu, Z., & Wu, D. (2026). Metabolic and inflammatory traits and depression: a Mendelian randomization study with late-adolescent population-based and clinical triangulation. Frontiers in Psychiatry, 17, Article 1935185. https://doi.org/10.3389/fpsyt.2026.1935185

Image Credits: AI Generated

DOI: 10.3389/fpsyt.2026.1935185

Keywords: Metabolic, inflammatory, traits, depression, Mendelian, randomization, late-adolescent, population-based, clinical, triangulation, scientific research

White matter hyperintensities, usually abbreviated WMH, are far more than a radiological curiosity. They represent areas where the deep and periventricular white matter—the cabling that connects distant brain regions—has been injured by the gradual failure of the brain’s smallest blood vessels. On fluid-attenuated inversion recovery, or FLAIR, MRI sequences, these damaged zones appear as hyperintense signals because the tissue has accumulated excess fluid, gliosis, and loss of myelin. In the elderly, WMH are nearly ubiquitous: in this study, 325 of 428 participants, or 75.9 percent, already had them at baseline. Clinically, they are linked to gait disturbance, cognitive decline, stroke risk, and vascular dementia, yet they often progress for years without any obvious symptoms, which is why researchers are so eager to find cheap, accessible indicators of who is most at risk.

The research team, led by Zhaoxia Liu and colleagues at the Huai’an Hospital of Traditional Chinese Medicine in China, enrolled consecutively hospitalized patients aged 60 or above who underwent baseline cranial MRI. WMH severity was graded using the Fazekas scale, a widely used three-point radiological system that separately scores periventricular hyperintensities and deep white matter hyperintensities and then combines them into an overall grade. At the same time, the investigators measured three peripheral blood inflammatory markers: the absolute neutrophil count, or NC; the neutrophil-to-lymphocyte ratio, or NLR; and the white blood cell-to-lymphocyte ratio, or WLR. All three are derived from the standard complete blood count, meaning they require no additional blood draw, no specialized assay, and essentially no added cost.

The technical logic behind these markers is worth unpacking. Neutrophils are the front-line soldiers of the innate immune system, rising rapidly during acute infection and systemic inflammation. Lymphocytes, by contrast, mediate adaptive immunity and tend to fall under chronic inflammatory stress. The NLR therefore captures the balance between pro-inflammatory activation and immune regulation in a single ratio, and it has emerged in recent years as a robust composite index of systemic inflammation in cardiovascular and cerebrovascular disease. The WLR extends the same principle to the entire white cell population divided by the lymphocyte count. Because both ratios are readily calculable from any standard count, they have attracted attention as potential risk stratification tools in settings where advanced biomarkers are unavailable.

Using multivariable logistic regression adjusted for confounders, the team found that higher NC, NLR, and WLR were each independently associated with the presence of WMH, with all associations reaching statistical significance at P less than 0.05. The picture became more nuanced when severity was considered. NLR and WLR were associated with both moderate and severe WMH, suggesting these ratios track disease across its stages, while NC was associated only with severe WMH, positioning the raw neutrophil count as a marker of advanced disease rather than early change.

Dose-response analysis strengthened the case. When participants were divided into quartiles of each marker, the highest quartile, Q4, was associated with severe WMH after Benjamini-Hochberg false discovery rate correction, a statistical method that guards against spurious findings when many comparisons are made. The adjusted odds ratios were 2.033 for NC, 1.503 for NLR, and 1.581 for WLR. In other words, older adults whose inflammatory markers fell in the top quarter of the distribution carried roughly one-and-a-half to two times the odds of severe white matter damage compared with those in the lowest quartile, even after accounting for other clinical variables.

The most striking results came from the longitudinal arm of the study. Among 338 patients with follow-up imaging, the investigators assessed radiological progression over three years, defined as an increase of at least one point on the Fazekas score. Baseline Q4 levels of all three markers strongly predicted this future progression: the odds ratios were 4.035 for NC, 5.184 for NLR, and 4.076 for WLR. A single routine blood count taken at baseline, in other words, carried roughly four- to five-fold odds of identifying who would show measurable worsening of white matter damage on MRI three years later. This predictive power for future progression is what elevates the findings beyond a simple cross-sectional correlation.

The markers also delivered a modest but measurable boost to predictive performance. Adding them to a basic clinical model improved the area under the curve, or AUC, from 0.753 to a range of 0.757 to 0.762. The improvement is small in absolute terms, and the authors are careful not to oversell it, but it demonstrates that inflammatory profiling adds incremental information to established clinical variables rather than duplicating them. Notably, the WLR, despite being the simplest of the three indices to calculate, showed predictive value comparable to the more widely studied NLR, which may make it the more practical candidate for everyday screening.

What might be happening biologically? Systemic inflammation is increasingly implicated in cerebral small vessel disease, the underlying pathology of WMH. Elevated circulating neutrophils can damage the endothelium, the delicate single-cell lining of blood vessels, through oxidative burst and protease release, promoting the blood-brain barrier dysfunction and endothelial injury that characterize small vessel disease. Chronic inflammation also favors the atherosclerotic and arteriosclerotic changes that stiffen the brain’s perforating arteries, starving the deep white matter of adequate perfusion. The lymphocyte component of the ratios may reflect the depletion of immune regulation that accompanies chronic inflammatory aging, sometimes called inflammaging. The new study does not prove these mechanisms directly, but its longitudinal design is consistent with the hypothesis that systemic inflammation is not merely a bystander in white matter damage.

The authors are explicit about the limits of their work. The cohort consisted of hospitalized patients rather than healthy community dwellers, which may limit generalizability, and the markers were measured at baseline rather than repeatedly over time, so fluctuations in inflammatory status could not be captured. The AUC improvement was modest, and the study cannot establish causation. Before these markers can be integrated into cerebral small vessel disease risk stratification frameworks, the team calls for external validation in community-based cohorts with repeated inflammatory profiling. Still, the appeal of the approach is hard to deny: if a standard complete blood count, already ordered millions of times a day in hospitals worldwide, can help flag older adults at risk of progressive white matter damage, it could open a low-cost route to earlier monitoring, more aggressive vascular risk management, and closer MRI surveillance for the patients who need it most.

Subject of Research: Neuroscience

Article Title: Association of peripheral blood inflammatory markers with white matter hyperintensities in the elderly

Article References: Liu, Z., Shi, K., Shu, Z., Zhang, K., Yu, Q., & Wang, B. (2026). Association of peripheral blood inflammatory markers with white matter hyperintensities in the elderly. BMC Geriatrics. https://doi.org/10.1186/s12877-026-08474-8

Image Credits: AI Generated

DOI: 10.1186/s12877-026-08474-8

Keywords: white matter hyperintensities, inflammation, neutrophil-to-lymphocyte ratio, cerebral small vessel disease, brain MRI, aging, biomarkers, BMC Geriatrics, Association, peripheral, blood, inflammatory

The researchers, led by Mami Amaki and Yasutomo Imai, hypothesized that caspase-1 might control IL-33 release from keratinocytes in vivo. Their reasoning drew on a parallel case: IL-1α, like IL-33, is a nuclear cytokine stored under steady-state conditions, and its extracellular release requires caspase-1. Previous studies, however, had suggested that IL-33 release is independent of caspase-1, but those conclusions came largely from non-cutaneous tissues or in vitro systems. In the airway epithelium, for example, allergen protease-activated stress granule assembly and gasdermin D fragmentation have been shown to control IL-33 secretion without caspase-1. The Japanese team suspected that the skin might operate by different rules, and their new findings support that idea.

The first technical step was to establish where caspase-1 actually resides in skin. Using immunofluorescence staining of mouse skin sections with a Cy3-conjugated anti-caspase-1 P10 polyclonal antibody, the researchers detected caspase-1 immunoreactivity in the nuclei of epidermal keratinocytes. No specific staining appeared in caspase-1/11-deficient mice, which served as negative controls. This was a significant observation because earlier studies had concluded that caspase-1 expression was restricted to hematopoietic cells, conclusions based largely on the absence of detectable interleukin-1 beta-processing activity and the limited sensitivity of the detection methods available at the time. Subsequent work with improved methodologies has revealed low-level but functional caspase-1 expression in epithelial cells, including keratinocytes. For caspase-1 to be involved in the release of a nuclear alarmin like IL-33, the protease would need to be present in keratinocyte nuclei, and the new staining data confirm exactly that.

Next, the team examined what happens to nuclear IL-33 when the skin is stimulated. They applied 20 microliters of 0.5 percent 2,4-dinitrofluorobenzene (DNFB), a contact-sensitizing hapten dissolved in acetone and olive oil, to the left ear of mice while the right ear received vehicle alone. Six hours later, they processed the ear skin for immunofluorescence staining for IL-33, using an affinity-purified rabbit anti-mouse IL-33 polyclonal antibody detected with a biotinylated goat anti-rabbit IgG secondary antibody and streptavidin-conjugated Alexa Fluor 594, with nuclei counterstained using DAPI. The disappearance of nuclear IL-33 staining in keratinocytes was interpreted as evidence that IL-33 had been released into the extracellular space, an established surrogate readout that parallels findings in experimental allergic rhinitis, where allergen challenge induces a rapid loss of IL-33 staining in nasal epithelial cells alongside increased IL-33 levels in nasal lavage fluids.

The result was striking. In wild-type mice, IL-33 fluorescence in the epidermis was substantially reduced six hours after DNFB treatment, consistent with the team’s previous report that cutaneous stimulation triggers extracellular IL-33 release in vivo. In caspase-1/11-deficient mice, however, IL-33 immunoreactivity remained clearly detectable in the nuclei of epidermal keratinocytes at the same time point. In other words, deleting caspase-1/11 prevented the DNFB-induced loss of keratinocyte IL-33. Notably, quantitative real-time PCR showed that DNFB application increased Il33 mRNA expression in both wild-type and caspase-1/11-deficient mice, even though nuclear IL-33 staining persisted in the knockout animals. This indicates that Il33 transcription is induced by DNFB independently of IL-33 release, meaning the protease is specifically required for the release step rather than for the transcriptional response.

To test whether this release mechanism matters for actual disease, the researchers crossed their caspase-1/11-deficient mice with the hK14mIL33tg transgenic line, which overexpresses murine IL-33 in keratinocytes under the control of the human keratin-14 promoter. These IL33tg mice spontaneously develop atopic dermatitis-like skin inflammation. When caspase-1/11 was deleted in this background, the resulting IL33tg Casp1/11KO mice exhibited markedly attenuated skin inflammation compared with IL33tg mice. Histological examination of hematoxylin and eosin-stained skin sections showed pronounced leukocyte and eosinophil infiltration accompanied by epidermal hyperplasia in IL33tg mice, while these pathological features were minimal in the double-deficient animals, indicating a substantially reduced inflammatory response in the absence of caspase-1/11.

The molecular signature of the type 2 immune response told the same story. Quantitative PCR analysis of skin tissue, performed with a TaqMan RNA-to-Ct Kit and an ABI7900HT sequence detection system, revealed significant reductions in the expression of type 2 cytokines including Il4, Il5, and Il13, as well as Prg2, which encodes eosinophil peroxidase and serves as a specific marker of murine eosinophils. The reduction in Prg2 expression was consistent with the histological findings showing markedly reduced eosinophil infiltration in IL33tg Casp1/11KO mice. Together, these data indicate that caspase-1/11 deficiency suppresses IL-33-driven type 2 immune responses in the skin, dampening the entire downstream allergic cascade that IL-33 normally sets in motion through ILC2 activation.

The findings carry important caveats that the authors address candidly. The knockout mice used in the study have historically been described as caspase-1-deficient, but they are now recognized to carry a combined deficiency of both caspase-1 and caspase-11, because the Casp1 and Casp11 genes lie in close genomic proximity within the same gene cluster, resulting in simultaneous disruption of both loci in this strain. The potential contribution of caspase-11 therefore cannot be formally excluded. However, previous studies indicate that epithelial inflammasome-related responses, including IL-33 regulation, are mainly mediated by caspase-1 rather than caspase-11. Caspase-11 is primarily implicated in noncanonical inflammasome signaling in myeloid cells and localizes predominantly in the cytoplasm, making its direct involvement in the nuclear export of IL-33 from keratinocytes less likely. The authors also note that loss of nuclear staining does not directly quantify extracellular IL-33 levels, so future studies using biochemical measurements will be needed to confirm the release mechanism.

There is another puzzle worth noting. Several studies have suggested a role for caspase-1 in IL-33 inactivation rather than release, since IL-33 can be inactivated after maturation by caspase-1. If caspase-1-mediated inactivation were essential in vivo, IL-33-transgenic mice lacking caspase-1/11 would be expected to show exacerbated skin inflammation, yet the opposite was observed. The authors also point out that pharmacological inhibition of caspase-1 may not fully reflect its role in alarmin release, because for IL-1α the presence of caspase-1 protein, rather than its enzymatic activity, can be required for secretion. Because caspase-1/11 was deleted in all cells in the mice used, the possibility that caspase-1 deficiency in immune cells influences IL-33-induced skin inflammation cannot be excluded, though the marked reduction in inflammation suggests that caspase-1/11 deficiency affects an early step in IL-33-driven skin inflammation, most likely IL-33 release from keratinocytes.

The broader implication is that alarmin biology may be tissue-specific in ways the field has not fully appreciated. IL-33 can be released independently of caspase-1 in other tissues, notably the airway epithelium, where gasdermin D-mediated pathways dominate. But in the skin, the new evidence suggests that caspase-1 is involved in the pathogenic release of IL-33 from keratinocytes in vivo, and that this release step is a critical control point for atopic dermatitis-like inflammation. If the findings hold up in biochemical assays and in human tissue, they could reshape how researchers think about targeting IL-33 in atopic dermatitis, pointing to the release machinery within keratinocytes as a potential therapeutic frontier alongside the IL-33-blocking antibodies already in clinical development.

Subject of Research: Immunology

Article Title: Deficiency of inflammatory caspases attenuates IL-33–mediated dermatitis

Article References: Amaki, M., Murata, T., Kanazawa, N., & Imai, Y. (2026). Deficiency of inflammatory caspases attenuates IL-33–mediated dermatitis. Journal of Cutaneous Immunology and Allergy, 9, Article 16358. https://doi.org/10.3389/jcia.2026.16358

Image Credits: AI Generated

DOI: 10.3389/jcia.2026.16358

Keywords: atopic dermatitis, IL-33, caspase-1, keratinocytes, alarmin, skin inflammation, type 2 cytokines, innate lymphoid cells, Deficiency, inflammatory, caspases, attenuates

The study, published in Neurocritical Care by Ye-Ting Chen, Yi-Si Shan, Shen-Nan Zhao, Wen-Ping Cao, and Jian-Feng Pu of Zhangjiagang Second People’s Hospital and Zhangjiagang Traditional Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, focused on the TLR/TRAF6/NF-κB pathway, a signaling cascade long implicated in stroke-related neuroinflammation. Toll-like receptors (TLRs), particularly TLR4 and TLR9, act as sentinels of the innate immune system. When they detect danger signals released by dying cells during reperfusion, they recruit the adaptor protein TRAF6, which in turn activates NF-κB, a transcription factor that commands the production of proinflammatory cytokines. In the brain, this cascade can transform a survivable insult into a devastating one.

To test whether electroacupuncture could interrupt this pathway, the researchers used male Sprague-Dawley rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R), a widely used rodent model of ischemic stroke. The animals were randomly assigned to four groups: a sham group that underwent surgery without vessel occlusion, an MCAO/R group that experienced 60 minutes of ischemia followed by reperfusion, a sham electroacupuncture (SEA) group, and an electroacupuncture (EA) group. The SEA and EA groups received 30 minutes of treatment after the ischemic period, allowing the team to evaluate whether real stimulation at defined acupoints offered benefits beyond the mere act of needle placement.

Twenty-four hours after the procedure, the differences between groups were striking. Rats treated with electroacupuncture showed significantly improved neurological function and reduced infarct volume compared with untreated MCAO/R animals. Body weight, measured before and after the procedure, provided an additional indicator of overall recovery. The results suggest that a single post-ischemia session of electroacupuncture was enough to produce measurable neuroprotection within a day, a timeframe relevant to the acute phase of human stroke care.

At the molecular level, the team used western blot and reverse-transcription polymerase chain reaction (RT-PCR) to quantify protein and messenger RNA expression of TLR4, TLR9, TRAF6, and NF-κB in brain tissue. In electroacupuncture-treated rats, expression of all four components was down-regulated compared with the MCAO/R group. This finding places the pathway squarely in the crosshairs of the treatment: rather than acting downstream on individual cytokines, electroacupuncture appears to suppress the upstream signaling machinery that drives their production.

The downstream consequences were equally telling. Using RT-PCR and enzyme-linked immunosorbent assay (ELISA), the researchers measured inflammatory markers in the injured cortex. Electroacupuncture reduced both mRNA and protein levels of the proinflammatory cytokines TNF-α, IL-6, and IL-1β, molecules that promote neuronal death, edema, and further immune cell recruitment when overproduced after reperfusion. At the same time, expression of the anti-inflammatory cytokine IL-10 increased, suggesting the treatment did not simply blunt the immune response but actively shifted it toward a resolution phenotype. This rebalancing of the cytokine profile may explain the improved neurological outcomes observed in the treated animals.

The study builds on a growing body of evidence that electroacupuncture, which combines traditional needle placement with controlled electrical stimulation, engages well-defined neuroimmune mechanisms rather than vague energetic effects. Previous work from the same field has shown that electroacupuncture pretreatment can inhibit the TLR4/NF-κB/TXNIP/NLRP3 signaling pathway and modulate microglial polarization to alleviate cerebral I/R injury in rats. Other studies have implicated the alpha7 nicotinic acetylcholine receptor, the delta-opioid receptor-BDNF/TrkB axis, vagus nerve activation, and even gut microbiota in electroacupuncture’s neuroprotective repertoire. The new findings add the TLR/TRAF6/NF-κB cascade to this mechanistic map and clarify how a single pathway connects needle stimulation to cytokine output.

What makes the results particularly compelling is the specificity of the pathway involved. TRAF6, the ubiquitin E3 ligase at the center of the cascade, has been shown in independent research to exacerbate ischemic stroke by ubiquitinating and activating Rac1, and to drive NLRP3-related pyroptosis, a form of inflammatory cell death, after cerebral I/R. NF-κB, the transcription factor at the pathway’s end, commands a broad inflammatory program in neurological tissue. By suppressing TLR4, TLR9, TRAF6, and NF-κB simultaneously, electroacupuncture appears to act at multiple nodes of the same axis, a strategy that may prove more robust than targeting any single molecule with a drug.

The clinical implications are significant. Stroke remains a leading cause of death and disability worldwide, and while thrombolysis and thrombectomy can restore blood flow, no approved therapy directly addresses the reperfusion injury that follows. Electroacupuncture is already used in some stroke rehabilitation settings, and randomized controlled trials have examined its effects on post-stroke recovery. If the TLR/TRAF6/NF-κB pathway proves to be a conserved target in humans, electroacupuncture could offer a low-cost, mechanistically grounded adjunct to acute stroke care, potentially narrowing the gap between reperfusion and inflammation control.

Important caveats remain. The findings come from a rodent model, and the treatment window, stimulation parameters, and acupoint selection in rats may not translate directly to human patients. The study measured outcomes at a single 24-hour timepoint, leaving longer-term effects on tissue repair and functional recovery unexplored. Still, by identifying a specific molecular pathway through which electroacupuncture ameliorates cerebral I/R-induced inflammation, the researchers have transformed what might seem like an esoteric complementary therapy into a testable neuroprotective strategy. The next step will be to determine whether the same pathway can be engaged safely and effectively in the human brain, where the stakes of every hour after reperfusion could not be higher.

Subject of Research: Neuroscience

Article Title: Electroacupuncture Ameliorating Cerebral I/R-Induced Inflammatory Response through the TLR/TRAF6/NF-κB Pathway

Article References: Chen, Y.-T., Shan, Y.-S., Zhao, S.-N., Cao, W.-P., & Pu, J.-F. (2026). Electroacupuncture Ameliorating Cerebral I/R-Induced Inflammatory Response through the TLR/TRAF6/NF-κB Pathway. Neurocritical Care. https://doi.org/10.1007/s12028-026-02680-3

Image Credits: AI Generated

DOI: 10.1007/s12028-026-02680-3

Keywords: Electroacupuncture, Ameliorating, Cerebral, R-Induced, Inflammatory, Response, TRAF6, Pathway, scientific research

That rising prevalence matters for reasons that go far beyond body weight. Obesity has been linked to a more severe course of inflammatory bowel disease, including lower rates of corticosteroid-free remission, increased risk of surgery among patients receiving anti-tumor necrosis factor alpha therapy, biologic treatment failure, and shorter intervals between disease flares. It may also help explain a persistent therapeutic gap: 40 to 60 percent of patients with Crohn’s disease and ulcerative colitis fail to respond to advanced therapies. One proposed culprit is the hormonally active visceral fat packed around the intestines. A multi-center prospective study found that patients with greater intra-abdominal visceral adipose tissue were less likely to achieve corticosteroid-free or endoscopic remission when starting biologic therapy. Crohn’s patients who did not respond to biologics had higher visceral fat levels than responders, and those non-responders with elevated visceral fat also carried increased serum levels of the inflammatory signaling molecules interleukin-6 and tumor necrosis factor alpha.

Against that backdrop, the Jefferson team set out to evaluate the safety and clinical effectiveness of GLP-1 receptor agonists in patients with inflammatory bowel disease, and to summarize the theorized anti-inflammatory mechanisms that could make these metabolic drugs useful beyond weight loss alone. Because the existing literature is heterogeneous in interventions and outcomes, the authors chose a narrative review rather than a systematic one. They searched PubMed through July 2026 using index terms combining GLP-1 receptor agonists with inflammatory bowel disease, Crohn’s disease, and ulcerative colitis alongside safety, effectiveness, and outcomes. The initial search yielded 187 results, expanded through forward and backward citation chaining. Studies focused on GLP-2 analogs, short bowel syndrome, DPP-4 inhibitors, or microbiota effects on the GLP-1 axis were excluded, and preprint data was omitted. Two reviewers extracted data independently, resolving discrepancies through discussion.

The weight loss findings were strikingly consistent. In an 18-month analysis, patients with inflammatory bowel disease taking semaglutide lost a mean of 16 pounds, statistically indistinguishable from the 18 pounds lost by a non-IBD control cohort. In case series, 58.3 percent of patients achieved at least 5 percent weight reduction at six months, while another cohort reported a significant drop in mean body mass index from 34 to 31 kilograms per square meter alongside a median total body weight loss of 8.15 kilograms. Clarke and colleagues reported that 64.7 percent of IBD patients achieved at least 5 percent weight loss and 46.1 percent achieved 10 percent within one year. Systematic reviews of retrospective cohort studies confirmed significant body weight reductions. Which specific agent works best remains contested: one study found semaglutide associated with the greatest weight loss at 12 to 24 weeks, while another reported tirzepatide outperformed semaglutide, highlighting the need for head-to-head prospective trials.

Metabolic outcomes were more modest and less consistent. In a subgroup of patients with inflammatory bowel disease and type 2 diabetes, GLP-1 receptor agonists produced a modest 0.3 percent reduction in hemoglobin A1c at six months, though one cohort study found no significant difference in A1c or total cholesterol, and a systematic review noted inconsistent effects on HDL, triglycerides, LDL, and total cholesterol. The safety profile, however, emerged as largely reassuring. Gastrointestinal adverse effects, chiefly nausea, vomiting, and diarrhea, were the most frequently reported problems and often limited treatment continuity. One retrospective cohort found 11 percent of IBD patients on GLP-1 therapy experienced these symptoms, and of 25 patients who had side effects, 23 discontinued therapy. Another cohort found 24 percent stopped the drugs, with roughly half citing gastrointestinal intolerance. Yet a study of 271 patients comparing pre- and post-treatment periods found no significant difference in gastrointestinal adverse events, calling into question whether the symptoms were truly drug-related.

More serious concerns appear largely unfounded. Although ileus, a potentially dangerous halt in intestinal movement, has been raised as a theoretical risk in the general population, a Danish nationwide cohort study of 61,927 patients with inflammatory bowel disease found that GLP-1 receptor agonists were not associated with increased risk of ileus or intestinal obstruction. In a retrospective study of 272 IBD patients, only 7 percent of reported adverse effects were non-gastrointestinal, and no serious adverse events occurred. Hypoglycemia, injection site reactions, and death each occurred in 1.1 percent of cases in another study, rates comparable to non-IBD populations. No differences or reduced risk were observed in gallbladder disease, pancreatitis, or acute kidney injury compared to IBD patients not taking the drugs.

The effects on inflammatory biomarkers told a more nuanced story. One retrospective study reported a significant reduction in C-reactive protein from 9.0 to 1.6 milligrams per deciliter at 12 to 24 weeks after initiation, independent of any change to IBD therapy, though a smaller study of 36 patients found no significant CRP difference. Fecal calprotectin, a stool marker of intestinal inflammation, showed no consistent change across studies. On clinical outcomes, the evidence was mixed but not alarming. Large-scale studies found GLP-1 therapy associated with a significant reduction in a composite outcome of steroid-dependence, advanced therapy initiation, IBD-related surgery, and hospitalization, along with decreased risk of recurrent pouchitis. Notably, these improved outcomes were not seen in individuals without obesity. Conversely, several studies found no difference in steroid use, hospitalization, medication changes, or surgeries after one year of therapy, and two of 26 patients in one Spanish study clinically worsened. Surgical outcomes appeared favorable, with reduced colectomy rates in ulcerative colitis and lower likelihood of abdominal surgery in Crohn’s disease, with semaglutide the only agent to significantly reduce IBD-related surgery risk in Crohn’s patients. Endoscopic data remains sparse, though one case report described a Mayo score dropping from 5 to 2 after 25 years of active disease on liraglutide.

Beneath the clinical findings lies a web of proposed molecular mechanisms. GLP-1 receptor agonists may inhibit the AKT/NF-κB signaling pathway, a transcriptional hub that regulates proinflammatory cytokines including tumor necrosis factor alpha, interleukin-6, interleukin-1 beta, and COX-2, all implicated in the intestinal barrier disruption seen in Crohn’s disease and ulcerative colitis. The drugs may also reduce recruitment of inflammatory cells by inhibiting chemokine production from colonic smooth muscle cells. Additional mechanisms include maintenance of regulatory T cell levels that counteract proinflammatory Th17 cells, expansion of group 3 innate lymphoid cells that regulate intestinal immunity, upregulation of barrier-protective genes such as IL-33, CCL20, and MUC5B, promotion of anti-inflammatory cytokines like IL-10, protection against reactive oxygen species, and increased signaling through the AMPK pathway. The authors caution that most of these mechanisms have been identified in non-human models, and their translational relevance in patients remains to be established.

The review also offers practical prescribing guidance. Clinicians should establish baseline disease activity before initiation, using inflammatory biomarkers or endoscopic evaluation, so that new-onset diarrhea or abdominal pain can be properly differentiated between drug side effects and a genuine flare. Persistent upper gastrointestinal symptoms with normal inflammatory markers may warrant upper endoscopy and gastric emptying studies, while lifestyle modifications such as smaller, more frequent meals and avoiding spicy or high-fat foods can help manage symptoms. Starting at the lowest possible dose with slow titration is recommended, and switching to an alternate agent within the class may help patients who cannot tolerate a particular drug. Immediate discontinuation is reserved for confirmed acute pancreatitis without other etiology, new hepatobiliary pathology, and the drugs remain contraindicated in patients with a family history of medullary thyroid cancer or MEN syndrome type 2. Women of reproductive age should use contraception given unknown pregnancy safety.

The authors acknowledge significant limitations: the retrospective nature of existing studies, small sample sizes, heterogeneity in agents and dosages, and the absence of prospective randomized controlled trials to establish causal effects. Still, the overall message is cautiously optimistic. GLP-1 receptor agonists have not been associated with worsening of inflammatory bowel disease across multiple studies, and there is emerging evidence of benefit in systemic inflammation and some clinical outcomes. As obesity becomes an increasingly recognized modifiable factor in IBD management, these metabolic drugs may prove to be more than weight-loss tools, potentially serving as adjuvant therapy that addresses the inflammatory burden carried by hormonally active visceral fat. Longitudinal studies will be required to clarify their long-term impact on clinical and endoscopic outcomes, but for now, the convergence of two of medicine’s biggest stories, the GLP-1 revolution and the quest to tame inflammatory bowel disease, offers a compelling new frontier for patients and clinicians alike.

Subject of Research: GLP-1 receptor agonists show promise for patients with inflammatory bowel disease and obesity

Article Title: Glucagon like peptide 1 receptor agonists in patients with inflammatory bowel disease: safety, clinical effectiveness and anti-inflammatory mechanisms

Article References: Fernando, S., Zhao, J., Josloff, K., Zubair, N., Desai, A., Shivashankar, R., Kozuch, P. L., Choudhary, C., Lichtenstein, G., & Sehgal, P. (2026). Glucagon like peptide 1 receptor agonists in patients with inflammatory bowel disease: safety, clinical effectiveness and anti-inflammatory mechanisms. Frontiers in Gastroenterology, 5, Article 1864456. https://doi.org/10.3389/fgstr.2026.1864456

Image Credits: AI Generated

DOI: 10.3389/fgstr.2026.1864456

Keywords: Glucagon, like, peptide, receptor, agonists, patients, inflammatory, bowel, disease, safety, clinical, effectiveness

The research team, led by Anne Caroline Rodrigues dos Santos Cavalcante and Suelen Adriani Marques, set out to answer a question that has lingered beneath years of encouraging rehabilitation data: when treadmill training improves locomotor recovery after spinal cord injury, what is actually happening inside the tissue? Previous work from the same group had shown that adjusting exercise volume according to the stage of injury maximises functional recovery, but the cellular and molecular mechanisms behind those behavioural gains remained largely opaque. To probe them, the researchers turned to a compressive injury model in fifty-two adult female mice, applying a 30-gram vascular clip to the spinal cord at the ninth thoracic vertebra for just ten seconds—a method that produces a reproducible, clinically relevant lesion while sparing the dura mater.

The rehabilitation protocol itself was deliberately conservative. Training began seven days after injury, during the subacute phase, and continued until fifty-six days post-injury. From day seven to day twenty-eight, animals completed two ten-minute treadmill sessions per training day, separated by a ten-minute rest interval; after day twenty-eight, this was reduced to a single ten-minute session. Sessions were held only three times per week, a frequency chosen to mirror what is actually feasible in clinical rehabilitation rather than to maximise exercise volume. The speeds ranged from six to twelve metres per minute, individually adjusted according to each animal’s locomotor performance and tolerance. This phase-adjusted design reflected the team’s earlier finding that exercise dosage must be tailored to the temporal evolution of the injury rather than simply intensified.

The behavioural results were striking. Untreated injured mice remained trapped in the earliest stage of locomotor recovery throughout the entire fifty-six-day follow-up, scoring just 1.48 on the Basso Mouse Scale by the end of the study. Treadmill-trained animals, by contrast, reached 4.02—a statistically significant difference that emerged from twenty-one days post-injury onward and persisted until the end of the experiment. On the Ladder Walking Test, which challenges animals to cross a horizontal ladder with irregularly spaced rungs, trained mice took significantly more total steps from thirty-five days post-injury and, more importantly, placed their paws significantly more accurately from forty-two days onward, indicating improved fine motor coordination rather than simply gross movement.

Sensory function also benefited. Using an electronic von Frey anesthesiometer, the researchers measured the pressure required to trigger a paw withdrawal reflex. Untreated injured animals showed markedly elevated thresholds—2.20 grams on the right paw and 2.01 on the left—reflecting profound sensory loss. Trained animals averaged 1.10 and 1.15 grams respectively, significantly closer to the uninjured baseline of roughly 0.61 grams. This partial preservation of sensory processing suggests that the rehabilitation protocol protected ascending pathways as well as descending motor tracts, a finding consistent with the broader tissue preservation documented throughout the study.

Electrophysiological recordings provided objective confirmation that neural conduction itself was preserved. At fifty-six days post-injury, the researchers exposed the cervical spinal cord and delivered supramaximal electrical stimuli while recording compound muscle action potentials from the gastrocnemius muscle. Untreated injured animals showed a dramatic reduction in signal amplitude—0.59 compared with 1.55 in uninjured controls—along with prolonged latency. Trained animals recorded amplitudes of 1.18, statistically indistinguishable from the uninjured group. Although such recordings do not directly demonstrate axonal regeneration, they provide compelling functional evidence that the descending motor pathways remained conductive in exercised animals, complementing the behavioural and morphological findings.

The molecular heart of the study lies in its analysis of the inflammatory microenvironment. Using ELISA assays on spinal cord tissue cultured for twenty-four hours, the team quantified six cytokines. Untreated injured animals exhibited a clear pro-inflammatory profile, with elevated levels of tumour necrosis factor-alpha, interleukin-1 beta and interleukin-6. Trained animals showed the opposite pattern: reduced pro-inflammatory cytokines alongside increased levels of the anti-inflammatory mediators interleukin-10, interleukin-13 and transforming growth factor-beta. This shift matters because sustained production of inflammatory cytokines after spinal cord injury drives microglial activation, immune cell infiltration, demyelination and neuronal apoptosis. During moderate exercise, skeletal muscle releases interleukin-6 as a myokine, which in turn promotes anti-inflammatory signalling and suppresses tumour necrosis factor-alpha production—a mechanism the authors cite as particularly relevant to their findings.

Immunofluorescence labelling revealed how this cytokine shift translated into changes in glial cell behaviour. The researchers used TMEM119 to mark the general microglial population, arginase-1 to identify anti-inflammatory M2-like microglia, and inducible nitric oxide synthase to flag pro-inflammatory M1-like cells. In trained animals, Pearson’s correlation between TMEM119 and arginase-1 reached 0.85, indicating that the majority of resident microglia had adopted an anti-inflammatory phenotype. In untreated injured animals, this correlation fell to 0.46, while the correlation between TMEM119 and the pro-inflammatory marker iNOS climbed to 0.836—compared with just 0.33 in trained mice. The team also documented reduced GFAP immunoreactivity in trained animals, suggesting attenuated reactive astrogliosis and a less restrictive glial scar, alongside significantly lower expression of cleaved caspase-3, a hallmark of apoptotic cell death.

Structural preservation followed the molecular changes. Transmission electron microscopy of semithin cross-sections at the lesion epicentre revealed that trained animals retained 1,658 myelinated nerve fibres on average, compared with just 200 in untreated injured animals. The g-ratio—the relationship between inner axonal diameter and total fibre diameter—shifted toward the optimal range of 0.6 to 0.7 in trained mice, indicating more efficient myelination. Micro-computed tomography confirmed that the lesion area was significantly smaller in trained animals (0.243 square millimetres versus 0.382), and scanning electron microscopy showed better organisation of both grey and white matter, with smaller cavitations at the injury site.

The benefits extended beyond the spinal cord itself. Trained animals preserved significantly more muscle mass in both the soleus and gastrocnemius, retained more neuromuscular junctions with their characteristic pretzel morphology, and maintained bladder wall thickness close to normal levels. Untreated injured animals developed dramatic bladder muscular hypertrophy—574.963 micrometres compared with 127.857 in controls—accompanied by inflammatory remodelling. The authors note that these autonomic complications are major contributors to urinary tract infections and repeated hospitalisation after human spinal cord injury. While the study used only female mice, a deliberate choice to reduce behavioural variability and avoid genital injury during recovery, the authors acknowledge that future work must include both sexes to confirm broader applicability. Taken together, the findings reframe treadmill rehabilitation not simply as locomotor training but as a coordinated biological therapy—one that appropriately dosed exercise can deploy to shift the injured spinal cord from a hostile inflammatory state toward one permissive for tissue repair and neural conduction.

Subject of Research: Neuroscience

Article Title: Treadmill Exercise Can Modulate the Inflammatory Microenvironment and Promote Regeneration After Compressive Spinal Cord Injury in Female Mice

Article References: Cavalcante, A. C. R. D. S., Laurindo, R. P., Heringer, L. D. S., Toledo, A. L. M. M., Souza, G. S., da Silva, G. F. Q., dos Santos, A. C. C., Branco, M. T. L. C., Martinez, A. M. B., & Marques, S. A. (2026). Treadmill Exercise Can Modulate the Inflammatory Microenvironment and Promote Regeneration After Compressive Spinal Cord Injury in Female Mice. Journal of Cellular and Molecular Medicine, 30(20), Article e71351. https://doi.org/10.1111/jcmm.71351

Image Credits: AI Generated

DOI: 10.1111/jcmm.71351

Keywords: spinal cord injury, treadmill exercise, neuroinflammation, microglia, rehabilitation, neuroregeneration, Treadmill, Exercise, Modulate, Inflammatory, Microenvironment, Promote

The study, led by Melanie Dratva and Tiffany Ho of the University of California, Los Angeles, together with colleagues at the University of California, San Francisco and other institutions, enrolled 60 regularly menstruating women aged 21 to 54. Thirty-five had a diagnosis of MDD and 25 were psychiatrically healthy controls. Rather than pinning each participant to a specific cycle phase, the researchers used a continuous measure called days since last period, or DSLP, recorded as the number of days elapsed since the start of each woman’s most recent menstrual period. This approach allowed them to model biomarker levels as a function of cycle timing across the entire cycle, rather than collapsing women into broad categories such as follicular or luteal phase.

The team focused on four molecules with well-established links to depression biology. The first was brain-derived neurotrophic factor, or BDNF, a protein that supports the survival, growth and plasticity of neurons and has been repeatedly implicated in the brain’s ability to adapt to stress. The other three were markers of peripheral inflammation: interleukin-6, or IL-6, a cytokine involved in acute immune signaling; tumor necrosis factor-alpha, or TNF-α, another pro-inflammatory cytokine; and C-reactive protein, or CRP, a liver-produced protein that rises in response to systemic inflammation. Elevated levels of several of these markers have been reported in subsets of patients with depression, feeding a broader theory that neuroimmune dysregulation contributes to the disorder.

When the researchers compared average biomarker levels between the two diagnostic groups, they found no significant differences. On its face, that null result might seem unremarkable, and it is precisely the kind of finding that has fueled skepticism about peripheral markers of depression. But the picture changed dramatically once cycle timing entered the statistical models. In women with MDD, higher DSLP, meaning a later point in the cycle, was associated with higher circulating BDNF, with a standardized effect of β = 0.23 and a p-value of 0.02. In healthy controls, no such relationship emerged. The BDNF signal was not uniform across the MDD group either. Age moderation analyses revealed that the association was statistically significant specifically among women with MDD under 36 years of age, suggesting that the cycle-linked dynamics of this neurotrophic protein are most pronounced in younger reproductive-aged adults with the disorder.

The inflammatory markers moved in the opposite direction. Within the MDD group, higher DSLP was associated with lower levels of TNF-α, with β = -0.03 and p = 0.03, and showed a similar trend for CRP, with β = -0.04 and p = 0.06, just short of conventional significance thresholds. Again, these relationships were absent in the control group, and the TNF-α association was significant specifically among women with MDD under 35 years of age. IL-6, the fourth marker examined, did not show a comparable cycle-linked pattern. Taken together, the results describe a diagnostic divergence in how the menstrual cycle sculpts the peripheral neuroimmune landscape: in depression, BDNF climbs as the cycle progresses while inflammatory markers drift downward, whereas in health, these molecules remain comparatively stable across the same interval.

Perhaps the most consequential finding is what did not appear. Neither cycle timing nor any of the biomarker levels were associated with clinician-rated depressive symptom severity. The cycle-sensitive biological dynamics, in other words, appear partially dissociable from a woman’s concurrent depressive state. This dissociation carries real technical weight for the field. It implies that the peripheral neuroimmune changes tied to the menstrual cycle in MDD are not simply a biological echo of how depressed a person feels at the moment of measurement. Instead, they may reflect deeper, state-independent differences in how cycle-related processes operate in the bodies of women with the disorder, differences that persist regardless of current symptom levels.

The age dependence of the effects adds another layer of complexity. The BDNF association was concentrated in women with MDD under 36, and the TNF-α association in those under 35. Reproductive biology changes across the late twenties and thirties, and the study’s age range of 21 to 54 spans substantial variation in ovarian function and cycle regularity. The concentration of effects in younger participants raises the possibility that the cycle-linked neuroimmune dynamics are most robust when ovarian cycling is at its most vigorous, or alternatively that age-related changes in inflammation and neurotrophic signaling progressively mask the cycle signal in older adults. Disentangling these possibilities will require larger samples and longitudinal designs that follow individual women across multiple cycles.

The methodological implications may be the study’s most viral takeaway. Many canonical biomarkers of MDD, including BDNF and CRP, are influenced by physiological changes across the menstrual cycle, yet a large share of published depression biomarker studies have either ignored cycle timing entirely or collapsed it into coarse phase categories. If BDNF rises and TNF-α falls across the cycle in women with depression but not in controls, then a study that samples women at different, unrecorded points in their cycles will inject systematic noise into group comparisons. Depending on the phase distribution of participants, this noise could produce spurious group differences, mask real ones, or explain why findings across the depression biomarker literature have been so stubbornly inconsistent. The authors argue that accounting for menstrual cycle timing when examining peripheral biomarkers of MDD is not an optional refinement but a necessary control.

The study also speaks to the broader question of why depression disproportionately affects women. Sex differences in depression rates are well documented, but the mechanisms underlying elevated risk in reproductive-aged females remain poorly understood. The new findings suggest that the menstrual cycle is not merely background physiology in this population. In women with MDD, the cycle appears to modulate neurotrophic and inflammatory pathways that are themselves implicated in depression pathophysiology, hinting that cycle-sensitive neuroimmune processes could be part of the biological substrate of the elevated risk. Whether these dynamics contribute causally to vulnerability or are a downstream correlate of the disorder remains an open question that the cross-sectional design cannot settle.

Several caveats frame the work. The sample of 60 women is modest, and the effect sizes, while statistically significant, are small in absolute terms. The participants were recruited between 2011 and 2020 at the University of California, San Francisco, before the COVID-19 pandemic, which limits potential confounding from infection-related immune changes but also means the findings await replication in contemporary cohorts. DSLP itself is an imperfect proxy for cycle phase, since cycle length varies between women and ovulation timing is not directly verified. Nonetheless, the core message stands: peripheral neurotrophic and inflammatory factors show menstrual cycle-related variation in women with MDD that is absent in healthy controls, most evident in younger adults, and independent of current symptom severity. For a field that has struggled to reconcile conflicting biomarker findings, the menstrual cycle may be the overlooked variable that has been hiding in plain sight all along.

Subject of Research: Neuroscience

Article Title: Menstrual cycle-related neurotrophic and inflammatory variation differs between adult females with and without Major Depressive Disorder

Article References: Dratva, M. A., Wu, G. W. Y., Rampersaud, R., Reus, V. I., Mellon, S. H., Lindqvist, D., Dhabhar, F. S., Irwin, M. R., Wolkowitz, O. M., & Ho, T. C. (2026). Menstrual cycle-related neurotrophic and inflammatory variation differs between adult females with and without Major Depressive Disorder. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-01003-7

Image Credits: AI Generated

DOI: 10.1186/s13293-026-01003-7

Keywords: Menstrual, cycle-related, neurotrophic, inflammatory, variation, differs, between, adult, females, without, Major, Depressive