Metabolic Disturbances in a Mouse Model of MPTP/Probenecid-Induced Parkinson's Disease: Evaluation Using Liquid Chromatography-Mass Spectrometry.

Purpose: Parkinson's disease (PD) is a common neurodegenerative disease that severely affects patients' daily lives and places a significant burden on the global economy. There are currently no specific biomarkers for distinguishing between the different stages of PD. Methods: We divided 78 mice into six equal groups, including five model PD groups (W1-W5; based on the PD stage induced by length of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/propofol induction time) and a control group. Then, we used metabolomics technology to detect the serum small-molecule metabolites present in each group. Ultimately, we screened for potential biomarkers using the variable importance in the projection of the orthogonal partial least squares discriminant analysis and the coefficient value of LASSO ordinal logistic regression. Results: We identified 12 potential biomarkers, including dehydroepiandrosterone sulfate, pipecolic acid, N-acetylleucine, 2-aminoadipic acid, L-tyrosine, uric acid, and 5-hydroxyindoleacetaldehyde. Pathway analysis revealed their involvement in amino acid metabolism, caffeine metabolism, steroid hormone biosynthesis, and purine metabolism. Additionally, the receiver operating characteristic curve indicated that a biomarker panel comprising the 12 biomarkers could differentiate between the different PD stages. Conclusion: Different PD stages are characterized by different metabolites. The biomarkers identified in this study are helpful to understand the PD process.

Intraperitoneal spread in uterine sarcoma following unprotected laparoscopic transvaginal uterine morcellation: a case report and literature review.

Clinically and through auxiliary examinations, distinguishing uterine leiomyoma from early-stage uterine sarcoma presents significant challenges. A 48-year-old patient underwent a laparoscopic hysterectomy for uterine leiomyoma, during which a large uterus was excised through the vagina and extracted. Four months post-operation, the patient developed abdominal distension, indicative of extensive pelvic-abdominal dissemination of uterine sarcoma. We hypothesize that unprotected fibroid fragmentation increases the risk of uterine sarcoma spread, thereby worsening the prognosis. Our literature review aims to thoroughly understand the risks associated with unprotected transvaginal laparoscopic tumor division.

Low-rank prior-based Fast-RPCA for clutter filtering and noise suppression in non-contrast ultrasound microvascular imaging.

Accurate and real-time separation of blood signal from clutter and noise signals is a critical step in clinical non-contrast ultrasound microvascular imaging. Despite the widespread adoption of singular value decomposition (SVD) and robust principal component analysis (RPCA) for clutter filtering and noise suppression, the SVD's sensitivity to threshold selection, along with the RPCA's limitations in undersampling conditions and heavy computational burden often result in suboptimal performance in complex clinical applications. To address those challenges, this study presents a novel low-rank prior-based fast RPCA (LP-fRPCA) approach to enhance the adaptability and robustness of clutter filtering and noise suppression with reduced computational cost. A low-rank prior constraint is integrated into the non-convex RPCA model to achieve a robust and efficient approximation of clutter subspace, while an accelerated alternating projection iterative algorithm is developed to improve convergence speed and computational efficiency. The performance of the LP-fRPCA method was evaluated against SVD with a tissue/blood threshold (SVD1), SVD with both tissue/blood and blood/noise thresholds (SVD2), and the classical RPCA based on the alternating direction method of multipliers algorithm through phantom and in vivo non-contrast experiments on rabbit kidneys. In the slow flow phantom experiment of 0.2 mm/s, LP-fRPCA achieved an average increase in contrast ratio (CR) of 10.68 dB, 9.37 dB, and 8.66 dB compared to SVD1, SVD2, and RPCA, respectively. In the in vivo rabbit kidney experiment, the power Doppler results demonstrate that the LP-fRPCA method achieved a superior balance in the trade-off between insufficient clutter filtering and excessive suppression of blood flow. Additionally, LP-fRPCA significantly reduced the runtime of RPCA by up to 94-fold. Consequently, the LP-fRPCA method promises to be a potential tool for clinical non-contrast ultrasound microvascular imaging.

Study on the effects of rapamycin and the mTORC1/2 dual inhibitor OSI-027 on the metabolism of colon cancer cells based on UPLC-MS/MS metabolomics.

mTORC1/2 dual inhibitors may be more effective than mTORC1 inhibitor rapamycin. However, their metabolic impacts on colon cancer cells remain unexplored. We conducted a comparative analysis of the anti-proliferative effects of rapamycin and the novel OSI-027 in colon cancer cells HCT-116, evaluating their metabolic influences through ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Our results demonstrate that OSI-027 more effectively inhibits colon cancer cell proliferation than rapamycin. Additionally, we identified nearly 600 metabolites from the spectra, revealing significant differences in metabolic patterns between cells treated with OSI-027 and rapamycin. Through VIP value screening, we pinpointed crucial metabolites contributing to these distinctions. For inhibiting glycolysis and reducing glucose consumption, OSI-027 was likely to be more potent than rapamycin. For amino acids metabolism, although OSI-027 has a broad effect as rapamycin, their effects in degrees were not exactly the same. These findings address the knowledge gap regarding mTORC1/2 dual inhibitors and lay a foundation for their further development and research.

Energy-efficient dynamic sensor time series classification for edge health devices.

BACKGROUND AND OBJECTIVE: Time series data plays a crucial role in the realm of the Internet of Things Medical (IoMT). Through machine learning (ML) algorithms, online time series classification in IoMT systems enables reliable real-time disease detection. Deploying ML algorithms on edge health devices can reduce latency and safeguard patients' privacy. However, the limited computational resources of these devices underscore the need for more energy-efficient algorithms. Furthermore, online time series classification inevitably faces the challenges of concept drift (CD) and catastrophic forgetting (CF). To address these challenges, this study proposes an energy-efficient Online Time series classification algorithm that can solve CF and CD for health devices, called OTCD. METHODS: OTCD first detects the appearance of concept drift and performs prototype updates to mitigate its impact. Afterward, it standardizes the potential space distribution and selectively preserves key training parameters to address CF. This approach reduces the required memory and enhances energy efficiency. To evaluate the performance of the proposed model in real-time health monitoring tasks, we utilize electrocardiogram (ECG) and photoplethysmogram (PPG) data. By adopting various feature extractors, three arrhythmia classification models are compared. To assess the energy efficiency of OTCD, we conduct runtime tests on each dataset. Additionally, the OTCD is compared with state-of-the-art (SOTA) dynamic time series classification models for performance evaluation. RESULTS: The OTCD algorithm outperforms existing SOTA time series classification algorithms in IoMT. In particular, OTCD is on average 2.77% to 14.74% more accurate than other models on the MIT-BIH arrhythmia dataset. Additionally, it consumes low memory (1 KB) and performs computations at a rate of 0.004 GFLOPs per second, leading to energy savings and high time efficiency. CONCLUSION: Our proposed algorithm, OTCD, enables efficient real-time classification of medical time series on edge health devices. Experimental results demonstrate its significant competitiveness, offering promising prospects for safe and reliable healthcare.

A partial siphon operational strategy strengthens nitrogen removal performance in partially saturated vertical flow constructed wetlands.

The carbon‒oxygen balance has always been problematic in constructed wetlands (CWs), putting pressure on stable and efficient nitrogen removal. In this study, a novel partial siphon operational strategy was developed to further optimize the carbon and oxygen distributions of a partially saturated vertical flow CW (SVFCW) to enhance nitrogen removal. The removal performances of the partial siphon SVFCW (S-SVFCW) were monitored and compared with those of the SVFCWs at different partial siphon depths (15 cm, 25 cm and 35 cm) in both the warm and cold seasons. The results showed that the partial siphon operating strategy significantly facilitated the removal of ammonia and total nitrogen (TN) in both the warm and cold seasons. When the partial siphon depth was 25 cm, the S-SVFCWs had the highest TN removal efficiency in both the warm (71%) and cold (56%) seasons, with an average improvement of 46% and 52%, respectively, compared with those of the SVFCWs. The oxidation‒reduction potential (ORP) results indicated that richer OPR environments and longer hydraulic detention times were obtained in the S-SVFCWs, which enriched the denitrification bacteria. Microbial analysis revealed greater nitrification and denitrification potentials in the unsaturated zone with enriched functional genes (e.g., amo_AOA, amo_AOB, nxrA and nirK), which are related to nitrification and denitrification processes. Moreover, the strengthening mechanism was the intensified oxygen supply and carbon utilization efficiency based on the cyclic nitrogen profile analysis. This study provides a novel partial siphon operational strategy for enhancing the nitrogen removal capacity of SVFCWs without additional energy or land requirements.

LC-MS-based rheumatoid arthritis serum metabolomics reveals the role of deoxyinosine in attenuating collagen-induced arthritis in mice.

Rheumatoid arthritis (RA) is a persistent autoimmune condition with no identified cure currently. Recently, scientists have applied metabolomics to investigate altered metabolic profiles and unique diseases-associated metabolic signatures. Herein, we applied metabolomics approach to analyze serum samples of 41 RA patients and 42 healthy controls (HC) with the aim to characterize RA patients' metabolic profile, investigate related underlying pathological processes, and identify target metabolites. By utilizing ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry, we found 168 proposed metabolites and 45 vital metabolic pathways. Our analysis revealed that deoxyinosine (DI), a metabolite of the purine metabolic pathway, was the most significant reduced metabolite in RA patients. Furthermore, through targeted detection, we confirmed lower concentration of DI in RA patients' peripheral blood. Moreover, DI inhibited lipopolysaccharide-induced inflammation both in vitro and in vivo. We further assessed DI's therapeutic potential in a collagen-induced arthritis (CIA) murine model. The results revealed that DI attenuated CIA, as evidenced by significantly lowered clinical scores of arthritis, alleviated joint swelling, and mitigated bone destruction. Moreover, we elucidated the underlying mechanism by which DI increased the population of myeloid-derived suppressor cells (MDSCs) and suppressed the proliferation of induced T cells. Collectively, these findings suggested that DI potentially ameliorated RA by inducing immunosuppressive MDSCs. The study provides key observations on RA pathogenesis and may contribute to developing novel therapeutic strategies for this debilitating condition.

PlexinA1 promotes gastric cancer migration through preventing MICAL1 protein ubiquitin/proteasome-mediated degradation in a Rac1-dependent manner.

Metastasis promotes the development of tumors and is a significant cause of gastric cancer death. For metastasis to proceed, tumor cells must become mobile by modulating their cytoskeleton. MICAL1 (Molecule Interacting with CasL1) is known as an actin cytoskeleton regulator, but the mechanisms by which it drives gastric cancer cell migration are still unclear. Analysis of gastric cancer tissues revealed that MICAL1 expression is dramatically upregulated in stomach adenocarcinoma (STAD) samples as compared to noncancerous stomach tissues. Patients with high MICAL1 expression had shorter overall survival (OS), post-progression survival (PPS) and first-progression survival (FPS) compared with patients with low MICAL1 expression. RNAi-mediated silencing of MICAL1 inhibited the expression of Vimentin, a protein involved in epithelial-mesenchymal transition. This effect correlates with a significant reduction in gastric cancer cell migration. MICAL1 overexpression reversed these preventive effects. Immunoprecipitation experiments and immunofluorescence assays revealed that PlexinA1 forms a complex with MICAL1. Importantly, specific inhibition of PlexinA1 blocked the Rac1 activation and ROS production, which, in turn, impaired MICAL1 protein stability by accelerating MICAL1 ubiquitin/proteasome-dependent degradation. Overexpression of PlexinA1 enhanced Rac1 activation, ROS production, MICAL1 and Vimentin expressions, and favored cell migration. In conclusion, this study identified MICAL1 as an important facilitator of gastric cancer cell migration, at least in part, by affecting Vimentin expression and PlexinA1 promotes gastric cancer cell migration by binding to and suppressing MICAL1 degradation in a Rac1/ROS-dependent manner.

The Efficacy and Safety of Nirmatrelvir/Ritonavir Against COVID-19 in Elderly Patients.

Objective: To assess the key factors influencing the effectiveness of nirmatrelvir/ritonavir in treating elderly patients with COVID-19. Methods: This study was conducted on patients aged ≥60 who were admitted to the Second Affiliated Hospital of Soochow University for COVID-19 infection and were treated with nirmatrelvir/ritonavir. Clinical information was collected from patients and steady-state blood concentrations of nirmatrelvir and ritonavir were measured. Factors associated with treatment effects were searched by univariate and multivariate analysis. Results: A total of 68 (51 males and 17 females) patients had a median age of 80 (73.0-84.8) years were enrolled in this study. The blood concentration measurements (trough concentrations) of nirmatrelvir and ritonavir were 5.1 (2.6-7.1) and 0.4 (0.2-0.9) µg/mL, respectively. Adverse drug reaction was reported in 4 (5.9%) patients. Univariate analysis showed that age, clinical classification, APACHE II score, total bilirubin (TBil), aspartate transaminase (AST), lactate dehydrogenase (LDH), and total cholesterol (TC) were significantly associated with the effectiveness of treatment (P value <0.05). Concentration of nirmatrelvir was also associated with treatment outcome (P value <0.1). Based on the results of univariate analysis, the above factors were introduced into the multiple linear regression equation as independent variables, and the results showed that clinical classification was included in the regression equation model and was the most important factor affecting the treatment outcome. By receiver operating characteristic curve analysis, the area under curve of age + biochemical indicators + APACHE II score + clinical classification was 0.968 (95% CI = 0.919-1.000; P <0.0001). Among the 68 patients included in the study, 4 cases experienced adverse drug reactions. Conclusion: Age, clinical classification, APACHE II score, TBil, AST, LDH, and TC were significantly associated with the effectiveness of treatment in elderly patients with COVID-19.

Role of metabolomic profile as a potential marker to discriminate membranous nephropathy from IgA nephropathy.

BACKGROUND: Membranous nephropathy (MN) and IgA nephropathy (IgAN) are the most common primary glomerulopathies worldwide. The systemic metabolic changes in the progression of MN and IgAN are not fully understood. METHODS: A total of 87 and 70 patients with MN and IgAN, respectively, and 30 healthy controls were enrolled in this study. Untargeted metabolomics was performed to explore the differential metabolites and metabolic pathways in the early stage of MN and IgAN. To judge the diagnostic ability of biomarkers, receiver operating characteristic curve analysis (ROC) were performed. RESULTS: Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) suggested that patients with MN and IgAN showed an obvious separation trend from the healthy controls. In addition, 155 and 148 metabolites were identified to be significantly altered in the MN and IgAN groups, respectively. Of these, 70 metabolites were markedly altered in both disease groups; six metabolites, including L-tryptophan, L-kynurenine, gamma-aminobutyric acid (GABA), indoleacetaldehyde, 5-hydroxyindoleacetylglycine, and N-alpha-acetyllysine, showed the opposite tendency. The most affected metabolic pathways included the amino acid metabolic pathways, citrate cycle, pantothenate and CoA biosynthesis, and hormone signaling pathways. CONCLUSIONS: Substantial metabolic disorders occurred during the progression of MN and IgAN. L-tryptophan, L-kynurenine, GABA, indoleacetaldehyde, 5-hydroxyindoleacetylglycine, and N-alpha-acetyllysine may show potential as biomarkers for the identification of MN and IgAN.

Associations of hypertensive disorders of pregnancy with cognition, dementia, and brain structure: a Mendelian randomization study.

BACKGROUND: Observational studies have found associations between hypertensive disorders of pregnancy and an increased risk of cognitive dysfunction and reduced brain volume. However, the results of observational studies may have been influenced by confounding factors. This study applied two-sample Mendelian randomization (MR) to explore the causal associations of hypertensive disorders of pregnancy with cognition, dementia, and brain structure. METHODS: Summary data on hypertensive disorders of pregnancy and their main subtypes, cognition, dementia, and brain structure were obtained from recent European genome-wide association studies. We computed the inverse-variance weighted, MR-Egger, and weighted median MR estimates. Cochran's Q statistics and the MR-Egger intercept test were used to quantify the heterogeneity and horizontal pleiotropy of the instrumental variables. RESULTS: Genetically predicted preeclampsia or eclampsia was inversely associated with gray matter volume [beta = -0.072; 95% confidence interval (CI) = -0.131 to -0.014; P  = 1.53 × 10 -2 ]; possibly with brain volume (beta = -0.064; 95% CI = -0.117 to -0.012; P  = 1.68 × 10 -2 ). However, the association of hypertensive pregnancy disorders or gestational hypertension with brain structure was not significant. We did not find any significant association between hypertensive disorders of pregnancy, gestational hypertension, or preeclampsia or eclampsia and cognition and dementia-related outcomes. CONCLUSION: This study provided genetic evidence supporting an association between preeclampsia or eclampsia and reduced brain volume. This supports the view of PE as a risk factor for gray matter volume reduction.

Association between CD10 expression and phyllodes tumor: A retrospective case control study.

The present study aimed to explore the association between immunohistochemical markers and phyllodes tumor (PT). The retrospective case control study included biopsies from patients with PT who underwent surgical treatment, and patients with fibronenoma (FA), diagnosed in our hospital from October 2014 to May 2021. Differences in microscopic histopathological characteristics and expressions of common immunohistochemical markers (CD10, cluster of differentiation 117 marker, cluster of differentiation 34 marker, tumor protein P53, cell proliferation antigen) for different grades of PT and FA were analyzed. A total of 69 patients were enrolled, of them 34 with PT (12 with benign PT, 13 with borderline PT, and 9 with malignant PT) and 35 with FA. With the increase of tumor malignancy, significant enlargement trend was noted; for FA, most tumor boundaries were well-defined, the stromal distribution was homogeneous, the stromal cellularity was small. In contrast for PT, as the degree of malignancy increased, tumor boundary gradually became ill-defined and the stromal distribution was heterogeneous; stromal cellularity and stromal overgrowth had increased significantly (All P < .05). Multivariate analysis showed that among other markers only CD10 expression (OR = 0.67, 95%CI: -0.88, 2.22, P < .05) was independently associated with PT. The study showed that in addition to histological features, CD10 expression was independently associated with PT and has a potential to be used as a differentiation marker.

Population pharmacokinetic modeling and simulation for nirmatrelvir exposure assessment in Chinese older patients with COVID-19 infection.

Nirmatrelvir is an effective component of Paxlovid, the first oral antiviral drug granted emergency use authorization by the FDA. Nirmatrelvir is prescribed extensively in older adult patients to treat the coronavirus disease 2019 (COVID-19) infection. In this study, population pharmacokinetic modeling with clinical study data was employed to explore the pharmacokinetic profile of nirmatrelvir in older adult Chinese patients with COVID-19 infection. The result suggests that the pharmacokinetic profile of nirmatrelvir can be described by a one-compartment model with first-order absorption and elimination in this study population. The calculated apparent clearance (CL/F), apparent volumes of distribution (V/F), and absorption rate constant (ka) for the typical patient were 4.16 L/h, 39.1 L, and 0.776, respectively. The area under the curve (AUC) of nirmatrelvir in the typical Chinese older adult was approximately three-fold higher than the AUCs in Chinese and Western young adult volunteers. At the same doses, the simulated AUCs were increased by 26%, 43%, 72%, and 135% in virtual populations with creatinine clearances of 60, 45, 30, and 15 mL/min, respectively. Our research provides an instructive reference for nirmatrelvir dose selection in older Chinese adults.

Prognostic impact of MICALL1 and associates with immune infiltration in liver hepatocellular carcinoma patients.

BACKGROUND: Liver hepatocellular carcinoma (LIHC) is one of the most malignancy over the world. Previous studies have proven that Molecules Interacting with CasL-Like 1 (MICALL1) participated in cellular trafficking cascades, while there has no study to explore the function and carcinogenic mechanism MICALL1 in LIHC. METHODS: We aimed to investigate the relationship between MICALL1 mRNA expression and LIHC using TCGA database. The expression of MICALL1 protein in clinic samples were examined by UALCAN database. Kaplan-Meier method was used for survival analysis. Logistic regression and Cox regression were performed to evaluate the prognostic significance of MICALL1. The MICALL1-binding protein were built by the STRING tool. Enrichment analysis by GO, KEGG and GSEA was used to explore possible function of MICALL1. The ssGSEA method was used to investigate the association between MICALL1 expression and the immune infiltration level in LIHC. RESULTS: The expression and prognostic value of different MICAL family members in LIHC were evaluated. The expression of MICALL1 was significantly increased at both the transcript and protein levels in LIHC tissues. Further, the LIHC patients with high MICALL1 levels showed a worse OS, DSS and PFI. Some clinicopathologic features were identified to be related to MICALL1 expression in LIHC included clinical T stage, pathologic stage, histologic grade and AFP concentration. Univariate and multivariate survival analysis showed that MICALL1 was an independent prognostic marker for OS and DSS. Further enrichment analysis revealed that the K-RAS, TNFα/NF-κB and inflammatory response were significantly enriched in the high MICALL1 expression group. Immune infiltration analysis showed that high MICALL1 expression was correlated with infiltration level of macrophage cells, Th2 cells and some other immune cell types, including TFH. CONCLUSIONS: MICALL1 expression was significantly associated with immune cell infiltration and may regarded as a promising prognostic biomarker for LIHC patients.

Cytoplasmic localization of IRF5 induces Wnt5a/E-cadherin degradation and promotes gastric cancer cells metastasis.

IRF5, a nucleoplasm shuttling protein, is a pivotal transcription factor regulating immune system activity. It's well known that immunosuppression is involved in the development of gastric cancer. However, no data exist for the expression and function of IRF5 in gastric cancer. This study demonstrated that IRF5 was cytoplasm-enriched in gastric cancer cells. IRF5 promoted gastric cancer cell migration, which involved the inhibition of Wnt5a and E-cadherin proteins expression. IRF5 (LA) localized in nucleus had no significant effect on Wnt5a and E-cadherin expressions, while mutation of IRF5 (ΔNLS), which prevents IRF5 nuclear translocation, had more impact on these inhibitory effects. In addition, degradation rates of both Wnt5a and E-cadherin were enhanced by resiquimod, an IRF5 agonist. Further in vivo experiments indicated that IRF5 knockout of gastric cancer cells repressed their pulmonary metastasis in nude mice. Finally, the expression and clinical significance of IRF5 were analyzed using gastric cancer tissue microarrays, which suggested that the expression of IRF5 varied procedurally in different progressive stages of gastric cancer. Our data revealed that IRF5 cytoplasmic localization were associated with Wnt5a and E-cadherin degradation and gastric cancer cell metastasis. Inhibiting IRF5 expression and/or its cytoplasmic localization may provide a novel target for gastric cancer therapy.

Outcome of antithrombotic therapy in cancer patients with catheter-related thrombosis: a systematic review.

Introduction: The guidelines' recommendations for anticoagulation in cancer patients with catheter-related thrombosis are unclear. The aim of this systematic review was to assess anticoagulation management in cancer patients with catheter-related thrombosis (CRT) based on previously published studies. Methods: As of June 10, 2023,we searched databases including PubMed, Embase, and Cochrane and included 11 observational studies that met the criteria. We evaluated 770 adults with active cancer and objectively confirmed patients with CRT who were using drugs including warfarin, LMWH, and new oral anticoagulants as antithrombotic therapy. Results: We extracted outcome data, including thrombosis recurrence, catheter dysfunction, major bleeding, and death, and performed a meta-analysis. Discussion: In this study we found that the risk of VTE recurrence was higher with rivaroxaban, the risk of bleeding and death appeared to be greater with warfarin, and although the risk of catheter dysfunction due to LMWH is a concern, it is still a more reasonable option for cancer patients with catheter-related thrombosis. Systematic Review Registration: http://www.clinicaltrials.gov, identifier (CRD42022367979).

Andrographolide elevates tumor necrosis factor-related apoptosis-inducing ligand lethality through reactive oxygen species accumulation and gasdermin E cleavage in breast cancer cells.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is selectively lethal to cancer cells and harmless to normal cells, making it a potential agent for cancer therapy. However, some breast cancer cells are resistant to TRAIL. This study revealed that andrographolide (Andro), an extract from Andrographis paniculate, a natural compound, sensitized breast cancer cells to TRAIL-induced tumor suppression; it identified apoptosis-associated protein regulation, reactive oxygen species accumulation, mitochondria membrane potential disruption, caspase cascade activation, and gasdermin-E cleavage to be involved in the tumor lethality mediated by Andro combined with TRAIL treatment. The flow cytometry results showed the combination of Andro and TRAIL repressed breast cancer cells by cell death induction, and the assessment of combined index indicated that the combined treatment with Andro and TRAIL repressed breast cancer cells synergistically. Blotting results displayed Andro and TRAIL combination elevated TRAIL-associated receptors, death receptors 4 and 5, at protein levels. These results provided critical insight into breast cancer patients' therapy and exploration direction for TRAIL clinical application.

Elevation of effective p53 expression sensitizes wild-type p53 breast cancer cells to CDK7 inhibitor THZ1.

BACKGROUND: The cyclin-dependent kinase 7 (CDK7) inhibitor THZ1 represses multiple cancer cells. However, its tumor-repressive efficiency in wild-type p53 breast cancer cells remains controversial. METHODS: We conducted various assays, including CCK8, colony formation, flow cytometry, western blotting, and lactate dehydrogenase release detection, to clarify whether p53 elevation sensitizes breast cancer cells to THZ1. RESULTS: We found that upregulating functional p53 contributes to the increased sensitivity of breast cancer cells to THZ1. Increased THZ1 sensitivity requires active p53 and an intact p53 pathway, which was confirmed by introducing exogenous wild-type p53 and the subsequent elevation of THZ1-mediated tumor suppression in breast cancer cells carrying mutant p53. We confirmed that p53 accumulates in the nucleus and mitochondria during cell death. Furthermore, we identified extensive transcriptional disruption, rather than solely CDK7 inhibition, as the mechanism underlying the nutlin-3 and THZ1-induced death of breast cancer cells. Finally, we observed the combined nutlin-3 and THZ1 treatment amplified gasdermin E cleavage. CONCLUSION: Enhanced sensitivity of breast cancer cells to THZ1 can be achieved by increasing effective p53 expression. Our approach may serve as a potential treatment for patients with breast cancer resistant to regular therapies. Video Abstract.

MICAL2 contributes to gastric cancer cell migration via Cdc42-dependent activation of E-cadherin/ß-catenin signaling pathway.

BACKGROUND: Gastric cancer is a common and lethal human malignancy worldwide and cancer cell metastasis is the leading cause of cancer-related mortality. MICAL2, a flavoprotein monooxygenase, is an important regulator of epithelial-to-mesenchymal transition. The aim of this study was to explore the effects of MICAL2 on gastric cancer cell migration and determine the underlying molecular mechanisms. METHODS: Cell migration was examined by wound healing and transwell assays. Changes in E-cadherin/ß-catenin signaling were determined by qPCR and analysis of cytoplasmic and nuclear protein fractions. E-cadherin/ß-catenin binding was determined by co-immunoprecipitation assays. Cdc42 activity was examined by pulldown assay. RESULTS: MICAL2 was highly expressed in gastric cancer tissues. The knockdown of MICAL2 significantly attenuated migratory ability and ß-catenin nuclear translocation in gastric cancer cells while LiCl treatment, an inhibitor of GSK3ß, reversed these MICAL2 knockdown-induced effects. Meanwhile, E-cadherin expression was markedly enhanced in MICAL2-depleted cells. MICAL2 knockdown led to a significant attenuation of E-cadherin ubiquitination and degradation in a Cdc42-dependent manner, then enhanced E-cadherin/ß-catenin binding, and reduced ß-catenin nuclear translocation. CONCLUSIONS: Together, our results indicated that MICAL2 promotes E-cadherin ubiquitination and degradation, leading to enhanced ß-catenin signaling via the disruption of the E-cadherin/ß-catenin complex and, consequently, the promotion of gastric cell migration. Video Abstract.