Abstract Psoriasis is a chronic immune-mediated skin disease characterized by proliferation of abnormal keratinocytes and immune dysregulation. Paeoniflorin (Pae), the main active component in total glucosides of the flowering plant paeony, has strong anti-inflammatory and immunomodulatory effects but faces limitations due to poor skin penetration and low oral bioavailability. To address this, a self-adhesive, sustained-release microneedle patch (MHAP MNs) was developed, incorporating dopamine and methacrylic anhydride and loaded with Pae. This patch enhances skin penetration, tissue adhesion, and controlled drug release. It effectively reduces immune cell infiltration, modulates inflammatory factors, and downregulates the IL-17 pathway, alleviating skin and systemic inflammation. Additionally, the microneedle backing made of polyvinylpyrrolidone allows quick separation for improved patient compliance. MHAP MNs show promise as a novel therapeutic strategy for psoriasis and potentially other autoimmune and inflammatory diseases by delivering precise, sustained treatment directly to affected sites.

Type 2 diabetic melitus (T2DM) is characterized by insulin resistance (IR) and dysregualted glucose-lipid metabolism, with hepatic IR representing a critical early pathological event. Current hypoglycemic drugs often have adverse effects and suboptimal efficacy, promoting interest in natural, safe bioactive products with hypoglycemic and lipid-regulatory properties. Turnip (Brassica rapa var. rapa), a traditional food-medicinal homologous crop, contains bioactive components with potential metabolic regulatory effects, yet their systematic isolation and mechanistic elucidation remain insufficient. In this study, we systematically isolated and identified bioactive components from turnip, and found its n-butanol subfraction T-3B exerts potent anti-T2DM effects in db/db mice. T-3B dose-dependently reduces fasting blood glucose (FBG), enhances hepatic and skeletal muscle glucose uptake, and ameliorates dyslipidemia—effects mediated by synergistic activation of the IRβ-IRS1-AKT insulin and AMPK lipid metabolic pathway, which forms a positive feedback loop to modulate systemic metabolism. Six monomeric compounds were isolated from T-3B, among which C2 and C6 exhibited potent hypoglycemic and lipid-regulatory activities. Notably, C2 as the core bioactive component, replicated T-3B’s therapeutic effects in an in vitro hepatocyte model induced by high glucose-high fat (HGF), alleviating lipid metabolism disorders and oxidative stress-induced damage. This study provides a scientific foundation for the medicinal potential of turnip and highlights T-3B, C2 and C6 as promising candidate agents for T2DM therapy.

ETHNOPHARMACOLOGICAL RELEVANCE:Smilacis Chinae Rhizoma (SCR), derived from the rhizome of Smilax china L., has long been utilized in traditional Chinese medicine for the treatment of inflammatory dermatological disorders, including cutaneous abscesses. AIM OF THE STUDY:This study aimed to evaluate the therapeutic potential and underlying mechanisms of Smilacis Chinae Rhizoma ethyl acetate fraction (SCR-EA) in psoriasis, with a focus on its immunomodulatory effects on T-cell responses and the IL-17 signaling pathway. MATERIALS AND METHODS:A psoriasis-like mouse model was induced via topical imiquimod (IMQ) application. Mice were treated with SCR-EA (100 or 200 mg/kg) or methotrexate (MTX, 1 mg/kg). Psoriasis severity was assessed using the Psoriasis Area and Severity Index (PASI). Histopathological alterations, KC proliferation, and inflammatory cytokine mRNA levels (IL-6, TGF-β1, IL-1β, S100A9) were analyzed. T-cell subset distribution in the spleen was examined by flow cytometry. Key IL-17 pathway proteins (IL-17A, RORγt, p-STAT3, STAT3) were assessed by Western blot. Network pharmacology and molecular docking were used to predict potential targets and pathways, followed by experimental validation. RESULTS:SCR-EA significantly alleviated IMQ-induced psoriatic lesions, reduced epidermal thickness, and inhibited KC hyperproliferation. It suppressed pro-inflammatory cytokine expression and corrected the IMQ-induced imbalance of Th1, Th2, and Th17 cell subsets in the spleen. Network pharmacology identified the IL-17 signaling pathway as a major target, which was validated by SCR-EA's inhibition of IL-17A, RORγt, and STAT3 activation. Molecular docking revealed strong binding affinities between SCR-EA's primary constituents (astilbin, engeletin, resveratrol) and IL-6 and TNF-α. CONCLUSION:SCR-EA mitigates IMQ-induced psoriasis by modulating T-cell differentiation and inhibiting the IL-17 signaling pathway. This study provides a pharmacological foundation for the traditional use of SCR in treating inflammatory skin conditions and positions SCR-EA as a promising multi-target candidate for psoriasis therapy.

The rise of triple-negative breast cancer (TNBC) warrants the urgent need to identify novel therapies. Herein, untargeted metabolomics-guided isolation revealed the metabolome fingerprints of Polygonum bistorta (PB) and Polygonum viviparum (PV) in correlation with their TNBC inhibitory activity. Phytochemical analysis annotated 209 metabolites, with flavonoids (45 compounds) as the major class, followed by phenolic acids (25), tannins (24), and hydroxycinnamic acids (18). Multivariate data analysis identified chlorogenic acid, 6-O-galloylarbutin, and procyanidin B1 as key markers of PV, whereas naringenin-O-glucoside, catechin, and crataegunin D characterized PB. Among different polar extracts, ethyl acetate extract of PB (PB-EA) and the n-butanol extract of PV (PV-NB) exhibited the strongest cytotoxicity against 4T1 cells, with IC50 values of 23.28 ± 0.90 and 39.11 ± 2.36 μg/mL, respectively. Subsequently, the same extracts significantly suppressed tumor growth in the 4T1-Luc orthotopic xenograft mouse model compared with their respective model groups (p < 0.001, p < 0.01). Bioassay-guided isolation yielded 8 compounds, including crataegunin D, which isolated from Polygonaceae plants for the first time, displaying IC50 values of 24.91 ± 2.43 and 20.65 ± 1.77 μM against 4T1 and MDA-MB-231 cells, respectively. Molecular docking revealed binding free energies (ΔG) ranging from -52 to -48 kcal/mol targeting EGFR and CDK receptors.

Ulcerative colitis (UC) is a chronic relapsing disease characterized by the destruction of the intestinal epithelial barrier and dysregulation of immune homeostasis. Despite advancements in therapeutic strategies, current conventional treatments are often hampered by systemic side effects and variable responses. To address these issues, we innovatively developed a self-assembled hydrogel (BBH@PH) incorporating small-molecule phytochemicals (puerarin, berberine and baicalin). Specifically, BBH@PH possessed favorable mechanical strength and pH-sensitive swelling behavior as well as controlled drug release, with less than 20% drug leakage in simulated gastric fluid and over 75% cumulative release in simulated colonic fluid. Moreover, this gel exhibited effective ROS-scavenging activity and modulation of macrophage polarization toward the M2 phenotype in living cells. Subsequent investigations into its protective effects on the intestinal barrier revealed that BBH@PH efficiently alleviated LPS-induced damage in Caco-2 monolayers, preserved the integrity of intercellular tight junctions and facilitated epithelial cell wound healing. In vivo, this gel achieved prolonged gastrointestinal retention (1.60-fold higher than that of free ICG at 24 h) and enhanced transepithelial absorption (3.10-, 1.92- and 4.02-fold increases compared to free berberine, baicalin, and puerarin, respectively). Benefiting from its unique properties, BBH@PH significantly suppressed the secretion of pro-inflammatory cytokines and M1 macrophage polarization, upregulated the expression of intestinal tight junction proteins and rebalanced the dysregulated intestinal microbiota in DSS-induced colitis mice. Notably, the absence of toxic manifestations indicated a favorable safety profile for BBH@PH. Overall, these findings present an innovative therapeutic option for UC, underscoring the synergistic effects of phytochemicals.

Injectable hydrogels derived from natural extracellular matrices exhibit excellent adhesion to endothelial cells in vitro and are ideal for many biomedical applications. However, their applicability in vivo is limited by the risk of infection or immunogenicity, and the current injectables also suffer from degradation, viscosity, and drug release. In this study, a multifunctional hydrogel scaffold (COB hydrogels) was constructed by incorporating bioactive glass nanoparticles with a Schiff base crosslinking-based hydrogel composed of carboxymethyl chitosan and oxidized cellulose. The incorporation of nanoparticles not only shortened the gelation time of the COB hydrogels, but also enhanced the performance of the hydrogel in terms of function, such as drug loading capacity. The prepared hydrogels also have self-healing ability, injectability, drug loading and sustained release, antibacterial properties and biocompatibility. In addition, given their no cytotoxicity and mild inflammation in vivo, the hydrogel scaffolds will be important for tissue engineering and drug delivery applications.

BRT enhances CD8+ T cell response by activating Mitogen-Activated Protein Kinase (MAPK) signaling and Protein Kinase C (PKC) signaling pathways through gut microbiota mediated diacylglycerol (DAG) synthesis, and exerts its anti-tumor effect.

INTRODUCTION:Hirsutella sinensis fungus (HSF)is an artificial substitute for Cordyceps sinensis and has shown promising therapeutic effects in various diseases including cancer. Previous studies have demonstrated that HSF can affect macrophage polarization and activate systemic immune response. In our preliminary experiments, we validated that HSF inhibited the proliferation of lung cancer (LC) cells, but the underlying mechanism is elusive. We intended to explore the mechanism of HSF in promoting anti-tumor immunity. METHODS:In vivo experiments were performed to confirm inhibitory effect of HSF on LC growth, and sequencing results revealed abnormal expression of CCRL2. Knockdown and overexpression of CCRL2 were conducted to investigate its effect on macrophage polarization, and co-culture with T cells was to assay the impact of HSF+CCRL2 on CD8+ T cell activation by flow cytometry. RESULTS:Overexpression of CCRL2 promoted macrophage polarization toward M1 and activated the proliferation and effector function of CD8+ T cells. HSF promoted CCRL2 expression and affected M1 polarization via CCRL2, which in turn affected CD8+ T cell-mediated anti-tumor immunity. DISCUSSION:Our study demonstrated that HSF promoted macrophage M1 polarization and activated CD8+ T cells via CCRL2, thereby inhibiting the progression of LC.

ETHNOPHARMACOLOGICAL RELEVANCE:Smilax china L. is a traditional Chinese herb. Smilax china L. Rhizome (SCR) have historically been used in ethnomedicine for their anti-inflammatory, anti-tumor, and immunomodulatory properties. AIM OF THE STUDY:This study aimed to evaluate the anti-tumor efficacy of SCR in the MMTV-PyMT mouse mammary tumor model and elucidate its immunomodulatory mechanisms within the tumor microenvironment (TME). MATERIALS AND METHODS:SCR was administered to MMTV-PyMT mice to assess its effects on tumor progression and metastasis. Immune cell profiling (M1/M2-like macrophages, CD8+ T cells) was conducted via flow cytometry. In vitro macrophage polarization assays under IL-4 stimulation and mechanistic studies (MAPK/ERK signaling) were performed using Western blot and pharmacological inhibitors. Diosgenin, a key SCR constituent, was identified and validated through phytochemical analysis and functional assays. RESULTS:SCR treatment significantly slowed primary tumor growth and reduced lung metastases. SCR induces a shift in macrophage polarization from immunosuppressive M2-like to proinflammatory M1-like and promotes increased CD8+ T cell infiltration. In vitro, SCR inhibited IL-4-induced M2 polarization and suppressed ERK1/2 phosphorylation, a critical node in the MAPK pathway. Diosgenin was identified as a pivotal bioactive compound contributing to SCR's anti-tumor and immunomodulatory effects. CONCLUSIONS:These findings provide a theoretical basis for the potential clinical application of SCR in cancer treatment, highlighting its critical role in remodeling the tumor immune microenvironment.

Total glucosides of paeony (TGP), an active ingredient extracted from the dried root of Paeonia lactiflora Pall., has been approved in China for the treatment of various autoimmune diseases. However, the role and mechanism of TGP in UC have yet to be fully elucidated. This study aims to investigate the regulatory effects and underlying mechanisms of TGP on intestinal homeostasis disruption and immune imbalance in a mouse model of dextran sulfate sodium (DSS)-induced colitis. The results showed that TGP alleviated DSS induced body weight loss, colonic shortening and histopathological changes in mice, and also enhanced the integrity of the intestinal barrier by up-regulating the expression of ZO-1, Occludin and tight junction protein in the colon. The results of 16S and antibiotic cocktail (ABX) experiments showed that TGP alleviated colitis by inhibiting Th17 cell differentiation by correcting intestinal microbial imbalance in UC mice. Mechanism studies showed that TGP inhibited the activation of JAK2/STAT3 signaling pathway in UC mice, and decreased the levels of inflammatory factors in colon supernatant and serum. Importantly, TGP regulates JAK2/STAT3 to inhibit Th17 cell differentiation depending on gut flora. In addition, TGP can also improve the metabolic imbalance in UC mice, especially purine metabolism. In conclusion, TGP promotes the normalization of purine metabolism and relies on gut microbiota to regulate JAK2/STAT3 pathway, inhibit Th17 cell differentiation, and alleviate colitis. Our findings highlight TGP as a promising treatment candidate for ulcerative colitis.

One new polyketide asperfuranone D (1), four new sesquiterpenes derivatives aspergillone C-F (2-5) and three known compounds (6-8) were successfully isolated from Aspergillus nidulans LZ8, a fungicolous fungi from the macrofungal Ganoderma lingzhi. The structures of these compounds were elucidated by extensive spectroscopic analyses including ultraviolet-visible spectroscopy (UV), mass spectrometry (MS), nuclear magnetic resonance (NMR), and electronic circular dichroism (ECD) calculation. In addition, the anti-inflammatory activities of the new compounds were evaluated using LPS-induced RAW 264.7 cells. The results revealed that compound 5 showed moderate nitric oxide (NO) inhibitory activity with the IC50 value of 13.19 +/- 1.05 mu M, while the IC50 value of the positive control L-NMMA was 41.88 +/- 0.91 mu M.

Background and aim Diabetic nephropathy (DN) represents the primary contributor to end-stage renal disease worldwide, and its prevalence continues to grow, even with improvements in therapies aimed at lowering glucose levels. The progression of DN has been associated with lipid metabolism, yet the direct involvement of particular lipid species is still not fully understood. This study employs two-sample Mendelian randomization (TSMR) to investigate the causal effects of 179 plasma lipid species on DN risk. Methods and results Lipid exposure genetic instruments were sourced from a genome-wide association study (GWAS) found in the GWAS Catalog, whereas data on the DN outcomes were collected from the FinnGen R12 cohort. The main analytical approach employed was inverse-variance weighted (IVW) regression. To evaluate pleiotropy and heterogeneity, tests such as MR-Egger intercept, Cochran's Q, MR-PRESSO, and leave-one-out analyses were performed. The analysis identified 13 lipid species with significant associations after sensitivity analyses. Among these, seven lipid species were risk factors for DN, including phosphatidylcholine (PC) (O-16:1_18:1, 15:0_18:2, 18:1_18:1, 18:1_20:2, 18:2_18:2) levels, phosphatidylethanolamine (PE) (18:1_18:1), and triacylglycerol (TAG) (56:4). Conversely, six lipid species demonstrated protective effects, including lysophosphatidylcholine (LPC) (20:4), lysophosphatidylethanolamine (LPE) (18:1), PC (17:0_20:4), sterol ester (SE) (27:1/15:0, 27:1/18:3), and TAG (52:6). Conclusions This study provides robust genetic evidence linking specific lipid species to DN risk. PC and PE species were identified as risk factors, whereas LPC, LPE, and SE exhibited protective effects. Additionally, TAG species demonstrated a bidirectional influence. These findings refine the understanding of lipid-mediated renal dysfunction in DN, highlighting lipid metabolism as a potential therapeutic target.

[This corrects the article DOI: 10.1016/j.mtbio.2023.100878.].

Herein, we report a microenvironment self-adaptive multifunctional hydrogel (GBOD-PF) dressing with intrinsic hemostasis, antimicrobial and anti-inflammatory properties that promotes collagen deposition, activates the immune response, and angiogenesis, accelerates large-scale chronic wound healing. To address these needs, aldehyde-functionalized dextran (ODT) was first synthesized through oxidation, and an injectable hydrogel was prepared by mixing Gel and ODT solutions in the presence of borax and paeoniflorin (PF) through the formation of dynamic Schiff base bonds (GBOD-PF). This multifunctional hydrogel exhibits remodeling and self-healing properties, enhanced adhesion strength and biocompatibility. Moreover, it possesses broad-spectrum antibacterial activity and superior hemostasis, providing early-stage protection for complex wounds. Notably, GBOD-PF targets the TLR4/NF-κB signaling pathway, a core mediator of inflammation, thereby dampening the inflammatory cascade. The results demonstrate the application of the GBOD-PF hydrogel in an infection wound and diabetic model wound healing model, which enhanced immune response, induced M1-to-M2 macrophage repolarization to establish anti-inflammatory microenvironment, regulated MMP-9, promoted angiogenesis, thereby inducing a pro-regenerative response. Therefore, this work provides an effective strategy for the treatment of chronic wound repair and tissue regeneration.

Hirsutella sinensis fungus (HSF) is an edible fungus used in traditional chinese medicine. Although its potential in regulating immunity and improving the tumor microenvironment has been recognized, it has not been sufficiently studied in the context of Ulcerative colitis (UC). In this study, we used ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry to identify the nutritional components of HSF, and clarified its effect on UC by detecting the effects of HSF on gut microbiota, bile acid metabolism and T helper 17 (Th17) cells cell differentiation. Results from 16S rRNA sequencing, fecal microbiota transplantation (FMT), and antibiotics (ABX) experiments indicate that HSF exerts its protective effects against UC by correcting gut microbiota imbalances and modulating Th17 cell differentiation. Additionally, untargeted metabolomics and targeted bile acid analysis reveal that HSF regulates bile acid metabolism, particularly ursodeoxycholic acid (UDCA) synthesis, through remodeling the gut microbiota. Supplementation with exogenous UDCA inhibits Th17 cell differentiation and restores damaged intestinal barriers, thereby mitigating UC. Mechanistically, HSF regulates the imbalance of intestinal flora, especially the abundance of Ruminococcus and Lactobacillus, promotes UDCA synthesis, inhibits Interleukin-6 (IL-6)/ janus kinase 2 (JAK2)/ signal transducer and activator of transcription 3 (STAT3) signaling and Th17 cell differentiation. This study demonstrated that HSF modulates Th17 cell differentiation via the intestinal microbiota-UDCA metabolic axis and enhances intestinal barrier integrity, offering a promising new approach for the treatment of UC.

Background:Focal Adhesion Kinase (FAK) is a key tyrosine kinase often overexpressed in tumors, making it a promising target for cancer therapy. This study aims to screen and investigate the activity and mechanisms of Traditional Chinese Medicines (TCMs) targeting FAK within breast cancer. Materials and Methods:Using xCELLigence system, we identified TCMs affecting FAK signaling and validated its anti-tumor effects. The 4T1-Luc breast cancer models and MMTV-PyMT mice were used to evaluate Moutan Cortex Radicis (MCR) on tumor growth and lung metastasis, with flow cytometry assessing immune cell changes. We utilized CRISPR-Cas9 to investigate the anti-tumor mechanisms of MCR by specifically targeting the FAK signaling pathway. To elucidate the underlying molecular mechanisms, RNA sequencing was performed, and the results were subsequently validated through quantitative reverse transcription PCR (qRT-PCR) and Western blot analysis. Results:We have successfully developed the EGF-induced Time-dependent Cell Response Profilings (FAK-TCRPs) and discovered that MCR effectively attenuated EGF-mediated responses in a dose-dependent manner. Additionally, MCR significantly inhibited tumor growth and lung metastasis by partly targeting FAK. MCR increased CD8+ T cell infiltration and the proportion of CD44HiCD62LHi central memory and CD44HiCD62LLow effector memory T cells, while reducing regulatory T cells (Tregs) and CTLA-4 expression. MCR converted M2 tumor-associated macrophages (TAMs) to M1 within the tumor microenvironment (TME). In FAK-deficient mice, MCR did not affect on CD8+ cells, TAMs, or CTLA-4 expression. MCR modulated chemokine signaling and ECM-receptor interactions, decreasing CCL1, CCL5, TGF, IL-4, IL-10, TNF-α, and IL-6, while increasing CCL7, CXCL10, and IL-24. It significantly inhibited FAK mRNA in tumors. Cellular experiments demonstrated that MCR suppressed P-FAK and P-Erk activation and reduced MMP-2, MMP-9, Laminin, and Fibronectin levels. Conclusion:Collectively, MCR is identified as a FAK-targeting agent through FAK-TCRPs. MCR inhibits TAMs, CTLA-4, and chemokine transcription via the FAK/MMPs pathway, showing antitumor effects in breast cancer.