Discovery medicine最新文献

Background: Depression represents a significant clinical concern for individuals diagnosed with non-small cell lung cancer (NSCLC) following surgical resection. This study aimed to investigate the potential of preoperative peripheral blood parameters, including the neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), and platelet/lymphocyte ratio (PLR), as predictive indicators for the risk of developing depression within the initial 90-day postoperative period in NSCLC patients.

Methods: A prospective cohort study was conducted, enrolling 350 NSCLC patients, with 250 participants in the training set and 100 participants in the testing set. Participants were classified based on the presence or absence of depression 90 days after surgery. Preoperative blood parameters, including NLR, LMR, PLR, and inflammatory biomarkers, were measured. Statistical analyses, encompassing Logistics regression analysis and receiver operating characteristic (ROC) curve analysis, were performed to assess the significance and predictive value of these blood parameters. Multivariate predictive models were constructed based on the identified significant parameters.

Results: In the training set, statistically significant differences were observed between the non-depression and depression groups for NLR (4.35 ± 1.23 vs. 3.14 ± 0.82, t = 8.715, p < 0.001), LMR (3.84 ± 1.58 vs. 5.58 ± 1.23, t = 8.849, p < 0.001), PLR (187.46 ± 35.26 vs. 152.36 ± 32.46, t = 7.112, p < 0.001), and various blood parameters. Logistics regression analysis showed significant associations between NLR, LMR, PLR, and postoperative depression. ROC curve analysis indicated the predictive value of NLR [area under the curve (AUC) = 0.794], LMR (AUC = 0.800), and PLR (AUC = 0.766), with the multivariate model yielding an AUC of 0.931. These results were consistent in the testing set, where significant differences were observed between the non-depression and depression groups for NLR (4.23 ± 1.24 vs. 3.13 ± 0.75, t = 5.417, p < 0.001), LMR (3.17 ± 1.55 vs. 4.76 ± 1.22, t = 5.412, p < 0.001), PLR (189.46 ± 46.58 vs. 151.48 ± 34.26, t = 4.481, p < 0.001), and various blood parameters. The AUC values were 0.771, 0.791, and 0.755 for NLR, LMR, and PLR, respectively, while the multivariate model yielded an AUC of 0.928.

Conclusions: The study highlights the potential of preoperative peripheral blood NLR, LMR, and PLR as predictive indicators for the risk of postoperative 90-day depression in patients with NSCLC.

Clinical trial registration: Approval number: ChiCTR2300070375, https://www.chictr.org.cn/index.html.

Background: The role of tertiary lymphoid structures (TLSs) in stomach adenocarcinoma (STAD) remains unclear despite their known potential effects on tumor progression and prognosis.

Methods: Data were collected from 362 patients with STAD from The Cancer Genome Atlas (TCGA) database. Using single-sample genomic enrichment analysis, TLSs were quantified based on a 9-gene signature, and the patients were categorized into TLS-signature high (TLS-high) and TLS-signature low (TLS-low) groups. The association of TLS signature with prognosis, tumor microenvironment (TME) immune status, tumor mutation burden, and gene mutation status was evaluated. The GSE26253 cohort served as an external dataset to validate the prognostic predictive effect of the TLS signature in patients with STAD.

Results: The TLS-high group exhibited notably lower overall survival (OS) among male patients with STAD from the TCGA cohort (p = 0.01). Multivariate analysis revealed that the TLS signature was a significant independent negative predictor of OS in male patients with stage I-III STAD (hazard ratio (HR): 2.68; 95% confidence interval (CI): 1.19-6.00; p = 0.02). The TLS-high patients exhibited increased infiltration of immune cell subsets; however, cancer-immunity cycle analysis revealed both antitumor and protumor responses within the TME. Correlation analyses indicated that TLS was more strongly associated with immunosuppression-related cells than with antitumor immune cells. Furthermore, expressions of immunosuppressive cell-recruitment factors, immunosuppressive factors, and immune checkpoint receptors were higher in the TLS-high group than in the TLS-low group. Nonetheless, among male patients with stage I-III STAD who received adjuvant therapy, multivariate analysis identified TLS trait as a significant independent positive predictor of relapse-free survival in the GSE26253 cohort (HR: 0.61; 95% CI: 0.38-0.97; p = 0.04). Interaction of the TLS signature with adjuvant therapy exerted a significant positive effect on OS in these patients (HR: 0.41; 95% CI: 0.17-0.97; p = 0.04).

Conclusion: In the TCGA cohort, the TLS signature acted as an independent adverse prognostic factor for male patients with stage I-III STAD and was associated with immunosuppressive TME, which interacted to affect patient prognosis. However, adjuvant therapy may affect the prognostic predictive effect of TLS in male patients with stage I-III STAD.

Background: Osteoarthritis (OA) is one of the most prevalent arthritis types globally, with the knee being particularly susceptible due to its frequent and strenuous use. Urolithin B (UB) exhibits various biological properties, with meniscal repair playing an important role in preventing knee OA. This study aimed to explore the impact of UB on meniscal regeneration and OA progression.

Methods: Initially, we explored the effect of UB on meniscal cells. Utilizing the cell counting kit (CCK)-8 assay, we determined the optimum concentration of UB treatment. Enzyme-linked immunosorbent assay (ELISA) was used for detecting inflammation-related interleukin-1beta (IL-1β). Real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) was used for measuring the expression of extracellular matrix (ECM)-related proteins, ECM-degrading enzymes, and genes associated with joint formation in meniscal cells. Furthermore, 5-Bromo-2'-deoxyuridine (BrdU) staining was used to evaluate the proliferation of meniscal cells. Meniscal tissues were cultured in vitro, and western blot analysis was used to detect levels of proliferation-related markers such as proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF), as well as ECM protein collagen-1 (COL-1) and ECM degradation-related matrix metallopeptidase-13 (MMP-13). Mice were subjected to meniscus injury to establish a knee joint model of meniscus injury-induced osteoarthritis (MIOA) and to verify the effect of UB on meniscal cells in vivo. Pathological changes in knee joints were observed using hematoxylin-eosin (H&E) staining. Additionally, western blot was used to assess PCNA, VEGF, COL-1, and MMP-13 levels, while ELISA was used to detect inflammation-related tumor necrosis factor-alpha (TNF-α), IL-1β, IL-6, and interferon-gamma (IFN-γ) in mouse menisci.

Results: At concentrations up to 100 μM, UB exhibited non-toxicity and concomitantly decreased IL-1β in meniscal cells (p < 0.001). Moreover, UB increased the expression of ECM-related proteins (p < 0.001) and genes associated with joint formation (p < 0.001), while concurrently decreasing the expression of ECM-degrading enzymes (p < 0.001) in meniscal cells. UB promoted meniscal cell proliferation (p < 0.001). Additionally, UB increased PCNA, VEGF, and COL-1 while suppressing MMP-13 in menisci cultured in vitro (p < 0.001). Moreover, UB mitigated the pathological alterations observed in knee joints affected by meniscus injury. In murine models, MIOA led to decreased PCNA, VEGF, and COL-1 levels, alongside increased MMP-13, TNF-α, IL-1β, IL-6, and IFN-γ levels (p < 0.001), all of which were effectively reversed by UB treatment (p < 0.001).

Conclusion: UB effectively promotes meniscal regeneration and repair, while protecting against knee OA in mice, suggesting its po

Background: Angiotensin II (Ang II) and its receptor, Angiotensin II receptor type 1 (AGTR1), have been implicated in the proliferation of cancer cells across various tumor types. This study aims to examine the impact of Ang II and AGTR1 on esophageal squamous cell carcinoma (ESCC) cells.

Methods: The clonogenicity and proliferation of tumor cells were evaluated through Clone Formation and Cell Counting Kit-8 (CCK-8) assays. Cell migration and invasion were determined utilizing Transwell assays. Flow cytometry was employed to analyze the cell cycle. Additionally, to investigate the expressions of genes associated with cell growth, migration, infiltration, and Janus kinase-signal transducer and activator of transcription 3 (JAK/STAT3) signaling pathways, quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were utilized.

Results: In the current study, it was observed that increasing the concentration of Ang II significantly augmented the proliferation of ESCC cells. However, with the addition of its inhibitor losartan, the proliferative activity of ESCC cells was significantly reduced with the increase of losartan concentration (p < 0.05). The inhibition of AGTR1 also markedly reduced the proliferative activity of ESCC cells, counteracting the effect induced by Ang II treatment (p < 0.05). Additionally, Ang II was found to stimulate the migration and invasion of ESCC cells, facilitate the transition of these cells from the first gap (G1) to the synthesis (S) phase, and impede apoptosis (p < 0.05). However, treatment with losartan and AGTR1 inhibition significantly diminished the number of migratory and invasive cells, inhibited the transition from G1 to S phase, and promoted apoptosis in ESCC cells (p < 0.05). Regarding the mechanism, our research team found that Ang II and AGTR1 can enhance the proliferation and invasion of ESCC cells and inhibit their apoptosis via the JAK/STAT3 signaling pathway. Nevertheless, the AGTR1 blocker, losartan, effectively obstructed this process.

Conclusion: The activation of the JAK/STAT3 signaling pathway by Ang II and AGTR1 promotes the advancement of ESCC tumors. Consequently, targeting Ang II and AGTR1 could potentially emerge as a promising strategy for ESCC treatment.

Background: Traditional Chinese medicines exhibit tremendous beneficial effects on the control of hyperlipidemia and hyperlipidemia-associated disorders. In the present study, we investigated the effects of four Coreopsis tinctoria Nutt. extracts, including luteolin, marein, naringenin (NGN) and chlorogenic acid (CQA), on lipid accumulation and oxidative stress induced by oleic acid (OA) in HepG2 cells.

Methods: Oleic acid was employed to create a high-lipid milieu in a cellular setting in vitro using HepG2 cells. After treatment by luteolin, marein, NGN, and CQA, cell counting kit-8 assay was used for measuring cell viability. Lipid accumulation, lipid metabolism and oxidative stress were examined by means of enzyme-linked immunosorbent assay, Oil red O staining, quantitative real-time polymerase chain reaction (qRT-PCR) and 2',7'-dichlorodihydro fluorescein diacetate assays. Western blot and qRT-PCR assays were applied to determine the expression of genes and proteins, respectively.

Results: In OA-treated HepG2 cells, the administration of the four active flavonoids of Coreopsis tinctoria Nutt. (luteolin, marein, NGN and CQA) enhanced cell viability (p < 0.05 or p < 0.01); reduced lactate dehydrogenase releasing, lipid deposition and production of triglyceride, total cholesterol and low-density lipoprotein-cholesterol (p < 0.05 or p < 0.01); and elevated high-density lipoprotein-cholesterol production (p < 0.05 or p < 0.01 or p < 0.001). Moreover, after luteolin, marein, NGN or CQA treatment, the expression of lipid metabolism-related genes including 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), low-density lipoprotein receptor (LDLR) and apical sodium-dependent bile acid transporter (ASBT) was downregulated (p < 0.01 or p < 0.001) but the expression of cytochrome P450 family 7 subfamily A member 1 (CYP7A1) was upregulated (p < 0.05 or p < 0.01 or p < 0.001) in OA-treated HepG2 cells. Similarly, luteolin, marein, NGN or CQA treatment greatly enhanced the anti-oxidant activities (p < 0.05 or p < 0.01 or p < 0.001) and decreased reactive oxygen species production (p < 0.01 or p < 0.001) in OA-treated HepG2 cells. Sterol regulatory element-binding protein, a major transcription factor that moderates the biosynthesis of fatty acid, cholesterol and triglyceride, was also inhibited after luteolin, marein, NGN or CQA treatment (p < 0.05 or p < 0.01 or p < 0.001).

Conclusion: These findings demonstrated that luteolin, marein, NGN or CQA can effectively reduce OA-induced oxidative stress and lipid accumulation, corroborating their potential in hyperlipidemia treatment.

Background: Zinc finger proteins (ZNFs) have been proved to play important roles in driving the progression of breast cancer (BC), one of the most common cancers among women. This study aimed to investigate the involvement of zinc-finger SWIM domain-containing protein 3 (ZSWIM3) in promoting BC cell progression by regulating lipid metabolism.

Methods: Differential expression of ZSWIM3 in BC was confirmed by comparing its expression in normal human mammary epithelial cells and BC cells. MCF7 cells, a BC cell line, were subjected to ZSWIM3 knockdown/overexpression experiments. The lipid contents in MCF7 cells were measured by assay kits and immunofluorescence test. The lipogenic enzymes in the cells were detected by enzyme-linked immunosorbent assay (ELISA). The cells were also subjected to further transfection experiments to manipulate the expression of sterol regulatory element-binding transcription factor 1 (SREBF1)/SREBF2 in ZSWIM3-regulated MCF7 cells to verify whether the ZSWIM3 targets SREBF1/SREBF2. Subsequently, the lipid contents in the transfected cells were determined, and the cell viability, proliferation and metastasis were measured.

Results: ZSWIM3 was overexpressed in BC cells. ZSWIM3 knockdown/overexpression led to a significant decrease/increase of the lipid contents including triglyceride, free fatty acid, cholesterol, phospholipid and neutral lipid, and lipogenic enzymes (p < 0.01). The ZSWIM3 knockdown decreased the expression of SREBF1 and SREBF2 (p < 0.01). Our findings showed that lipid content reduction induced by ZSWIM3 knockdown was reversed by SREBF1/SREBF2 overexpression. MCF7 cell viability, proliferation and metastasis, which were all suppressed by ZSWIM3 knockdown (p < 0.001), were reversible through SREBF1/SREBF2 overexpression (p < 0.001). On the other hand, the ZSWIM3 overexpression increased SREBF1 and SREBF2 expression (p < 0.001). Lipid content elevation, as well as increased MCF7 cell viability, proliferation and metastasis, which were induced by ZSWIM3 overexpression, could be counteracted by SREBF1/SREBF2 downregulation (p < 0.001).

Conclusion: ZSWIM3 promotes BC progression by enhancing lipid synthesis. This study reveals the malevolent effect of ZSWIM3 on BC, underpinned by the reprogramming of lipid metabolism, providing insights into potential therapeutic targets for BC treatments.

Background: Cytoskeleton-associated protein 2 like (CKAP2L) has been demonstrated to mediate the cell cycle in cancer cells. However, it is unknown whether CKAP2L impacts colorectal cancer (CRC). The purpose of this study was to investigate the role of CKAP2L in CRC.

Methods: CKAP2L and regulatory factor X 5 (RFX5) expression profiles in colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) were analyzed in UALCAN. Human colorectal adenocarcinoma epithelial cells, DLD1, were transfected with small interfering RNA targeting RFX5 and CKAP2L-overexpressing vectors (OE-CKAP2L). The interaction between CKAP2L and RFX5 was identified by dual-luciferase assay and chromatin immunoprecipitation. Epithelial-mesenchymal transition (EMT)- and protein kinase B/mammalian target of the rapamycin (AKT/mTOR) pathway-associated proteins were evaluated by western blotting.

Results: RFX5 and CKAP2L expression was increased in CRC based on the UALCAN database. RFX5 downregulation inhibited proliferation, migration, invasion, and EMT while promoting G1/S phase arrest (p < 0.01). RFX5 knockdown downregulated CKAP2L expression and mediated the inactivation of the AKT/mTOR pathway (p < 0.001). RFX5 acted as an upstream transcription factor of CKAP2L. CKAP2L overexpression attenuated the restriction of RFX5 downregulation on CRC cell malignant phenotypes (p < 0.01).

Conclusion: CKAP2L transcriptionally activated by RFX5 accelerates CRC proliferation and metastasis by promoting the cell cycle and EMT. This study provides potential molecular targets for treating CRC.

Background: Glioblastoma multiforme (GBM) is one of the deadliest and most heterogeneous forms of brain cancer, characterized by its resistance to conventional therapies. Within GBM, a subpopulation of slow-cycling cells, often linked to quiescence and stemness, plays a crucial role in treatment resistance and tumor recurrence. This study aimed to identify novel biomarkers associated with these slow-cycling GBM cells.

Methods: We utilized The Cancer Genome Atlas (TCGA)-GBM dataset and presented the reproducible bioinformatics analysis for our results.

Results: Our analysis highlighted Membrane-Associated Protein 17 (MAP17) as strongly associated with the slow-cycling phenotype. We found that the protein cargo MAP17 expression is related to mesenchymal signatures and stem cell-related pathways. Also, MAP17 was linked to a distinct metabolic profile, characterized by significant enrichment in pathways related to folate, zinc, and fatty acids. Moreover, the immune cell distribution analysis revealed that MAP17 correlates with key molecular immune processes, including interferon-gamma (IFN-γ) signaling and antigen presentation, as well as immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) and macrophages. MAP17-high tumors also showed elevated expression of several immune checkpoint inhibitors, indicating an immunosuppressive microenvironment.

Conclusion: These findings provide insight into the role of MAP17 in quiescence, stemness, and immune evasion, positioning it as a promising therapeutic target.

Background: Long non-coding RNA (lncRNA) zinc finger protein 667-antisense RNA 1 (ZNF667-AS1) is closely related to the advancement of a variety of cancers, but its functional role in colorectal cancer remains unclear. This study was designed to explore the function and molecular mechanisms of lncRNA ZNF667-AS1 in colorectal cancer.

Methods: Reverse transcriptase real-time quantitative polymerase chain reaction (RT-qPCR) was used for the detection of ZNF667-AS1 and proline-rich nuclear receptor co-activator protein 2 (PNRC2) expression level. Cell counting kit-8 (CCK-8), 5-Ethynyl-2'- deoxyuridine (EdU), and colony formation assays were conducted to assess cell proliferation; flow cytometry and transwell invasion assay were performed separately to measure cell apoptosis and invasion. RNA immunoprecipitation (RIP) assay was utilized to analyze the relationship between ZNF667-AS1 and PNRC2. Western blot was to test the PNRC2 protein expression. The in vivo role of ZNF667-AS1 in the advancement of colorectal cancer was evaluated by tumor xenograft assay.

Results: LncRNA ZNF667-AS1 and PNRC2 were both decreased in colorectal cancer tissue samples and cells (p < 0.05). ZNF667-AS1 overexpression remarkably restrained proliferation and invasion in HCT-116 and LOVO cells, but enhanced cell apoptosis (p < 0.0001). Moreover, ZNF667-AS1 directly targeted PNRC2, and positively regulated its expression. The influence of ZNF667-AS1 overexpression on invasion, apoptosis, and proliferation was suppressed by PNRC2 knockdown in HCT-116 and LOVO cells. Additionally, ZNF667-AS1 overexpression markedly inhibited tumor growth via upregulation of PNRC2 in mice in vivo (p < 0.05).

Conclusion: LncRNA ZNF667-AS1 expressed low in colorectal cancer. LncRNA ZNF667-AS1 repressed proliferation and invasion, and enhanced apoptosis of colorectal cancer cells by targeting PNRC2.