Muscone restores anoikis sensitivity in TMZ-resistant glioblastoma cells by suppressing TOP2A via the EGFR/Integrin ß1/FAK signaling pathway.

BACKGROUND: Temozolomide (TMZ) resistance is the main obstacle faced by glioblastoma multiforme (GBM) treatment. Muscone, one of the primary active pharmacological ingredients of Shexiang (Moschus), can cross the blood-brain barrier (BBB) and is being investigated as an antineoplastic medication. However, muscone treatment for GBM has received little research, and its possible mechanisms are still unclear. PURPOSE: This study aims to evaluate the effect and the potential molecular mechanism of muscone on TMZ-resistant GBM cells. METHODS: The differentially expressed genes (DEGs) between TMZ-resistant GBM cells and TMZ-sensitive GBM cells were screened using GEO2R. By progressively raising the TMZ concentration, a relatively stable TMZ-resistant human GBM cell line was established. The drug-resistance traits of U251-TR cells were assessed via the CCK-8 assay and Western Blot analysis of MGMT and TOP2A expression. Cell viability, cell proliferation, cell migration ability, and drug synergism were detected by the CCK-8 assay, colony formation assay, wound healing assay, and drug interaction relationship test, respectively. Anoikis was quantified by Calcein-AM/EthD-1 staining, MTT assay, and flow cytometry. Measurements of cell cycle arrest, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were performed using cell cycle staining, Annexin V-FITC/PI labeling, JC-1 assay, and ROS assay, respectively. DNA damage was measured by TUNEL assay, alkaline comet assay, and γ-H2AX foci assay. GEPIA was used to investigate the link between the anoikis marker (FAK)/drug resistance gene and critical proteins in the EGFR/Integrin ß1 signaling pathway. Molecular docking was used to anticipate the probable targets of muscone. The intracellular co-localization and expression of EGFR and FAK were shown using immunofluorescence. The U251-TR cell line stably overexpressing EGFR was constructed using lentiviral transduction to assess the involvement of EGFR-related signaling in anoikis resistance. Western Blot was employed to detect the expression of migration-related proteins, cyclins, anoikis-related proteins, DNA damage/repair-related proteins, and associated pathway proteins. RESULTS: DEGs analysis identified 97 deregulated chemotherapy-resistant genes and 3779 upregulated genes in TMZ-resistant GBM cells. Subsequent experiments verified TMZ resistance and the hyper-expression of DNA repair-related genes (TOP2A and MGMT) in continuously low-dose TMZ-induced U251-TR cells. Muscone exhibited dose-dependent inhibition of U251-TR cell migration and proliferation, and its co-administration with TMZ showed the potential for enhanced therapeutic efficacy. By downregulating FAK, muscone reduced anoikis resistance in anchorage-independent U251-TR cells. It also caused cell cycle arrest in the G2/M phase by upregulating p21 and downregulating CDK1, CDK2, and Cyclin E1. Muscone-induced anoikis was accompanied by mitochondrial membrane potential collapse, ROS production, an increase in the BAX/Bcl-2 ratio, as well as elevated levels of Cytochrome c (Cyt c), cleaved caspase-9, and cleaved caspase-3. These findings indicated that muscone might trigger mitochondrial-dependent anoikis via ROS generation. Moreover, significant DNA damage, DNA double-strand breaks (DSBs), the formation of γ-H2AX foci, and a reduction in TOP2A expression are also associated with muscone-induced anoikis. Overexpression of EGFR in U251-TR cells boosted the expression of Integrin ß1, FAK, ß-Catenin, and TOP2A, whereas muscone suppressed the expression levels of EGFR, Integrin ß1, ß-Catenin, FAK, and TOP2A. Muscone may influence the expression of the key DNA repair enzyme, TOP2A, by suppressing the EGFR/Integrin ß1/FAK pathway. CONCLUSION: We first demonstrated that muscone suppressed TOP2A expression through the EGFR/Integrin ß1/FAK pathway, hence restoring anoikis sensitivity in TMZ-resistant GBM cells. These data suggest that muscone may be a promising co-therapeutic agent for enhancing GBM treatment, particularly in cases of TMZ-resistant GBM with elevated TOP2A expression.

Soil Nitrogen and Flooding Intensity Determine the Trade-Off between Leaf and Root Traits of Riparian Plant Species.

The investigation into trade-offs among plant functional traits sheds light on how plants strategically balance growth and survival when facing environmental stress. This study sought to evaluate whether trade-offs observed at both community and individual species levels could indicate adaptive fitness across an intensity of flooding intensity. The study was conducted at 25 sampling sites spanning approximately 600 km along the riparian zone in the Three Gorges Reservoir area, China. The findings revealed that, along the flooding gradient, the overall riparian community did not exhibit significant trade-offs between leaf and root traits. Examining three broadly distributed dominant species (Cynodon dactylon, Xanthium strumarium, and Abutilon theophrasti), perennial plants showed pronounced trade-offs under low flooding intensity, while annuals exhibited trade-offs under moderate and low flooding intensity. The trade-offs were evident in traits related to nitrogen-carbon resources, such as specific leaf area, root tissue density, and photosynthetic rate. However, under strong flooding intensity, the relationship between leaf and root traits of the species studied was decoupled. Furthermore, the study identified a significant correlation between soil nitrogen and the trade-off traits under moderate and low flooding intensity. Integrating results from the CSR (Competitors, Stress-tolerators, Ruderals) strategy model, species niche breath analysis, and nitrogen-regulated trade-off, the study revealed that, in the face of high flooding intensity, perennial species (C. dactylon) adopts an S-strategy, demonstrating tolerance through a conservative resource allocation that decouples leaf-root coordination. Annual species (X. strumarium and A. theophrasti), on the other hand, exhibit niche specialization along the flooding gradient, employing distinct strategies (R- and C-strategy). As flooding stress diminishes and soil nitrogen level decreases, plant strategies tend to shift towards an R-strategy with a competition for reduced N resources. In conclusion, the study highlighted the pivotal roles of soil nitrogen and flooding intensity acting as the dual determinants of species growth and tolerance. These dynamics of growth-tolerance balance were evident in the diverse trade-offs between leaf and root traits of individual plant species with different life histories, underscoring the array of adaptive strategies employed by riparian plants across the flooding intensity gradient.

Real-world application of nirmatrelvir/ritonavir in hospitalized COVID-19 patients with onset of symptoms beyond 5 days: a comparative study.

PURPOSE: Physicians may administer Nirmatrelvir-ritonavir to patients who have been symptomatic for more than 5 days. There is currently no clear evidence to support this approach. METHODS: A real-world study was conducted to investigate the potential relationship between the administration of Nirmatrelvir-ritonavir and the rates of intubation or in-hospital mortality among COVID-19 patients who experienced symptoms for more than 5 days. The end point was a composite event of intubation or in-hospital mortality. The outcomes between those patients who received Nirmatrelvir-ritonavir and those who did not were compared. RESULTS: A total of 847 patients were included in the analysis. Among them, 312 patients (36.84%) received Nirmatrelvir-ritonavir. Within the entire population, 86 patients (10.15%) experienced intubation or in-hospital mortality. The main analysis indicated that there was a significant association between the application of Nirmatrelvir-ritonavir and intubation or in-hospital mortality, with an odds ratio of 0.50 (95% confidence interval, 0.28 to 0.87; P = 0.0153) using inverse probability of treatment weighting. The finding was consistent with multiple sensitivity analyses. CONCLUSIONS: The application of Nirmatrelvir-ritonavir was associated with a significantly reduced risk of intubation or death in hospitalized COVID-19 patients who experienced symptoms for more than 5 days as compared to those who did not receive the treatment.

Intranasal Delivery of Curcumin Nanoparticles Improves Neuroinflammation and Neurological Deficits in Mice with Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) represents one of the most severe subtypes of stroke. Due to the complexity of the brain injury mechanisms following ICH, there are currently no effective treatments to significantly improve patient functional outcomes. Curcumin, as a potential therapeutic agent for ICH, is limited by its poor water solubility and oral bioavailability. In this study, mPEG-PCL is used to encapsulate curcumin, forming curcumin nanoparticles, and utilized the intranasal administration route to directly deliver curcumin nanoparticles from the nasal cavity to the brain. By inhibiting pro-inflammatory neuroinflammation of microglia following ICH in mice, reprogramming pro-inflammatory microglia toward an anti-inflammatory function, and consequently reducing neuronal inflammatory death and hematoma volume, this approach improved blood-brain barrier damage in ICH mice and promoted the recovery of neurological function post-stroke. This study offers a promising therapeutic strategy for ICH to mediate neuroinflammatory microenvironments.

Effect of Al/Ni Ratio on the Microstructure and Properties of Nickel-Aluminum Bronze Alloys.

To study the effect of aluminum and nickel elements on the microstructures and properties of the nickel-aluminum bronze (NAB) alloy, four kinds of alloys with different compositions, ZCuAl7-7-4-2, ZCuAl8-6-4-2, ZCuAl9-5-4-2, and ZCuAl10-4-4-2, are prepared by vacuum-melting technology. The effects of different Al/Ni ratios on the microstructures of NAB are investigated using a metalloscope, scanning electron microscopy, transmission electron microscopy, and XPS analysis. The mechanical property is evaluated with microhardness testing and tensile mechanical testing. The corrosion resistance is evaluated using mass-loss testing, electrochemical testing, and corrosion-product characterization. The results show that with the increase of the Al/Ni ratio, the content of precipitated phases increases, while ß' and hard κ, which have a different morphology, appear. As the Al/Ni ratio rises from 1 to 2.5, the hardness increases from 104 HV to 202 HV, and the tensile strength increases by 394 MPa from 356 MPa to 751 MPa, but the elongation decreases substantially from 50.50% to 11.00%. The best corrosion resistance is shown on ZCuAl7-7-4-2, with a corrosion rate of 0.00267 mm/a after 30 d of static immersion corrosion in 3.5 wt.% NaCl solution. Through electrochemical testing and corrosion-product characterization, it is found that ZCuAl7-7-4-2 has the largest polarization resistance Rp, and the selective corrosion of the surface is mild.

A Targeted and Responsive Nanoprodrug Delivery System for Synergistic Glioma Chemotherapy.

Doxorubicin (DOX) is widely used as a chemotherapeutic agent for both hematologic and solid tumors and is a reasonable candidate for glioma treatment. However, its effectiveness is hindered by significant toxicity and drug resistance. Moreover, the presence of the blood-brain barrier (BBB) brings a crucial challenge to glioma therapy. In response, a GSH-responsive and actively targeted nanoprodrug delivery system (cRGD/PSDOX-Cur@NPs) are developed. In this system, a disulfide bond-bridged DOX prodrug (PEG-SS-DOX) is designed to release specifically in the high glutathione (GSH) tumor environment, markedly reducing the cardiotoxicity associated with DOX. To further address DOX resistance, curcumin, serving as a P-glycoprotein (P-gp) inhibitor, effectively increased cellular DOX concentration. Consequently, cRGD/PSDOX-Cur@NPs exhibited synergistic anti-tumor effects in vitro. Furthermore, in vivo experiments validated the superior BBB penetration and brain-targeting abilities of cRGD/PSDOX-Cur@NPs, showcasing the remarkable potential for treating both subcutaneous and orthotopic gliomas. This research underscores that this nanoprodrug delivery system presents a novel approach to inhibiting glioma while addressing resistance and systemic toxicity.

Serum uric acid is inversely associated with lung function in US adults.

The relationship between serum uric acid and lung function has been controversial. This study aims to determine whether there is an independent relationship between serum uric acid and lung function in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2012. Serum uric acid was considered the exposure variable, and lung function (FEV1 and FVC) was the outcome variable. Multivariable linear regression was conducted with adjustments for potential confounders. The total number of participants from NHANES (2007-2012) was 30,442, of which 7514 were included in our analysis after applying exclusion criteria. We observed that serum uric acid was negatively associated with FEV1 and FVC after adjusting for confounders (ß for FEV1 [- 24.77 (- 36.11, - 13.43)] and FVC [- 32.93 (- 47.42, - 18.45)]). Similarly, serum uric acid showed a negative correlation with FEV1 and FVC after adjusting for confounding variables both in male and female populations. The relationship between serum uric acid and FEV1 and FVC remained consistent and robust in various subgroups within both male and female populations, including age, race, BMI, alcohol consumption, smoking status, and income-poverty ratio. Serum uric acid is negatively associated with FEV1 and FVC in the US general healthy population. This negative relationship is significant in both the male and female populations.

Tumor-Microenvironment-Activatable Nanoparticle Mediating Immunogene Therapy and M2 Macrophage-Targeted Inhibitor for Synergistic Cancer Immunotherapy.

Immunotherapy has achieved prominent clinical efficacy in combating cancer and has recently become a mainstream treatment strategy. However, achieving broad efficacy with a single modality is challenging, and the heterogeneity of the tumor microenvironment (TME) restricts the accuracy and effectiveness of immunotherapy strategies for tumors. Herein, a TME-responsive targeted nanoparticle to enhance antitumor immunity and reverse immune escape by codelivering interleukin-12 (IL-12) expressing gene and colony-stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (PLX) is presented. The introduction of disulfide bonds and cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGD) peptides conferred reduction reactivity and tumor targeting to the nanoparticles, respectively. It is hypothesized that activating host immunity by the local expression of IL-12, while modulating the tumor-associated macrophages (TAM) function through blocking CSF-1/CSF-1R signaling, could constitute a feasible approach for cancer immunotherapy. The fabricated functional nanoparticle successfully ameliorated the TME by stimulating the proliferation and activation of T lymphocytes, promoting the repolarization of TAMs, reducing myeloid-derived suppressor cells (MDSCs), and promoting the maturation of dendritic cells (DC) as well as the secretion of antitumor cytokines, which efficiently suppressed tumor growth and metastasis. Finally, substantial changes in the TME were deciphered by single-cell analysis including infiltration of different cells, transcriptional states, secretory signaling and cell-cell communications. These findings provide a promising combinatorial immunotherapy strategy through immunomodulatory nanoparticles.

Comprehensive Analysis on Prognostic Signature Based on T Cell-Mediated Tumor Killing Related Genes in Gastric Cancer.

Although immunotherapy is a valuable treatment for gastric cancer (GC), identifying the patients who would benefit most from this approach presents a challenge. In this study, GC patients were divided into two subtypes by consensus clustering according to T cell-mediated tumor killing related genes (TTKRGs), and there were significant differences in tumor-infiltrating immune cells, signaling pathways, and gene expression of immunomodulators and inhibitory immune checkpoints between the two subtypes. Then, we developed an individualized signature based on TTKRGs, and its clinical and predictive value in GC patients for chemotherapeutic and immunotherapeutic responses was assessed. We confirmed the expression levels of signature genes in GC tumor tissue using quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, to improve the accuracy of GC prognosis predictions, we established a nomogram. We further identified some compounds as sensitive drugs targeting GC risk groups. The signature showed significant predictive ability across RNA-seq, microarray, and qRT-PCR cohorts, which could assist in predicting survival, immunotherapeutic and chemotherapeutic outcomes in GC patients.

Career Adaptability and Academic Achievement Among Chinese High School Students: A Person-centered Longitudinal Study.

Career adaptability, essential for high school students' career development, is closely associated with academic achievement. However, it is still unclear whether there exist multiple subgroups among Chinese high school students that exhibit distinct combinations of the career adaptability dimensions and whether these subgroups display significant differences in academic achievement. Using latent profile analysis, this study identified career adaptability profiles in Chinese high school students and examined their effects on academic achievement through a longitudinal design. Chinese high school students (Wave 1: N = 1783, 42.9% boys, Mage = 15.17, SD = 0.86; Wave 2: N = 1395, 42.9% boys, 82.4% science students, Mage = 16.19, SD = 0.88) completed a packet of measures on two occasions at eight-month intervals. Career adaptability was assessed at Wave 1, and academic achievement was assessed at Wave 2. Five distinct career adaptability profiles were identified: (1) Low control and confidence; (2) Below average; (3) Control dominant and low confidence; (4) Above average; (5) High. Profiles of career adaptability displayed significant differences in academic achievement. High, Above average, and Control dominant and low confidence students' achievements were significantly higher than Low control and confidence students. These findings indicate that students with an overall high level of career adaptability or more robust career control are more likely to achieve higher academic achievement. In addition, level (average scores of all dimensions across different profiles) and shape (distinct forms displayed by the specific combination of dimensions) effects exist in the influence of career adaptability profiles on academic achievement. This highlights the dynamic and diverse nature of adolescent career development within the Chinese high school context.

Nanodelivery Systems as a Novel Strategy to Overcome Treatment Failure of Cancer.

Despite the tremendous progress in cancer treatment in recent decades, cancers often become resistant due to multiple mechanisms, such as intrinsic or acquired multidrug resistance, which leads to unsatisfactory treatment effects or accompanying metastasis and recurrence, ultimately to treatment failure. With a deeper understanding of the molecular mechanisms of tumors, researchers have realized that treatment designs targeting tumor resistance mechanisms would be a promising strategy to break the therapeutic deadlock. Nanodelivery systems have excellent physicochemical properties, including highly efficient tissue-specific delivery, substantial specific surface area, and controllable surface chemistry, which endow nanodelivery systems with capabilities such as precise targeting, deep penetration, responsive drug release, multidrug codelivery, and multimodal synergy, which are currently widely used in biomedical researches and bring a new dawn for overcoming cancer resistance. Based on the mechanisms of tumor therapeutic resistance, this review summarizes the research progress of nanodelivery systems for overcoming tumor resistance to improve therapeutic efficacy in recent years and offers prospects and challenges of the application of nanodelivery systems for overcoming cancer resistance.

Sensitizing chemotherapy for glioma with fisetin mediated by a microenvironment-responsive nano-drug delivery system.

Drug resistance has become an obstacle to successful cancer chemotherapies, with therapeutic agents effectively traversing the blood-brain barrier (BBB) remaining a great challenge. A microenvironment responsive and active targeting nanoparticle was constructed to enhance the penetration of drugs, leading to improved therapeutic effects. Dynamic light scattering demonstrated that the prepared nanoparticle had a uniform size. The cRGD modification renders the nanoparticle with active targeting capabilities to traverse the BBB for chemotherapy. The disulfide-bond-containing nanoparticle can be disintegrated in response to a high concentration of endogenous glutathione (GSH) within the tumor microenvironment (TME) for tumor-specific drug release, resulting in more effective accumulation. Notably, the released fisetin further increased the uptake of doxorubicin by glioma cells and exerted synergistic effects to promote apoptosis, induce cellular G2/M cycle arrest, and inhibit cell proliferation and migration in vitro. Moreover, the nanoparticle showed favorable anti-glioma effects in vivo. Our study provides a new strategy to overcome drug resistance by utilizing a natural product to sensitize conventional chemotherapeutics with well-designed targeted nanodelivery systems for cancer treatment.

Robotic versus laparoscopic hepatectomy: A single-center, propensity score- matched study.

BACKGROUND: Although the effectiveness of robotic hepatectomy (RH) has been evaluated in several studies, the superiority of RH over other approaches has not been definitely established. Therefore, in the present propensity score-matched cohort study, we compared RH and laparoscopic hepatectomy (LH) in terms of perioperative and oncologic outcomes. METHODS: This retrospective study included patients who underwent RH or LH for benign and malignant liver lesions at a single center in Taiwan at any time between 2014 and 2020. Confounding factors, specifically age, sex, body mass index, American Society of Anesthesiologists score, IWATE criteria, and Charlson comorbidity index, were adjusted through propensity score matching (PSM). RESULTS: A total of 329 patients were finally included in this study. Two homogeneous groups (RH and LH; n, 72 each) were formed using PSM. The RH group had a longer operative time (median: 231 vs.180 min, respectively; P = .001) and lower conversion (to open surgery) rate (9.7% vs.0.0%, respectively; P = .013) than did the LH group. However, the two groups did not differ in terms of other perioperative outcomes, specifically blood loss, hospital stay, intensive care unit admission, mortality, morbidity, or tumor margin status. CONCLUSIONS: The rate of conversion to open surgery is lower in RH than in LH. Although operative time is longer in RH than in LH, RH is feasible and safe for patients with benign or malignant liver lesion. Our study also demonstrated comparable oncological results in patients with hepatocellular carcinoma between LH and RH group.

Measurement and influencing factors of industrial carbon unlocking efficiency under the background of "double carbon".

Based on the panel data of 11 provinces and cities in the Yangtze River Economic Belt of China from 2011 to 2018, the DEA model and Malmquist index were used to calculate the industrial carbon unlocking efficiency of the Yangtze River Economic Belt in a static and dynamic way, and the Tobit model was used to empirically test its influencing factors. The results show that (1) the overall efficiency of industrial carbon unlocking in the Yangtze River Economic Belt is on the rise, but there are regional differences. The efficiency of industrial carbon unlocking in the lower reaches of the Yangtze River is higher than that in the upper and middle reaches. (2) The total factor productivity of industrial carbon unlocking in the Yangtze River Economic Belt has increased steadily on the whole, and technological progress is the main source of growth. (3) Industrial carbon unlocking efficiency is affected by many factors. Environmental regulation and degree of openness have a promoting effect on industrial carbon unlocking efficiency, while government investment and innovation level have a restraining effect on industrial carbon unlocking efficiency.

Quercetin induces MGMT+ glioblastoma cells apoptosis via dual inhibition of Wnt3a/ß-Catenin and Akt/NF-κB signaling pathways.

BACKGROUND: Surgical resection combined with radiotherapy and chemotherapy remains a common clinical treatment for glioblastoma multiforme (GBM). However, the therapeutic outcomes have not been satisfying due to drug resistance and other factors. Quercetin, a phytoingredient capable of crossing the blood-brain barrier, has shown effectiveness in the treatment of various solid tumors. Nevertheless, the potential of quercetin in GBM treatment has not been adequately explored. PURPOSE: This study aims to investigate the effects and mechanisms of quercetin on MGMT+GBM cells. METHODS: The potential targets and mechanisms of quercetin in glioma treatment were predicted based on network pharmacology and molecular docking. The effects of quercetin on cell inhibition rate, cell migration ability, cell cycle arrest, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), Mitochondrial superoxide formation and apoptosis were measured by the CCK8 assay, wound healing assay, PI/RNase staining, JC-1 assay, DCFH-DA assay, MitoSOX staining and Annexin V-FITC/PI double staining, respectively. The methylation status of the MGMT promoter was assessed through methylation-specific polymerase chain reaction (MS-PCR). DNA damage was quantified by alkaline/neutral comet assay and TUNEL assay. The intracellular localization and expression of NF-κB and MGMT were revealed by immunofluorescence. The expression of migration-related proteins, matrix metalloproteinases, apoptosis-related proteins, cyclins, DNA damage/repair enzymes and related pathway proteins was detected by Western blot. RESULTS: Network pharmacology identified 96 targets and potential molecular mechanisms of quercetin in glioma treatment. Subsequent experiments confirmed the synergistic effect of quercetin in combination with temozolomide (TMZ) on T98G cells. Quercetin significantly suppressed the growth and migration of human GBM T98G cells, induced apoptosis, and arrested cells in the S-phase cell cycle. The collapse of mitochondrial membrane potential, ROS generation, enhanced Bax/Bcl-2 ratio, and strengthened cleaved-Caspase 9 and cleaved-Caspase 3 suggested the involvement of ROS-mediated mitochondria-dependent apoptosis in the process of quercetin-induced apoptosis. In addition, quercetin-induced apoptosis was accompanied by intense DNA double-strand breaks (DSBs), γH2AX foci formation, methylation of MGMT promoter, increased cleaved-PARP, and reduced MGMT expression. Quercetin may influence the expression of the key DNA repair enzyme, MGMT, by dual suppression of the Wnt3a/ß-Catenin and the Akt/NF-κB signaling pathways, thereby promoting apoptosis. Inhibition of Wnt3a and Akt using specific inhibitors hindered MGMT expression. CONCLUSION: Our study provides the first evidence that quercetin may induce apoptosis in MGMT+GBM cells via dual inhibition of the Wnt3a/ß-Catenin pathway and the Akt/NF-κB signaling pathway. These findings suggest that quercetin could be a novel agent for improving GBM treatment, especially in TMZ-resistant GBM with high MGMT expression.

Galectin-1-mediated MET/AXL signaling enhances sorafenib resistance in hepatocellular carcinoma by escaping ferroptosis.

Sorafenib, a small-molecule inhibitor targeting several tyrosine kinase pathways, is the standard treatment for advanced hepatocellular carcinoma (HCC). However, not all patients with HCC respond well to sorafenib, and 30% of patients develop resistance to sorafenib after short-term treatment. Galectin-1 modulates cell-cell and cell-matrix interactions and plays a crucial role in HCC progression. However, whether Galectin-1 regulates receptor tyrosine kinases by sensitizing HCC to sorafenib remains unclear. Herein, we established a sorafenib-resistant HCC cell line (Huh-7/SR) and determined that Galectin-1 expression was significantly higher in Huh-7/SR cells than in parent cells. Galectin-1 knockdown reduced sorafenib resistance in Huh-7/SR cells, whereas Galectin-1 overexpression in Huh-7 cells increased sorafenib resistance. Galectin-1 regulated ferroptosis by inhibiting excessive lipid peroxidation, protecting sorafenib-resistant HCC cells from sorafenib-mediated ferroptosis. Galectin-1 expression was positively correlated with poor prognostic outcomes for HCC patients. Galectin-1 overexpression promoted the phosphorylation of AXL receptor tyrosine kinase (AXL) and MET proto-oncogene, receptor tyrosine kinase (MET) signaling, which increased sorafenib resistance. MET and AXL were highly expressed in patients with HCC, and AXL expression was positively correlated with Galectin-1 expression. These findings indicate that Galectin-1 regulates sorafenib resistance in HCC cells through AXL and MET signaling. Consequently, Galectin-1 is a promising therapeutic target for reducing sorafenib resistance and sorafenib-mediated ferroptosis in patients with HCC.

High-intensity laser therapy on pain relief in symptomatic knee osteoarthritis: A systematic review and meta-analysis.

BACKGROUND: Osteoarthritis is one of the leading causes of global disability and pain. OBJECTIVE: To investigate whether High-Intensity Laser therapy has superior pain-relieving effects in individuals with symptomatic knee osteoarthritis. METHODS: Searches were conducted using CENTRAL, MEDLINE, CINAHL, EMBASE, Web of Science, PEDro, and related reference lists with language limed to English. Clinical trials investigating the effectiveness of High-Intensity Laser therapy compared to other laser therapies, conventional therapies or exercises on knee osteoarthritis pain were included. The screening and selection of studies, data extraction, and methodological quality assessment were performed by two independent researchers. Studies were quantitatively integrated using the Review Manager Software and qualitative analysis using the criteria recommended by the Cochrane Collaboration. RESULTS: Nine studies meeting the eligibility criteria were identified, among which only one study was identified as excellent methodology quality, six was marked as good quality, and the remaining two studies were regarded as fair or poor quality. All studies reported positive effects of High-Intensity Laser therapy on knee osteoarthritis pain. Two studies (136 people) gave indication that there was moderate evidence that High-Intensity Laser therapy could be a promising new possibility in pain relief among patients with knee osteoarthritis compared with sham laser therapy in a short-term treatment (MD, -2.04, 95% CI, -2.12 to -1.96; Z= 51.01, P< 0.01). Four studies (160 people) showed that High-Intensity Laser therapy could be an effective modality on treating pain compared to conventional physiotherapies in decreasing visual analog scale score (MD, -0.98, 95% CI, -1.19 to -0.76; Z= 9.02, P< 0.01). Three studies (123 people) demonstrated that High-Intensity Laser therapy combined with exercises was more effective than placebo laser or lower-intensity laser combined with exercises in alleviating pain in patients with knee osteoarthritis (MD, -1.54, 95% CI, -1.84 to -1.24; Z= 10.06, P< 0.01). CONCLUSION: High-Intensity Laser therapy could be a promising and recommended modality in alleviating knee osteoarthritis pain, especially when it was implemented in combination with exercises.

The Relationship between Blood Lead Level and Chronic Pain in US Adults: A Nationwide Cross-Sectional Study.

INTRODUCTION: Lead toxicity has been a major public health problem worldwide, yet no study has investigated the association between lead exposure and chronic pain. METHODS: We used data from three cycles of National Health and Nutrition Examination Survey (NHANES) with chronic pain status. We conducted univariate and multivariate logistic regression analyses to investigate the association between chronic pain and blood lead level (BLL). Subgroup analyses were performed to explore which confounding factor modified the association between chronic pain and BLL. RESULTS: A total of 13,485 participants were included in our final analysis, out of which 1950 (14.46%) had chronic pain. In the fully adjusted model, a 1 µg/dL increase of BLL was associated with 3% higher risk of chronic pain. The highest BLL quartile (BLL > 2.40 µg/dL) was associated with a 32% increase in the risk of chronic pain compared with the lowest BLL quartile (BLL < 0.90 µg/dL). In the subgroup analyses, hypertension (P for interaction = 0.018) and arthritis (P for interaction = 0.004) status modified the association between BLL and chronic pain. Higher quartiles of BLL were associated with a higher risk of chronic pain only in individuals with hypertension or arthritis but not those without these conditions. CONCLUSION: A higher BLL was associated with a higher risk of chronic pain. Further research is warranted to investigate whether a causal relationship exists between the two, as well as potential underlying mechanisms.

ZNF451 favors triple-negative breast cancer progression by enhancing SLUG-mediated CCL5 transcriptional expression.

Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited effective therapies because of the absence of definitive targets. Here, we demonstrate that the expression of ZNF451, a poorly characterized vertebrate zinc-finger protein, is upregulated in TNBC and associated with a poor prognosis. Elevated ZNF451 expression facilitates TNBC progression by interacting with and enhancing the activity of the transcriptional activator snail family transcriptional repressor 2 (SLUG). Mechanistically, the ZNF451-SLUG complex preferentially recruits the acetyltransferase p300/CBP-associated factor (PCAF) to the CCL5 promoter, selectively facilitating CCL5 transcription by enhancing the acetylation of SLUG and local chromatin, leading to recruitment and activation of tumor-associated macrophages (TAMs). Disturbing the ZNF451-SLUG interaction using a peptide suppresses TNBC progression by reducing CCL5 expression and counteracting the migration and activation of TAMs. Collectively, our work provides mechanistic insights into the oncogene-like functions of ZNF451 and suggests that ZNF451 is a potential target for development of effective therapies against TNBC.

Xihuang Pill-destabilized CD133/EGFR/Akt/mTOR cascade reduces stemness enrichment of glioblastoma via the down-regulation of SOX2.

BACKGROUND: Our previous study found that XHP could induce GBM cells to undergo apoptosis. A lot of evidence suggests that glioma stem-like cells (GSCs) are key factors that contribute to disease progression and poor prognosis of glioblastoma multiforme (GBM). Traditional Chinese medicine has been applied in clinical practice as a complementary and alternative therapy for glioma. PURPOSE: To evaluate the effect and the potential molecular mechanism of Xihuang pill (XHP) on GSCs. METHODS: UPLC-QTOF-MS analysis was used for constituent analysis of XHP. Using network pharmacology and bioinformatics methods, a molecular network targeting GSCs by the active ingredients in XHP was constructed. Cell viability, self-renewal ability, apoptosis, and GSC markers were detected by CCK-8 assay, tumor sphere formation assay and flow cytometry, respectively. The interrelationship between GSC markers (CD133 and SOX2) and key proteins of the EGFR/Akt/mTOR signaling pathway was evaluated using GEPIA and verified by western blot. A GBM cell line stably overexpressing Akt was constructed using lentivirus to evaluate the role of Akt signaling in the regulation of glioma stemness. The effect of XHP on glioma growth was analyzed by a subcutaneously transplanted glioma cell model in nude mice, hematoxylin-eosin staining was used to examine pathological changes, TUNEL staining was used to detect apoptosis in tumor tissues, and the expression of GSC markers in tumor tissues was identified by western blot and immunofluorescence. RESULTS: Bioinformatics analysis showed that 55 matched targets were related to XHP targets and glioma stem cell targets. In addition to causing apoptosis, XHP could diminish the number of GBM 3D spheroids, the proportion of CD133-positive cells and the expression level of GSC markers (CD133 and SOX2) in vitro. Furthermore, XHP could attenuate the expression of CD133, EGFR, p-Akt, p-mTOR and SOX2 in GBM spheres. Overexpression of Akt significantly increased the expression level of SOX2, which was prohibited in the presence of XHP. XHP reduced GSC markers including CD133 and SOX2, and impeded the development of glioma growth in xenograft mouse models in vivo. CONCLUSION: We demonstrate for the first time that XHP down-regulates stemness, restrains self-renewal and induces apoptosis in GSCs and impedes glioma growth by down-regulating SOX2 through destabilizing the CD133/EGFR/Akt/mTOR cascade.