Naunyn-Schmiedeberg's archives of pharmacology最新文献

{"title":"Curcumin analogues suppress cellular pro-inflammatory mediators and reduce edema.","authors":"Kifayat Ullah, Wenyun Zhu, Syed Wadood Ali Shah, Haya Hussain, Abid Ullah, Farman Ali Khan, Nasir Mehmood Khan, Naveed Ullah Khan, Shujaat Ahmad, Guoqiang Xu","doi":"10.1007/s00210-026-05629-7","DOIUrl":"10.1007/s00210-026-05629-7","url":null,"abstract":"<p><p>Inflammation is a normal physiological response to adverse stimuli mediated by numerous pro-inflammatory cytokines and signaling pathways. Although curcumin modulates key inflammatory pathways, the role of its analogues in inflammation is not fully elucidated. This study explores the anti-inflammatory potential of curcumin analogues (K1-K4) in vitro and in vivo models. Four curcumin analogues (K1-K4) were successfully synthesized and assessed for their anti-inflammatory efficacy at doses of 10 and 20 mg/kg body weight. All the curcumin analogues, particularly K1 and K4 demonstrated significant attenuation of absolute post-injection carrageenan-induced paw edema in mice, exhibiting a significant response at both doses. The maximum inhibition of paw edema was achieved after 2 h, i.e., 62.45% for K1 and 62.09% for K4 at a dose of 20 mg/kg compared to diclofenac (66.10%). The analogues markedly ameliorated ear edema and prominently alleviated the absolute post-injection paw edema mediated by histamine in mice. Among the analogues, K1 and K4 exhibited the highest activity and markedly attenuated the edema in all models. Mechanistically, the curcumin analogues except K2 significantly downregulated iNOS, COX2, and p-p65 protein levels in RAW264.7 cells. The mRNA expression of inflammatory cytokines was also notably diminished in RAW264.7 cells. Moreover, K1 was observed to affect markers associated with apoptosis among the curcumin analogues. The findings demonstrate that curcumin analogues suppress key pro-inflammatory mediators in cells and reduce edema in vivo, highlighting their preliminary anti-inflammatory activity in acute inflammation models.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"20345-20358"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of CXCL16/ADAM10 signaling in methotrexate-induced nephrotoxicity and its modulation by simvastatin.","authors":"Alulu Alradhi, Abdulrahman A Alelowi, Ahmad H Alhowail, Maha A Aldubayan, Mohamed S Abdel-Bakky","doi":"10.1007/s00210-026-05658-2","DOIUrl":"10.1007/s00210-026-05658-2","url":null,"abstract":"<p><p>Methotrexate (MTX) is a widely used chemotherapeutic and immunosuppressive agent; however, one of clinical limitations of its use is renal toxicity. CXCL16 is a transmembrane chemokine that can be cleaved by ADAM family proteases, particularly ADAM10, to generate a soluble form that acts as a chemoattractant for CXCR6-expressing cells such as T lymphocytes. This process may contribute to inflammatory renal injury. This study investigated the role of CXCL16/ADAM10 in MTX-induced nephrotoxicity and assessed the renoprotective effects of simvastatin (SIM). Fifty male Wistar rats were randomly assigned to five groups: control, SIM (40 mg/kg), MTX (20 mg/kg) and two combination groups receiving MTX with SIM (10 or 40 mg /kg). SIM was administered orally for 10 days, while MTX was administered as a single i.p. dose on day 4. Hematological parameters, markers of renal function, and renal histopathology were assessed. In addition, the expression of CXCL16, ADAM10, CD3, and fibrinogen was evaluated. MTX administration significantly elevated renal function markers compared with the control and SIM groups. Histopathological analysis revealed glomerular atrophy and mononuclear inflammatory cell infiltration in MTX-treated rats. Moreover, MTX markedly increased the expression of CXCL16, ADAM10, CD3, and fibrinogen in the glomeruli and tubulointerstitial regions. Treatment with SIM significantly improved renal function markers, attenuated histopathological damage, and reduced the expression of these inflammatory and injury-related proteins. CXCL16 and its processing enzyme ADAM10 play important roles in MTX-induced renal toxicity. SIM demonstrated a dose-dependent protective effect against MTX-induced renal injury, likely through modulation of inflammatory pathways involving CXCL16/ADAM10 signaling.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"20359-20373"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148369290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luteolin alleviates inflammation by inhibiting the PI3K-Akt-FOXO3a pathway.","authors":"Leyuan Zeng, Jinxian Lu, Ronghua Liu, Junwei He, Li Yang","doi":"10.1007/s00210-026-05722-x","DOIUrl":"10.1007/s00210-026-05722-x","url":null,"abstract":"<p><p>Luteolin is a flavonoid commonly found in various plants and has been shown to possess a wide range of biological activities through the modulation of multiple signaling pathways. Despite its well-documented effects, the underlying molecular mechanism responsible for its anti-inflammatory properties remains unclear. Network pharmacology suggested that luteolin may exert anti-inflammatory effects by modulating the PI3K/Akt/FOXO3a signaling cascade. Consistent with this prediction, in an LPS-stimulated RAW264.7 macrophage model, luteolin significantly decreased the phosphorylation of PI3K, Akt, and FOXO3a, while also lowering the ratios of p-PI3K/PI3K, p-Akt/Akt, and p-FOXO3a/FOXO3a. Additionally, Molecular docking combined with molecular dynamics simulations indicated that luteolin can bind to PI3K, Akt, and FOXO3a to form stable protein-ligand complexes, supporting the presence of strong binding affinity/interactions between luteolin and these targets. Further validation using cellular thermal shift assay, isothermal dose-response, and drug affinity response target stability techniques confirmed that luteolin directly interacts with PI3K. These results provide compelling evidence supporting luteolin's potential clinical use, enhance our understanding of the mechanisms driving inflammation, and lay the groundwork for the development of novel anti-inflammatory therapies inhibiting the PI3K-Akt-FOXO3a pathway.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"21373-21389"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated bulk and single-cell transcriptomic analyses and experimental validation reveal the pathogenic role of chondrocyte pyroptosis in osteoarthritis and the therapeutic potential of curcumin via its targeted modulation.","authors":"Juan Huang, Chi Zhang, Qingchuan He, Yuan Chen, Ruyan Chen, Shibin Yang","doi":"10.1007/s00210-026-05721-y","DOIUrl":"10.1007/s00210-026-05721-y","url":null,"abstract":"<p><p>Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by progressive cartilage destruction. Emerging evidence suggests that chondrocyte pyroptosis, a pro-inflammatory programmed cell death pathway, contributes to OA pathogenesis. However, the molecular mechanisms underlying pyroptosis in OA and potential therapeutic interventions remain incompletely understood. Bulk RNA-seq datasets (GSE114007 and GSE254844) were analyzed to identify differentially expressed genes (DEGs) and co-expression modules via DESeq2 and WGCNA. Shared key DEGs (SKDEGs) were subjected to GO and KEGG enrichment analyses to reveal relevant pathways. Pyroptosis-related DEGs (PRDEGs) were intersected with SKDEGs and used for drug prediction in EnrichR. Predicted compounds were further examined for potential targets using TCMSP, HIT, and SwissTargetPrediction databases to identify hub genes. Single-cell RNA-seq data (GSE169454) were analyzed to determine the cellular localization, differential expression, and pathway activity of hub genes. Finally, in vitro experiments with primary human normal and OA chondrocytes were performed to validate the effects of the identified compound on cell proliferation and pyroptosis. Analysis of bulk RNA-seq data identified 146 SKDEGs, with pyroptosis emerging as the most significantly enriched pathway. Six PRDEGs were identified, and curcumin was predicted as a key therapeutic compound. Intersection of curcumin targets with PRDEGs revealed four hub genes (CASP1, IL1B, IL18, NLRP3), all upregulated in OA. Single-cell analysis confirmed that these hub genes were predominantly expressed in OA-associated chondrocyte subtypes, with increased pathway activity and expression along pseudotime trajectories. In vitro, curcumin (10 µM) promoted chondrocyte proliferation and significantly suppressed the mRNA and protein expression of the hub genes, indicating inhibition of pyroptosis. Chondrocyte pyroptosis is a critical contributor to OA progression, and curcumin can alleviate OA by targeting pyroptosis-related pathways. This integrative study provides mechanistic insights and a potential therapeutic strategy for OA.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"21263-21281"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148520575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Edaravone provides neuroprotection against chronic heat stress-induced behavioral dysfunction through adaptive proteomic remodeling.","authors":"Shab M M Alkhoujah, Ruba A Zenati, Munazza Ahmed, Sana'a Jaber, Ahmad Y Abuhelwa, Shereen M Aleidi, Shirin Farheen, Amgad Albohy, Omar F Khabour, Majed M Masadeh, Zainab M AlShareef, Yasser Bustanji, Karem H Alzoubi, Mohammad H Semreen","doi":"10.1007/s00210-026-05686-y","DOIUrl":"10.1007/s00210-026-05686-y","url":null,"abstract":"<p><p>Heat stress is an increasing global health concern associated with high mortality and multi-organ dysfunction. The brain is particularly vulnerable to heat stress, which can lead to behavioral impairments. At the molecular level, heat stress disrupts proteins involved in synaptic communication, mitochondrial function, and cellular homeostasis. Current treatments are mainly symptomatic, highlighting the need for targeted neuroprotective strategies. Edaravone, a potent free-radical scavenger with anti-inflammatory properties, has demonstrated neuroprotective effects in various neurological conditions. This study aimed to evaluate the neuroprotective effects of edaravone against heat stress-induced behavioral dysfunction and to investigate the underlying molecular mechanisms using proteomic analysis. Male Wistar rats (n = 54) were assigned to four groups: control, heat stress (HS), edaravone (Edv), and heat stress plus edaravone (HS + Edv). Heat stress exposure and edaravone treatment were administered for 12 weeks. Behavioral assessments, including radial arm water maze (RAWM), open field test (OFT), elevated plus maze (EPM), and tail suspension test (TST), were conducted. Proteomic analysis of the cortex, hippocampus, and cerebellum was performed using LC-MS/MS with a nanoElute-QTOF-MS system. Heat stress impaired memory retention and increased anxiety-like behavior, while evidence for depressive-like behavior was modest. Proteomic analysis revealed region-specific alterations, with the hippocampus showing the largest number of significantly altered proteins, while the cortex showed the strongest multivariate separation between groups. The HS + Edv group showed partial normalization of behavioral outcomes and modulation of key proteomic pathways, including improved mitochondrial function, reduced oxidative stress, and preservation of synaptic and cytoskeletal integrity. These findings suggest that edaravone attenuates heat stress-induced brain dysfunction by promoting adaptive proteomic remodeling rather than complete restoration.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"20843-20867"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148422620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simvastatin enhances the antitumor activity of temsirolimus through AMPK-associated metabolic modulation in clear-cell renal cell carcinoma.","authors":"Hsuan-Yu Chen, Chien-Jui Cheng, Te-Hsing Hsu, Szu-Yu Tung, Fang-Ning Chou, Mantosh Kumar Satapathy, Shu-Hui Juan","doi":"10.1007/s00210-026-05733-8","DOIUrl":"10.1007/s00210-026-05733-8","url":null,"abstract":"<p><p>Clear-cell renal cell carcinoma (ccRCC) is characterized by VHL-associated metabolic reprogramming, including enhanced glycolysis and lipid biosynthesis, which may create therapeutic vulnerabilities. However, mTOR inhibitors such as temsirolimus often show limited efficacy due to adaptive metabolic compensation. We investigated whether simvastatin-induced metabolic stress enhances sensitivity to mTOR inhibition in a context-dependent manner in ccRCC. VHL-mutant (A498) and VHL-wild-type (Caki1) ccRCC cells were treated with simvastatin and temsirolimus, alone or in combination. Cell viability, colony formation, migration, Seahorse metabolic flux analysis, and Western blotting were performed. Mechanistic studies included shRNA-mediated knockdown of LKB1/AMPKα1/α2 and pharmacological modulation using Compound C and AICAR. Antitumor efficacy was evaluated in a Caki1 subcutaneous xenograft model in nude mice. Temsirolimus induced modest growth inhibition, whereas simvastatin produced stronger dose- and time-dependent effects. Combination treatment (simvastatin 2.5 µM + temsirolimus 100 nM) further reduced cell viability. Interaction analysis revealed a cell-dependent response, with synergism in A498 cells (combination index (CI), 0.31-0.77) and antagonistic-to-additive effects in Caki1 cells (CI, 1.6-2.7). Mechanistically, simvastatin activated LKB1-AMPK signaling, suppressed AKT/mTOR activity, reduced glycolysis (↓pPFKFB2), increased FBP1 expression, and downregulated lipid biosynthesis enzymes (FASN, SCD), thereby promoting ER stress and apoptosis. In vivo, combination therapy significantly suppressed tumor growth compared with monotherapy and alleviated temsirolimus-induced hypercholesterolemia without apparent toxicity. Simvastatin-induced metabolic perturbation enhances mTOR inhibition in a cell-dependent manner, supporting dual metabolic targeting as a potential therapeutic strategy in ccRCC.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"21639-21652"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148579470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated transcriptomic and experimental validation reveal that N‑acetylcysteine ameliorates acute liver failure through multi‑target synergistic regulation of pyroptosis and related signaling networks.","authors":"Huazhu Wei, Shubing Yuan, Ziyuan Liang, Qinglan Shi","doi":"10.1007/s00210-026-05678-y","DOIUrl":"10.1007/s00210-026-05678-y","url":null,"abstract":"<p><p>Pyroptosis is a major contributor to the pathophysiology of acute liver failure (ALF), a condition with high mortality. Although N‑acetylcysteine (NAC) is used clinically for ALF, its mechanisms of regulating pyroptosis and multiple signaling pathways to achieve hepatoprotection remain incompletely understood. We integrated public transcriptomic data (GSE14668, GSE96851, GSE38941) and performed differential expression analysis, weighted gene co‑expression network analysis, protein-protein interaction network construction, and machine learning to identify ALF‑related pyroptosis signature genes. Network pharmacology and molecular docking were used to predict the core therapeutic targets and mechanisms of NAC. An in vitro cellular inflammation model (LPS/D‑GalN‑treated L02 hepatocytes) was established, and the effects of NAC on target proteins and signaling pathways were validated by CCK‑8, LDH release, Western blot, ELISA, and qPCR. Six core targets-IL18, BCL2, TLR4, CASP1, CCNB1, and CAV1-were identified. Molecular docking predicted binding affinities between NAC and these targets in the moderate range (- 4.2 to - 5.3 kcal/mol). In vitro, NAC (10 mM) significantly reduced total CASP1 and GSDMD protein levels. More importantly, we further assessed NLRP3 expression, cleaved caspase‑1 (p20 subunit), and the N‑terminal cleavage fragment of GSDMD (GSDMD‑NT); NAC markedly suppressed all three markers, providing direct evidence that it inhibits the canonical NLRP3/caspase‑1/GSDMD pyroptotic axis. NAC also restored BCL2, CCNB1, and CAV1 expression, reversed TLR4 overexpression, and normalized the LC3B‑II/I ratio and p62 levels, indicating restoration of autophagic flux. Compared with a pyroptosis inhibitor (Ac‑YVAD‑CMK), NAC showed superior efficacy in reversing TLR4 upregulation and cell‑cycle‑related protein abnormalities. NAC exerts a comprehensive hepatoprotective effect that surpasses that of a simple pyroptosis inhibitor by synergistically modulating pyroptosis, apoptosis, cell cycle, inflammatory recognition, and endocytosis pathways through multiple targets. These findings provide a theoretical foundation for expanding the clinical application of NAC in ALF.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"20649-20671"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148405274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lapatinib mitigates acetic acid-induced ulcerative colitis and hepatic damage in rats.","authors":"Abdullah S Al-Resheedi, Hoda E Kafl, Ghada M Suddek","doi":"10.1007/s00210-026-05680-4","DOIUrl":"10.1007/s00210-026-05680-4","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is an inflammatory condition of the colon. In some cases, current treatments produce no response or may not be enough for remission, fostering a need for more effective medications. Tyrosine kinase inhibitors have shown to be effective in some inflammatory diseases. This study aimed to investigate the potential protective effect of lapatinib (LAP), a dual tyrosine kinase inhibitor, against acetic acid (AA)-induced UC in rats. Four groups were formed from twenty-four rats (6 rats each) as control, AA, AA + LAP (50 mg/kg) and AA + LAP (75 mg/kg). LAP (50 or 75 mg/kg/day) was administered orally for 7 days prior to induction of UC. On the 8th day, UC was induced by instillation of AA (4%) intrarectally. The rats were sacrificed 1 day following UC induction, colons and livers were collected for biochemical, histopathological and immunohistochemical examination. LAP markedly alleviated histological damage of both the colon and the liver. LAP effectively reduced the oxidative stress status by diminishing MDA, upregulating GSH and Nrf2 contents and enhancing SOD activity in colonic and hepatic tissues. Mechanistically, LAP significantly suppressed NF-κB p65 and TNF-α, pJAK2, pSTAT3 and the proinflammatory cytokines IL-17 and IL-23. Additionally, it decreased apoptosis by downregulating caspase-3 expression in colonic and hepatic tissues. Conclusion: LAP prevented AA-induced colitis and associated hepatic damage in rats, at least partially, via targeting IL-23/IL-17/JAK2/STAT3 axis., inhibiting NF-κB/TNF-α pathway, enhancement of Nrf2-mediated antioxidant defense, and suppression of caspase-3-dependent apoptosis.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"21099-21117"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148456517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of gossypetin's effects on gut microbiota profile and TLR4, Myd88, NFKB, and NLRP3 signaling pathways in rats.","authors":"Onder Akkas, Demet Celebi, Ozgur Celebi, Sumeyye Baser, Sıla Ektas Kalayci, Betül Ari, Mustafa Can Guler, Bulent Dabanlıoglu, Selahattin Celebi, Metin Kılıclıoglu, Serkan Yıldırım","doi":"10.1007/s00210-026-05717-8","DOIUrl":"10.1007/s00210-026-05717-8","url":null,"abstract":"<p><p>Gut microbiota plays a crucial role in maintaining host homeostasis by regulating metabolic processes and immune responses. Disruptions in microbial composition are closely associated with inflammatory diseases and are often linked to the activation of key signaling pathways such as Toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa TLR4/MyD88/NF-κB and NLR family pyrin domain-containing 3 (NLRP3) inflammasome. Natural bioactive compounds, particularly flavonoids, have gained attention due to their potential to modulate both gut microbiota and inflammation-related pathways. In this context, the present study aimed to evaluate the effects of gossypetin on gut microbiota composition and its regulatory role on TLR4, MyD88, NF-κB, and NLRP3 signaling pathways in a rat model. Adult female Wistar albino rats were divided into control and gossypetin-treated groups (50 mg/kg, oral gavage/56 days dose). Gut microbiota was analyzed by 16S rRNA sequencing, and protein expression levels were assessed using Western blot. Histopathological, immunohistochemical, and immunofluorescence analyses were also in liver, intestinal, and spleen tissue performed. Gossypetin administration reduced microbial diversity and altered microbiota composition, with increases in Mediterraneibacter spp., Blautia spp., and Lactobacillus spp. Western blot results showed significant decreases in NLRP3 (p ≤ 0.01) and NF-κB (p ≤ 0.05) levels, while TLR4 and MyD88 remained unchanged. Histological analyses revealed mild tissue alterations and increased oxidative stress markers. These results suggest that gossypetin modulates microbiota composition and exerts selective anti-inflammatory effects, highlighting its potential in microbiota-associated inflammatory regulation.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":"21465-21480"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148549828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vildagliptin attenuates the development of CCl₄-induced liver fibrosis: associations with gut-liver axis modulation and LPS/notch-related signaling.","authors":"Aya M Eid, Ahmed O El-Gendy, Mohamed Gamal El-Din Ewees","doi":"10.1007/s00210-026-05961-y","DOIUrl":"https://doi.org/10.1007/s00210-026-05961-y","url":null,"abstract":"<p><p>Liver fibrosis is a progressive pathological condition closely linked to gut microbiota dysbiosis and impaired intestinal barrier integrity. Vildagliptin, a dipeptidyl peptidase-4 inhibitor used in type 2 diabetes, exhibits pleiotropic anti-inflammatory and antioxidant properties; however, its impact on the gut-liver axis during hepatic fibrogenesis remains insufficiently defined. This experimental study investigated whether concomitant vildagliptin administration attenuates the development of CCl₄-induced liver fibrosis and whether this effect is associated with alteration in gut microbial composition, intestinal barrier-related markers, and circulating lipopolysaccharide (LPS), and hepatic fibrosis-associated molecular changes. Male rats were allocated to five groups: normal control, Vildagliptin alone (20 mg/kg/day), CCl₄-fibrosis, and CCl₄ + Vildagliptin (10 or 20 mg/kg/day). Liver fibrosis was induced by CCl₄ administration for six weeks, with concomitant daily oral Vildagliptin in the treatment groups. Liver function indices, fibrotic markers, oxidative stress parameters, and serum LPS were assessed. Intestinal barrier-related changes were assessed by measuring colonic ZO-1 and occludin levels, while circulating LPS was quantified as a marker of systemic endotoxemia. Hepatic ADAM17, Notch-1, DNMT3A, and Smad7 protein levels and β-Klotho mRNA expression were assessed. Liver and colon histopathology was examined, and gut microbiota composition was profiled using 16S rRNA gene amplicon sequencing. Vildagliptin significantly ameliorated CCl₄-induced liver injury and fibrosis, evidenced by improved biochemical parameters, reduced collagen deposition and hydroxyproline, and attenuation of hepatic stellate cell activation. These effects were accompanied by increased colonic ZO-1 and occludin levels, reduced circulating LPS, decreased hepatic ADAM17, Notch-1, and DNMT3A protein levels, increased β-Klotho mRNA expression and Smad7 protein levels, and alterations in gut microbiota composition. Collectively, concomitant vildagliptin administration attenuated the development of CCl₄-induced liver fibrosis and was associated with modulation of gut-liver axis -related changes and alterations in LPS- and Notch-related molecular markers.</p>","PeriodicalId":18876,"journal":{"name":"Naunyn-Schmiedeberg's archives of pharmacology","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149112275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}