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Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used but often cause small intestinal ulcers (SIUs), for which effective therapies are lacking. Sishen Pill (SSP), a traditional Chinese medicine, shows therapeutic promise, yet its mechanisms remain unclear. This study integrates network pharmacology, molecular docking, and experimental validation to systematically investigate SSP's protective mechanisms against NSAID-induced SIUs. Active SSP ingredients were screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Encyclopedia of Traditional Chinese Medicine (ETCM) databases. SIU-related targets were retrieved from GeneCards and DisGeNET. Protein-protein interaction (PPI) networks were constructed via STRING and Cytoscape, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Molecular docking (AutoDock Vina, PyMOL) validated ligand-target interactions. In vivo validation employed an indomethacin-induced SIU rat model to assess SSP's effects on ulcer severity, inflammation, oxidative stress, and PI3K/AKT signaling. We identified 66 bioactive SSP ingredients, 222 drug targets, and 144 SIU-related targets. Molecular docking revealed high binding affinity of SSP components (quercetin, bavachinin, rutaecarpine, evodiamine) to key targets (AKT1, HSP90AA1, IL6, MAPK1, BCL2). KEGG analysis highlighted the PI3K/AKT pathway as central. In vivo, SSP reduced ulcer indices, suppressed pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and attenuated oxidative stress. SSP also downregulated PI3K and AKT1 mRNA expression, confirming pathway modulation. This study elucidates SSP's multi-target mechanism against NSAID-induced SIUs, emphasizing its role in suppressing inflammation, oxidative stress, and PI3K/AKT signaling. These findings provide a scientific foundation for SSP's clinical application and highlight its potential as a safe, effective alternative to conventional therapies.

Neuropathic pain (NP) induced by spinal cord injury (SCI) often causes long-term disturbance for patients, but the mechanisms behind remains unclear. Here, our study showed SCI-induced ectopic expression of Nav1.7 in abundant neurons located in deep and superficial laminae layers of the spinal dorsal horn (SDH) and upregulation of Nav1.7 expression in dorsal root ganglion (DRG) neurons in mice. Pharmacologic studies demonstrated that the efficacy of the blood–brain-barrier (BBB) permeable Nav1.7 inhibitor GNE-0439 for attenuation of NP in SCI mice was significantly better than that of the BBB non-permeable Nav1.7 inhibitor PF-05089771. Moreover, more than 20% of Nav1.7-expressing SDH neurons in SCI mice were activated to express FOS when there were no external stimuli, suggesting that the ectopic expression of Nav1.7 made SDH neurons hypersensitive and Nav1.7-expressing SDH neurons participated in central sensitization and in spontaneous pain and/or walking-evoked mechanical pain. Further investigation showed that NGF, a strong activator of Nav1.7 expression, and its downstream JUN were upregulated after SCI in SDH neurons with similar distribution patterns and in DRG neurons too. In conclusion, our findings showed that the upregulation of Nav1.7 was induced by SCI in both SDH and DRG neurons through increased expression of NGF/JUN, and the inhibition of Nav1.7 in both peripheral and spinal neurons alleviated mechanical pain in SCI mice. These data suggest that BBB permeable Nav1.7 blockers might relieve NP in patients with SCI and that blocking the upregulation of Nav1.7 in the early stage of SCI via selective inhibition of the downstream signaling pathways of NGF or Nav1.7-targeted RNA drugs could be a strategy for therapy of SCI-induced NP.

Inflammatory bowel disease (IBD) is a chronic disease involving multiple genes, and the current available targeted drugs for IBD only deliver moderate efficacy. Whether there is a single gene that systematically regulates IBD is not yet known. plays a pivotal role in repression of innate immunity, but its function in the intestinal inflammation is sort of controversy, and the genetic regulatory networks regulated by miR-146a in IBD has not been revealed. RT-qPCR was employed to detect the expression of in IBD patients and in a mouse IBD model induced by dextran sulfate sodium (DSS), and then we generated a knock-out mouse line with C57/Bl6N background. The disease activity index was scored in DSS-treated miR-146a deficiency mice and their wild type ( ) littermates. Bulk RNA-sequencing, RT-qPCR and immunostaining were done to illustrate the downstream genetic regulatory networks of in flamed colon. Finally, the modified mimics were used to treat DSS-induced IBD in knock-out and IBD mice. We showed that the expression of in the colon was elevated in dextran sulfate sodium (DSS)-induced IBD mice and patients with IBD. DSS induced dramatic body weight loss and more significant rectal bleeding, shorter colon length, and colitis in knock-out mice than mice. The miR-146a mimics alleviated DSS-induced symptoms in both and mice. Further RNA sequencing illustrated that the deficiency of de-repressed majority of DSS-induced IBD-related genes that cover multiple genetic regulatory networks in IBD, and supplementation with mimics inhibited the expression of many IBD-related genes. Quantitative RT-PCR or immunostaining confirmed that , MMP3, MMP8, MMP10, IL1A, IL1B, IL6, CXCL2, CXCL3, S100A8, S100A9, TRAF6, P65, p-P65, and IRAK1 were regulated by miR-146a in DSS induced IBD. Among them, , and were involved in the active stage of IBD in humans. Our date demonstrated that miR-146a acts as a top regulator in C57/BL6N mice to systematically repress multiple genetic regulatory networks involved in immune response of intestine to environment factors, and combinatory treatment with and mimics attenuates DSS-induced IBD in mice through down-regulating multiple genetic regulatory networks which were increased in colon tissue from IBD patients. Our findings suggests that is a top inhibitor of IBD, and that and mimics might be potential drug for IBD.

Decoy receptor 3 (DcR3) is a tumor necrosis factor receptor, which may inhibit apoptosis. The aim of the present study was to investigate the clinical significance of DcR3 upregulation in patients with chronic hepatitis B (CHB) and hepatic fibrosis. A total of 128 patients with a clinical diagnosis of CHB who underwent liver biopsy were included in the present study. The expression levels of DcR3, hyaluronic acid (HA), type III procollagen, type IV collagen (IV-C) and laminin protein were assessed. The diagnostic value of DcR3 in patients with CHB with hepatic fibrosis was determined using receiver operating characteristic (ROC) curve analysis. DcR3 was significantly upregulated in patients with CHB, particularly in patients with active CHB. The expression of DcR3 was significantly increased in patients with CHB with liver fibrosis and liver cirrhosis, compared with patients with CHB without liver fibrosis. The area under the ROC curve for the diagnosis of CHB liver fibrosis based on DcR3 or DcR3 combined with IV-C/HA was 0.807 or 0.869, with a sensitivity and specificity of 76.9 and 77.8% or 84.6 and 81.2%, respectively. DcR3 is a marker for liver fibrosis in patients with hepatitis B infection. The use of DcR3 in combination with IV-C and HA may further increase its diagnostic value for liver fibrosis.

Neuropathic pain (NP) affects 7%-10% of population, with current treatments often proving inadequate. Here we show that Na 1.7 and Na 1.8 form supramolecular active complexes (SMACs) with polygonal lattice structure in dorsal root ganglion (DRG) neurons of mouse models and patients with severe chronic NP. TrkB signaling facilitates the formation of Na 1.7/Na 1.8 SMACs. Targeting these SMACs with combined Na 1.7 and Na 1.8 blockers inhibits action potentials of both human and mouse pathological DRG neurons and synergistically alleviates chronic NP in spared nerve injury (SNI) and diabetic mouse models. The SMAC formation is promoted by five cytoskeletal proteins (SPTAN1, DSP, AHNAK, MPZ and PRX). Functional study demonstrates that these SMACs create a Na potential difference to amplify sodium currents, promoting DRG neuron hyperexcitability. Moreover, knockdown of these five cytoskeletal proteins prevents action potential generation in DRG neurons and eliminates NP in SNI mice. Our findings support that SMACs can be a potential pathological hallmark and novel promising therapeutic target for severe chronic NP.

Neuropathic pain (NP) affects 7%-10% of population, with current treatments often proving inadequate. Here we show that Nav1.7 and Nav1.8 form supramolecular active complexes (SMACs) with polygonal lattice structure in dorsal root ganglion (DRG) neurons of mouse models and patients with severe chronic NP. TrkB signaling facilitates the formation of Nav1.7/Nav1.8 SMACs. Targeting these SMACs with combined Nav1.7 and Nav1.8 blockers inhibits action potentials of both human and mouse pathological DRG neurons and synergistically alleviates chronic NP in spared nerve injury (SNI) and diabetic mouse models. The SMAC formation is promoted by five cytoskeletal proteins (SPTAN1, DSP, AHNAK, MPZ and PRX). Functional study demonstrates that these SMACs create a Na+ potential difference to amplify sodium currents, promoting DRG neuron hyperexcitability. Moreover, knockdown of these five cytoskeletal proteins prevents action potential generation in DRG neurons and eliminates NP in SNI mice. Our findings support that SMACs can be a potential pathological hallmark and novel promising therapeutic target for severe chronic NP.Neuropathic pain (NP) affects 7%-10% of population, with current treatments often proving inadequate. Here we show that Nav1.7 and Nav1.8 form supramolecular active complexes (SMACs) with polygonal lattice structure in dorsal root ganglion (DRG) neurons of mouse models and patients with severe chronic NP. TrkB signaling facilitates the formation of Nav1.7/Nav1.8 SMACs. Targeting these SMACs with combined Nav1.7 and Nav1.8 blockers inhibits action potentials of both human and mouse pathological DRG neurons and synergistically alleviates chronic NP in spared nerve injury (SNI) and diabetic mouse models. The SMAC formation is promoted by five cytoskeletal proteins (SPTAN1, DSP, AHNAK, MPZ and PRX). Functional study demonstrates that these SMACs create a Na+ potential difference to amplify sodium currents, promoting DRG neuron hyperexcitability. Moreover, knockdown of these five cytoskeletal proteins prevents action potential generation in DRG neurons and eliminates NP in SNI mice. Our findings support that SMACs can be a potential pathological hallmark and novel promising therapeutic target for severe chronic NP.

Exploring anode materials with an excellent electrochemical performance is of great significance for supercapacitor applications. In this work, a N-doped-carbon-nanofiber (NCNF)-supported Fe3C/Fe2O3 nanoparticle (NCFCO) composite was synthesized via the facile carbonizing and subsequent annealing of electrospinning nanofibers containing an Fe source. In the hybrid structure, the porous carbon nanofibers used as a substrate could provide fast electron and ion transport for the Faradic reactions of Fe3C/Fe2O3 during charge–discharge cycling. The as-obtained NCFCO yields a high specific capacitance of 590.1 F g−1 at 2 A g−1, superior to that of NCNF-supported Fe3C nanoparticles (NCFC, 261.7 F g−1), and NCNFs/Fe2O3 (NCFO, 398.3 F g−1). The asymmetric supercapacitor, which was assembled using the NCFCO anode and activated carbon cathode, delivered a large energy density of 14.2 Wh kg−1 at 800 W kg−1. Additionally, it demonstrated an impressive capacitance retention of 96.7%, even after 10,000 cycles. The superior electrochemical performance can be ascribed to the synergistic contributions of NCNF and Fe3C/Fe2O3.

Defective autophagy is thought to contribute to the pathogenesis of many diseases, including cancer. Human plasmacytoma variant translocation 1 (PVT1) is an oncogenic long non-coding RNA that has been identified as a prognostic biomarker in pancreatic ductal adenocarcinoma, but how PVT1 operates in the regulation of autophagy in pancreatic ductal adenocarcinoma (PDA) is unclear. PVT1 expression level was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and hybridization in situ (ISH). Western blot or qRT-PCR was performed to assess the ULK1 protein or mRNA level. Autophagy was explored via autophagic flux detection under a confocal microscope and autophagic vacuoles investigation under a transmission electron microscopy (TEM). The biological role of PVT1 in autophagy and PDA development was determined by gain-of-function and loss-of-function assays. We found that PVT1 levels paralleled those of ULK1 protein in PDA cancer tissues. PVT1 promoted cyto-protective autophagy and cell growth by targeting ULK1 both in vitro and in vivo. Moreover, high PVT1 expression was associated with poor prognosis. Furthermore, we found that PVT1 acted as sponge to regulate miR-20a-5p and thus affected ULK1 expression and the development of pancreatic ductal adenocarcinoma. The present study demonstrates that the \"PVT1/miR-20a-5p/ULK1/autophagy\" pathway modulates the development of pancreatic ductal adenocarcinoma and may be a novel target for developing therapeutic strategies for pancreatic ductal adenocarcinoma.

The rational construction of Ti3C2Tx MXene‐based composites has been deemed as a popular way to improve their electrochemical energy storage performances owing to the unique two‐dimensional (2D) structure, excellent conductivity, and good flexibility. However, it remains a major challenge to assemble mesoporous carbon onto Ti3C2Tx with fewer oxygen‐containing groups by using surfactants with short hydrophilic segments. In the work, we propose a molecular engineering assembly strategy for the growth of N,P co‐doped mesoporous carbon onto Ti3C2Tx nanosheets (NPMC/Ti3C2Tx) under the assistance of phytic acid by using melamine‐formaldehyde resin and pluronic P123 (PEO20PPO70PEO20) as the carbon/nitrogen source and soft template, respectively. The detailed investigations reveal that phytic acid with abundant hydroxyl groups can effectively enhance the hydrogen bond interactions among P123, carbon precursor, and Ti3C2Tx nanosheets, thus ensuring the efficient assembly of mesoporous carbon onto Ti3C2Tx. The obtained NPMC/Ti3C2Tx composite demonstrates a set of merits, including cylindrical mesopore, N,P co‐doping, and a good combination of mesoporous carbon and Ti3C2Tx nanosheets. As a result, it exhibits an improved lithium‐ion storage performance, delivering a high reversible capacity of 556.3 mA h g−1 after 100 cycles at 0.1 A g−1. The present work provides a feasible molecular engineering assembly route for the rational design of high‐performance Ti3C2Tx MXene‐based electrodes. A molecular engineering assembly strategy has been proposed for assembling the N, P co‐doped mesoporous carbon onto 2D Ti3C2Tx nanosheets with the assistance of phytic acid. The delicate design endows the as‐made NPMC/Ti3C2Tx anode with an enhanced lithium‐ion storage performance.