Surface modification of Cu current collectors (CCs) is proven to be an effective method for protecting lithium metal anodes. However, few studies have focused on the quality and efficiency of modification layers. Herein, a novel home-made filtered cathode vacuum arc (FCVA) co-deposition system with high modification efficiency, good repeatability and environmental friendliness is proposed to realize the wide range regulation of film composition, structure and performance. Through this system, ZnMgTiAl quaternary alloy films, which have good affinity with Li are successfully constructed on Cu CCs, and the fully enhanced electrochemical performances are achieved. Symmetrical cells constructed with modified CCs maintained a fairly low voltage hysteresis of only 13 mV after 2100 h at a current density of 1 mA cm-2. In addition, the capacity retention rate is as high as 75.0% after 100 cycles in the full cells. The influence of alloy films on the dynamic evolution process of constructing stable artificial solid electrolyte interphase (SEI) layer is revealed by in situ infrared (IR) spectroscopy. This work provides a promising route for designing various feasible modification films for LMBs, and it displays better industrial application prospects than the traditional chemical methods owing to the remarkable controllability and scale-up capacity.
Laryngeal cancer (LC) is the second most common head and neck cancer and has a decreasing 5-year survival rate worldwide. Circular RNAs regulate cancer development in diverse ways based on their distinct biogenesis mechanisms and expansive regulatory roles. However, currently, there is little research on how exosomal circular RNAs are involved in the development of laryngeal cancer. Here, we demonstrated that circPVT1, a circular RNA derived from the well-studied long noncoding RNA PVT1, is correlated with disease progression in LC and promotes angiogenesis both in vivo and in vitro. Mechanistically, circPVT1 is loaded into LC cell-secreted exosomes and taken up by vascular epithelium cells. By sponging miR-30c-5p, exosomal circPVT1 promotes Rap1b expression, which dramatically enhances VEGFR2 and PI3K/AKT pathway activation, ultimately resulting in the induction of angiogenesis. Furthermore, our xenograft models demonstrated that the combination of shRNA-circPVT1 and cetuximab showed high efficacy in inhibiting tumor growth and angiogenesis. Collectively, these findings uncover a novel mechanism of exosomal circular RNA-mediated angiogenesis modulation and provide a preclinical rationale for testing this analogous combination in patients with LC.
Identifying active compounds for target proteins is fundamental in early drug discovery. Recently, data-driven computational methods have demonstrated promising potential in predicting compound activities. However, there lacks a well-designed benchmark to comprehensively evaluate these methods from a practical perspective. To fill this gap, we propose a Compound Activity benchmark for Real-world Applications (CARA). Through carefully distinguishing assay types, designing train-test splitting schemes and selecting evaluation metrics, CARA can consider the biased distribution of current real-world compound activity data and avoid overestimation of model performances. We observed that although current models can make successful predictions for certain proportions of assays, their performances varied across different assays. In addition, evaluation of several few-shot training strategies demonstrated different performances related to task types. Overall, we provide a high-quality dataset for developing and evaluating compound activity prediction models, and the analyses in this work may inspire better applications of data-driven models in drug discovery.
PREMISE: Theories of plant-herbivore interactions hold that seedlings are more vulnerable to herbivory in warmer and more stable climates at lower elevations. Hypotheses of plant apparency, resource concentration, and resource availability have been proposed to explain variability in leaf herbivory. However, seasonal differences in the effects of these hypotheses on leaf herbivory on seedlings remain unclear. METHODS: We evaluated the three herbivory hypotheses by comparing the percentage and frequency of leaf herbivory in understory broadleaf seedlings in a subtropical forest in May (spring) and October (autumn) along an elevational gradient (290-1370 m a.s.l.). In total, we measured 2890 leaves across 696 seedlings belonging to 95 species and used beta regressions to test the effects of plant apparency (e.g., leaf area, seedling height), resource concentration (e.g., plant species diversity), and resource availability (e.g., canopy openness, soil available N and P) on leaf herbivory. RESULTS: Seedlings exhibited unimodal patterns of leaf herbivory along elevation, with drivers of leaf herbivory varying by the month. Variation in the frequency of leaf herbivory was best explained by the resource concentration hypothesis (e.g., plant species diversity) in both months, and herbivory was lower on seedlings in sites with higher plant diversity. Plant apparency hypothesis (e.g., leaf area, seedling height) was weakly supported only in spring, and the evidence for resource availability hypothesis (e.g., canopy openness, soil nutrients) was mixed. CONCLUSIONS: This study supports the resource concentration hypothesis and reveals the importance of seasonal difference on understanding leaf herbivory patterns and the drivers of plant diversity in subtropical forests.
Purpose: For many decades, patients recovering from wound closure have been instructed not to bathe. Although studies have shown that earlier postoperative bathing does not increase the risk of wound infection, it remains rare in practice for patients to be allowed earlier postoperative bathing. We performed this meta-analysis to determine how earlier bathing affected rates of wound infection, other complications, and patient satisfaction. Methods: This systematic review conforms to PRISMA guidelines. The PubMed, EMBASE, Medline, Web of Science, and the Cochrane Central Register of Controlled Trials were searched from their inception dates to December 31, 2022. We estimated pooled values for the efficacy of trial of earlier bathing versus delayed bathing using the odds ratio and their associated 95% CI, and we used the I 2 statistic to assess heterogeneity between studies contributing to these estimates. Results: Of the 1813 articles identified by our search, 11 randomized controlled trials including 2964 patients were eligible for inclusion. The incidence of wound infection did not differ significantly between the earlier bathing and delayed bathing groups, nor did rates of other wound complications such as redness and swelling, or wound dehiscence. However, the incidence of hematoma in the delayed bathing group was higher than in the earlier bathing group. Reported patient satisfaction was significantly higher in the earlier bathing group. Conclusion: The medical community, health authorities, and government should create and disseminate clinical practice guidelines to guide patients to evidence-based beneficial treatment.
Introduction: Cynaroside exhibits various biological properties, including anti-inflammatory, antiviral, antitumor, and cardioprotective effects. However, its involvement in methotrexate (MTX)-induced intestinal inflammation remains inadequately understood. Thus, we investigated the impact of cynaroside on MTX-induced intestinal inflammation and its potential mechanisms. Methods: To assess the protective potential of cynaroside against intestinal inflammation, Sprague-Dawley rats were subjected to a regimen of 7 mg/kg MTX for 3 days, followed by treatment with cynaroside at varying doses (10, 20, or 40 mg/kg). Histopathological evaluations were conducted alongside measurements of inflammatory mediators to elucidate the involvement of the NLRP3 inflammasome in alleviating intestinal inflammation. Results: Administration of 7 mg/kg MTX resulted in decreased daily food intake, increased weight loss, and elevated disease activity index in rats. Conversely, treatment with cynaroside at 20 or 40 mg/kg ameliorated the reductions in body weight and daily food intake and suppressed the MTX-induced elevation in the disease activity index. Notably, cynaroside administration at 20 or 40 mg/kg attenuated inflammatory cell infiltration, augmented goblet cell numbers and lowered serum levels of tumor necrosis factor-α, interleukin (IL)-1ß, and IL-18, as well as the CD68-positive cell rate in the intestines of MTX-induced rats. Furthermore, cynaroside downregulated the expression levels of NLRP3, cleaved caspase 1, and cleaved IL-1ß in MTX-induced rats. Discussion: Collectively, our findings indicated that cymaroside alleviates intestinal inflammatory injury by inhibiting the activation of NLRP3 inflammasome in MTX-induced rats.
Enteritis , Inflammasomes , Methotrexate , NLR Family, Pyrin Domain-Containing 3 Protein , Rats, Sprague-Dawley , Animals , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Inflammasomes/metabolism , Rats , Male , Enteritis/chemically induced , Enteritis/drug therapy , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Cytokines/metabolism , Glucosides/pharmacology , Glucosides/therapeutic use , Disease Models, Animal
Breast cancer ranks as the most prevalent malignancy, presenting persistent therapeutic challenges encompassing issues such as drug resistance, recurrent occurrences, and metastatic progression. Therefore, there is a need for targeted drugs that are less toxic and more effective against breast cancer. Kuwanon C, an isoamylated flavonoid derived from mulberry resources, has shown promise as a potential candidate due to its strong cytotoxicity against cancer cells. The present study focused on investigating the anticancer activity of kuwanon C in two human breast cancer cell lines, MDA-MB231 and T47D cells. MTS assay results indicated a decrease in cell proliferation with increasing concentrations of kuwanon C. Furthermore, kuwanon C upregulated the expression levels of the cyclin-dependent kinase inhibitor p21 and effectively inhibited cell DNA replication and induced DNA damage. Flow cytometry confirmed that kuwanon C induced cell apoptosis and upregulated the expression levels of pro-apoptotic proteins (Bax and c-caspase3). Additionally, it stimulated the production of reactive oxygen species (ROS) in the cells. Transmission electron microscopy and Fluo-4 AM-calcium ion staining experiments provided insights into the endoplasmic reticulum (ER), revealing that kuwanon C induced ER stress. Kuwanon C upregulated the expression levels of unfolded protein response-related proteins (ATF4, GADD34, HSPA5, and DDIT3). Overall, the present findings suggested that kuwanon C exerts a potent inhibitory effect on breast cancer cell proliferation through modulating of the p21, induction of mitochondrial-mediated apoptosis, activation of ER stress and induction of DNA damage. These results position kuwanon C as a potential targeted therapeutic agent for breast cancer.
Objective: To maximize successful repair of bicuspid aortic valves by adding figure-of-8 hitch-up stitches at commissures. Methods: From 2000 to 2022, bicuspid aortic valve repair was performed on 1112 patients at Cleveland Clinic, with 367 patients receiving figure-of-8 hitch-up stitches along with classical techniques, including Cabrol suture, cusp plication, raphe resection, and valve-sparing root replacement. Operative outcomes, repair durability, and survival were assessed in the figure-of-8 hitch-up stitches cohort, and outcomes were compared among 195 balancing-score-matched patient pairs who underwent bicuspid aortic valve repair with and without figure-of-8 hitch-up stitches. Results: Patients who underwent bicuspid aortic valve repair with figure-of-8 stitches had an operative mortality of 0.3% (1 of 367) and in-hospital reoperation for aortic valve dysfunction of 1.1% (4 of 367). At 10 years, prevalence of severe aortic regurgitation was 8.6%, mean gradient 24 mm Hg, freedom from aortic valve reoperation 75%, and survival 98%. In matched cohorts, operative mortality was similar (0.51% vs 0%; P > .9) as were morbidities, including in-hospital reoperation due to aortic valve dysfunction (1.0% vs 1.5%; P > .9). Comparable long-term outcomes were observed at 10 years (prevalence of severe aortic regurgitation of 8.7% vs 5.0% [P = .11], mean gradient 18 vs 17 mm Hg [P = .40]; freedom from aortic valve reoperation 80% vs 81% [P = .73]; and survival 99.5% vs 94.6% [P = .18]). Conclusions: Figure-of-8 hitch-up stitch is a safe bicuspid aortic valve repair technique. It increases the likelihood of a successful repair without increasing risk of cusp tear and achieves satisfactory long-term survival and durability when added to classical repair techniques.
Mycotoxins are toxic secondary metabolites produced by fungal species that can cause acute, subacute, and chronic toxicity in humans and animals. Thus, these toxins pose a significant threat to health and safety. Owing to the lack of effective antimold measures in the agricultural industry, feed ingredients such as corn, peanuts, wheat, barley, millet, nuts, oily feed, forage, and their byproducts are prone to mold and mycotoxin contamination, which can affect animal production, product quality, and safety. Cyclopiazonic acid (CPA), which is mainly biosynthesized from mevalonate, tryptophan, and diacetate units, is a myotoxic secondary metabolite produced by Penicillium and Aspergillus fungi. CPA is widely present as a copollutant with aflatoxins in various crops. Compared with some common mycotoxins such as aflatoxins, fumonisins, ochratoxins, zearalenones, and their metabolites, CPA has not been well investigated. In the United States, a survey showed that 51% of corn and 90% of peanut samples contained CPA, with a maximum level of 2.9 mg/kg. In Europe, CPA was found in Penicillium-contaminated cheeses as high as 4.0 mg/kg. Some studies have shown that CPA can cause irreversible damage to organs such as the liver and spleen in mice. Therefore, the establishment of a rapid and efficient analytical method for CPA is of great significance for the risk assessment of CPA in feeds, the development of standard limits, and the protection of feed product quality and safety. The QuEChERS method, a sample pretreatment method that is fast, simple, cheap, effective, and safe, is widely used in the analysis of pesticide residues in food. In this study, a modified QuEChERS method combined with ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine CPA levels in feeds. The chromatographic separation and MS detection of CPA as well as the key factors affecting the extraction efficiency of CPA, including the type of extraction solvent, type of inorganic salt, and type and dosage of adsorbent, were optimized in detail. During the optimization of the chromatographic-separation step, the acid and salt concentrations of the mobile phase affected the separation and detection of CPA. During the optimization of the QuEChERS method, the addition of a certain amount of acetic acid improved the extraction efficiency of CPA because of its acidic nature; in addition, GCB and PSA significantly adsorbed CPA from the feed extract. Under optimal conditions, the CPA in the feed sample (1.0 g) was extracted with 2 mL of water and 4 mL of acetonitrile (ACN) containing 0.5% acetic acid. After salting out with 0.4 g of NaCl and 1.6 g of MgSO4, 1 mL of the ACN supernatant was purified by dispersive solid-phase extraction using 150 mg of MgSO4 and 50 mg of C18 and analyzed by UPLC-MS/MS. The sample was separated on a Waters HSS T3 column (100 mm×2.1 mm, 1.8 µm) using 2 mmol/L ammonium acetate aqueous solution with 0.5% formic acid and ACN as the mobile phases and then analyzed by positive electrospray ionization in multiple reaction monitoring mode. CPA exhibited good linearity in the range of 2-200 ng/mL, with a high correlation coefficient (r=0.9995). The limits of detection and quantification of CPA, which were calculated as 3 and 10 times the signal-to-noise ratio, respectively, were 0.6 and 2.0 µg/kg, respectively. The average recoveries in feed samples spiked with 10, 100, and 500 µg/kg CPA ranged from 70.1% to 78.5%, with an intra-day precision of less than 5.8% and an inter-day precision of less than 7.2%, indicating the good accuracy and precision of the proposed method. Finally, the modified QuEChERS-UPLC-MS/MS method was applied to the analysis of CPA in 10 feed samples obtained from Wuhan market. The analysis results indicated that the developed method has good applicability for CPA analysis in feed samples. In summary, an improved QuEChERS method was applied to the extraction and purification of CPA from feeds for the first time; this method provides a suitable analytical method for the risk monitoring, assessment, and standard-limit setting of CPA in feed samples.
Animal Feed , Food Contamination , Indoles , Tandem Mass Spectrometry , Tandem Mass Spectrometry/methods , Animal Feed/analysis , Chromatography, High Pressure Liquid/methods , Food Contamination/analysis , Indoles/analysis , Mycotoxins/analysis
BACKGROUND: PTEN loss has been identified in various tumor types and is linked to unfavorable clinical outcomes. In addition to PTEN mutation, multiple mechanisms contribute to PTEN loss during tumor development. However, the natural selection process of PTEN-deficient tumor cells remains unclear. Here, we aimed at further elucidating the role of PTEN-L in tumor progression. METHODS: PTEN knockout cell lines were generated using CRISPR/Cas9 technology. Ni-NTA affinity column chromatography was employed for PTEN-L purification. Tumor cell metastasis was evaluated in murine models and observed using the IVIS Spectrum Imaging System. RNA-sequencing, western blotting, PCR, flow cytometry, and cell proliferation assays were employed to investigate tumor cell dormancy and related mechanisms. RESULTS: The chemotherapeutic drugs, cisplatin, paclitaxel, and doxorubicin, induced tumor cells to secrete PTEN-long (PTEN-L), which shields PTEN-deficient tumor cells from chemotherapy-induced apoptosis better than it shields PTEN-intact cells. Further investigation revealed that PTEN-L treatment induced dormancy in PTEN-null tumor cells, characterized by an increase in p16 and p27 levels, cell-cycle arrest, reduced cell proliferation, and enhanced DNA repair. Furthermore, PTEN-L treatment selectively promoted the accumulation and growth of PTEN-null tumor cells in the lungs of C57BL/6J mice, while evading immune surveillance. Mechanistically, PTEN-L induced dormancy in PTEN-null tumor cells by activating the p38 signaling pathway. Addition of a p38 inhibitor effectively reversed dormancy and growth of PTEN-deficient tumor cells in the lungs. We also demonstrated that PTEN expression played a pivotal role in determining the outcome of PTEN-L-mediated antitumor therapy. CONCLUSIONS: In summary, PTEN-L was identified as a potent inducer of dormancy in PTEN-deficient tumor cells, which increased their efficient selection within the tumor microenvironment.
PTEN Phosphohydrolase , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics , Animals , Mice , Humans , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Cell Proliferation , Apoptosis , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Neoplasms/genetics
BACKGROUND: Ultrasound has a long history as a diagnostic and therapeutic tool. Low-intensity pulsed ultrasound (LIPUS), whose intensity is below 300 mW/cm2, has been widely used in orthopedic rehabilitation treatment. However, the detailed bioeffects and underlying mechanisms of LIPUS treatment need to be explored. OBJECTIVE: To make a comprehensive view of the field, bibliometric and visualization analysis was used to reveal the global research trends of LIPUS in orthopedics and rehabilitation treatment between 1994 and 2023. METHODS: All literature data on LIPUS were retrieved from the Web of Science Core Collection database. VOSviewer and CiteSpace were applied for the bibliometric and visualization analysis. RESULTS: A total of 760 publications were included. The distribution of publications generally showed an unstable rising trend. China had the highest number of publications (28.0%), and Chong Qing Medical University was the organization with the highest number of publications (5.8%). Ultrasound in Medicine and Biology had the highest number of publications (8.8%), while BMJ-British Medical Journal had the highest impact factor among the retrieved journals. Ling Qin from the Chinese University of Hong Kong was the most active researcher. Our overlay visualization map showed that the keywords such as pain, knee osteoarthritis, apoptosis, chondrocytes, cartilage, and autophagy, which link to osteoarthritis, have becoming the new research trends and hotspots. CONCLUSION: LIPUS is a popular and increasingly important area of orthopedic rehabilitation, and collaboration of authors from different countries should be further strengthened. Predictably, clinical application of LIPUS on chronic inflammation-related diseases and regenerative medicine, and in-depth biological mechanisms are the orientations of LIPUS in orthopedic rehabilitation treatment.
Inspired by the carbon monoxide dehydrogenase (CODH) active site where two metal ions synergistically catalyze the interconversion between CO2 and CO, we have developed a family of rhenium dipyridine derivatives (1-3), in which potassium 1-aza-18-crown-6-ether (KN18C6) moiety functions as a Lewis acid to assist the CO2 reduction reaction (CO2RR). We found that such design leads to dramatically strong deposition on the electrode under CO2 in the presence of potassium cation, and a clear trend for the deposition rate was observed following the flexibility of linkage between the framework and the KN18C6 moiety; the more flexible, the faster. The origin of deposition was further characterized by a series of control experiments and infrared spectroelectrochemistry (IR-SEC). Unfortunately, the deposition suppresses the subsequent C-O bond cleavage reaction.
Small interfering RNA (siRNA) is a powerful tool for sequence-specific silencing of disease-related genes. In this study, we established and validated a stem-loop reverse transcription-quantitative polymerase chain reaction (RT-qPCR) method applicable for both chemically unmodified and modified siRNA, aiming to elucidate mechanistic intracellular pharmacokinetic and pharmacodynamic (PK/PD) properties of siRNA. We conducted a comprehensive evaluation of factors affecting intracellular siRNA quantification. Our study revealed that immobilization-based siRNA extraction introduced high variation, making it unsuitable for absolute quantification. Conversely, direct cell lysis followed by stem-loop RT-qPCR demonstrated excellent reproducibility, with a quantification range from 0.0002 to 20 femtomole (fmole) for unmodified siRNA and 0.02 to 20 fmole for modified siRNA. The design of a 6-bp overlapping RT primer facilitated the distinction of full-length antisense from its 3'-metabolites, and pre-annealing of antisense to RT primer enhanced sensitivity and reproducibility. Differences in siRNA loss during storage and sample processing were noted among microcentrifuge tubes from various manufacturers. Endogenous miR-16 served as a reference for normalizing cytoplasmic siRNA, while protein concentration post-immunoprecipitation lysis was used to normalize RNA-induced silencing complex (RISC)-loaded siRNA levels. This method successfully enabled a detailed characterization of the time profiles of cytoplasmic and RISC-loaded siRNA, advancing the in vitro-in vivo translation of siRNA therapeutics.
The adoptive immunotherapy mediated by tumor-infiltrating lymphocytes (TILs) has shown definite efficacy against various solid tumors. However, the inefficiency of the conventional method based on in vitro expansion of TILs fails to achieve the cell count and high tumor-killing activity required for therapeutic purposes. This study investigated the effect of 3D tumor spheroids on the activation and expansion of TILs in vitro, aiming to provide a novel approach for the expansion of TILs. We procured TILs and primary tumor cells from surgical samples of lung cancer patients and then compared the impacts of lung cancer cell line NCI-H1975 and primary lung cancer cells cultured under 2D and 3D conditions on the activation, expansion, and anti-tumor activity of TILs. Furthermore, we added the programmed cell death protein 1 (PD-1) antibody into the co-culture of primary tumor cells and TILs within a 3D environment to assess the effects of the antibody on TILs. The results showed that compared with 2D cultured tumor cells, the 3D cultured H1975 cells significantly enhanced the expansion of TILs, increasing the proportion of CD3+/CD8+ cells in TILs to 61.6%. The 3D primary tumor model also enhanced the proportion of CD3+/CD8+ cells in TILs (45.5%, 54.4%), induced apoptosis of tumor epithelial cells and decreased the overall tumor cells survival rate (16.7%) after co-culture. PD-1 antibodies further improved the in vitro expansion capacity of TILs mediated by 3D tumor spheroids, resulting in the proportions of 50.9% and 57.0% for CD3+/CD8+ cells and enhancing the antitumor activity significantly (reducing the overall tumor survival rate to 9.36%). In summary, the use of 3D tumor spheroids significantly promoted the expansion and improved the anti-tumor effect of TILs, and the use of the PD-1 antibody further promoted the expansion and tumor-killing effect of TILs.
Lung Neoplasms , Lymphocytes, Tumor-Infiltrating , Spheroids, Cellular , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Spheroids, Cellular/immunology , Cell Line, Tumor , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Programmed Cell Death 1 Receptor/immunology , Immunotherapy, Adoptive , Coculture Techniques , Cell Culture Techniques , Tumor Cells, Cultured , Cell Proliferation
With the gradual penetration of the Internet into the study and life of college students, the Internet not only brings convenience to young adults but also becomes a new channel for them to engage in deviant behaviors. This study explores the relationship between stressful life events and college students' online deviant behaviors, as well as the mediating role of negative automatic thoughts and the moderating role of perceived social support. Data is drawn from 448 college students (Mage = 20.10, SDage = 1.74). Results showed that stressful life events were significantly positively correlated with online deviant behaviors, and negative automatic thoughts mediated the relationship between stressful life events and online deviant behaviors. The relationship between stressful life events and online deviant behaviors, as well as that between negative automatic thoughts and online deviant behaviors, were both moderated by perceived social support. This study provides a practical guiding value for effectively preventing and intervening in college students' online deviant behaviors and maintaining the regular order of the online society.
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.
Ischemia-reperfusion injury (IRI) remains inevitable in liver surgeries, macrophages play a critical role in the development of IRI, but little is known about the macrophages regulate pathogenesis of IRI. Based on target-guided screening, we identified a small 3 kDa peptide (SjDX5-271) from various schistosome egg-derived peptides that induced M2 macrophage polarization. SjDX5-271 treatment protected the mice against liver IRI through promoting M2 macrophage polarization, the protective effect was abrogated when the macrophages were depleted. Transcriptomic sequencing showed that the TLR signaling pathway was significantly inhibited in macrophages derived from the SjDX5-271 treatment group. We further identified that SjDX5-271 promotes M2 macrophage polarization by inhibiting the TLR4/MyD88/NF-κB signaling pathway and further alleviates hepatic inflammation in liver IRI. Collectively, SjDX5-271 exhibits promising therapeutic effects in IRI and represents a novel therapeutic approach for IRI, even in immune-related diseases. This study revealed the development of a new biologic from the parasite and enhanced our understanding of host-parasite interplay, providing a blueprint for future therapies for immune-related diseases.
BACKGROUND: Bladder cancer metastasis is an essential process in the progression of muscle-invasive bladder cancer. EMT plays a crucial role in facilitating the spread of cancer cells. Identifying compounds that can inhibit these abilities of cancer cells is a significant international endeavor. OBJECTIVE: To explore the migration and invasion effect of Moscatilin on the bladder and clarify the mechanism of action Method: The anti-bladder cancer effect of Moscatilin was observed by a cell proliferation experiment. The migration and invasion of bladder cancer cells inhibited by Moscatilin were detected by Transwell and Wound healing. The effects of Moscatilin on EMT-related proteins E-cadherin, N-cadherin, Snail1, Vimentin, and TGF-ß signaling pathways were detected by Western blot, and nucleic acid levels were verified by qPCR Results: Our study revealed that Moscatilin reduced the viability of bladder cancer cells in vitro and impeded their migration and invasion in experimental settings. Furthermore, we observed that Moscatilin decreased the activation levels of active proteins, specifically Smad3, Samd2, and MMP2. Additionally, we found that moscatilin significantly reduced the expression level of TGF-ß and was also capable of reversing the overexpression effect of TGF-ß. Treatment with Moscatilin also led to significant inhibition of interstitial cell markers Ncadherin and Snail1, which are associated with EMT. CONCLUSION: These findings indicate that Moscatilin impedes the migration and invasion of bladder cancer cells by influencing cell survival, modulating TGF-ß/Smad signaling, and inhibiting EMT.
Bone metastases occur in more than 70% of advanced prostate cancer (PCa) patients, leading to a poor prognosis. Resistance to detachment-induced apoptosis, also known as anoikis, plays a crucial role in the onset of tumor metastasis. Targeting anoikis resistance is of immense therapeutic significance in repression of metastatic spread. In this study, based on an anoikis-related prognostic risk model of PCa, we identify TUBB3 as a key anoikis-related prognostic gene that is highly expressed in bone metastatic PCa. TUBB3 expression is increased in anoikis-resistant PCa cells, and TUBB3 depletion significantly reverses anoikis resistance during extracellular matrix (ECM) detachment and inhibits anoikis-resistance-induced PCa cell invasion and migration as well as epithelial-mesenchymal transition (EMT) process. TUBB3 knockdown significantly reduces αvß3/FAK/Src axis activation, blocking its downstream oncogenic signaling. In addition, we develop bone-targeting lipid nanoparticles (BT-LNP) based on bisphosphonate-modified ionizable lipid for systemic delivery of siRNA targeting TUBB3 (siTUBB3). BT-LNP-delivered siTUBB3 therapy with localization in the bone microenvironment significantly attenuate PCa bone metastasis progression in vivo upon intravenous administration. These findings pinpoint that TUBB3, as a key regulator of anoikis resistance, is an effective therapeutic target in bone metastatic PCa and that BT-LNP-mediated systemic delivery of siTUBB3 can be developed as a novel therapeutic strategy for this disease. This article is protected by copyright. All rights reserved.
Selinexor, a selective inhibitor of nuclear export (SINE), is gaining recognition beyond oncology for its potential in anti-inflammatory therapy. This review elucidates Selinexor's dual action, highlighting its anti-tumor efficacy in various cancers including hematologic malignancies and solid tumors, and its promising anti-inflammatory effects. In cancer treatment, Selinexor has demonstrated benefits as monotherapy and in combination with other therapeutics, particularly in drug-resistant cases. Its role in enhancing the effectiveness of bone marrow transplants has also been noted. Importantly, the drug's impact on key inflammatory pathways provides a new avenue for the management of conditions like sepsis, viral infections including COVID-19, and chronic inflammatory diseases such as Duchenne Muscular Dystrophy and Parkinson's Disease. The review emphasizes the criticality of managing Selinexor's side effects through diligent dose optimization and patient monitoring. Given the complexities of its broader applications, extensive research is called upon to validate Selinexor's long-term safety and effectiveness, with a keen focus on its integration into clinical practice for a diverse spectrum of disorders.
Hydrazines , Triazoles , Humans , Hydrazines/therapeutic use , Triazoles/therapeutic use , Triazoles/pharmacology , Anti-Inflammatory Agents/therapeutic use , Neoplasms/drug therapy , Neoplasms/therapy , Neoplasms/immunology , COVID-19/immunology , SARS-CoV-2 , Antineoplastic Agents/therapeutic use
