Fungal-derived chitosan (FCS) has emerged as a sustainable alternative to animal-derived chitosan (ACS) for biomedical applications. In this study, FCS fibers were fabricated via wet spinning and systematically compared with ACS fibers. FCS fibers exhibited a smaller fiber diameter, slightly lower crystallinity, and higher elongation, while maintaining a comparable chemical structure and thermal stability to ACS fibers. FCS fibers were subsequently twisted into yarns and functionalized with copper ions (Cu2 +) to prepare antibacterial sutures (Cu@FCS). Cu2+ loading onto FCS yarns increased with copper solution concentration, reaching 9.32 ± 4.01‰ (Cu-L@FCS), 30.83 ± 3.43‰ (Cu-M@FCS), and 126.25 ± 21.11‰ (Cu-H@FCS). Importantly, both Cu-L@FCS and Cu-M@FCS exhibited excellent cytocompatibility and hemocompatibility, whereas Cu-H@FCS showed cytotoxicity. Both Cu-L@FCS and Cu-M@FCS demonstrated potent antibacterial activity against S. aureus and E. coli. These groups also significantly enhanced L929 cell migration, achieving wound closure rates of 95.17 ± 2.78% and 96.97 ± 1.93% at 24 h. In vivo, Cu-M@FCS sutures effectively reduced inflammatory cell infiltration and promoted the healing of infected wounds. Collectively, Cu@FCS sutures combine sustainability, robust antibacterial activity, and enhanced wound-healing performance, underscoring their considerable promise for clinical translation in biomedical applications.

Dysregulated macrophage polarization is a critical pathological driver of sepsis-induced acute lung injury (ALI). However, the absence of novel therapeutic targets constitutes a significant translational barrier, underscoring the urgent need for advancements in precision medicine. In this study, we demonstrate that the natural product luteolin (LU) effectively promotes LPS-induced M1-to-M2 macrophage polarization by modulating the expression of pro-inflammatory and anti-inflammatory cytokines. Subsequently, thermal proteome profiling identifies receptor-type protein tyrosine phosphatase α (RPTPα) as a direct cellular target of LU in macrophages, which is validated by drug affinity responsive target stability, microscale thermophoresis, and surface plasmon resonance assays. Meanwhile, LU treatment inhibits RPTPα phosphatase activity. Molecular docking suggests that LU interacts with the 405PFTP408 motif, impairing substrate recognition and subsequently suppressing the enzymatic activity of RPTPα. Furthermore, transcriptomic profiling reveals that LU significantly dysregulates 1,402 genes. Integrated kyoto encyclopedia of genes and genomes (KEGG) and gene set enrichment analysis demonstrate that LU suppresses the tumor necrosis factor (TNF) signaling pathways, which is reversed upon RPTPα silencing. In vivo, LU exhibits potent anti-inflammatory effects in both BALB/c mice with sepsis-induced ALI and CuSO4-induced zebrafish inflammation models. Collectively, our study reveals that RPTPα is a potential therapeutic target for modulating macrophage polarization. Moreover, LU may serve as a lead compound targeting RPTPα for the treatment of sepsis-induced ALI.

Autoimmune myocarditis can result in dilated cardiomyopathy and heart failure, but effective drugs and clear therapeutic targets are still lacking. Experimental autoimmune myocarditis (EAM) serves as the primary animal model utilized for investigating human myocarditis. Puerarin (PUE), a compound derived from the root of Pueraria lobata, exhibits a broad spectrum of antioxidant and anti-inflammatory effects; nevertheless, its underlying mechanism remains elusive. The findings of this study suggested that PUE may attenuate the infiltration of inflammatory cells into the cardiac tissue by suppressing the secretion of chemokine CCL2 from endothelial cells and macrophages at the site of injury, as well as inhibiting the interaction between CCR2 and CCL2 in recruited inflammatory cells such as macrophages and Th1 cells. In this study, the focus was on investigating the impact of PUE on the chemotactic signal axis TNF-α/CCL2/CCR2. Through the utilization of Small Animal Ultrasound, Real-Time quantitative PCR, Co-Immunoprecipitation (Co-IP), and Immunofluorescence techniques on both cellular and animal models, it has been demonstrated that PUE effectively inhibits the production of CCL2 by disrupting the TNF-α/TNFR signaling pathway in macrophages and endothelial cells through its binding affinity with TNF-α. Additionally, PUE disrupts the transmission of chemotactic signals mediated by CCL2/CCR2 interaction through its binding to CCR2.This ultimately leads to a reduction in the infiltration of inflammatory cells into the heart. Moreover, the study highlights that PUE can effectively inhibit the transduction of the TNF-α/CCL2/CCR2 chemotactic signal, resulting in decreased infiltration of macrophages and Th1 cells in the heart and subsequently reducing inflammatory damage to myocardial tissue in EAM mice.

Prostate cancer is significantly influenced by cancer-associated fibroblasts (CAFs), which are key in determining the clinical outcomes of the disease. To address this, we developed a CAF-targeted redox-responsive biodegradable diselenide-bond-containing organosilica moieties nanosystem (Se@A&F) which could specifically deliver the CXCR4 antagonist AMD3100 to CAFs by targeting fibroblast activation protein-alpha (FAP-alpha) with FAP-alpha antibody, leading to the downregulation of C - X - C motif chemokine receptor 4 (CXCR4). The regulation initiates a cascade of alterations that lead to the inactivation of CAFs, thereby transforming the microenvironment of the malignant prostate tumor. Reducing the expression of CXCR4 can effectively deactivate CAFs and produce a range of antitumor benefits. Additionally, reshaping the prostate tumor microenvironment through CAF inactivation with the redox-responsive biodegradable diselenide-bond-containing organosilica moieties nanosystem can augment immune cell infiltration and suppress metastasis. Se@A&F triggered the release of tumor-associated antigens, which activated cytotoxic T lymphocytes. It also effectively reprogrammed tumorassociated macrophages, converting them to the tumoricidal M1 phenotype, thereby potentiating the antitumor action. Targeting and deactivating CAFs offers a novel strategy for inhibiting the spread and progression of malignant prostate tumors.

Myocarditis refers to localized or diffuse inflammatory lesions of the myocardium. Experimental autoimmune myocarditis (EAM) in mice is commonly utilized as an animal model for studying the pathogenesis of myocarditis. Baicalein (BAI), the main active component extracted from Scutellaria baicalensis root, has been proven to possess diverse effects such as anti-inflammatory, anti-tumor, and antioxidant activities. However, further investigation is warranted to elucidate the mechanism of action underlying BAI's efficacy in EAM. The aim of this study is to the potential of BAI in combination with TNF-α to downregulate the TNF-α/TNFR1-AP-1 signaling pathway. Furthermore, we will explore whether BAI exhibits an inhibitory effect on the CCL2/CCR2-ROCK1 signaling pathway. In this study, we employed the EAM animal model to investigate the inhibitory effect of BAI on macrophage and Th1 cell chemotaxis towards cardiac tissue in EAM mice. Techniques such as HE staining, immunofluorescence, and other methods were utilized for assessment. Additionally, computer-simulated molecular docking, Streptavidin pull-down, and co-immunoprecipitation experiments were conducted to explore the potential binding of BAI with TNF-α and CCR2. Furthermore, real-time quantitative polymerase chain reaction (qPCR), western blotting, and flow cytometry were employed to elucidate the impact of BAI on the TNF-α/TNFR1-CCL2/CCR2 signaling pathway. BAI suppressed the expression of chemokine CCL2 in EAM mouse myocardial tissue and attenuated the infiltration of macrophages and Th1 cells. In vitro, BAI exhibited binding affinity to TNF-α, leading to downregulation of the TNF-α/TNFR1-AP-1 signaling pathway and subsequent inhibition of CCL2 secretion by macrophages and vascular endothelial cells. Additionally, BAI demonstrated binding capability to CCR2, resulting in downregulation of the CCL2/CCR2-ROCK1 pathway and consequent inhibition of chemotactic migration of macrophages and Th1 cells. This study demonstrates that BAI can downregulate the secretion of CCL2 and the CCL2/CCR2-ROCK1 signaling pathway by binding with TNF-α and CCR2, thereby inhibiting the migration of macrophages and Th1 cells to the lesion site, thus alleviating the inflammation severity in EAM.

Recent studies have shown that homozygous and compound heterozygous variants in the 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) gene contribute to a novel early onset neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), a severe neurodevelopmental disorder characterized by impaired psychomotor development in infancy. Using whole-exome sequencing and Sanger sequencing, we identified and verified a novel compound heterozygous variant in HPDL, c.502 T > C (p.Cys278Arg)/c.833G > A (p.Gly278Asp), which may lead to lethal NEDSWMA, with individual differences in severity. We systematically summarized the clinical characteristics of the patients and their family members and analyzed the genetic characteristics such as homozygosity, conservatism, and pathogenicity of the variants by various prediction methods. Further in vitro functional experiments showed that the identified variants inhibited the proliferative capacity but not apoptosis of SH-SY5Y cells by altering HPDL expression at the mRNA and protein levels and negatively affecting endogenous CoQ10 secretion. Our study further contributes to the assessment of genotype-phenotype correlations, and firstly provides new insights for elucidating specific pathogenesis mechanisms and identifying precision-targeted therapies.

Although electrical stimulation (ES) and drugs are desirable for wound healing, dressings that combine ES and drugs are scarce. In this study, an electroactive drug-loaded nanofibrous dressing (PUE-Zn/AB@CA) was prepared by loading zinc/acetylene black nanoparticle particles (Zn/AB) in Puerarin/cellulose acetate (PUE/CA) nanofibres, respectively. Due to the different potentials, many galvanic couples can be formed between Zn and AB, generating electrical stimulation that promotes cell migration and proliferation. Benefiting from the synergistic effect of Zn/AB electrical stimulation and PUE, PUE-Zn/AB@CA exhibits excellent antioxidant, antibacterial, and anti-inflammatory properties. The whole-layer wound defect model experiment showed that PUE-Zn/AB@CA can significantly accelerate wound closure and promote granulation tissue formation, collagen deposition, and angiogenesis at the wound. Moreover, PUE-Zn/AB@CA could inhibit the inflammatory infiltration of M1-type macrophages in damaged wounds. In addition, flow cytometry and Western blot (WB) revealed that PUE-Zn/AB@CA could effectively down-regulate the lipopolysaccharide (LPS)-induced macrophage polarisation towards M1-type and reduce the protein level of pro-inflammatory cytokines (iNOS) in the cells. This work provided an effective wound healing strategy based on drug/electroactivity synergistic effects.

Myocarditis is an inflammatory lesion of the myocardium that is caused by a variety of factors. At present, treatment of symptoms remains the main clinical intervention, but it cannot reduce the myocarditis damage caused by inflammation. M1 macrophages are thought to contribute significantly to the occurrence and development of inflammation by secreting a large number of proinflammatory factors. Puerarin is an isoflavone derivative isolated from pueraria that can be used as a dietary supplement and exerts wide range of anti-inflammatory and antioxidant effects. However, the mechanism underlying its anti-inflammatory effects needs to be further studied. The objective of this study was to investigate whether puerarin inhibited M1 polarization by affecting the JAK-STAT signaling pathway in a mouse model of autoimmune myocarditis, thus inhibiting the occurrence of inflammation in experimental autoimmune myocarditis (EAM) model mice. The results showed that EAM model mice treated with puerarin showed milder clinical symptoms and inflammatory infiltration than EAM model mice. Puerarin suppressed the in vivo and in vitro JAK1/2-STAT1 signal transduction in macrophages, thus inhibiting M1 polarization, reducing the secretion of proinflammatory factors, and ultimately decreasing IFN-γ and TNF-α levels in vivo, which led to myocardial apoptosis. Thus, puerarin could alleviate myocardial damage caused by inflammation. The conclusion of this study was that puerarin reduced myocardial damage in EAM model mice by regulating the polarization of macrophages toward M1, and this inhibitory effect may be achieved by inhibiting JAK1/2-STAT1 signaling.

4009 Background: Integrating immunotherapy with trastuzumab and chemotherapy has shown a significant improvement in overall response rate (ORR) and progression-free survival (PFS) in HER2-overexpression gastric or gastroesophageal junction cancer (GC/GEJC). However, the overall survival (OS) did not achievestatistical significance, and there was no benefit in patients with a PD-L1 combined positive score (CPS) <1. RC48, an antibody-drug conjugate drug, has proven its effect in advanced HER2-positive (HER2 3+ or 2+ by IHC, regardless of FISH positivity) GC/GEJC in later-line treatment setting. This trial was to assess the efficacy and safety of combining RC48, immunotherapy (Tislelizumab), and S-1 as a first-line treatment for HER2-overexpressing GC/GEJC. Methods: This was a single-arm, multi-center, phase II trial conducted in patients with HER2-overexpressing metastatic or unresectable GC/GEJC for first-line treatments. Participants received RC48 (2.5 mg/kg), Tislelizumab (200 mg), and S-1 (40-60 mg BID for 14 days) every 3 weeks until disease progression or intolerable toxicities. The primary endpoint was ORR, while the secondary endpoints included disease control rate (DCR), PFS, OS, and safety. Results: A total of 47 patients were enrolled from 8 centers, median 65 (39 ~ 81) years old, 37 male, 37 GC and 8 GEJC, and all adenocarcinoma. Of them, 30 (63.8%) were HER2 IHC 3+, 11 (23.4%) HER2 IHC 2+/FISH+, and 6 (12.8%) IHC 2+/FISH-. Patients with PD-L1 CPS≥5, ≥1 accounted for 14.9%, 36.2% respectively. With a median follow-up duration of 116.5 days, patients received a median of 5.0 treatment cycles. As of January 20, 2024, 40 patients were included for efficacy analysis, and 44 patients for safety. The ORR reached 95.0% (38/40, 95% CI: 83.1-99.4%), clinical Complete Response rate was 20.0% (5/40, 95% CI: 4.2-26.8%), and the DCR was 100.0% (95% CI: 91.2-100.0%). The median PFS and OS were not reached, while the 6-month and 9-month PFS rates were 100.0% and 80.8%, the 6-month and 9-month OS rates were 100.0% and 83.8%. ORR among the HER2 IHC 3+, IHC 2+/FISH+, and IHC 2+/FISH- groups showed no significant difference (93.3%, 100.0%, 100.0%). ORR for patients with CPS≥1 or < 1 were 100.0%, 92.9%, respectively. One stage IVA GC patient (cT4bN3M0, HER2 3+, CPS 0) and another stage IVB GEJC one (cT3N2M1, HER2 2+/FISH+, CPS≥5) received radical surgery and both achieved pathological complete response. Grade 3/4 treatment-related adverse events occurred in 40.9% of patients, notably neutropenia, fatigue, and diarrhea. Conclusions: The combination of RC48, Tislelizumab, and S-1 showed notable efficacy with manageable safety in the first-line treatment of advanced HER2-overexpressing GC/GEJC patients. These findings support further exploration in this context. Clinical trial information: NCT05586061 .

Background: Urine-derived stem cells (USCs) were considered to be an ideal source of stem cells for repairing urological diseases. However, the proliferative ability of USCs significantly decreased when cultured on plastic dishes, which limited their clinical application. It was found that collagen gels could promote the proliferation of USCs, but the underlying molecular mechanisms were unclear. Objective: The study aims to investigate the role of the mechanically activated cation channel Piezo1 and the transcriptional coactivator YAP in the regulation of proliferation of USCs on collagen gels. Methods: USCs were cultured on collagen gels (group COL), or plastic dishes (group NON). MTT assay, Scratch assay, EDU staining, and immunofluorescence (IF) of Ki67 were performed to evaluate the proliferation of USCs; IF of YAP was conducted to observe its nuclear localization; calcium imaging experiment was executed to evaluate the function of Piezo1; western blot was used to compare changes in protein expression of YAP, LATS1, ERK1/2, and p-ERK1/2. In addition, the regulatory effect of YAP on the proliferative capacity of USCs was confirmed by intervening YAP with its inhibitor verteporfin (VP); and the inhibitor or activator of Piezo1, GsMTx4 or Yoda1 was used to explore the effect of Piezo1 on the nuclear localization of YAP, the proliferation of USCs and the regeneration of injured bladder. Results: The results showed that cell proliferation was significantly enhanced in USCs in the COL group with the nuclear accumulation of YAP compared with the NON group and VP attenuated these effects. The expression and function of Piezo1 were higher in the COL group compared with the NON group. Blockage of Piezo1 by GsMTx4 decreased nuclear localization of YAP, the proliferation of USCs, and caused the failure of bladder reconstruction. Activation of Piezo1 by Yoda1 increased the nuclear expression of YAP, and the proliferation of USCs, which further improved the regeneration of the injured bladder. Finally, the ERK1/2 rather than LATS1 was revealed to participate in the Piezo1/YAP signal cascades of USCs proliferation. Conclusion: Taken together, Piezo1-ERK1/2-YAP signal cascades were involved in regulating the proliferation ability of USCs in collagen gels which would be beneficial for the regeneration of the bladder.

Cisplatin (CDDP) can combat various types of cancers, employing a multifaceted approach against these malignant diseases. Despite its efficacy, resistance to CDDP remains a significant clinical challenge, often resulting in treatment failure and disease progression. Currently, efforts are underway to unravel the mechanisms of CDDP drug resistance in cancer treatment. The elevated presence of glutathione S-transferase pi-1 (GSTP1-1) within tumor cells plays a pivotal role in the development of resistance toward the effects of CDDP. GSTP1-1 contributes to detoxification by conjugating glutathione (GSH) to CDDP, reducing its accumulation and effectiveness in the tumor cells. In this study, the efficacy of gliquidone, an antidiabetic drug, demonstrated its capacity to impede tumor cell proliferation in both lung cancer A549 cell lines and A549/CDDP cell lines. This was achieved by suppressing the expression of GSTP1-1 within tumor cells (IC50: 16.8 +/- 0.8 mu M). Furthermore, through the establishment of a nude mouse model featuring lung adenocarcinoma A549/CDDP cell transplantation tumors, gliquidone demonstrated a significant therapeutic effect on the mice tumors, while avoiding discernible side effects. These findings suggest that gliquidone could potentially be repurposed as an adjunct therapy in CDDP-resistant lung cancer.

BackgroundThe experimental autoimmune myocarditis (EAM) model is valuable for investigating myocarditis pathogenesis. M1-type macrophages and CD4+ T cells exert key pathogenic effects on EAM initiation and progression. Baicalein (5,6,7-trihydroxyflavone, C15H10O5, BAI), which is derived from the Scutellaria baicalensis root, is a primary bioactive compound with potent anti-inflammatory and antioxidant properties. BAI exerts good therapeutic effects against various autoimmune diseases; however, its effect in EAM has not been thoroughly researched.PurposeThis study aimed to explore the possible inhibitory effect of BAI on M1 macrophage polarisation and CD4+ T cell differentiation into Th1 cells via modulation of the JAK-STAT1/4 signalling pathway, which reduces the secretion of pro-inflammatory factors, namely, TNF-α and IFN-γ, and consequently inhibits TNF-α- and IFN-γ-triggered apoptosis in cardiomyocytes of the EAM model mice.Study design and MethodsFlow cytometry, immunofluorescence, real-time quantitative polymerase chain reaction (q-PCR), and western blotting were performed to determine whether BAI alleviated M1/Th1-secreted TNF-α- and IFN-γ-induced myocyte death in the EAM model mice through the inhibition of the JAK-STAT1/4 signalling pathway.ResultsThese results indicate that BAI intervention in mice resulted in mild inflammatory infiltrates. BAI inhibited JAK-STAT1 signalling in macrophages both in vivo and in vitro, which attenuated macrophage polarisation to the M1 type and reduced TNF-α secretion. Additionally, BAI significantly inhibited the differentiation of CD4+ T cells to Th1 cells and IFN-γ secretion both in vivo and in vitro by modulating the JAK-STAT1/4 signalling pathway. This ultimately led to decreased TNF-α and IFN-γ levels in cardiac tissues and reduced myocardial cell apoptosis.ConclusionThis study demonstrates that BAI alleviates M1/Th1-secreted TNF-α- and IFN-γ-induced cardiomyocyte death in EAM mice by inhibiting the JAK-STAT1/4 signalling pathway.

Objective To explore the effects of polydopamine (PDA) plus luteolin (LUT) with photothermal therapy on tumor killing by cytotoxic lymphocytes (CTL). Methods The synthesized PDA was characterized by using a scanning electron microscope (SEM) and a contact angle analyzer. RAW264.7 cells were divided into control group, LPS group (2 μg/L), and PDA' group (50 000 μg/L). After 48 h culture, cell viability was determined by cell counting kit-8. The effect of LUT on the differentiation of RAW264.7 cells was determined by flow cytometry. Female C57BL/6 mice were randomly divided into model group, PDA group, LUT group, and PDA+LUT group. B16F10 melanoma cells were subcutaneously injected into the back of mice in each group. On the 10th day after modeling, the PDA and PDA+LUT groups received injection of PDA into the tumor as well as photothermal therapy. The mice in the four groups received injection of PBS, PDA (2.5 μg/piece), LUT (500 μg/piece), and PDA (2.5 μg/piece) plus LUT (500 μg/piece) into the muscle of the right thigh, respectively. We observed the tumor growth and survival of the model mice. On days 3 and 7 after treatment, the spleen of each mouse was taken to prepare a single cell suspension for analysis of macrophage differentiation and T cell expression by flow cytometry. Results SEM showed that the synthesized PDA had good adhesion and affinity for water. CCK8 showed that the PDA did not affect cell viability (P>0.05). Significant differences were found in the mean fluorescence intensities of CD206 and iNOS between different groups of RAW264.7 cells (F=30.72,1 516.00,P<0.05). There were significant differences in tumor size and the expression levels of iNOS, CD206, IFN-γ+CD4+, and TNF-α+CD8+ of immune cells between mice with and without LUT injection, under the condition of either injecting or not injecting PDA (F=23.10-235.52,P<0.05). There were significant differences in tumor size and the expression levels of iNOS, CD206, IFN-γ+CD4+, and TNF-α+CD8+ of immune cells between mice with and without PDA injection, under the condition of either injecting or not injecting LUT (F=8.98-200.67,P<0.05). The survival rate of the PDA+LUT group was significantly higher than those of the other groups (χ2=9.70,P<0.01). Conclusion LUT could inhibit the differentiation of macrophages to M2 and promote the differentiation to M1 in mice. PDA combined with LUT could effectively inhibit tumor growth, improve survival rate, and enhance the tumor-kil-ling effect of CTL in mice.

Exudate management and bioelectric signals are critical to promoting wound healing. In this study, the thermoplastic polyurethane (TPU) nanofiber is directly electrospun on the cotton microfibers (Cotton) to prepare a Janus dressing (TPU/Cotton), which can unidirectionally drain the excess exudate. Then, Ag/Zn dot electrodes are deposited on the TPU layer, which can produce an electric field penetrating the wound when activated by wound exudate. The hydro‐activated Ag/Zn's electrical stimulation (ES) can promote the migration of fibroblast cells and shows excellent antibacterial activity against E. coli and S. aureus . Furthermore, in vivo experiments show that the exudate management coupled with ES accelerated wound healing at multiple stages by promoting re‐epithelization, collagen deposition, and vascularization. Moreover, the Ag/Zn@TPU/Cotton dressing shows excellent biocompatibility in the vitro cytotoxicity experiments. These findings may shed some light on developing the next generation of wound dressings with self‐activated electrical stimulation and exudate management.

The epithelial-mesenchymal transition (EMT) is a complicated biological process in which cells with epithelial phenotype are transformed into mesenchymal cells with loss of cell polarity and cell–cell adhesion and gain of the ability to migrate. EMT and the reverse mesenchymal-epithelial transitions (METs) are present during cancer progression and metastasis. Using the dynamic switch between EMT and MET, tumour cells can migrate to neighbouring organs or metastasize in the distance and develop resistance to traditional chemotherapy and targeted drug treatments. Growing evidence shows that reversing or inhibiting EMT may be an advantageous approach for suppressing the migration of tumour cells or distant metastasis. Among different levels of modulation of EMT, alternative splicing (AS) plays an important role. An in-depth understanding of the role of AS and EMT in cancer is not only helpful to better understand the occurrence and regulation of EMT in cancer progression, but also may provide new therapeutic strategies. This review will present and discuss various splice variants and splicing factors that have been shown to play a crucial role in EMT.

Abstract Helper T cells (Th) play a crucial role in the pathogenesis of multiple sclerosis (MS) and experimental encephalomyelitis (EAE). Th1/17 cells contribute to neuroinflammation through inflammatory infiltration and cytokine secretion, however, effective therapeutic interventions are currently lacking. Baicalein (BAI), the principal component of Scutellaria baicalensis, is a dietary supplement that has demonstrated efficacy in the fields of anti-inflammatory, neuroprotection, and immunomodulation. The activation the JAK-STAT signalling pathway in Th1/17 cells may play a pivotal role in the initiation and progression of inflammation associated with MS/EAE. Therefore, this study aimed to investigate whether BAI could mitigate the inflammatory response of Th1/17 cells by modulating JAK-STAT signaling. Flow cytometry, quantitative real-time PCR and western blotting were used to detect the ratio of Th1 and Th17 cells, the expression of related cytokines in EAE model mice treated with BAI, as well as the expression of proteins related to the JAK/STAT signaling pathway. The findings demonstrated that BAI exhibited therapeutic efficacy in EAE mice by significantly reducing the proportion of Th1 and Th17 cell populations along with the expression levels of relevant inflammatory cytokines. Moreover, transcription factors T-bet and ROR-γt showed significant downregulation in response to BAI treatment. This effect may be attributed to BAI's ability to inhibit STAT1/3 phosphorylation. Subsequently, molecular docking, pull-down and immunofluorescence experiments confirmed that BAI bound to STAT1/3, and caused p-STAT1/3 to remain in the cytoplasm, hindering JAK/STAT signal transduction and thus inhibiting the inflammatory response of the Th1/17 cells.

Curcumin is a chemical with various pharmacological activities used for cancer treatment. It inhibits hepatocellular carcinoma (HCC) by inducing apoptosis. Here, the mechanism underlying the effect of curcumin on the apoptosis of HCC cells was studied. Cell counting kit-8 and plate cloning assays were used to assess the proliferation of HCC cells, and acridine orange/ethidium bromide and Annexin V/PI staining were used to analyze their apoptosis. HCC xenograft tumor models were established to validate anti-cancer effects of curcumin. Expression levels of XRCC4 protein in tumor tissues were assessed by immunohistochemistry. Correlation between XRCC4 expression and the prognosis of patients with HCC was analyzed by integrating publicly available gene expression data. Curcumin inhibited HCC cells proliferation in a dose-dependent manner. Compared with the control group, curcumin significantly promoted the apoptosis of HCC cells in vitro and in vivo. Immunohistochemical analysis revealed that curcumin downregulated XRCC4 expression levels in HCC tissues. Prognosis of HCC patients with high XRCC4 expression was poorer than that of patients with low XRCC4 expression. Therefore, curcumin exerts anti-cancer effects by inhibiting cell proliferation and promoting cell apoptosis in HCC. This may be due to curcumin interference in the repair process of the nonhomologous DNA terminal link of HCC cells by downregulating XRCC4 expression.

Adjuvants are an indispensable component of vaccines, but there are few adjuvants for human vaccines. H2 receptor blockers, inhibiting gastric acid secretion, have immune enhancement effects. Ranitidine (RAN) is a water-soluble H2 receptor blocker, and whether it has an immune-enhancing effect is still unknown. In this study, flow cytometry, western blotting, and immunofluorescence methods were used to analyze whether RAN could activate macrophage polarization to the M1 phenotype in vivo and in vitro. Here, we found that the M1 inflammatory cytokine levels and surface markers in RAW264.7 cells were upregulated by NF-κB activation, possibly through the PI3K-Akt2 signaling pathway, after RAN treatment. Endocytic function was also enhanced by feedback regulation of Akt2/GSK3β/Dynmin1 signaling. Furthermore, to evaluate the adjuvant function of RAN, we used OVA plus RAN as a vaccine to inhibit the growth of B16-OVA tumors in mice. We also found that in the RAN adjuvant group, macrophage polarization to M1, Th1 cell differentiation, and cytotoxic T lymphocyte (CTL) activation were significantly upregulated. The tumor growth of mice was inhibited, and the survival rate of mice was significantly improved. This study provides new evidence for the mechanism by which RAN activates the immune response and is expected to provide a new strategy for the research and development of tumor vaccine adjuvants.

目的 研究靶向碱性成纤维细胞生长因子(bFGF)、尿源干细胞(USCs)复合膀胱脱细胞基质(BAM)用于膀胱再生修复的可行性.方法 制备多孔结构的BAM.将24只雄性SD大鼠随机分为BAM组、BAM/USCs组、BAM/USCs/靶向bFGF组和假手术组(n=6),除假手术组均行膀胱半切术建立膀胱缺损模型.BAM组支架材料为BAM材料加少量PBS,BAM/USCs组将1×106密度的USCs负载至BAM材料上,BAM/USCs/靶向bFGF组将1×106密度的USCs和10 μmol/L的靶向bFGF共同负载至BAM材料上,将支架材料缝合于切除膀胱的位置.术后90 d测定各组尿动力学,处死大鼠取下再生的膀胱组织进行组织学检查,评估膀胱再生情况.结果 术后90 d,BAM组、BAM/USCs组、BAM/USCs/靶向bFGF组、假手术组膀胱顺应性依次增大(F=345.800,P＜0.01).组织学观察显示,4组膀胱平滑肌的再生程度及再生区域的血管再生程度依次增加(F=65.870～619.100,P＜0.01).结论 靶向bFGF蛋白、USCs复合多孔结构的BAM材料具有良好的促膀胱再生能力,是一种具有可行性的修复支架材料.

目的 疫情背景下基于《组织与胚胎学》课程特点,探讨传统教学模式和混合式教学模式的教学效果差异.方法 整群抽样取2020级临床医学(五年制)专业7、8班56名学生为对照组,9、10班57名学生为观察组,对照组采用线下面授的传统教学模式,观察组采用线上线下结合的混合式教学模式.采用形成性评价成绩、线上期中考试成绩和线下期终考试成绩结合(最终成绩)的方式评价两组教学效果.结果 观察组教学模式的满意度明显高于对照组(P<0.05);观察组的形成性评价成绩、线上期中考试成绩、线下期末考试成绩和最终成绩(86.09±4.74、87.18±4.73、84.40±5.01和85.75±4.01)分均显著高于对照组(77.36±5.59、78.34±6.02、75.45±10.30和75.98±10.50)分,差异均具有统计学意义(P<0.05).结论 混合式教学模式有利于学生课程成绩的提高,有利于"教"与"学"的良性循环,有利于学生专业知识的贯通和融合.