Exploring the therapeutic mechanisms of Coptidis Rhizoma in gastric precancerous lesions: a network pharmacology approach.

BACKGROUND: Gastric precancerous lesions are a critical stage in the development of gastric cancer or gastric adenocarcinoma, and their outcome plays an important role in the malignant progression of gastric cancer. Coptidis Rhizoma has a good effect on Gastric precancerous lesions. However, the specific mechanisms of its action remain incompletely elucidated. METHODS: Network pharmacology and molecular docking techniques were used to explore the active ingredients and molecular mechanism of Coptidis Rhizoma in treating gastric precancerous lesions. The active compounds of Coptidis Rhizoma and their potential gastric precancerous lesions related targets were obtained from TCMSP, GeneCards, and OMIM databases. An interaction network based on protein-protein interactions (PPIs) was constructed to visualize the interactions between hub genes. Analysis of GO enrichment and KEGG pathway were conducted using the DAVID database. An investigation of interactions between active compounds and potential targets was carried out by molecular docking. Finally, animal experiments were conducted to verify the effect and mechanism of Coptidis Rhizoma in treating precancerous lesions of gastric cancer. RESULTS: A total of 11 active compounds and 95 anti-gastric precancerous lesions targets of Coptidis Rhizoma were screened for analysis. GO enrichment analysis showed that the mechanism of Coptidis Rhizoma acting on gastric precancerous lesions involves gene expression regulation and apoptosis regulation. KEGG pathway enrichment analysis showed that Coptidis Rhizoma against gastric precancerous lesions involving the AKT /HIF-1α/VEGF signalling pathway. Molecular docking simulations indicated potential interactions between these compounds and core targets involved in anti-gastric precancerous lesions activity. In addition, it was confirmed in vivo that Berberine and Coptidis Rhizoma may reverse atrophy and potential intestinal metaplasia by inhibiting the expression of p-AKT, HIFA, and VEGF. CONCLUSION: Bioactive compounds in Coptidis Rhizoma have the potential to prevent atrophy and intestinal metaplasia. These compounds function by regulating the proteins implicated in AKT /HIF-1α/VEGF signalling pathways that are crucial in gastric epithelial cell differentiation, proliferation and maturation.

Intra-Ocular Inflammation and Occlusive Retinal Vasculitis Following Intravitreal Injections of Faricimab: A Case Report.

PURPOSE: Faricimab is a bispecific antibody that inhibits angiopoietin-2 and vascular endothelial growth factor-A action and has been approved for the treatment of neovascular age-related macular degeneration and diabetic macular edema. Clinical trials have demonstrated its favorable safety profile. This report presents a case of intra-ocular inflammation and occlusive retinal vasculitis following a second intravitreal injection of faricimab. METHODS: A single case report was obtained from a tertiary referral center. RESULTS: A 73-year-old Asian man diagnosed with polypoidal choroidal vasculopathy presented with decreased vision in the left eye (OS) 2 weeks after the second faricimab administration. In the fourth week after the second faricimab injection, swept-source optical coherence tomography (OCT) revealed hyperreflective dots in the vitreous cavity, indicating vitreous cells. Color fundus photography showed new-onset perivenular hemorrhages and pallor of the inferonasal retina OS, of which OCT revealed retinal inner layer thickening, suggestive of retinal arteriolar occlusions. Retinal fluorescein angiography revealed delayed filling of the inferior temporal vein. The patient was diagnosed with intraocular inflammation and occlusive retinal vasculitis OS associated with repeated intravitreal faricimab administrations. Intravitreal dexamethasone implant was used instead of faricimab at this visit. CONCLUSIONS: The findings of this case hint towards the potential risk of retinal occlusive events associated with intravitreal faricimab injections.

TACE combined Lenvatinib plus Camrelizumab versus TACE alone in efficacy and safety for unresectable hepatocellular carcinoma: a propensity score-matching study.

BACKGROUNDS: To compare the efficacy and safety of transcatheter arterial chemoembolization (TACE) combined Lenvatinib plus Camrelizumab (TLC) in unresectable hepatocellular carcinoma (uHCC) with those of TACE alone . METHODS: A retrospective analysis was performed on 222 patients with uHCC who were treated between September 2013 and Jun 2023. One group received TACE + lenvatinib + camrelizumab (TLC) (n = 97) and another group received TACE alone (n = 151). Efficacy and safety were compared after propensity score matching between the TLC and TACE groups. RESULTS: After propensity matching, the TLC group had higher objective response rate (ORR) (88.6% vs. 28.6%, P < 0.001), disease control rate (DCR) (94.3%% vs. 72.9%, P < 0.001), and conversion rates before and after propensity matching were 44.1% and 41.4%, respectively, compared with the TACE group. The median progression free survival (PFS) was longer in the TLC group than in the TACE group (12.7 vs. 6.1 months, P = 0.005). The median overall survival (OS) was longer in the TLC group than in the TACE group (19.4 vs. 13.0 months, P = 0.023). Cox multivariate analysis with different modes of adjustment showed that treatment was an independent influencing factor of PFS and OS. The interaction analysis showed that cirrhosis and Child-Pugh stage an interactive role in the PFS of different treatment. Decreased AFP after treatment portends higher ORR and DCR. CONCLUSION: TACE combined Lenvatinib plus Camrelizumab regimen was safe and superior to TACE alone in improving PFS, OS, and tumor response rates for unresectable recurrent HCC patients.

Exploring the Mechanism of Zhishi-Xiebai-Guizhi Decoction for the Treatment of Hypoxic Pulmonary Hypertension Based on Network Pharmacology and Experimental Analyses.

BACKGROUND: Hypoxic Pulmonary Hypertension (HPH), a prevalent disease in highland areas, is a crucial factor in various complex highland diseases with high mortality rates. Zhishi-Xiebai-Guizhi Decoction (ZXGD), traditional Chinese medicine with a long history of use in treating heart and lung diseases, lacks a clear understanding of its pharmacological mechanism. OBJECTIVE: This study aimed to investigate the pharmacological effects and mechanisms of ZXGD on HPH. METHODS: We conducted a network pharmacological prediction analysis and molecular docking to predict the effects, which were verified through in vivo experiments. RESULTS: Network pharmacological analysis revealed 51 active compounds of ZXGD and 701 corresponding target genes. Additionally, there are 2,116 target genes for HPH, 311 drug-disease co-target genes, and 17 core target genes. GO functional annotation analysis revealed that the core target genes primarily participate in biological processes such as apoptosis and cellular response to hypoxia. Furthermore, KEGG pathway enrichment analysis demonstrated that the core targets are involved in several pathways, including the phosphatidylinositol- 3 kinase/protein kinase B (PI3K/Akt) signaling pathway and Hypoxia Inducible Factor 1 (HIF1) signaling pathway. In vivo experiments, the continuous administration of ZXGD demonstrated a significant improvement in pulmonary artery pressure, right heart function, pulmonary vascular remodeling, and pulmonary vascular fibrosis in HPH rats. Furthermore, ZXGD was found to inhibit the expression of PI3K, Akt, and HIF1α proteins in rat lung tissue. CONCLUSION: In summary, this study confirmed the beneficial effects and mechanism of ZXGD on HPH through a combination of network pharmacology and in vivo experiments. These findings provided a new insight for further research on HPH in the field of traditional Chinese medicine.

Salidroside modulates repolarization through stimulating Kv2.1 in rats.

BACKGROUND: Voltage-gated potassium (Kv) channel growth is strongly associated with the development of arrhythmia. Salidroside (Sal), an active component from Rhodiola crenulata, has been shown to exert protective effects against heart disease. The present study was conducted to investigate the effects of Sal on Kv2.1 channel, and explored the ionic mechanism of anti-arrhythmic. METHODS: In this study, we utilized cisapride (Cis., A stimulant that prolongs the QT interval and causes cardiac arrhythmias) by intravenous injection to establish an arrhythmia model, and detected the effects of Sal on electrocardiography (ECG) and pressure volume loop (P-V loop) in SD rats. The effect of Sal on ECG of citalopram (Cit., a Kv2 channel inhibition)-evoked arrhythmia rat models was further evaluated by monitoring the dynamic changes of multiple indicators of ECG. Then, we detected the effect of Sal on the viability of hypoxic H9c2 cells using CCK-8 assay. After that, the effect of Sal on Kv channel currents (IKv) and Kv2.1 channel currents (IKv2.1) in H9c2 cells under normal and hypoxic conditions was examined using whole-cell patch clamp technique. In addition, the effect of Sal on IKv and IKv2.1 in H9c2 cells was determined under the inhibition of Kv and Kv2.1 channels. HEK293 cells stably transfected with Kv2.1 plasmids were also used to investigate the IKv2.1 changes under Sal pre-treated and co-incubated conditions. In addition, potential interactions of Sal with Kv2.1 protein were predicted and tested by molecular docking, molecular dynamics simulation (MDS), localized surface plasmon resonance (LSPR), and cellular thermal shift assay (CETSA) techniques, respectively. Furthermore, gene and protein levels of Kv2.1 in Sal-treated H9c2 cell were estimated by qRT-PCR, Western blot (WB) and immunofluorescence (IF) analysis. RESULTS: Sal shortened the prolongated QT interval and ameliorated the cardiac impairment associated with arrhythmia in SD rats caused by Cis., as reflected in the ECG and P-V loop data. And Sal was also protective against arrhythmia in rats caused by Kv2 channel inhibition. At the cellular level, Sal increased cell viability after CoCl2-induced hypoxic injury in H9c2 cells. Whole-cell patch clamp assay confirmed that Sal inhibited both IKv and IKv2.1 in normal H9c2 cells, while enhanced IKv and IKv2.1 in cardiomyocytes after hypoxic injury. And Sal enhanced IKv inhibited by 1.5 mM 4-AP and upregulated all inhibition of Kv2 channels induced by 20 mM 4-AP administration, antagonized the IKv2.1 inhibitory effect of Cit. Moreover, Sal pre-administration for 24 h and immediate administration increased IKv2.1 in HEK293 cells stably transfected with Kv2.1 plasmids. Molecular docking demonstrated the potential binding of Sal to the Kv2.1 protein, with calculated binding energy of -5.4 kcal/mol. MDS test illustrated that the average hydrogen bonding of the Sal-Kv2.1 complexes was 30.89%. LSPR results verified the potential binding of Sal to Kv2.1 protein with an affinity value of 9.95 × 10-4 M. CETSA assay confirmed Sal can enhance the expression of Kv2.1 protein in H9c2 cells treated with heat, which suggests that Sal may bind to Kv2.1 protein. The results of WB, qRT-PCR, and IF further argued that Sal pre-administration for 24 h enhanced the levels of the Kv2.1 gene and protein (with no effects on the Kv2.1 gene and protein for H9c2 cells co-incubated with Sal for 6 h and 12 h). CONCLUSION: Overall, our findings indicate that Sal can resistant drug-induced arrhythmias in SD rats, partially by modulating repolarization through stimulating Kv2.1.

Comprehensive analysis of INTS family related to expression, prognosis, diagnosis and immune features in hepatocellular carcinoma.

Purpose: The integrator subunit (INTS) family, a group exclusive to metazoans, participates in various biologic processes. However, their roles in hepatocellular carcinoma (HCC) remain largely unexplored. Methods: Public databases were utilized to investigate the transcriptional and protein expression, and clinical relevance of the INTS family in HCC. Meanwhile, the effects of INTS13 knockdown and overexpression on cell proliferation and apoptosis were studied using HCC cell lines. Results: The mRNA expression of most INTSs were higher in tumor than normal tissues. Higher expression of INTS1/2/3/4/7/8/9/11/12/13 were correlated with poorer overall survival (OS) in Kaplan-Meier Survival Analysis. Multivariate analysis revealed higher level of INTS13 was an independent prognostic factor for shorter OS. Furthermore, genetic alteration of INTS3/6/7/8/9/10 were found in HCC patients and was associated with shorter disease-free survival and progression-free survival. INTS1/2/3/5/7/11/13/14 were associated with activation of tumor-induced immune response and immune infiltration in HCC. Knockdown of INTS13 inhibited cell proliferation and induced apoptosis in HCC cell lines, while overexpression of INTS13 had the opposite effect. Conclusion: Our results indicate that INTS13 is an independent prognostic biomarker in HCC. Furthermore, INTS13 enhances cell proliferation and decreases cell apoptosis in HCC cell lines leading to a poorer OS in HCC patients.

Droplet Energy Harvesting System Based on Total-Current Nanogenerator.

The droplet-based nanogenerator (DNG) is a highly promising technology for harvesting high-entropy water energy in the era of the Internet of Things. Yet, despite the exciting progress made in recent years, challenges have emerged unexpectedly for the AC-type DNG-based energy system as it transitions from laboratory demonstrations to real-world applications. In this work, we propose a high-performance DNG system based on the total-current nanogenerator concept to address these challenges. This system utilizes the water-charge-shuttle architecture for easy scale-up, employs the field effect to boost charge density of the triboelectric layer, adopts an on-solar-panel design to improve compatibility with solar energy, and is equipped with a novel DC-DC buck converter as power management circuit. These features allow the proposed system to overcome the existing bottlenecks of DNG and empower the system with superior performances compared with previous ones. Notably, with the core architecture measuring only 15 cm × 12.5 cm × 0.3 cm in physical dimensions, this system reaches a record-high open-circuit voltage of 4200 V, capable of illuminating 1440 LEDs, and can charge a 4.7 mF capacitor to 4.5 V in less than 24 min. In addition, the practical potential of the proposed DNG system is further demonstrated through a self-powered, smart greenhouse application scenario. These demonstrations include the continuous operation of a thermohygrometer, the operation of a Bluetooth plant monitor, and the all-weather energy harvesting capability. This work will provide valuable inspiration and guidance for the systematic design of next-generation DNG to unlock the sustainable potential of distributed water energy for real-world applications.

DDX58 variant triggers IFN-ß-induced autophagy in trabecular meshwork and influences intraocular pressure.

Singleton-Merten syndrome (SMS) is a rare immunogenetic disorder affecting multiple systems, characterized by dental dysplasia, aortic calcification, glaucoma, skeletal abnormalities, and psoriasis. Glaucoma, a key feature of both classical and atypical SMS, remains poorly understood in terms of its molecular mechanism caused by DDX58 mutation. This study presented a novel DDX58 variant (c.1649A>C [p.Asp550Ala]) in a family with childhood glaucoma. Functional analysis showed that DDX58 variant caused an increase in IFN-stimulated gene expression and high IFN-ß-based type-I IFN. As the trabecular meshwork (TM) is responsible for controlling intraocular pressure (IOP), we examine the effect of IFN-ß on TM cells. Our study is the first to demonstrate that IFN-ß significantly reduced TM cell viability and function by activating autophagy. In addition, anterior chamber injection of IFN-ß remarkably increased IOP level in mice, which can be attenuated by treatments with autophagy inhibitor chloroquine. To uncover the specific mechanism underlying IFN-ß-induced autophagy in TM cells, we performed microarray analysis in IFN-ß-treated and DDX58 p.Asp550Ala TM cells. It showed that RSAD2 is necessary for IFN-ß-induced autophagy. Knockdown of RSAD2 by siRNA significantly decreased autophagy flux induced by IFN-ß. Our findings suggest that DDX58 mutation leads to the overproduction of IFN-ß, which elevates IOP by modulating autophagy through RSAD2 in TM cells.

Low MBOAT7 expression, a genetic risk for MASH, promotes a pro-fibrotic pathway involving hepatocyte TAZ upregulation.

BACKGROUND AND AIMS: The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established MASLD dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear. APPROACH AND RESULTS: We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity, and increased IHH mRNA. CONCLUSIONS: This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis; adds new insight into an established genetic locus for MASH; and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7.

Black soldier fly larvae bioconversion and subsequent composting promote larval frass quality during pig and chicken manure transformation process.

This research systematically assessed the changes in carbon, nitrogen and microbial profiling during pig and chicken manure transformation by black soldier fly larvae (BSFL) and subsequent composting process. BSFL had higher conversion efficiency for chicken manure. The pH, phosphorus and potassium contents in fresh BSFL frass increased than raw manure, but conductivity, total-/nitrate-/ammonium-nitrogen decreased. After BSFL conversion, pig manure had a larger nitrogen loss (25 %) while chicken manure had a larger carbon loss (32 %). During subsequent composting, the indicator changes (e.g. humus, ammonium nitrogen) in frass composts basically remained stable after 20-30 days. Compared to natural composts, frass composts had higher humification degree, cellulase activities, and more cellulose-degrading bacteria. Subsequent composting further reduced potential pathogens (reduced by 98.9 %-99.7 % than raw manure), and elevated the aromaticity and humification of frass. The findings gave an insight into the maturation management of manure-sourced insect frass.

Short cell-penetration peptide conjugated bioreducible polymer enhances gene editing of CRISPR system.

CRISPR-based gene therapy offers precise targeting and specific editing of disease-related gene sequences, potentially yielding long-lasting treatment effects. However, efficient delivery remains a significant challenge for its widespread application. In this study, we design a novel short peptide-conjugated bioreducible polymer named TSPscp as a safe and effective delivery vector for the CRISPR system. Our results show that TSPscp markedly boosts transcriptional activation and genome editing activities of multiple CRISPR systems as confirmed by decomposition-seq and Deep-seq, which is resulted from its capability in facilitating delivery of plasmid DNA by promoting cellular uptake and lysosomal escape. Additionally, TSPscp further enhances genome editing of CRISPR by delivery of minicircle DNA, a condensed form of regular plasmid DNA. More importantly, TSPscp significantly improves delivery and genome editing of CRISPR system in vivo. In summary, our study highlights TSPscp as a promising delivery tool for CRISPR applications in vivo.

Chloramphenicol alleviates 5-fluorouracil-induced cellular senescence through activation of autophagy.

5-Fluorouracil (5-FU) is a first-line treatment for colorectal cancer, but side effects such as severe diarrhea are common in clinical use and have been linked to its induction of normal cell senescence. Chloramphenicol (CAP) is an antibiotic commonly used to treat typhoid or anaerobic infections, but its senescence-related aspects have not been thoroughly investigated. Here, we used 5-FU to induce senescence in human umbilical vein endothelial cells (HUVECs) and investigated the relationship between CAP and cellular senescence at the cellular level. In a model of cellular senescence induced by 5-FU treatment, we discovered that CAP treatment reversed the rise in the percentage of senescence-associated galactosidase (SA-ß-gal)-positive cells and decreased the expression of senescence-associated proteins (p16), senescence-associated genes (p21), and senescence-associated secretory phenotypes (SASPs: IL-6, TNF-α). In addition, CAP subsequently restored the autophagic process inhibited by 5-FU and upregulated the levels of autophagy-related proteins. Mechanistically, we found that CAP restored autophagic flux by inhibiting the mTOR pathway, which in turn alleviated FU-induced cellular senescence. Our findings suggest that CAP may help prevent cellular senescence and restore autophagy, opening up new possibilities and approaches for the clinical management of colorectal cancer.

Downregulation of RCN1 inhibits esophageal squamous cell carcinoma progression and M2 macrophage polarization.

Reticulocalbin 1 (RCN1) is a calcium-binding protein involved in the regulation of calcium homeostasis in the endoplasmic reticulum. The aim of this study was to explore the clinical value and biological role of RCN1 in esophageal squamous cell carcinoma (ESCC). In addition, we investigated the effect of RCN1 on the polarization of tumor-associated macrophages (TAMs). The GSE53625 dataset from the Gene Expression Omnibus database was used to analyze the expression of RCN1 mRNA and its relationship with clinical value and immune cell infiltration. Immunohistochemistry was used to validate the expression of RCN1 and its correlation with clinicopathological characteristics. Subsequently, transwell and cell scratch assays were conducted to evaluate the migration and invasion abilities of ESCC cells. The expression levels of epithelial-mesenchymal transition (EMT)-related proteins were evaluated by western blot, while apoptosis was detected by flow cytometry and western blot. Additionally, qRT‒PCR was utilized to evaluate the role of RCN1 in macrophage polarization. RCN1 was significantly upregulated in ESCC tissues and was closely associated with lymphatic metastasis and a poor prognosis, and was an independent prognostic factor for ESCC in patients. Knockdown of RCN1 significantly inhibited the migration, invasion, and EMT of ESCC cells, and promoted cell apoptosis. In addition, RCN1 downregulation inhibited M2 polarization. RCN1 is upregulated in ESCC patients and is negatively correlated with patient prognosis. Knocking down RCN1 inhibits ESCC progression and M2 polarization. RCN1 can serve as a potential diagnostic and prognostic indicator for ESCC, and targeting RCN1 is a very promising therapeutic strategy.

Tibetan Mesenchymal Stem Cell-derived Exosomes Alleviate Pulmonary Vascular Remodeling in Hypoxic Pulmonary Hypertension Rats.

Hypoxic pulmonary hypertension (HPH) is characterized by progressive pulmonary vasoconstriction, vascular remodeling, and right ventricular hypertrophy, causing right heart failure. This study aimed to investigate the therapeutic effects of exosomes from Tibetan umbilical cord mesenchymal stem cells on HPH via the TGF-ß1/Smad2/3 pathway, comparing them with exosomes from Han Chinese individuals. An HPH rat model was established in vivo, and a hypoxia-induced injury in the rat pulmonary artery smooth muscle cells (rPASMCs) was simulated in vitro. Exosomes from human umbilical cord mesenchymal stem cells were administered to HPH model rats or added to cultured rPASMCs. The therapeutic effects of Tibetan-mesenchymal stem cell-derived exosomes (Tibetan-MSC-exo) and Han-mesenchymal stem cell-derived exosomes (Han-MSC-exo) on HPH were investigated through immunohistochemistry, Western blotting, EdU, and Transwell assays. The results showed that Tibetan-MSC-exo significantly attenuated pulmonary vascular remodeling and right ventricular hypertrophy in HPH rats compared with Han-MSC-exo. Tibetan-MSC-exo demonstrated better inhibition of hypoxia-induced rPASMCs proliferation and migration. Transcriptome sequencing revealed upregulated genes (Nbl1, Id2, Smad6, and Ltbp1) related to the TGFß pathway. Nbl1 knockdown enhanced hypoxia-induced rPASMCs proliferation and migration, reversing Tibetan-MSC-exo-induced downregulation of TGFß1 and p-Smad2/3. Furthermore, TGFß1 overexpression hindered the therapeutic effects of Tibetan-MSC-exo and Han-MSC-exo on hypoxic injury. These findings suggest that Tibetan-MSC-exo favors HPH treatment better than Han-MSC-exo, possibly through the modulation of the TGFß1/Smad2/3 pathway via Nbl1.

Tedizolid phosphate alleviates DSS-induced ulcerative colitis by inhibiting senescence of cell and colon tissue through activating AMPK signaling pathway.

Ulcerative colitis (UC) is a subtype of inflammatory bowel disease. Previous studies have suggested a link between senescence process and the body's inflammatory reaction, indicating that senescence may exacerbate UC, yet the relation between UC and senescence remains unclear. Tedizolid Phosphate (TED), a novel oxazolidinone antimicrobial, is indicated in acute bacterial skin infections, its impact on senescence is not known. Our research revealed that the UC inducer dextran sulfate sodium (DSS) triggers senescence in both colon epithelial NCM460 cells and colon tissues, and TED that screened from a compound library demonstrated a strong anti-senescence effect on DSS treated NCM460 cells. As an anti-senescence medication identified in this research, TED efficiently alleviated UC and colonic senescence in mice caused by DSS. By proteomic analysis and experimental validation, we found that DSS significantly inhibits the AMPK signaling pathway, while TED counteracts senescence by restoring AMPK activity. This research verified that the development of UC is accompanied with colon tissue senescence, and TED, an anti-senescence medication, can effectively treat UC caused by DSS and alleviate colon senescence. Our work suggests anti-senescence strategy is an effective approach for UC treatment.

A novel anoikis-related signature predicts prognosis risk and treatment responsiveness in diffuse large B-cell lymphoma.

BACKGROUND: Although anoikis plays a role in cancer metastasis and aggressiveness, it has rarely been reported in diffuse large B cell lymphoma (DLBCL). METHODS: We obtained RNA sequencing data and matched clinical data from the GEO database. An anoikis-related genes (ARGs)-based risk signature was developed in GSE10846 training cohort and validated in three other cohorts. Additionally, we predicted half-maximal inhibitory concentration (IC50) of drugs based on bioinformatics method and obtained the actual IC50 to some chemotherapy drugs via cytotoxicity assay. RESULTS: The high-risk group, as determined by our signature, was associated with worse prognosis and an immunosuppressive environment in DLBCL. Meanwhile, the nomogram based on eight variables had more accurate ability in forecasting the prognosis than the international prognostic index in DLBCL. The prediction of IC50 indicated that DLBCL patients in the high-risk group were more sensitive to doxorubicin, IPA-3, lenalidomide, gemcitabine, and CEP.701, while patients in the low-risk group were sensitive to cisplatin and dasatinib. Consistent with the prediction, cytotoxicity assay suggested the higher sensitivity to doxorubicin and gemcitabine and the lower sensitivity to dasatinib in the high-risk group in DLBCL. CONCLUSION: The ARG-based signature may provide a promising direction for prognosis prediction and treatment optimization for DLBCL patients.

ARHGAP4 promotes colon cancer metastasis through the TGF-ß signaling pathway and may be associated with T cell exhaustion.

BACKGROUND: Colon cancer is a prevalent invasive neoplasm in the gastrointestinal system with a high degree of malignancy. Despite extensive research, the underlying mechanisms of its recurrence and metastasis remain elusive.Rho GTPase activating protein 4 (ARHGAP4), a member of the small GTPases protein family, may be closely related to tumor metastasis, and its expression is increased in colon cancer. However, the role of ARHGAP4 in colon cancer metastasis is uncertain. This study investigates the impact of ARHGAP4 on the metastasis of colon cancer cells. Our objective is to determine the role of ARHGAP4 in regulating the invasive behavior of colon cancer cells. METHODS: We downloaded colon adenocarcinoma (COAD) data from the Cancer Genome Atlas (TCGA), and performed differential analysis and survival analysis. By using the CIBERSORT algorithm, we evaluated the proportion of infiltrating immune cells in colon cancer. We further analyzed whether ARHGAP4 is associated with T cell exhaustion. Finally, we investigated the impact of ARHGAP4 knockdown on the migration and invasion of colon cancer cells through in vitro cell experiments. Additionally, we utilized western blotting to assess the expression of protein related to the TGF-ß signaling pathway and epithelial-mesenchymal transition (EMT). RESULTS: We found that ARHGAP4 is upregulated in colon cancer. Subsequent survival analysis revealed that the high-expression group had significantly lower survival rates compared to the low-expression group. Immune infiltration analysis showed that ARHGAP4 was not only positively correlated with CD8+ T cells, but also positively correlated with T cell exhaustion markers programmed cell death 1 (PDCD-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and lymphocyte activating 3 (LAG-3). In vitro cell experiments, the knockdown of ARHGAP4 inhibited the migration and invasion of colon cancer cells. Among EMT-related proteins, when ARHGAP4 was knocked down, the expression of E-cadherin was increased, while the expression of N-cadherin and Vimentin was decreased. Meanwhile, the expression of TGF-ß1, p-Smad2, and p-Smad3, which are associated with the TGF-ß/Smad pathway, all decreased. CONCLUSION: ARHGAP4 promotes colon cancer metastasis through the TGF-ß/Smad signaling pathway and may be associated with T cell exhaustion. It plays an important role in the progression of colon cancer and may serve as a potential target for diagnosis and treatment of colon cancer.

The Therapeutic Effects of Baicalein on the Hepatopulmonary Syndrome in the Rat Model of Chronic Common Bile Duct Ligation.

Background and Aims: Hepatopulmonary syndrome (HPS) is characterized by arterial oxygenation defects due to pulmonary vascular dilation in liver disease. To date, liver transplantation remains the only effective treatment for HPS. This study aimed to explore the preventative role of baicalein in HPS development. Methods: Sixty male rats were randomly assigned to three groups: sham, common bile duct ligation (CBDL), and baicalein, receiving intraperitoneal injections of baicalein (40 mg·kg-1·d-1, diluted in saline) for 21 days. Survival rate, liver and kidney function, and bile acid metabolism levels were evaluated. Liver and lung angiogenesis and hepatic glycogen staining were assessed, and the expression of relevant proteins was evaluated by immunohistochemistry. Results: Baicalein improved survival rates and hypoxemia in rats post-CBDL, reducing angiogenic protein levels and enhancing glucose homeostasis. Compared to the untreated group, baicalein suppressed the expression of vascular endothelial growth factor, placental growth factors, matrix metalloprotease 9 and C-X-C motif chemokine 2, and it increased the expression of glycemic regulatory proteins, including dipeptidyl peptidase-4, sirtuin 1, peroxisome proliferator-activated receptor gamma co-activator 1α, and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3. Conclusion: Baicalein significantly improves hepatic function and hypoxia in HPS rats by attenuating pathological angiogenesis in the liver and lungs, showing promise as a treatment for HPS.

Portable Arduino-Based Multi-Sensor Device (SBEDAD): Measuring the Built Environment in Street Cycling Spaces.

The built environment's impact on human activities has been a hot issue in urban research. Compared to motorized spaces, the built environment of pedestrian and cycling street spaces dramatically influences people's travel experience and travel mode choice. The streets' built environment data play a vital role in urban design and management. However, the multi-source, heterogeneous, and massive data acquisition methods and tools for the built environment have become obstacles for urban design and management. To better realize the data acquisition and for deeper understanding of the urban built environment, this study develops a new portable, low-cost Arduino-based multi-sensor array integrated into a single portable unit for built environment measurements of street cycling spaces. The system consists of five sensors and an Arduino Mega board, aimed at measuring the characteristics of the street cycling space. It takes air quality, human sensation, road quality, and greenery as the detection objects. An integrated particulate matter laser sensor, a light intensity sensor, a temperature and humidity sensor, noise sensors, and an 8K panoramic camera are used for multi-source data acquisition in the street. The device has a mobile power supply display and a secure digital card to improve its portability. The study took Beijing as a sample case. A total of 127.97 G of video data and 4794 Kb of txt records were acquired in 36 working hours using the street built environment data acquisition device. The efficiency rose to 8474.21% compared to last year. As an alternative to conventional hardware used for this similar purpose, the device avoids the need to carry multiple types and models of sensing devices, making it possible to target multi-sensor data-based street built environment research. Second, the device's power and storage capabilities make it portable, independent, and scalable, accelerating self-motivated development. Third, it dramatically reduces the cost. The device provides a methodological and technological basis for conceptualizing new research scenarios and potential applications.

Activation of farnesoid X receptor enhances the efficacy of normothermic machine perfusion in ameliorating liver ischemia-reperfusion injury.

The shortage of transplant organs remains a severe global issue. Normothermic machine perfusion (NMP) has the potential to increase organ availability, yet its efficacy is hampered by the inflammatory response during machine perfusion. Mouse liver ischemia-reperfusion injury (IRI) models, discarded human liver models, and porcine marginal liver transplantation models were utilized to investigate whether farnesoid X receptor (FXR) activation could mitigate inflammation-induced liver damage. FXR expression levels before and after reperfusion were measured. Gene editing and coimmunoprecipitation techniques were employed to explore the regulatory mechanism of FXR in inflammation inhibition. The expression of FXR correlates with the extent of liver damage after reperfusion. Activation of FXR significantly suppressed the inflammatory response triggered by IRI, diminished the release of proinflammatory cytokines, and improved liver function recovery during NMP, assisting discarded human livers to reach transplant standards. Mechanistically, FXR disrupts the interaction between p65 and p300, thus inhibiting modulating the nuclear factor kappa-B signaling pathway, a key instigator of inflammation. Our research across multiple species confirms that activating FXR can optimize NMP by attenuating IRI-related liver damage, thereby improving the utilization of marginal livers for transplantation.