Том 27, № 7 (2024)

Background:Houshiheisan (HSHS) has been effective in the treatment of ischemic stroke (IS) for centuries. However, its mechanisms are still underexplored.

Objective:The objective of this study is to identify the active ingredients and mechanisms of HSHS in treating IS.

Methods:We searched the main active compounds in HSHS and their potential targets, and key targets related to IS. Based on the common targets of HSHS and IS, we further expanded genes by KEGG database to obtain target genes and related genes, as well as gene interactions in the form of A→B, and then constructed a directed network including traditional Chinese medicines (TCMs), active compounds and genes. Finally, based on enrichment analysis, independent cascade (IC) model, and molecular docking, we explored the mechanisms of HSHS in treating IS.

Results:A directed network with 6,348 nodes and 64,996 edges was constructed. The enrichment analysis suggested that the AGE pathway, glucose metabolic pathway, lipid metabolic pathway, and inflammation pathway played critical roles in the treatment of IS by HSHS. Furthermore, the gene ontologies (GOs) of three monarch drugs in HSHS mainly involved cellular response to chemical stress, blood coagulation, hemostasis, positive regulation of MAPK cascade, and regulation of inflammatory response. Several candidate drug molecules were identified by molecular docking.

Conclusion:This study advocated potential drug development with targets in the AGE signaling pathway, with emphasis on neuroprotective, anti-inflammatory, and anti-apoptotic functions. The molecular docking simulation indicated that the ligand-target combination selection method based on the IC model was effective and reliable.

Objective:SOCS2 is a member of the suppressor of cytokine signaling (SOCS) protein family associated with the occurrence and development of multiple cancers. This study revealed the expression and molecular mechanisms of SOCS2 in cervical cancer.

Methods:In this study, RT-qPCR, Western Blot, and immunohistochemistry were used to detect the expression level of SOCS2 in cervical cancer tissues and tumor cells. We overexpressed SOCS2 in SiHa cells via lentivirus. In-vitro experiments were used to investigate the changes in cervical cancer cell proliferation, migration, and invasion ability before and after SOCS2 overexpression. Western Blot was used to detect the expression of IL-6/JAK2/STAT3 pathway and EMTrelated proteins. M0 macrophages were co-cultured with the tumor-conditioned medium. The effect of SOCS2 on macrophage polarization was examined by RT-qPCR.

Results:SOCS2 expression level was significantly downregulated in cervical cancer tissues. SOCS2 was negatively correlated with CD163+M2 macrophages. Overexpression of SOCS2 inhibited the proliferation, migration, and invasion of cervical cancer cells. The expressions of Twist- 2, N-cadherin, and Vimentin were decreased, while the expression of E-cadherin was increased. Moreover, the expression of IL-6, p-JAK2, and p-STAT3 were decreased. After the addition of RhIL-6, the expression of E-cadherin protein in the LV-SOCS2 group was reversed. CM in the LV-SOCS2 group inhibited the polarization of M2 macrophages.

Conclusion:SOCS2 acts as a novel biological target and suppressor of cervical cancer through IL- 6/JAK2/STAT3 pathway.

Background:Pancreatic adenocarcinoma (PAAD) is a frequent malignant tumor with a high mortality rate. Searching for novel biomarkers that can influence its prognosis may help patients. It has been shown that tropomodulin-3 (TMOD3) may influence tumor progression, but its role in pancreatic cancer is not clear. We aimed to explore the expression and prognostic value of TMOD3 in PAAD.

Methods:We used bioinformatics analysis to analyze the relationship between TMOD3 expression and clinicopathological features and prognosis and verified it with clinical data from tissue microarray. We also conducted in vitro cell experiments to explore the effects of TMOD3 on the function of PAAD cells.

Results:TMOD3 expression was found to be significantly higher in PAAD tissues than in matched paracancerous tissues (p < 0.05). Meanwhile, high TMOD3 expression was associated with significantly poorer overall survival (p < 0.05). Analysis of relevant clinicopathological characteristics data obtained from TCGA showed that high TMOD3 expression correlated with age, TNM stage, N stage, and M stage (p < 0.05). Analysis of correlation data obtained from tissue microarrays showed that high TMOD3 expression was associated with lymph node invasion, nerve invasion, macrovascular invasion, and TNM stage (p < 0.05). In addition, siRNA knockdown of TMOD3 significantly reduced the migration and invasion of PAAD cells.

Conclusion:Our study shows that TMOD3 may be associated with the progression of PAAD cells, and that it is an independent risk factor for poor pathological features and prognosis of PAAD. It may be helpful as a prognostic indicator of clinical outcomes in PAAD patients.

Background:Acute kidney injury (AKI) is one of the most severe complications of sepsis. This study was conducted to analyze the role of urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary kidney injury molecular-1 (uKIM-1), and urinary angiotensinogen (uAGT) in the early diagnosis and mortality prediction of septic AKI.

Methods:The prospective study enrolled 80 sepsis patients in the ICU and 100 healthy individuals and divided patients into an AKI group and a non-AKI group. uNGAL, uKIM-1, uAGT, serum creatinine/procalcitonin/C-reaction protein, and other indicators were determined, and clinical prediction scores were recorded. The sensitivity and specificity of uNGAL, uKIM-1, and uAGT in diagnosis and mortality prediction were analyzed by the receiver operator characteristic (ROC) curve and the area under the curve (AUC).

Results:uNGAL, uKIM-1, and uAGT levels were higher in sepsis patients than healthy controls, higher in AKI patients than non-AKI patients, and higher in AKI-2 and AKI-3 patients than AKI-1 patients. At 0 h after admission, the combined efficacy of three indicators in septic AKI diagnosis (ROC-AUC: 0.770; sensitivity: 82.5%; specificity: 70.0%) was better than a single indicator. At 24 h, uNGAL, uKIM-1, and uAGT levels were higher in sepsis non-survivals than survivals and higher in septic AKI non-survivals than septic AKI survivals. The combined efficacy of three indicators in the prediction of sepsis/septic AKI mortality (ROC-AUC: 0.828/0.847; sensitivity: 71.4%/100.0%; specificity: 82.7%/66.7%) was better than a single indicator.

Conclusion:uNGAL, uKIM-1, and uAGT levels were increased in septic AKI, and their combination helped the early diagnosis and mortality prediction.

Aim:To analyze the sequencing results of circular RNAs (circRNAs) in cardiomyocytes between the doxorubicin (DOX)-injured group and exosomes treatment group. Moreover, to offer potential circRNAs possibly secreted by exosomes mediating the therapeutic effect on DOX-induced cardiotoxicity for further study.

Methods:The DOX-injured group (DOX group) of cardiomyocytes was treated with DOX, while an exosomes-treated group of injured cardiomyocytes were cocultured with bone marrow mesenchymal stem cells (BMSC)-derived exosomes (BEC group). The high-throughput sequencing of circRNAs was conducted after the extraction of RNA from cardiomyocytes. The differential expression of circRNA was analyzed after identifying the number, expression, and conservative of circRNAs. Then, the target genes of differentially expressed circRNAs were predicted based on the targetscan and Miranda database. Next, the GO and KEGG enrichment analyses of target genes of circRNAs were performed. The crucial signaling pathways participating in the therapeutic process were identified. Finally, a real-time quantitative polymerase chain reaction experiment was conducted to verify the results obtained by sequencing.

Results:Thirty-two circRNAs are differentially expressed between the two groups, of which twenty-three circRNAs were elevated in the exosomes-treated group (BEC group). The GO analysis shows that target genes of differentially expressed circRNAs are mainly enriched in the intracellular signalactivity, regulation of nucleic acid-templated transcription, Golgi-related activity, and GTPase activator activity. The KEGG analysis displays that they were involved in the autophagy biological process and NOD-like receptor signaling pathway. The verification experiment suggested that mmu_circ_0000425 (ID: 116324210) was both decreased in the DOX group and elevated in BEC group, which was consistent with the result of sequencing.

Conclusion:mmu_circ_0000425 in exosomes derived from bone marrow mesenchymal stem cells (BMSC) may have a therapeutic role in alleviating doxorubicin-induced cardiotoxicity (DIC).

Background:Anti-angiogenic agents could enhance tumor immunity response, and anti- angiogenesis plus immunotherapy has become a novel treatment option for advanced non-small cell lung cancer (NSCLC). The efficacy of this combination therapy remains controversial and obscure.

Aim:We conducted a meta-analysis to evaluate the clinical efficacy and safety of this therapeutic strategy in patients with advanced NSCLC and provide more guidance for treating NSCLC clinically.

Methods:A systematic literature search was performed in PubMed, Embase, Web of Science, CNKI, and Wanfang databases to identify relevant studies published up to December 2021. The primary endpoint was the objective response rate (ORR). Second endpoints were progression-free survival (PFS), overall survival (OS), and grade ≥3 AEs adverse events (AEs). The sensitivity analysis was conducted to confirm the stability of the results. STATA 15.0 was utilized for all pooled analyses.

Results:Eleven studies were eventually included in the meta-analysis, involving 533 patients with advanced NSCLC. The pooled ORR rate was 27% (95% CI 18% to 35%; I2 =84.2%; p(<0.001), while the pooled median PFS and OS was 5.84 months (95% CI 4.66 to 7.03 months; I2=78.4%; p(<0.001) and 14.20 months (95% CI 11.08 to 17.32 months; I2=82.2%; p=0.001), respectively. Most common grade ≥3 AEs included hypertension, hand-foot syndrome, diarrhea, adrenal insufficiency, hyponatremia, proteinuria, rash, thrombocytopenia, and fatigue.

Conclusion:Anti-angiogenesis combined with immunotherapy demonstrated satisfactory antitumor activity and an acceptable toxicity profile in patients with advanced NSCLC. The pooled results of our meta-analysis provided further evidence supporting the favorable efficacy and safety of this therapeutic strategy.