Current molecular medicine最新文献

Background: Ovarian cancer is one of the deadliest gynecologic cancers, with chemotherapy resistance as the greatest clinical challenge. Autophagy occurrence is associated with cisplatin (DDP)-resistant ovarian cancer cells. Herein, the role and mechanism of alpha-synuclein (SNCA), the autophagy-related gene, in DDP resistance of ovarian cancer cells are explored.

Methods: Differentially expressed genes in DDP resistance of ovarian cancer cells were analyzed by GEO2R tools. DDP-resistant ovarian cancer cells (A2780/DDP) were transfected and treated with 2.5 μg/mL DDP for 72 h, followed by the determination of cell viability, proliferation, apoptosis, and expressions of SNCA, lysine demethylase 4A (KDM4A), histone H3 lysine 9 trimethylation (H3K9me3), and mitophagy-related proteins. The H3K9me3 demethylation of SNCA by KDM4A was confirmed by chromatin immunoprecipitation.

Results: SNCA and KDM4A were highly expressed in DDP-resistant ovarian cancer cells and their parental cells. KDM4A knockdown diminished expressions of KDM4A and SNCA and elevated H3K9me3 expression and H3K9me3 enrichment on SNCA promoter in A2780/DDP cells. SNCA or KDM4A knockdown inhibited cell viability, proliferation, and levels of LC3-II/LC3-I and Parkin while inducing cell apoptosis and upregulating Cyt-C expression of A2780/DDP cells with/without DDP treatment; however, SNCA overexpression not only did conversely but also reversed the effects of KDM4A knockdown on DDP-treated A2780/DDP cells and vice versa.

Conclusion: Silencing of KDM4A-mediated transcription inactivation of SNCA reduces mitophagy, thus inhibiting the resistance of ovarian cancer cells to cisplatin. KDM4A may be a promising drug target for DDP-resistant ovarian cancer cells.

Cancer stem cells (CSCs) are the key drivers of tumorigenesis and relapse. A growing body of evidence reveals the tremendous power of CSCs to directly resist innate and adaptive anti-tumor immune responses. The immunomodulatory property gives CSCs the ability to control the tumor immune microenvironment (TIME). CSCs hijack the anti-tumor capacity of immune cells to provide self-protection from immune attack and enhance the pro-tumor immune cell infiltration and activity. To date, cancer immunotherapy strategies have largely been designed without taking into account the immunosuppressive properties of CSCs. As a result, the clinical efficacy of cancer immunotherapy is altered, perpetuating tumor progression and relapse. Therefore, targeting the signals underlying CSC immune evasion is essential to improve immunotherapy efficacy and reduce tumor relapse. The aim of this mini-view is to comprehensively summarize the key immune escape mechanisms adopted by CSCs. This will provide necessary clues for the development of more effective cancer immunotherapy strategies.

Most chronic respiratory diseases often lead to the clinical manifestation of pulmonary fibrosis. Inflammation and immune disorders are widely recognized as primary contributors to the onset of pulmonary fibrosis. Given that macrophages are predominantly responsible for inflammation and immune disorders, in this review, we first focused on the role of different subpopulations of macrophages in the lung and discussed the crosstalk between macrophages and other immune cells, such as neutrophils, regulatory T cells, NKT cells, and B lymphocytes during pulmonary fibrogenesis. Subsequently, we analyzed the interaction between macrophages and fibroblasts as a possible new research direction. Finally, we proposed that exosomes, which function as a means of communication between macrophages and target cells to maintain cellular homeostasis, are a strategy for targeting lung drugs in the future. By comprehending the mechanisms underlying the interplay between macrophages and other lung cells, we aim to enhance our understanding of pulmonary fibrosis, leading to improved diagnostics, preventative measures, and the potential development of macrophage-based therapeutics.

Aim: The activation of the complement system is accompanied by the occurrence and development of preeclampsia, as well as kidney diseases. Here, the role of complement C3 [C3] in renal injury in preeclampsia was explored, and its potential application as an early diagnostic biomarker or drug target to ameliorate kidney injury induced by preeclampsia was preliminarily evaluated.

Method: A total of 48 subjects were included in the present study, and the complement C3 levels and renal function were analyzed.

Results: Patients with preeclampsia with severe features [sPe] had poorer renal function compared with the patients with preeclampsia. Urinary C3 levels could be used to distinguish between healthy controls, patients with preeclampsia, and patients with sPe. Increased renal inflammation and oxidative stress were notably increased in the preeclampsia mice with impaired renal function and attenuation of C3 activity using a C3 receptor antagonist, which reduced Pe-like symptoms and renal impairment, decreased serum blood urea nitrogen, creatinine, and urinary albumin levels, and decreased expression of the oxidative stress marker malondialdehyde, whilst increasing superoxide dismutase activity. In addition, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 ([HO-1) pathway was involved in the inhibition of complement C3 in the kidney.

Conclusion: Higher urinary C3 levels could be used to predict kidney damage as it was found that the activation of the Nrf2/HO-1 pathway attenuated C3 levels, and this resulted in increased renal impairment in preeclampsia.

Background: The anticancer activity and radiosensitizing effect of Auranofin, an an-tirheumatic and an approved gold metallic drug, have been investigated from multiple perspectives. In this study, the action of the new gold complex compound TPN-Au(I)-MM4 was compared with that of auranofin.

Methods: The inhibitory effect of 10 μM and 50 μM concentrations on cell proliferation was investigated using the human colon cancer cell lines HCT116 and SW480. The radiosensitizing effect of HCT116 cells was evaluated by measuring the ability to induce apoptotic cell death. The mechanism of action was qualitatively determined via western blotting analysis of the level of cleaved caspase-3 protein.

Results: Auranofin completely inhibited cell proliferation in both cell lines at both concentrations. In contrast, only 50 μM of TPN-Au(I)-MM4 significantly inhibited the proliferation of SW480 cells, but did not affect the proliferation of HCT116 cells. On the other hand, both compounds effectively increased the apoptotic cell death rate when combined with 4 Gy of X-ray irradiation. This mechanism was caused by a significant increase in the level of caspase-3, which is an apoptosis execution factor, by the combination of these two treatments.

Conclusion: Both compounds promoted the significant expression of caspase-3, an apoptosis execution factor, and exhibited radio-sensitizing effects. In particular, TPNAu( I)-MM4 showed no inhibitory effect on cell proliferation alone, but had a significant radiosensitising effect on HCT116 cells. Therefore, TPN-Au(I)-MM4 has the potential for use as a new radiosensitizer.

Long non-coding RNAs (lncRNAs) play vital roles in the development and progression of various tumors through multiple mechanisms. Among these, HOTTIP (HOXA transcript at the distal tip) stands out as an intriguing candidate with diverse functions in several malignancies, including breast cancer and gynecologic cancers such as ovarian, cervical, and endometrial cancers, which are significant global health concerns. HOTTIP interacts with key signaling pathways associated with these cancers, including Wnt/β-catenin, PI3K/AKT, and MEK/ERK pathways, enhancing their activation and downstream effects. Its influence extends to crucial aspects of cancer biology, such as cell proliferation, apoptosis, migration, invasion, angiogenesis, and epithelial-mesenchymal transition (EMT). Additionally, HOTTIP plays a pivotal role in the pathogenesis of breast and gynecologic tumors by sponging various microRNAs (miRNAs) and regulating the expression of mRNAs involved in critical molecular processes. This dysregulation is often associated with poor clinical outcomes, advanced disease stages, and distant metastases. Understanding the functional roles of HOTTIP in these cancers is essential for developing targeted therapeutic strategies. This review aims to explore the emerging roles of HOTTIP in breast and gynecologic cancers.

Purpose: This study aims to investigate the unique proteins in exosomes from mesenchymal stem cells derived from psoriatic lesions and compare them with those from healthy human skin. It seeks to identify potential regulatory factors that may influence the differential effects observed in these exosomes.

Methods: Dermal mesenchymal stem cell exosomes were isolated from healthy human skin (HDMSCs-EXO) and psoriatic lesion of patient (PDMSCs-EXO). The extracted exosomes were analyzed through label-free quantitative proteomics to identify differential proteins. Bioinformatics analyses, including GO and KEGG enrichment, were conducted.

Results: The comparative analysis using HDMSCs-EXO as a control group revealed 13 differential proteins. Notably, proteins such as B2R4D5, MFGE8, and MFAP5 are associated with the inflammatory mechanisms of psoriasis.

Conclusion: The study identifies several differentially expressed proteins in exosomes may play roles in the development of psoriasis. These finding offer valuable insights for further exploration of the inflammatory processes in psoriasis.

Ovarian cancer (OC) is a gynecologic disease characterized by the uncontrolled growth and proliferation of abnormal cells in the ovaries, fallopian tubes, or peritoneum. Emerging evidence has shown the pivotal role of non-coding RNAs (ncRNAs), such as miRNAs, in driving the pathogenesis of OC. miRNAs are recognized as small ncRNAs that play critical roles in regulating gene expression in normal development and in disease states, including OC. Among miRNAs, the expression of miR-34a was found to be downregulated in OC. Elevated levels of this miRNA are associated with the induction of apoptosis and the inhibition of OC cell proliferation by targeting various signaling pathways, including NOTCH1, P21/P53, STAT3, and BCL2 in OC. Therefore, miR-34a can be a therapeutic target in the management of OC. In this review, we summarized the functional significance of this miRNA in the treatment of OC.

Background: Gastric cancer is a major global cause of cancer-related deaths, necessitating investigation into Matrix Metalloproteinases' (MMPs) diagnostic and prognostic value. Our study aimed to analyze their significance in gastric cancer.

Methods: We evaluated MMP family genes' mRNA and protein expression using the University of Alabama at Birmingham (UALCAN) and Human Protein Atlas (HPA) databases. Then, we analyzed the relationship between their mRNA expression and gastric cancer staging and survival using Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier plotter. Furthermore, we assessed this family's gene mutation rates in gastric cancer patients using Search Tool for the Retrieval of Interaction Genes/Proteins (STRING) and explored potential pathways and mechanisms via Database for Annotation, Visualization, and Integrated Discovery (DAVID), cBioPortal, and R. Finally, we established a predictive model for gastric cancer based on these analyses to understand these genes' roles in cancer.

Results: Our findings revealed significantly upregulated mRNA expression of MMP1/2/3/7/9/10/11/12/13/14 in gastric cancer tissues (p<0.05). Higher levels of MMP2/7/10-encoded proteins (middle or high) were observed in tumor tissues, with MMP2/11/14 closely associated with different cancer stages (p<0.05). Additionally, MMP2/7/11/14/20 mRNA levels correlated with short-term overall survival (about 20 months), while MMP1/3/9/12/13 expression was associated with favorable overall survival (about 30 months). Gastric cancer patients exhibited a 21% mutation rate of MMP family genes, which correlated with favorable overall survival. Enrichment analysis and protein-protein interaction results underscored the close association of MMPs with gastric cancer development. The MMP2 model demonstrated a significant decline in survival rates for the high expression group, with a Hazard Ratio (HR) of 1.78 (95% CI 1.47-2.16) and a log-rank P value of 2.9e-09. Statistical significance was set at p < 0.05. Univariate Cox regression identified MMP2 as a risk factor for gastric cancer patients.

Conclusion: Our findings highlighted MMPs' essential role in gastric cancer progression, impacting patient survival. MMP2 emerged as a promising target for gastric carcinoma detection and treatment.

Objective: Nonalcoholic fatty liver disease (NAFLD) is a prevalent liver condition worldwide, and the statistics show that men have a higher incidence and prevalence than women, but its toxicological mechanism is not completely clear. This research is intended to explore the role of BaP in NAFLD and to study how the environmental pollutant BaP influences the AHR/ERα axis to mediate the progression of NAFLD.

Methods: In this study, we established NAFLD models in vivo and in vitro by treating HepG2 cells with a high-fat diet and Oleic acid (OA) in C57BL/6J mice. Liver injury indexes ALT, AST, and lipid metabolism indexes TG and TC were evaluated to verify the success of modeling. Then, the model was treated with BaP, and the mRNA and protein expressions of CYP1A1, ERα, and SREBP-1c were evaluated by RT-PCR and WB, and the changes of liver fat were evaluated by HE and oil red O staining. Next, BaP was added into the cells treated with or without estradiol (E2), and the lipid metabolism in the cells was evaluated by oil red O staining, and whether the above levels of CYP1A1, ERα and SREBP-1c were changed.

Results: Our results show that after exposure to BaP, ERα protein levels in mice and cells are inhibited, mRNA and protein levels of SREBP-1c are reduced, and lipid metabolism processes are obstructed. The addition of E2 can reduce the increase of SREBP-1c mRNA and protein expression induced by OA, and reduce the deposition of lipids in cells. However, BaP treatment can weaken the action of E2 and destroy the protection of E2 in cells.

Conclusion: The results showed that E2 could reduce SREBP-1c mRNA and protein levels. BaP can stimulate AHR, leading to the degradation of ERα protein, reducing the binding of E2 to ERα, and aggravating the progression of NAFLD. This reveals the toxicological mechanism by which environmental pollutant BaP influences E2 to mediate NAFLD, and provides strong evidence for differences in NAFLD between the sexes.