Type 2 diabetes mellitus (T2DM) is a complex metabolic disease characterized by insulin resistance and deficiency. Polysaccharides from Polygonatum cyrtonema Hua have garnered widespread attention for the prevention and management of metabolic diseases owing to their broad pharmacological activity. Therefore, this study aimed to investigate the effects and underlying mechanisms of the P. cyrtonema Hua polysaccharide component, PCP1, an agavin-type fructan with a molecular weight of 4650 Da, on T2DM mice. Mice were fed a high-fat, high-sugar diet and injected with a low-dose of streptozotocin to establish a T2DM model. During an 8-week intervention period, the mice were administered with different doses of PCP1 by gavage. Following, the biochemical, transcriptomic, and metabolomic analyses were performed. The results showed that PCP1 effectively improved insulin resistance, glycolipid metabolic disorders, oxidative stress, inflammatory responses, and liver injury in diabetic mice. Mechanistic studies revealed that PCP1 ameliorated gut microbiota dysbiosis, promoted the production of SCFAs, upregulated the expression of GPR43 in colon tissue, enhanced the secretion of GLP-1 and PYY, and activated the IRS1/PI3K/Akt signaling pathway in the liver. Further validation using NCI-H716 cells treated with the inhibitor GLPG0974 demonstrated that GLP-1 and PYY secretion were indirectly promoted by SCFAs through activating GPR43 receptor, but not entirely dependent on GPR43 pathway. In conclusion, this study indicated that PCP1 ameliorated T2DM probably through improving gut microbiota imbalance and glucose metabolism disorder, thereby establishing a theoretical foundation for the prebiotic development of P. cyrtonema Hua a polysaccharide.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with persistent colonic inflammation and inadequate therapeutic options. The medicinal and edible plant Polygonatum cyrtonema Hua from Jiuhua Mountain contains polysaccharides with potent anti-inflammatory activities. In this study, a low-molecular-weight fructan (Mw = 2087 Da), designated PCP2, was isolated and purified from its rhizome. Biologically, PCP2 administration markedly alleviated disease severity in dextran sulfate sodium (DSS)-induced colitis mice, as shown by the improvement in multiple indicators of colon injury and inflammation. Fecal microbiota transplantation and antibiotic depletion experiments revealed that the protective effects of PCP2 are mediated through both modulation of the gut microbiota and additional microbiota-independent pathways. Importantly, through molecular dynamics simulations, microscale thermophoresis, and surface plasmon resonance assays, follistatin (Fst) is identified as a direct binding target of PCP2. Functional validation using siRNA-mediated Fst knockdown in Caco-2 cells, combined with adenovirus-mediated knockdown in the murine colon, confirmed that PCP2 exerts its therapeutic effect by directly interacting with Fst and suppressing the BMP4/Smad1/ID1 signaling axis. In summary, PCP2 ameliorates ulcerative colitis via dual mechanisms involving restoration of gut microbiota homeostasis and direct targeting of Fst. These findings establish a novel therapeutic strategy and support the clinical development of P. cyrtonema Hua from Jiuhua Mountain as a functional food for intestinal health.

Hepatic inflammation and gut barrier dysfunction are core pathologies of alcohol-associated liver disease (ALD), yet effective therapies remain limited. Pueraria lobata polysaccharide (PLP1), a key active constituent of P. lobata Radix, has demonstrated hepatoprotective potential; however, its underlying mechanisms remain poorly understood. In this study, we sought to elucidate the therapeutic mechanism of PLP1 against experimental ALD by integrating proteomics, metabolomics, and gut microbiota analyses. We demonstrated that PLP1 initially functions through a microbiota-dependent pathway, transferable by fecal microbiota transplantation (FMT), to restore gut barrier integrity and suppress the gut‒LPS‒TLR4 inflammatory axis. Furthermore, PLP1 exerted a direct, microbiota-independent effect, maintaining its therapeutic efficacy in antibiotic-depleted mice. Mechanistically, PLP1 directly and specifically targets CXCL1, promoting its ubiquitin-mediated proteasomal degradation as confirmed by biophysical assays. The functional necessity of this interaction was definitively established via comprehensive genetic manipulation of CXCL1 in vitro and in vivo. Specifically, CXCL1 overexpression reversed PLP1’s benefits, whereas CXCL1 knockdown mimicked its effects and occluded any additional benefit from PLP1. Overall, PLP1 ameliorates ALD by independently targeting both extrinsic and intrinsic inflammatory triggers. This study reveals the multifaceted pharmacology of a natural polysaccharide and validates a dual-pronged therapeutic strategy for ALD.

BACKGROUND:Hepatic fibrosis, driven by oxidative stress and subsequent hepatocellular injury, represents a major worldwide health challenge. Pueraria lobata Radix, a traditional Chinese herb, contains polysaccharides with demonstrated hepatoprotective properties, though their mechanisms remain incompletely defined. PURPOSE:This study aims to characterize the structure of P. lobata polysaccharide (PLP2) and to decipher its protective mechanisms against hepatic fibrosis. METHODS:PLP2, a homogeneous, water-soluble polysaccharide, was purified from P. lobata and structurally characterized. Subsequently, the hepatoprotective activity of PLP2 was investigated in a CCl₄-induced murine model of hepatic fibrosis. RESULTS:Structural analysis indicated that PLP2 (Mw = 142.9 kDa) was mainly composed of (1→4)-α-D-Glc and (1→4)-α-D-GalA units, with a minor presence of →4,6)-α-D-Glc-(1→ residues. In a CCl₄-induced murine model of hepatic fibrosis, PLP2 treatment effectively ameliorated liver injury, histopathological damage, and inflammatory responses. Mechanistically, PLP2 treatment restored mitochondrial ultrastructure and hepatic ATP levels, thereby suppressing hepatic ferroptosis through the activation of the Nrf2/HO-1/GPX4 axis. The indispensable role of Nrf2 was further validated using the inhibitor ML385, which abolished PLP2's protection. Notably, the hepatoprotective effects of PLP2 were predominantly dependent on gut microbiota integrity, as direct PLP2 treatment failed to protect hepatocytes in vitro. This role was further confirmed by the abolition of protection with antibiotic treatment and the transfer of benefits via fecal microbiota transplantation. CONCLUSION:These findings provide evidence that PLP2 exerts its anti-fibrotic effects through the gut microbiota-dependent suppression of ferroptosis via the Nrf2/HO-1/GPX4 axis, providing a solid scientific foundation for the clinical application of P. lobata.

Cisplatin (DDP) remains a standard therapy for triple-negative breast cancer (TNBC), yet intrinsic or acquired resistance often limits its efficacy; here, we report that Ramulus Mori alkaloids (SZ-A), an approved botanical α-glucosidase inhibitors, synergize with DDP to suppress TNBC progression in vitro and in vivo by driving PLA2G2A-dependent ceramide accumulation. Combining SZ-A with DDP synergistically inhibits viability, clonogenicity, migration, and invasion, induces S-phase arrest and apoptosis, and attenuates tumor growth in xenograft models. Mechanistically, SZ-A directly binds to and stabilizes PLA2G2A, blocking its autophagic-lysosomal degradation, leading to accumulated PLA2G2A that suppresses fatty acid oxidation and triggers ceramide accrual via ADIPOR2 inhibition. Genetic ablation of PLA2G2A abrogates these effects. DDP further enhances SZ-A-induced PLA2G2A upregulation and ceramide accumulation, resulting amplified cytotoxicity. Our findings reveal SZ-A as a chemosensitizing agent that enhances the efficacy of DDP in TNBC.

Inflammation is a defensive immune response to tissue damage or infection. Polygonatum cyrtonema Hua (P. cyrtonema Hua, PCH) is bioactive on immune homeostasis due to its rich components and reportedly plays a therapeutic role in the treatment and prevention of diabetes. Flavonoids of PCH possess anti-inflammatory properties, but their molecular mechanisms remain elusive. Here, chemical profiling of key flavonoids was conducted using UPLC-QTOF-MS/MS and the Global Natural Products Social Molecular Networking (GNPS) platform. Network pharmacology predicted potential targets and pathways, validated by molecular docking, surface plasmon resonance (SPR), and western blotting. Totally, 67 compounds were identified, with methylophiopogonanone B (MOB) as the key bioactive flavonoid. Although MOB's anti-inflammatory activity has been previously noted, the present study provides the first evidence that this effect may be mediated through targeting SRC and modulating the PI3K/AKT signaling axis. Core therapeutic targets were identified as SRC, TNF, and AKT1 by topological analysis of network pharmacology. Molecular docking and SPR confirmed strong MOB-SRC binding affinity. Western blotting revealed MOB dose-dependently inhibited LPS-induced phosphorylation of SRC, PI3K, and AKT1, without altering total protein levels. Furthermore, MOB significantly suppressed the phosphorylation of NF-κB pathway proteins IκB and p65, confirming the involvement of NF-κB as a downstream effector. In conclusion, this study integrates chemical profiling and network pharmacology with experimental validation to define the flavonoid composition of PCH, and is the first to implicate the SRC-PI3K-Akt pathway in MOB's anti-inflammatory action and providing novel evidence supporting the mechanism and use of PCH in contemporary diabetes treatment.

This study aims to investigate the protective effects and mechanisms of polysaccharide extract PCP1 from Polygonatum cyrtonema in ameliorating cerebral ischemia-reperfusion(I/R) injury in rats through modulation of the Toll-like receptor 4(TLR4)/NOD-like receptor protein 3(NLRP3) signaling pathway. In vivo, SD rats were randomly divided into the sham group, model group, PCP1 group, nimodipine(NMDP) group, and TLR4 signaling inhibitor(TAK-242) group. A middle cerebral artery occlusion/reperfusion(MCAO/R) model was established, and neurological deficit scores and infarct size were evaluated 24 hours after reperfusion. Hematoxylin-eosin(HE) and Nissl staining were used to observe pathological changes in ischemic brain tissue. Transmission electron microscopy(TEM) assessed ultrastructural damage in cortical neurons. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of interleukin-1β(IL-1β), interleukin-6(IL-6), interleukin-18(IL-18), tumor necrosis factor-α(TNF-α), interleukin-10(IL-10), and nitric oxide(NO) in serum. Immunofluorescence was used to analyze the expression of TLR4 and NLRP3 proteins. In vitro, a BV2 microglial cell oxygen-glucose deprivation/reperfusion(OGD/R) model was established, and cells were divided into the control, OGD/R, PCP1, TAK-242, and PCP1 + TLR4 activator lipopolysaccharide(LPS) groups. The CCK-8 assay evaluated BV2 cell viability, and ELISA determined NO release. Western blot was used to analyze the expression of TLR4, NLRP3, and downstream pathway-related proteins. The results indicated that, compared with the model group, PCP1 significantly reduced neurological deficit scores, infarct size, ischemic tissue pathology, cortical cell damage, and the levels of inflammatory factors IL-1β, IL-6, IL-18, TNF-α, and NO(P<0.01). It also elevated IL-10 levels(P<0.01) and decreased the expression of TLR4 and NLRP3 proteins(P<0.05, P<0.01). Moreover, in vitro results showed that, compared with the OGD/R group, PCP1 significantly improved BV2 cell viability(P<0.05, P<0.01), reduced cell NO levels induced by OGD/R(P<0.01), and inhibited the expression of TLR4-related inflammatory pathway proteins, including TLR4, myeloid differentiation factor 88(MyD88), tumor necrosis factor receptor-associated factor 6(TRAF6), phosphorylated nuclear factor-kappaB dimer RelA(p-p65)/nuclear factor-kappaB dimer RelA(p65), NLRP3, cleaved-caspase-1, apoptosis-associated speck-like protein(ASC), GSDMD-N, IL-1β, and IL-18(P<0.05, P<0.01). The protective effects of PCP1 were reversed by LPS stimulation. In conclusion, PCP1 ameliorates cerebral I/R injury by modulating the TLR4/NLRP3 signaling pathway, exerting anti-inflammatory and anti-pyroptotic effects.

Ten withanolides (1-10) were isolated from Physalis minima L., a medicinal and edible plant. Among them, five (1-5) are previously undescribed. Their chemical structures were established through comprehensive spectroscopic and spectrometric analyses. In vitro bioassays revealed that compounds 2-5 and 8 significantly inhibited nitric oxide production in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 cells, exhibiting anti-inflammatory effects with IC50 values ranging from 4.29 to 25.54 μM. Compound 2, which was identified as phyminiolide B and was the most abundant and potent one, potently reduced inflammatory cytokines release and downregulated COX-2 and iNOS expression. Mechanistically, it inhibited the activation of the NF-κB and MAPK pathways by blocking the phosphorylation of IKKα/β, IκBα, ERK, JNK, and p38. Furthermore, molecular docking and molecular dynamics simulation revealed that phyminiolide B exhibited strong binding affinity for the TLR4/MD2 complex, with a calculated binding energy of -9.0 kcal/mol. Additionally, in vivo experiments confirmed that phyminiolide B markedly alleviated LPS-induced acute lung injury in animal models, underscoring its therapeutic potential for inflammatory diseases. The findings provided valuable insights into the structural diversity and anti-inflammatory mechanisms of withanolides from P. minima.

Diabetic cognitive dysfunction (DCD) is one of the major complications of type 2 diabetes mellitus (T2DM). At present, there is still no clinical consensus on the improvement and treatment of DCD, mainly due to limitations in understanding the pathogenesis and a lack of effective drugs. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, shows potential for alleviating DCD. However, its neuroprotective mechanisms remain inadequately explored. Herein, our findings showed that sitagliptin reduced fasting blood glucose, decreased body weight, lowered insulin resistance, and attenuated levels of inflammatory markers in diabetic mice. Moreover, sitagliptin treatment significantly ameliorated DM-induced disability of learning and memory. Subsequently, we observed that sitagliptin impedes neuronal ferroptosis both in diabetic mice and high glucose combined with palmitic acid (HG + PA)-stimulated primary neurons and PC12 neuronal cells, partly reflected in decreased lipid and intracellular reactive oxygen species (ROS) levels, increased glutathione (GSH) and superoxide dismutase (SOD) levels, reduced malondialdehyde (MDA) content, and elevated expression of ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), compared to the corresponding alterations observed in diabetic mice. Mechanistically, molecular docking and cellular thermal shift assays revealed that sitagliptin directly binds to and enhances the nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Moreover, genetic loss of Nrf2 by transfected Nrf2 siRNA significantly blunted sitagliptin-induced ferroptosis inhibition in primary neurons and PC12 neuronal cells under HG + PA conditions, whereas Nrf2 overexpression further augmented the beneficial effect of sitagliptin on impeding neuronal ferroptosis. These data indicated that sitagliptin regulated Nrf2 expression, which modulated the SLC7A11-GPX4 axis, inhibited neuronal ferroptosis, and finally ameliorated diabetic cognitive dysfunction.

BACKGROUND:Evidence for assessing the relationship between free triiodothyronine (FT3) and high-density lipoprotein cholesterol (HDL-C) remains limited. Therefore, the purpose of our study is to evaluate the relationship between FT3 and HDL-C in patients with type 2 diabetes. METHODS:From June 2022 to October 2023, 3011 patients with normal thyroid function and diagnosed with type 2 diabetes mellitus (T2DM) were collected continuously and non-selectively in a Chinese hospital. Then, we used a logistic regression model to explore the relationship between FT3 and HDL-C. Smooth curve fitting is used to identify the nonlinear relationship between FT3 and HDL-C. RESULTS:After adjusting for the influence of relevant factors, FT3 and HDL-C were negatively correlated -0.02 (-0.04, -0.00; p = 0.0162). There is also a nonlinear relationship between FT3 and HDL-C, with an inflection point of 3.48 pmol/L for FT3 (P for log- likelihood ratio test = 0.044). CONCLUSION:This study shows that there is a negative correlation and nonlinear relationship between FT3 and HDL-C in the Chinese population with diabetes. When FT3 is between 2.76-3.48 pmol/L, HDL-C tends to a stable state; When FT3 is between 3.48-6.45 pmol/L, HDL-C decreases with the increase of FT3 concentration (According to the reference range used by our hospital, the normal value of serum FT3 is 2.76-6.45 pmol/L). These findings suggest that maintaining FT3 within the range of 2.76 to 3.48 pmol/L may be most beneficial for mitigating the progression of cardiovascular disease in patients with T2DM.

Four previously undescribed physalins (1-4), along with six known ones (5-10) were isolated and identified from the whole plants of Physalis minima L., a medicinal and edible plant traditionally used in southwest China. Their structures were established through comprehensive spectroscopic analyses, including high-resolution electrospray ionization mass spectrometry and 1D/2D nuclear magnetic resonance spectroscopy. Moreover, the absolute configurations of 1-3, 5 and 7 were examined by X-ray diffraction analyses. Compound 1, an undescribed sulfur-containing physalin, exhibited the most protective effect against oxygen-glucose deprivation/reperfusion (OGD/R)-stimulated ischemia-reperfusion (I/R) injury in PC12 cells. Meanwhile, compound 1 was found to reduce the inflammatory response, with mechanistic studies indicating that it decreased pyroptosis-associated proteins, such as cleaved-caspase1, NLRP3, and GSDMD N-terminus. Importantly, GSDMD knockdown significantly reversed the protective effects of compound 1, highlighting the involvement of pyroptosis in the compound's protective mechanism against OGD/R-induced I/R injury in PC12 cells in vitro.

Ulcerative colitis (UC) is a chronic, complex inflammatory condition with a high global prevalence. Thesium chinense Turcz. is renowned for its antibacterial and anti-inflammatory properties. In this study, a novel branched polysaccharide (TP1) was isolated from Thesium chinense Turcz., primarily composed of fructose, glucose, and galactose with a molecular weight of 5377 Da. Its backbone includes →1)-β-D-Fruf-(2→, →1,6)-β-D-Fruf-(2→, →4)-α-D-Glcp-(1→, and →3,6)-β-D-Galp-(1→ residues, and the side chain is Fruf-(2→6)-β-D-Fruf-(2→ linked to the O-6 of the →1,6)-β-D-Fruf-(2→ residue, while β-D-Galp-(1→ linked to the O-6 of the →3,6)-β-D-Galp-(1→ residue. In DSS-induced UC mice, TP1 significantly ameliorated weight loss, colon shortening, and the intestinal barrier damage. Mechanistically, TP1 reestablished the gut microbiota, increased SCFAs concentrations, activated GPR41/43 receptors, and downregulated proteins expression in the IL-17/NF-κB/JAK2/STAT3 signaling axis. TP1 maintained Th17/Treg homeostasis may through the SCFAs-mediated GPR41/43 pathway and IL-17/NF-κB/JAK2/STAT3 pathway, thereby inhibiting intestinal inflammation to alleviate UC. This study provides new insights into therapeutic strategies for UC.

The investigation of the whole plants of Physalis minima led to the isolation of four novel withanolides, designated phyminiolides F-I, together with six known analogues. The structures of 1-4 were elucidated through comprehensive analysis of their spectroscopic data, including HRESIMS, NMR and ECD, while those of 5-10 were identified by comparing their spectroscopic data with the reported literature values. Biologically, compounds 1, 3-4, and 8-10 exhibited moderate anti-inflammatory activities by inhibiting nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated murine RAW 264.7 cells in vitro, with IC50 values ranging from 8.72 to 23.28 μM.

This study investigated the cardioprotective effects of hyperoside against myocardial ischemia-reperfusion injury(MIRI) and its impact on the protein kinase C(PKC)/mitochondrial ATP-sensitive potassium channel(mitoKATP) signaling pathway. A rat MIRI model was established by 30-minute left anterior descending coronary artery ligation followed by 2-hour reperfusion, while an in vitro MIRI model was created using H9c2 cardiomyocytes subjected to 12-hour hypoxia and 4-hour reoxygenation. The models were then treated with hyperoside alone or in combination with PKCα inhibitor bisindolylmaleimide I(BisI), PKCε inhibitor chelerythrine(CHE), or mitoKATP inhibitors 5-hydroxydecanoate(5-HD)/glibenclamide(GB). Myocardial infarct size was assessed by TTC staining; cardiomyocyte apoptosis was detected via TUNEL assay and flow cytometry; serum levels of creatine kinase-MB(CK-MB), superoxide dismutase(SOD), malondialdehyde(MDA), and adenosine triphosphate(ATP) were measured by ELISA; Western blot analyzed protein expression of nuclear factor erythroid 2-related factor 2(Nrf2), PKCε, inward rectifier potassium channel(Kir6.2), and caspase-3 in myocardial tissue and H9c2 cells; calcium ion(Ca~(2+)) levels were detected by immunofluorescence. RESULTS:: demonstrated that hyperoside treatment significantly reduced myocardial infarct area, attenuated tissue edema, fiber disruption, inflammatory infiltration, and decreased apoptosis compared with the model group. Consistent with in vivo findings, hyperoside markedly reduced H9c2 cell apoptosis and Ca~(2+) concentration versus hypoxia/reoxygenation group. Both in vivo and in vitro experiments confirmed that hyperoside decreased MDA content and CK-MB activity, increased SOD activity and ATP levels, upregulated Nrf2, PKCε and Kir6.2 expression, while downregulating caspase-3. These beneficial effects were significantly abolished by co-administration of BisI, CHE, or 5-HD/GB. These findings suggest that hyperoside alleviates MIRI potentially through activating the PKC/mitoKATP signaling pathway.

Polysaccharides from edible and medicinal plants are promising natural agents for intestinal health. In this study, a homogeneous polysaccharide (AMP) was isolated from Atractylodes macrocephala Koidz. Structural characterization revealed that AMP (Mw = 3.56 kDa) primarily consisted of fructose (92.4 %) and glucose (7.6 %), with β-D-fructofuranose and α-d-glucopyranose residues linked through →1)-β-D-Fruf-(2→, →1,6)-β-D-Fruf-(2→, and α-D-Glcp-(1 → glycosidic bonds. In vivo studies confirmed the efficacy of AMP against ulcerative colitis (UC) in a DSS-induced mouse model, as evidenced by a significant improvement in disease symptoms, including increased body weight, longer colon length, and elevated goblet cell counts, coupled with a reduction in the disease activity index and histological damage. Mechanistically, AMP attenuated inflammation by restoring intestinal barrier integrity and regulating the gut microbiota to maintain its homeostasis. These regulatory effects were further validated through fecal microbiota transplantation (FMT) and antibiotic intervention (Abx). Olink proteomics and western blotting demonstrated that the ameliorative effect of AMP on UC, mediated via the PI3K/Akt pathway, was entirely dependent on the homeostasis of the gut microbiota. Collectively, these findings position AMP as a promising functional food ingredient or natural therapeutic for UC, providing a scientific basis for the high-value exploitation of A. macrocephala.

[This corrects the article DOI: 10.3389/fphar.2021.692806.].

Melatonin (MLT) is a potentially effective therapeutic agent for mitigating brain injury under various pathological conditions. However, the molecular mechanisms of its ability to ameliorate diabetic cognitive dysfunction (DCD) require further elucidation. In this study, we demonstrated that MLT administration improved the learning and memory deficits in type 2 diabetes mellitus (T2DM) mice, concurrently attenuated acyl-CoA synthetase long-chain family member 4 (ACSL4) - dependent ferroptosis in diabetic brain tissue and neuronal cells exposed to high glucose/palmitic acid (HG + PA), as indicated by reduced lipid peroxidation, elevated GSH and SOD levels, increased GPX4 levels, and downregulated ACSL4 expression. Furthermore, MLT reversed nuclear receptor coactivator 4 (NCOA4) -mediated ferritinophagy in vivo and in vitro. This opinion was demonstrated by decreased intracellular ROS and Fe2+ levels, reduced NCOA4 expression, and increased Ferritin levels. Mechanistic investigations revealed that MLT directly binds to stimulator of interferon genes (STING) and suppresses its expression and activation, as determined by surface plasmon resonance, molecular docking, and cellular thermal shift assays. Consequently, MLT treatment disrupted the subsequent recruitment of NCOA4 and ACSL4 to STING. Pharmacological activation or genetic overexpression of STING attenuated the inhibitory effect of MLT on ferroptosis and ferritinophagy. In contrast, STING silencing had the opposite effects under the aforementioned conditions. Our findings revealed that melatonin exerts dual regulatory mechanisms, inhibiting ACSL4-dependent ferroptosis and suppressing NCOA4 axis-mediated ferritinophagy through directly targeting STING, thereby ameliorating diabetic cognitive dysfunction.

Mitogen-activated protein kinase-interacting kinases (MNKs) play a key role in the occurrence and migration of tumors and have become promising targets for tumor therapy. Nevertheless, the development progress on the MNKs inhibitors against cancer was relatively slow. In this study, compound 4s (MNK1/2 half-maximal inhibitory concentration [IC50] = 987/1048 nM), a promising MNKs inhibitor was discovered based on virtual screening. After the structural optimization of compound 4s, 18 novel thiophene [2,3-D] pyrimidine-thiazole derivatives were designed and prepared, and their inhibitory effect on MNKs was determined. Among which, compound 5l exhibited the best inhibitory activity on MNKs (MNK1/2 IC50 = 23/62 nM) and relatively high selectivity among 125 kinases. Results from in vitro experiments indicated that compound 5l could significantly inhibit the in vitro proliferation (IC50 = 0.8 +/- 0.1 mu M) and migration of breast cancer cells, which demonstrated that compound 5l is a promising MNK inhibitor to treat breast cancer and need further study.

Atherosclerosis, a chronic inflammatory disease, is characterized by lipid accumulation and inflammation in arterial walls. Polygonatum cyrtonema Hua, a traditional Chinese medicine and functional food, has long been used to treat cardiovascular diseases. In this study, we investigated the effects of a purified polysaccharide component (PCP1) from P. cyrtonema Hua on atherosclerosis. In vitro, the influence of PCP1 on lipid accumulation and inflammation in macrophages was assessed. In vivo, ApoE-/- mice fed a high-fat diet (HFD) for 12 weeks were treated with PCP1 via daily gavage. Subsequently, lipid levels, inflammatory markers, and atherosclerotic lesion development were evaluated. The results demonstrated that PCP1 significantly ameliorated atherosclerosis by inhibiting macrophage lipid accumulation and inflammation. Mechanistically, PCP1 downregulated CD36 and MSR1, which are involved in lipid uptake and reduced the expression of pro-inflammatory cytokines by blocking the TLR4/NF-κB signaling. Additionally, PCP1 mitigated the overactivation of aortic endothelial cells and suppressed inflammatory responses in smooth muscle cells. Overall, PCP1 uniquely exerted anti-atherosclerotic effects through dual modulation of lipid metabolism and inflammation, thereby validating its traditional use in cardiovascular conditions and highlighting its potential as a therapeutic agent.