贵阳医学院

High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of tumor biological processes. However, its effect on cervical cancer remains largely indistinct. In this study, we found that HMGA1 was generally overexpressed in cervical cancer tissues and was positively correlated with lymph node metastasis and advanced clinical stage. Via exogenously increasing or decreasing the expression of HMGA1, we showed that HMGA1 affected the proliferation, colony formation, migration and invasion of cervical cancer cells in vitro. Rescue experiments suggested that miR-221/222 could partly reverse HMGA1-mediated migration and invasion processes. Mechanistically, we discovered that HMGA1 accelerated the G1/S phase transition by regulating the expression of cyclin D1 and cyclin E1, which was consistent with the results of the in vivo experiment. Furthermore, we found that HMGA1 regulated the expression of the miR-221/222 cluster at the transcriptional level and that miR-221/222 targeted the 3'UTR of tissue inhibitor of metalloproteinases 3(TIMP3). We propose a fresh perspective that HMGA1 participates in the migration and invasion process via the miR-221/222-TIMP3-MMP2/MMP9 axis in cervical cancer. In summary, our study identified a critical role played by HMGA1 in the progression of cervical cancer and the potential mechanisms by which exerts its effects, suggesting that targeting HMGA1-related pathways could be conducive to the therapies for cervical cancer.

As innovative therapies for renal anemia, roxadustat and daprodustat are specifically indicated for populations with chronic kidney disease (CKD) who exhibit a significantly higher susceptibility to cardiovascular complications. Platelets are important participants in cardiovascular and cerebrovascular thrombotic diseases, and the effects of roxadustat and daprodustat on platelets have not been clarified. The study explored their modulatory effects on platelet functions (using human platelets) and antithrombotic activity in vivo (via mouse pulmonary embolism and mesenteric thrombus models). Mechanistically, thromboxane A2/cyclic adenosine monophosphate (TXA2/cAMP) levels were measured by ELISA, and protein expression by immunoblotting. Results revealed that roxadustat and daprodustat treatment could effectively inhibit platelet functions. Roxadustat and daprodustat inhibited collagen-induced platelet aggregation ex vivo and FeCl3-induced mesenteric arteriolar thrombosis in mice and were protective in pulmonary embolism models. Additionally, roxadustat and daprodustat caused a decrease in TXA2 production and an increase in cAMP signaling. Western blot assay results displayed that roxadustat and daprodustat downregulated collagen-induced platelet PI3K/AKT/HIF-1α pathway. Our study revealed the pharmacological effects of roxadustat and daprodustat in inhibiting platelet activation and thrombosis. The effects may provide some insights into the physiological activity of HIF and clinical medication safety.

To date, no reliable biological clock markers have been identified to elucidate the phylogenetic relationships among the three species within the Trichophyton mentagrophytes complex-namely T. interdigitale, T. mentagrophytes, and T. indotineae. This study, employing a polyphasic approach, confirmed that 62 clinical isolates of the T. mentagrophytes complex obtained from Guizhou tend to cluster into two distinct groups: Group I (42 isolates, comprising T. interdigitale and T. indotineae) and Group II (20 isolates, representing T. mentagrophytes). These groups exhibited statistically significant differences in molecular characteristics, phenotypic traits, MAT locus distribution, clinical pathogenicity, and antifungal susceptibility profiles. Notably, the identification of a cryptic sexual state in T. interdigitale revealed unexpected genetic affinities between the two groups. In particular, the hybrid strain JYP 23487, classified as T. mentagrophytes, and its granular variant JYP 23487 k, which occupies an intermediate position in the MAT1-1 gene phylogenetic tree (MAT1-1-1 genotype C), provide evidence for genetic continuity and suggest a potential link between fungal morphological variation and mating type gene composition. Collectively, the Guizhou isolates of the T. mentagrophytes complex demonstrate a dynamic pattern of genetic continuity and shared MAT genotypes that correlate with phenotypic traits, providing additional evidence for the blurred taxonomic boundaries between the traditionally defined species T. interdigitale and T. mentagrophytes. The occurrence of strains with dual mating type loci or intermediate genotypes may be attributed to frequent host switching, facilitating recombination and exchange of MAT gene regions.

Radioimmunotherapy for lung cancer is effective but could cause cardiac damage. Our previous research indicated that combining radiotherapy with PD-1 inhibitors leads to myocardial injury, marked by increased HMGB1 and pyroptosis-related proteins in heart tissue. Pyroptosis, a pro-inflammatory form of programmed death, releases abundant inflammatory cytokines that further amplify tissue damage. Notably, in addition to its pivotal role in cardiac injury, HMGB1 exerts context-dependent, dual effects within the tumor microenvironment—either tumor-promoting or tumor-suppressive—whose net impact remains undefined. Therefore, this study proposes to specifically block HMGB1 in a lung cancer model to determine whether this intervention can suppress pyroptosis, alleviate cardiac damage, and to concurrently evaluate its potential impact on the tumor control, thereby providing a novel therapeutic strategy to mitigate the cardiotoxicity of radiation–immunotherapy. We established a cardiac injury model in tumor-bearing mice using radiation and PD-1 inhibitors to assess the impact of HMGB1 blockade on heart and tumor treatment. We evaluated cardiac injury and fibrosis with HE and Masson staining, assessed cardiac function via echocardiography and detect the level of cytokine in heart by ELISA. Lymphocyte infiltration was analyzed by flow cytometry, while immunofluorescence, immunohistochemistry, Western blotting, and PCR examined changes of HMGB1 and pyroptosis pathways. Additionally, we monitored tumor growth and necrosis following HMGB1 blockade. Recent research demonstrates that the combination of radiotherapy and PD-1 inhibitors significantly exacerbates myocardial injury compared to radiotherapy alone. This exacerbation is evidenced by elevated levels of inflammatory cytokines, including HMGB1, IL-1β, and IL-18, within the myocardium, along with increased fibrosis and pyroptosis. Additionally, there is an upregulation of the pyroptosis pathway, specifically the HMGB1-Caspase-1-GSDMD axis. The incorporation of an HMGB1 neutralizing antibody into the combined treatment regimen has been shown to down-regulate HMGB1 and proteins associated with pyroptosis, thereby substantially reducing cardiotoxicity and myocardial injury. Notably, the administration of the antibody does not compromise the anti-tumor efficacy of the combined regimen, as indicated by comparable tumor growth, necrosis levels, and peripheral blood lymphocyte distribution relative to the group receiving the combined treatment without the antibody. HMGB1 blockade attenuates cardiac injury caused by radiotherapy combined with PD-1 inhibitor while maintaining the anti-tumor efficacy. This demonstrates that in the context of tumor treatment, targeting HMGB1 represents a promising option for alleviating the cardiac damage caused by combined therapy.

The proliferation and migration of vascular smooth muscle cells are significant in the development and progression of atherosclerosis and plaque rupture. Metformin is a widely used antidiabetic drug, which has been reported to inhibit cell growth and migration. The antiproliferative and antimigratory effects of metformin have been attributed to 5′ adenosine monophosphate-activated protein kinase (AMPK) activation. The purpose of the present study was to investigate the effects of metformin on primary human aortic muscle cells (HASMCs) in vitro and to clarify the underlying mechanism. We investigated the effectiveness of metformin in inhibiting the proliferation and migration of HASMCs in vitro using RNA extraction and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), cell number counting, cell viability assay, cell cycle assay and cell migration assay. Through transfection with small interfering (si)RNA targeting p53 and interferon-inducible protein 16 (IFI16), the roles of p53 and IFI16 in these processes were evaluated. The present study demonstrated that p53, IFI16 and AMPK were upregulated in senescent primary HASMCs, which exhibited a decrease in proliferation and migration. In addition, metformin was able to activate p53, IFI16 and AMPK, in order to inhibit proliferation and migration of HASMCs. Furthermore, siRNA-mediated knockdown of p53 and IFI16 attenuated AMPK activation and reversed the suppressive effects of metformin. Notably, in response to metformin, the activation of AMPK was not observed in p53- and IFI16-silenced HASMCs. These results indicated that metformin-induced activation of AMPK suppresses the proliferation and migration of HASMCs by upregulating p53 and IFI16. These findings suggested that metformin may have potential use in the treatment of atherosclerosis.