Search Results (1,015)

Background/Objective: Dysthyroid Optic Neuropathy (DON) is a severe complication of Thyroid Eye Disease (TED) leading to irreversible visual impairment. Its pathogenesis remains unclear, and early predictive tools are lacking. The study aims to investigate peripheral immune characteristics associated with DON, focusing on the IL-2⁺Th1/CD4⁺Tregs axis. Methods: A retrospective study was conducted in 37 TED patients, including DON (n = 22) and non-DON (n = 15) groups. Peripheral blood immune cell subsets were quantified using flow cytometry. Clinical data and peripheral blood immune indicators including T cell subsets, B cell subsets, T helper (Th) cell subsets, and regulatory T (Treg) cells populations were analyzed. Correlation and logistic regression analyses were applied to evaluate associations between immune indicators and DON. Receiver operating characteristic (ROC) analysis was used to assess the discriminatory performance of candidate variables and exploratory combined models. Results: Patients with DON showed higher IL-2⁺Th1 levels and lower CD4⁺Tregs levels compared with non-DON patients, along with an increased IL-2⁺Th1/CD4⁺Tregs ratio. Age and clinical activity score also differed significantly between groups. The IL-2⁺Th1/CD4⁺Tregs axis showed significant alterations associated with DON. The exploratory logistic regression model combining immune and clinical indicators showed potential discriminatory ability in differentiating DON from non-DON patients. Conclusions: This study identifies an imbalance between IL-2⁺Th1 and CD4⁺Tregs as a potential immune signature associated with DON. Integration of immune and clinical features may provide an exploratory framework for risk stratification in TED. Further prospective studies with larger cohorts are warranted to validate these findings. Full article

Hypogonadism is increasingly recognized as an independent cardiovascular risk factor, with testosterone deficiency associated with endothelial dysfunction, increased thrombotic risk, and adverse cardiovascular outcomes. Circulating biomarkers provide valuable insights into the vascular health status of hypogonadal men and the cardiovascular effects of testosterone replacement therapy (TRT). This comprehensive review examines the molecular basis of testosterone action on the cardiovascular system and synthesizes evidence on circulating cardiovascular biomarkers in hypogonadism, including endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), platelet markers, endothelial activators, adhesion molecules, and inflammatory/oxidative stress markers. We also compare the cardiovascular safety profiles of transdermal versus intramuscular testosterone formulations. Hypogonadal men exhibit reduced circulating EPCs, elevated EMPs, increased platelet reactivity, higher levels of endothelial activators (ICAM-1, VCAM-1, E-selectin, von Willebrand factor, endothelin-1, ADMA), and increased inflammatory markers (hsCRP, IL-6, TNF-α). TRT improves most of these biomarkers through androgen receptor (AR)-dependent and AR-independent mechanisms involving PI3K/Akt/eNOS signaling, VEGF upregulation, CXCL12/CXCR4 axis modulation, and NF-κB pathway suppression. Current evidence suggests that transdermal testosterone formulations may offer advantages regarding hematological safety and more stable testosterone exposure; however, definitive evidence demonstrating superior cardiovascular outcomes compared with intramuscular formulations remains limited. Circulating cardiovascular biomarkers are significantly altered in hypogonadism and improve with TRT. Available data suggest that transdermal testosterone formulations may offer a more favorable cardiovascular safety profile than intramuscular preparations, particularly with respect to erythrocytosis and pharmacokinetic stability, although head-to-head randomized trials with hard cardiovascular endpoints are still needed. Understanding the molecular mechanisms underlying these changes is essential for optimizing TRT in hypogonadal men with cardiovascular risk factors. The cardiovascular safety advantage of transdermal formulations is currently supported primarily by pharmacokinetic and hematological evidence; direct comparative evidence from randomized trials with hard cardiovascular endpoints remains unavailable. Full article

Hypertension or high blood pressure drives structural and functional cardiac remodelling through sustained pressure overload, oxidative stress, and chronic inflammation. Lifestyle modifications including regular exercise and a healthy diet including fruits and vegetables help in attenuating high blood pressure. Berries are small fruits abundant in polyphenols, vitamins and minerals which provide these fruits with antioxidant and anti-inflammatory properties. One such berry is the Saskatoon berry (Amelanchier alnifolia), which is rich in anthocyanins and procyanidins with demonstrated cardiometabolic activity, yet its effects on hypertension and cardiac remodelling have not been studied. This study evaluated the impact of 16-week Saskatoon berry supplementation on cardiovascular structure, function, inflammation, and oxidative stress in spontaneously hypertensive rats (SHRs). Age-matched Wistar Kyoto (WKY) rats served as normotensive controls. Saskatoon berry supplementation did not significantly lower systolic or diastolic blood pressure in SHRs; however, echocardiography results revealed trends towards attenuation of hypertensive cardiac remodelling. Saskatoon berry supplementation reduced interventricular septal and posterior wall thickness, decreased left ventricular (LV) mass, and partially preserved systolic function, as reflected by improved ejection fraction and fractional shortening. Diastolic relaxation (IVRT) remained impaired, indicating selective effects on systolic rather than lusitropic function. Serum TNF-α and TBARS were not significantly altered, whereas IL-10 was partially restored, suggesting a modest improvement in systemic inflammatory balance. Principal component analysis integrating all hemodynamic, echocardiographic, and biochemical variables revealed a dominant pathological remodelling axis that distinguished WKY from SHRs. Saskatoon berry supplementation shifted SHRs toward an intermediate multivariate phenotype, supporting a coordinated improvement across structural and functional domains despite persistent hypertension. Together, these findings indicate that Saskatoon berry exerts blood pressure-independent cardioprotective effects that mitigate hypertensive LV hypertrophy and preserve systolic performance. Saskatoon berry may represent a promising functional food ingredient for attenuating cardiac remodelling in hypertension. Full article

Background: Chronic atrophic gastritis (CAG) is a prevalent precancerous gastric disorder characterized by persistent inflammation, glandular atrophy, and progressive mucosal damage, for which effective multi-target therapeutic strategies remain insufficient. The Lian-Huo-Hua-Zhuo formula (LHHZ), a traditional Chinese herbal prescription, has demonstrated potential anti-inflammatory and gastrointestinal protective effects in clinical practice; however, its active constituents and mechanisms of action against CAG remain undefined. This study aimed to clarify the absorbed bioactive components of LHHZ and explore its therapeutic mechanism for CAG. Methods: Ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap high-resolution mass spectrometry was employed to identify the absorbed components of LHHZ in the gastric and intestinal tissues of mice. The therapeutic effects of LHHZ on CAG were assessed through histopathological staining, ultrastructural observation, and evaluation of serum and gastric functional indicators. Network pharmacology, molecular docking, and molecular dynamics simulations were integrated to predict the core targets and key signaling pathways, while the regulatory effects on the interleukin-17 (IL-17) signaling pathway were further validated by immunofluorescence staining, real-time quantitative polymerase chain reaction, and Western blotting. Additionally, 16S ribosomal RNA gene sequencing and targeted metabolomics were applied to investigate the effects of LHHZ on gut microbiota composition and short-chain fatty acid (SCFA) metabolism. Results: The results revealed that 55 and 48 absorbed components were identified in the gastric and intestinal tissues, respectively, predominantly derived from Coptis chinensis Franch. and Pogostemon cablin (Blanco) Benth. LHHZ significantly alleviated gastric mucosal lesions, reduced intestinal metaplasia, restored the ultrastructure of gastric mucosal cells, improved gastric functional indicators including pepsinogen I (PG I), pepsinogen II (PG II), and gastrin-17 (GAS-17), and decreased the levels of pro-inflammatory cytokines. Network pharmacology combined with in vitro and in vivo experiments demonstrated that the core bioactive components of LHHZ can target and regulate interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), attenuate activation of the IL-17 signaling pathway, and suppress the secretion of downstream pro-inflammatory factors. Furthermore, LHHZ enhanced the alpha diversity of gut microbiota, reduced the Firmicutes to Bacteroidetes (F/B) ratio, restored the abundance of SCFA-producing bacteria such as Bacteroidales and Oscillospirales, and normalized the aberrant levels of eight SCFAs. Significant correlations were also observed between gut microbiota composition and SCFA metabolism. Conclusions: These findings suggest that LHHZ alleviates CAG by inhibiting inflammation via the IL-17 signaling pathway and by modulating the gut microbiota–SCFA axis, thereby providing preclinical evidence supporting its further investigation and development for multi-target therapeutic strategies against CAG. Full article

The rising burden of diabetic kidney disease (DKD) and its associated lipid abnormalities underscores the need for new mechanistic insights. Uromodulin, a kidney-enriched protein, has been associated with metabolic disorders in human studies, yet its functional role in systemic lipid metabolism remains elusive. In this study, transcriptomic datasets were analyzed to investigate uromodulin expression and biological function in DKD. Subsequently, a diabetic model was induced in UMOD^+/+ and UMOD^−/− rats using a combination of a high-fat diet, unilateral nephrectomy, and streptozotocin to assess renal and metabolic phenotypes. Public RNA-seq data indicated that uromodulin expression was downregulated in DKD and was enriched in the fatty acid metabolism pathway. At baseline, UMOD^−/− rats resembled UMOD^+/+ rats in terms of growth, routine serum lipids, and major organ function. However, in diabetes, UMOD^−/− rats exhibited higher mortality and pronounced hyperlipidemia. Hyperlipidemia occurred prior to the onset of renal dysfunction. Of note, this exacerbated lipid dysregulation represented a lipodystrophy-like phenotype rather than secondary changes in the pancreas, liver, or circulating cytokines (IL-6, IL-1β, and TNF-α). Moreover, UMOD^−/− rats displayed exacerbated tubular injury and enhanced renal lipid accumulation in DKD relative to UMOD^+/+ rats. Collectively, uromodulin protects diabetic rats from death, prevents epididymal white adipose tissue from browning, and attenuates kidney injury. Our findings identify uromodulin as a novel regulator of the kidney–adipose axis. Full article

Redox homeostasis is the balance between oxidative processes and antioxidant defenses and is fundamental to cellular integrity. This review critically synthesizes current evidence on the phytochemical composition, redox-modulating mechanisms, and therapeutic bioactivities of Fagonia cretica L. (F. cretica), with the aim of evaluating its translational potential as a natural antioxidant and anticancer agent. F. cretica has emerged as a phytochemically rich candidate containing highly bioactive secondary metabolite for redox-targeted therapeutic applications. Its diverse secondary metabolite profile, including alkaloids, flavonoids, tannins, saponins, terpenoids, glycosides, and phenolic compounds, confers broad biological activity. Bioactive constituents, particularly kaempferol, catechin, quercetin, and arbutin, directly neutralize reactive oxygen species (ROS) and modulate inflammatory pathways through inhibition of COX-1, COX-2, and nitric oxide production. These compounds influence important major ROS-sensitive redox signaling pathways: activation of the Keap1/Nrf2/ARE axis to upregulate cytoprotective genes such as HO-1, NQO1, and GCL, suppression of the NF-κB pathway to attenuate pro-inflammatory cytokine transcription, including TNF-α, IL-1β, and IL-6, and interference with the MAPK-PI3K/Akt cascade to disrupt aberrant cancer cell survival and proliferation. Bioactive compound-rich extracts of F. cretica exhibit anticancer activity in MCF-7 breast cancer cells by inducing DNA damage, cell cycle arrest, and apoptotic signaling through the FOXO3a/p53 pathways. Similar effects have been reported in colorectal (HCT-116) and prostate (PC-3) cancer cells through DNA (cytosine-5)-methyltransferase 1 (DNMT1) downregulation, oxidative stress induction, and ER-β activation. Moreover, these extracts demonstrate cytotoxic effects in HepG2 and Caco-2 intestinal cancer cells, often associated with topoisomerase inhibition and caspase activation. Despite encouraging preclinical evidence, systematic studies encompassing pharmacokinetic profiling, toxicological characterization, and human clinical trials remain essential to translate these findings into safe, evidence-based therapeutic applications. Full article

Background/Objectives: Ferroptosis, an iron-dependent cell death driven by lipid peroxidation, is implicated in the pathogenesis of ulcerative colitis (UC). Tryptophan metabolism and its interaction with the aryl hydrocarbon receptor (AhR) and nuclear factor erythroid 2–related factor 2 (Nrf2) axis represent a crucial regulatory network in intestinal homeostasis. This study aimed to investigate whether the probiotic fermentation product postbiotic Nagqu4580 alleviates UC by modulating this network to inhibit intestinal epithelial ferroptosis. Methods: An acute UC model was induced in mice using 4% dextran sodium sulfate (DSS). The therapeutic effects of postbiotic Nagqu4580 were evaluated through disease activity index (DAI), colon length, histopathology, inflammatory cytokines, and intestinal barrier function. Ferroptosis was assessed by measuring lipid peroxidation (MDA, 4-HNE), antioxidant capacity (GSH/GSSG), and expression levels of GPX4 and ACSL4. Serum tryptophan metabolites were profiled using targeted metabolomics, the activation of the AhR/Nrf2 pathway was examined by Western blot, immunofluorescence, and qPCR, and gut microbiota composition was analyzed by 16S rRNA sequencing. Results: Postbiotic Nagqu4580 dose-dependently ameliorated DSS-induced UC in mice, as evidenced by reduced DAI scores, mitigated colon shortening and histological damage, decreased inflammatory cytokines (TNF-α, IL-1β, IL-6), and restored intestinal barrier function by upregulating tight junction proteins (Claudin-1, ZO-1, Occludin). Mechanistically, postbiotic Nagqu4580 inhibited intestinal epithelial ferroptosis by reducing MDA and 4-HNE levels, restoring the GSH/GSSG balance, downregulating ACSL4, and upregulating GPX4. Serum metabolomics revealed that postbiotic Nagqu4580 reshaped tryptophan metabolism, increasing beneficial metabolites such as 5-hydroxyindoleacetic acid (5-HIAA) and decreasing potentially harmful metabolites such as 3-indoxyl sulfate (3-IS). 16S rRNA sequencing further revealed that the postbiotic Nagqu4580 partially reversed DSS-induced gut microbiota dysbiosis, with a slight increase in the abundance of beneficial genera and a significant reduction in the abundance of pro-inflammatory genera. Furthermore, postbiotic Nagqu4580 significantly activated the AhR/Nrf2 signaling pathway, enhancing the expression of AhR, Nrf2, and their downstream antioxidant genes HO-1 and GPX4. Conclusions: Postbiotic Nagqu4580 alleviates UC by inhibiting intestinal epithelial ferroptosis. Our data suggest that this protective effect is associated with the remodeling of gut microbiota-related tryptophan metabolism and subsequent activation of the AhR/Nrf2 antioxidant axis. Our findings highlight the therapeutic potential of postbiotic Nagqu4580 as a postbiotic agent for UC. Full article

Lead (Pb) exposure induces liver injury through oxidative stress, inflammation, and gut–liver axis disruption. This study evaluated the protective effects and associated mechanisms of fucoidan (FU) against Pb-induced liver injury in mice. C57BL/6 mice were exposed to lead acetate and treated with FU. High-dose FU (FU-H) improved food intake, body weight, and liver index; decreased Pb levels in serum and liver; and increased fecal Pb content. Compared with the Model group, FU-H reduced serum ALT, AST, and ALP by 54.8%, 38.6%, and 21.7%, respectively. FU-H restored hepatic SOD and GSH by 10.9% and 46.5% and decreased hepatic MDA by 45.9%; it also restored serum SOD and GSH by 30.4% and 24.0%, decreased serum MDA by 19.6%, and suppressed TNF-α, IL-6, and IL-1β by 15.7%, 21.1%, and 14.9%, respectively. Integrated RNA sequencing and network toxicology suggested that insulin-like growth factor-binding protein 1 (IGFBP1) may be associated with FU-mediated protection, and recombinant IGFBP1 partly weakened FU-associated hepatoprotection. Moreover, 16S rRNA sequencing and untargeted metabolomics showed that FU reshaped Pb-disrupted gut microbiota and altered fecal tryptophan metabolism. Exogenous tryptophol supplementation partially alleviated Pb-induced liver injury. Overall, FU protection was associated with reduced Pb burden, IGFBP1-related redox modulation, and gut microbiota-derived tryptophol metabolism. Full article

Muscle wasting associated with gastric cancer represents a complex, multifactorial systems disorder involving inflammatory, anabolic, mechanosensory, calcium-regulatory, mitochondrial, and proteostatic disruption. This review synthesizes current evidence regarding the cellular and physiological mechanisms involved in skeletal muscle dysfunction in gastric cancer and provides a unifying framework centered on loss of signaling coherence. Specifically, it examines IL-6/STAT3 and NF-κB inflammatory signaling, the myostatin–activin–ACVR2B–SMAD pathway, PI3K/Akt/mTOR signaling, mechanotransduction, excitation–metabolism coupling, calcium homeostasis, mitochondrial function, and proteostasis. Although individual components of these pathways have been implicated in muscle wasting associated with chronic disease, current evidence suggests that they interact through positive feedback loops. Inflammation, anabolic resistance, impaired force-to-signal conversion, mitochondrial stress, altered intracellular calcium homeostasis, and disrupted protein quality control may reinforce one another, contributing to metabolic, structural, and transcriptional instability. Within this context, muscle wasting reflects not only loss of muscle mass or strength, but also loss of functional integrity resulting from disrupted integration of mechanical, metabolic, inflammatory, and anabolic signals. Given the systemic nature of these effects, this review proposes kinesitherapy as a potentially useful nonpharmacological adjunctive strategy that may modulate inflammation, restore responsiveness to mechanical stimuli, support calcium homeostasis and mitochondrial function, improve anabolic sensitivity, and maintain protein quality control. Overall, this review presents a systems-biology model of gastric cancer-associated muscle wasting and supports further investigation of exercise-based therapies for this condition. Full article

Background: Psoriasis is a chronic inflammatory skin disease characterized by abnormal epidermal hyperplasia and immune-inflammatory imbalance. Although celastrol (Cel) exhibits potent anti-inflammatory activity, its strong hydrophobicity and low local delivery efficiency limit its therapeutic application. Methods: To enhance its transdermal delivery and topical therapeutic efficacy, a Cel-loaded liposomal hydrogel microneedle system (Cel-lipo-MNs) was developed in this study. Cel-loaded liposomes were first prepared by the thin-film dispersion method, and Cel-lipo-MNs were subsequently fabricated using a multistep vacuum micromolding process combined with UV-induced photocrosslinking. Results: In vivo studies demonstrated that, in an imiquimod-induced psoriasis-like mouse model, Cel-lipo-MNs markedly alleviated erythema, scaling, and skin thickening, reduced PASI-like scores. Further investigation revealed that Cel-lipo-MNs significantly downregulated the serum levels of IL-17, IL-23, and IFN-γ, and exhibited superior therapeutic efficacy compared with free celastrol, conventional liposomes, and blank microneedles. Conclusions: These findings indicate that Cel-lipo-MNs can substantially enhance the therapeutic effect of celastrol against psoriasis-like skin lesions, possibly through suppression of the IL-23/IL-17 inflammatory axis and related immune-inflammatory responses, and provide a promising transdermal delivery strategy for topical psoriasis treatment. Full article

Background/Objectives: Glucocorticoid therapy remains clinically indispensable, yet its long-term use is profoundly constrained by insulin resistance (IR), hepatic steatosis, and progressive metabolic dysfunction. Methylsulfonylmethane (MSM), a naturally occurring sulfur-containing nutraceutical with established antioxidant and anti-inflammatory activities, has emerged as a promising metabolic modulator; however, its therapeutic relevance in glucocorticoid-induced hepatic IR has not previously been explored. Methods: Male Wistar rats received MSM (200 or 400 mg/kg/day, p.o.) for 14 days, while dexamethasone (DEX) (8 mg/kg/day, i.p.) was administered during the final 7 days to induce severe metabolic dysfunction. Results: DEX provoked profound IR, dyslipidemia, oxidative stress, hepatocellular injury, and steatotic degeneration accompanied by marked ultrastructural abnormalities. Remarkably, MSM conferred dose-dependent metabolic and hepatoprotective effects, significantly restoring glucose homeostasis, insulin responsiveness, lipid metabolism, and hepatic structural integrity. Mechanistically, MSM exerted a pleiotropic regulatory effect through suppression of the glucocorticoid-responsive kinase SGK1, restoration of AMPK/mTOR signaling balance, and normalization of insulin signaling pathways and metabolic transcriptional regulators. Furthermore, MSM effectively attenuated oxidative stress and inflammatory amplification consistent with modulation of the NLRP3/NF-κB/IL-6 axis. Importantly, the current work identifies angiogenic remodeling demonstrated by DEX-induced upregulation of VEGF and CD34, both of which were substantially suppressed by MSM treatment. Conclusions: This study provides novel evidence that MSM mitigates glucocorticoid-induced hepatic IR through coordinated modulation of glucocorticoid-responsive kinases, metabolic signaling networks, redox–inflammatory cascades, and pathological angiogenesis. Consequently, MSM may represent a promising candidate for further preclinical and clinical evaluation regarding its capacity to limit glucocorticoid-associated metabolic burdens. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) and male hypogonadism (HG) are prevalent disorders that frequently coexist, suggesting a bidirectional “liver–testis axis” as a potential pathophysiological link. This review explores the mechanistic basis and clinical implications of this axis. Molecularly, metabolically stressed hepatocytes release an altered hepatokine signature—marked by reduced sex hormone-binding globulin (SHBG) and elevated fibroblast growth factor 21 (FGF21)—along with pro-inflammatory cytokines (e.g., interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)), which enter the systemic circulation. These factors may contribute to the impairment of Leydig cell steroidogenesis, the perturbation of blood–testis barrier integrity, and the disruption of spermatogenesis. Conversely, testicular dysfunction and subsequent testosterone deficiency promote visceral adiposity, worsen insulin resistance and amplify chronic inflammation, thereby accelerating hepatic steatosis and fibrosis. Clinically, these molecular interactions manifest as mutually worsening of MASLD and HG. Thus, the liver–testis axis establishes a framework that reveals the bidirectional crosstalk between hepatic metabolism and gonadal function, providing novel pathophysiological insights into these interconnected conditions. Full article

Background/Objectives: Major depressive disorder (MDD) is increasingly recognized as involving inflammation and the microbiota–gut–brain axis. Few studies have simultaneously assessed systemic inflammatory markers and gut microbiota composition within the same cohort while accounting for metabolic confounders. Moreover, data from Middle Eastern and North African (MENA) populations remain limited, restricting our understanding of how diet may influence neuroimmune–microbiome interactions in depression. This study aimed to investigate associations between MDD, systemic inflammatory markers, and gut microbiota composition in Lebanese adults. To our knowledge, this is the first study of its kind in Lebanon, as well as in the MENA region. Methods: In this cross-sectional case–control study, we examined circulating inflammatory markers and gut microbial profiles in 46 adults with DSM-5-confirmed MDD and 25 healthy controls. Plasma C-reactive protein (CRP) and interleukin-6 (IL-6) were measured, and the gut microbiota composition was characterized using 16S rRNA gene sequencing. Multivariable models were adjusted for age, sex, body mass index (BMI), Mediterranean diet adherence, and fluoxetine exposure. Results: Depression status was not independently associated with CRP or IL-6 after adjustment, whereas BMI emerged as a significant determinant of systemic inflammation. At the genus level, MDD was associated with the enrichment of Dorea, Lachnoclostridium, Collinsella, Bilophila, and Klebsiella and the depletion of Christensenella, Mitsuokella, and Victivallis, independent of inflammatory biomarkers. Alpha diversity did not differ between groups, while beta diversity showed modest metric-dependent differences, primarily driven by presence/absence-based measures. Conclusions: Specific microbial taxa may contribute to gut–brain signaling pathways implicated in MDD and systemic inflammation. Further longitudinal and mechanistic studies are required to clarify causal interactions within inflammation–microbiome networks in MDD. Full article

Mulberroside A (MsA) possesses neuroprotective effects, but whether it alleviates Alzheimer’s disease (AD)-like cognitive impairment through the microbiota–gut–brain axis remains unclear. Using a scopolamine-induced mouse model of acute cognitive impairment (male ICR mice, n = 10/group), we demonstrated that daily administration of MsA (10, 20, and 30 mg/kg/day) for 5 weeks significantly ameliorated cognitive performance in novel object recognition and Morris water maze tests. At the optimal dose (30 mg/kg/day), MsA suppressed hippocampal microglial activation, reduced pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), and attenuated oxidative stress by decreasing malondialdehyde (MDA) while restoring superoxide dismutase (SOD) and glutathione (GSH) levels. MsA also strengthened intestinal barrier integrity (ZO-1, occludin) and significantly altered the gut microbiota, notably increasing the beneficial genus Dubosiella. Brain metabolomics indicated that MsA reversed scopolamine-induced metabolic disturbances, mainly restoring phospholipid balance. Correlation analysis demonstrated a strong gut–brain connection, with Dubosiella abundance positively associated with neuroprotective phospholipids and negatively with stress markers. Furthermore, fecal microbiota transplantation from MsA-treated donors successfully replicated these behavioral improvements in recipient mice, underscoring the functional involvement of the reshaped microbiome rather than a simple autonomous recovery. These results suggest that MsA alleviates AD-like cognitive impairment by reducing neuroinflammation and oxidative stress through microbiota remodeling, enhancing the intestinal barrier, and modulating the Dubosiella-associated gut–metabolite–brain axis, making MsA a promising multi-target nutraceutical for ameliorating AD-like cognitive deficits. Full article

In patients with myocardial infarction (MI), the level of sphingolipids, such as ceramide (Cer), is elevated and is associated with an increased risk of progression towards heart failure (HF). Dihydroceramide desaturase 1 (DES1) catalyses the conversion of dihydroceramide (dhCer) into Cer in the de novo sphingolipid pathway. While pharmacological inhibition of DES1 has shown therapeutic benefits in metabolic disease and cancer models, its role in cardiac remodelling remains unclear. This study aimed to determine whether pharmacological inhibition of DES1 using the novel compound, CIN038, attenuates cardiac remodelling following ischemia–reperfusion (I/R) injury. Three-month-old male C57Bl/6 mice underwent I/R or sham surgery (n = 8) and were treated with vehicle or CIN038 (50 mg/kg/day, i.p.) for 28 days. Cardiac function, molecular changes, and lipid profiles in circulation and liver were assessed at the endpoint. CIN038 reduced infarct size and cardiac myocyte hypertrophy compared to the I/R + vehicle group. Profibrotic signalling was reduced in the infarcted hearts, as evidenced by reduced expression of Col1a1, Col3a1, and Tgfb mRNA and decreased levels of α-SMA and TGFβ1 protein expression. Inflammatory signalling was attenuated with reduced ERK and NFkB phosphorylation and suppression of Il-6-STAT axis. Despite these structural and molecular improvements, no changes were observed in cardiac function. Lipidomic analysis revealed selective alterations in circulating and hepatic lipid species, including plasmalogen phosphatidylethanolamines and ether-linked triglycerides, suggesting modulation of lipid metabolism. Collectively, these findings indicate that CIN038 attenuates post-ischemic cardiac remodelling by suppressing inflammatory and profibrotic signalling, highlighting DES1 as a potential therapeutic target following MI. Full article