Journal of Translational Internal Medicine最新文献

Background and objectives: Histone deacetylase (HDAC) families regulate various physical processes and the development of several diseases. The role of HDACs in asthma development and progression worths further investigation. This study aims to evaluate the effect of HDACs in a mouse model of asthma.

Methods: HDAC8 selective inhibitor PCI-34051 was administered to a mouse model of ovalbumin-sensitized and challenged asthma. Airway responsiveness, serum cytokines, histological changes of the airway, and expression levels of α-SMA, β-actin, VEGFR, VEGF, GAPDH, HDAC8, TGF-β3, CD 105, p-ERK 1/2, ERK 1/2, PI3K, p-AKT, AKT, and PDK1 were evaluated. The miR-381-3p level was also measured.

Results: All classic histologic and cellular changes of asthma in inflammation and airway remodeling were altered by HDAC8 inhibitor PCI-34051 via regulation of the miR-381-3p level and its downstream gene, TGF-β3. Inhibition of TGF-β3 further reduced the activation of ERK, PI3K, AKT, and PDK1.

Conclusion: In a mouse model, HDAC8 inhibitor PCI-34051 exhibits comprehensive control of asthmatic changes, including inflammation and airway remodeling.

[This corrects the article DOI: 10.2478/jtim-2024-0004.].

Background and objective: Atrial fibrillation (AF) and coronary heart disease (CHD) are closely related to metabolic dysregulation. However, the metabolic characteristics of AF patients with concomitant CHD remain unclear. The aims of this study were to elucidate the metabolic profiles of patients with AF and CHD to seek new therapeutic targets and related factors of AF combined with CHD.

Methods: Untargeted metabolomics and targeted oxylipins profiling were performed to characterize the serum metabolome landscape of patients with AF, CHD, and AF comorbid CHD.

Results: The serum metabolic fingerprints of patients with AF comorbid CHD were significantly differentiated from normal controls (NC) and individuals with AF or CHD alone, and the differentiated metabolites dominated by a variety of lipid alterations in the phospholipid and fatty acid metabolism. Furthermore, the targeted profiles of oxylipins demonstrated that the levels of arachidonic acid derivatives including prostaglandins, leukotrienes, hydroxy-docosahexaenoic acids, hydroxy-eicostetraenoic acids and hydroxy-eicosatrienoic acids in patients with AF and CHD were significantly different from those in the NC, AF, and CHD groups. Several prostaglandins were positively associated with echocardiographic indicators of myocardial remodeling.

Conclusions: This study updates metabolic insights of AF and CHD and provides potential therapeutic targets for preventing or treating AF comorbid CHD.

Histological transformation from lung adenocarcinoma (ADC) to small cell lung carcinoma (SCLC), large cell neuroendocrine carcinoma (LCNEC), squamous cell carcinoma (SCC), and sarcomatoid carcinoma (PSC) after targeted therapies is recognized as a mechanism of resistance in ADC treatments. Patients with transformed lung cancer typically experience a poor prognosis and short survival time. However, effective treatment options for these patients are currently lacking. Therefore, understanding the mechanisms underlying histological transformation is crucial for the development of effective therapies. Hypotheses including intratumoral heterogeneity, cancer stem cells, and alteration of suppressor genes have been proposed to explain the mechanism of histological transformation. In this review, we provide a comprehensive overview of the known molecular features and signaling pathways of transformed tumors, and summarized potential therapies based on previous findings.

Background and objectives: Androgenetic alopecia is one of the common types of hair loss and has become a medical and social problem due to its increasingly young onset. Existing therapies, although effective, have serious side effects and therefore better treatments need to be sought. The aim of this study was to evaluate the efficacy of umbilical cord mesenchymal stem cell-derived exosomes in the treatment of androgenetic alopecia and to investigate the mechanism of exosome regulation of hair growth.

Methods: First, we randomly divided 20 C57BL/6J mice into blank group, model group, positive control group and exosomal hydrogel group, and mice were treated with hair removal on the back. The mice were injected intraperitoneally with dihydrotestosterone solution except for the blank group. At the end of the experiment, new hairs were collected and the differences in length, diameter and number of hair follicles were compared among the groups; the histopathological changes of hair follicles were observed by HE staining; the expression of androgen receptor mRNA and protein in skin tissues were compared; and the skin tissues were analyzed by real-time PCR, western blotting, immunofluorescence staining and transcriptome sequencing. Finally, the results of transcriptome sequencing experiments were verified by real-time PCR, western blotting and other techniques for the corresponding genes and proteins.

Results: Compared with the blank group, mice in the model group had shorter hair length and reduced hair diameter, and pathological observation showed that the total number of hair follicles was significantly reduced and the hair follicles were miniaturized; compared with the model group, mice in the positive control and exosome groups had longer hair length, larger hair diameter and more hair follicles; the androgen receptor mRNA content and protein expression in the skin tissue of mice in the model group were significantly higher than those in the blank group, and the protein expression in the exosome gel group was lower than that in the model group. Similarly, compared with the model group, the expression of stemness-related proteins K15 and CD200 in the skin tissues of mice in the exosome group increased, and the expression of PCNA, a protein related to cell proliferation, increased. The KEGG data showed that the differential genes were mainly enriched in the RAS/ERK pathway.

Conclusions: In this study, we demonstrated the therapeutic effect of umbilical cord MSC-derived exosomes on androgenetic alopecia and verified that exosomes regulate hair follicle stem cell stemness through the RAS/ERK pathway to promote hair proliferation and thus hair growth in mice with androgenetic alopecia, providing a potential therapeutic strategy for androgenetic alopecia.

Background: Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder associated with a range of cardiovascular and metabolic complications. However, the relationship between GERD and blood pressure components, lipid profile, and cardiovascular diseases remains unclear.

Methods: Leveraging genetic variants associated with GERD as instrumental variables, we performed this Mendelian randomization (MR) analyses. Blood pressure components, lipid profile parameters, as well as cardiovascular diseases were considered as outcomes. Furthermore, we conducted reverse MR analysis to explore the association of these factors with the risk of GERD.

Results: Our MR analysis discovered a potential causal influence of GERD on blood pressure components, with genetically predicted GERD positively associated with systolic blood pressure (β = 0.053, P = 0.036), diastolic blood pressure (β = 0.100, P < 0.001), and mean arterial pressure (β = 0.106, P < 0.001). Additionally, genetically predicted GERD showed a significant impact on lipid profile, leading to increased genetically predicted levels of low-density lipoprotein (LDL) cholesterol (β = 0.093, P < 0.001), and triglycerides (β = 0.153, P < 0.001), while having a negative effect on high-density lipoprotein (HDL) cholesterol (β = -0.115, P = 0.002). Furthermore, our study indicated a noteworthy causal association between genetically predicted GERD and increased risk of myocardial infarction [odds ratio (OR) = 1.272, P = 0.019)] and hypertension (OR = 1.357, P < 0.001). No significant association was found between GERD and pulse pressure, total cholesterol, heart failure, and atrial fibrillation (P > 0.05). Reverse MR analysis indicates that blood pressure components, lipid profile, and cardiovascular diseases do not lead to an increased risk of GERD (all P > 0.05). Furthermore, mediation MR analysis reveals that LDL cholesterol (proportion mediated: 19.99%, 95% CI: 4.49% to 35.50%), HDL cholesterol (proportion mediated: 11.71%, 95% CI: 5.23% to 18.19%), and hypertension (proportion mediated: 35.09%, 95% CI: 24.66% to 45.53%) mediated the effect of GERD on myocardial infarction, while other factors did not participate in this pathway.

Conclusions: This MR study provides evidence supporting a causal relationship between GERD and alterations in blood pressure components, lipid profile, and increased risk of cardiovascular diseases.

Objective: We aimed to investigate the pharmacokinetics, safety, efficacy, and immunogenicity of different dosing regimens (weekly and every three weeks) of inetetamab in combination with vinorelbine in human epidermal growth factor receptor 2 (HER2)+ patients with metastatic breast cancer who had received one or more chemotherapy regimens.

Methods: HER2+ patients with metastatic breast cancer who had received one or more chemotherapy regimens were included. Eligible patients received inetetamab administered weekly or every three weeks in combination with vinorelbine injection chemotherapy. Pharmacokinetics, safety, efficacy, and immunogenicity were compared between the groups.

Results: Sixty HER2+ patients were randomized into a single-week administration group ( n = 29) and a three-week administration group ( n = 31). After the final dose in the single-week administration group and the three-week administration group, the mean C_max values were 79.773 μg/mL and 146.083 μg/mL; the mean C_min values were 30.227 μg/mL and 11.926 μg/mL; the mean AUC_tau values were 7328.443 μg·h/mL and 22647.101 μg·h/mL; and the mean C_av values were 43.622 μg/ mL and 44.935 μg/mL, respectively. The best overall response (BOR) rates at 24 weeks and unconfirmed BOR rates at 24 weeks were both 40.7% in the single-week dosing group and 40.7% in the three-week dosing group, and the 24-week confirmed disease control rates (DCRs) were 88.9% and 81.5%, respectively. The incidence of adverse events (AEs) was generally consistent across all levels.

Conclusion: There were slight differences in the mean C_max, C_min, AUC_tau and C_av between the three-week dosing group and the single-week dosing group, and the mean steady-state concentrations of C_av were comparable; however, there were no differences in efficacy, safety or immunogenicity between the two groups.

Background and objectives: Actin-related protein 2/3 complex subunit 1B (ARPC1B) is an essential subunit of the actin-related protein 2/3 (Arp2/3) complex. While there have been numerous research reports on Arp2/3 in relation to tumors, there needs to be more research on ARPC1B and its role in tumors, particularly at the pan-cancer level.

Methods: Utilizing data from the cancer genome atlas (TCGA) and genotype-tissue expression (GTEx) databases, we analyzed ARPC1B expression differences in normal, tumor, and adjacent tissues, investigating its correlation with prognosis and clinical stages in various cancers. We conducted gene enrichment analysis and explored ARPC1B's connection to the tumor immune microenvironment and its impact on anti-tumor drug resistance. In addition, in vivo and in vitro experiments have also been carried out to find the mechanism of ARPC1B on ovarian cancer (OV) proliferation and invasion.

Results: ARPC1B was highly expressed in 33 tumor types, suggesting its role as a tumor-promoting factor. Its expression correlated with poor prognosis and served as a clinical staging marker in over 10 tumor types. ARPC1B is implicated in various biological processes and signaling pathways, uniquely associated with tumor immunity, indicating immunosuppressive conditions in high-expression cases. High ARPC1B expression was linked to resistance to six anti-tumor drugs. Further experiments showed that ARPC1B can affect the proliferation, apoptosis, migration, and invasion of OV cells through the AKT/PI3K/mTOR pathway.

Conclusion: ARPC1B is a biomarker for immune suppression, prognosis, clinical staging, and drug resistance, providing new insights for cancer therapeutics.

Background: Renal inflammation plays key roles in the pathogenesis of diabetic kidney disease (DKD). Immune cell infiltration is the main pathological feature in the progression of DKD. Sodium glucose cotransporter 2 inhibitor (SGLT2i) were reported to have antiinflammatory effects on DKD. While the heterogeneity and molecular basis of the pathogenesis and treatment with SGLT2i in DKD remains poorly understood.

Methods: To address this question, we performed a single-cell transcriptomics data analysis and cell cross-talk analysis based on the database (GSE181382). The single-cell transcriptome analysis findings were validated using multiplex immunostaining.

Results: A total of 58760 cells are categorized into 25 distinct cell types. A subset of macrophages with anti-inflammatory potential was identified. We found that Ccl3+ (S100a8/a9 high) macrophages with anti-inflammatory and antimicrobial in the pathogenesis of DKD decreased and reversed the dapagliflozin treatment. Besides, dapagliflozin treatment enhanced the accumulation of Pck1+ macrophage, characterized by gluconeogenesis signaling pathway. Cell-cross talk analysis showed the GRN/SORT1 pair and CD74 related signaling pathways were enriched in the interactions between tubular epithelial cells and immune cells.

Conclusions: Our study depicts the heterogeneity of macrophages and clarifies a new possible explanation of dapagliflozin treatment, showing the metabolism shifts toward gluconeogenesis in macrophages, fueling the anti-inflammatory function of M2 macrophages, highlighting the new molecular features and signaling pathways and potential therapeutic targets, which has provided an important reference for the study of immune-related mechanisms in the progression of the disease.