Current Molecular Medicine - Online First

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.

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

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.

Higher urinary C3 levels could be used to predict kidney damage in preeclampsia, and inhibition of C3 activity might ameliorate the renal impairment in preeclampsia through activation of Nrf2/HO-1 pathway.

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.

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.

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.

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.

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.

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.

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.

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.

Keloid formation is characterized by excessive production of extracellular matrix, leading to dysregulated fibroproliferative collagen response. N6-methyl-adenosine (m6A) modification plays an essential role in this process.

Our objective in this study was to explore the mechanism of m6A methyltransferase KIAA1429 in keloid formation.

We examined the impact of m6A methyltransferase KIAA1429 on keloid formation using qRT-PCR, Western blot, immunofluorescence, Transwell migration assay, and MeRIP-qPCR.

KIAA1429 was downregulated in keloid tissue. Overexpression of KIAA1429 suppressed fibroblast migration and reduced COL1A1 and α-SMA levels. Conversely, the knockdown of KIAA1429 promoted fibroblast migration and COL1A1 and α-SMA levels. Additionally, overexpression of KIAA1429 inhibited the TGF-β1/Smad pathway. Mechanistic experiments suggested that KIAA1429 regulated TGF-β1 m6A modification, maintained TGF-β1 mRNA stability, and participated in the regulation of keloid formation. Furthermore, TGF-β1 could reverse the effects of KIAA1429 overexpression on fibroblast migration and collagen deposition.

Taken together, our study suggested that KIAA1429 promoted keloid formation through the TGF-β1/Smad pathway, providing new insights for the treatment of keloid.

Endometriosis (EM) is a gynecological disease characterized by the benign growth of endometrial tissue outside the uterus. Upregulation of neuronally expressed developmentally downregulated 4 (NEDD4) has been reported to accelerate endometrial cancer progression.

We explored whether abnormal expression of NEDD4 is correlated with EM.

Endometrial tissue in patients without endometriosis was used to develop the original generation of endometrial stromal cells (ESCs). Different types of endometrial tissue of patients with endometriosis were used to measure the expression of NEDD4 by immunohistochemistry (IHC) and western blotting. Its biological functions in ESCs were investigated using a cell counting kit-8 assay, fluorescein diacetate (FDA) staining, and Transwell invasion assays. Additionally, its involvement in ferroptosis was assessed by measuring Fe2+, malondialdehyde (MDA), glutathione (GSH), and reactive oxygen species (ROS) levels and the expression of ferroptosis markers.

Compared with normal controls, NEDD4 levels were significantly elevated in the endometrial tissue of patients with EM. Furthermore, NEDD4 expression was higher in the ectopic endometrium than in the eutopic endometrium. NEDD4 knockdown reduced the viability and invasive capacity of ESCs, increased Fe2+, MDA, and ROS levels, and decreased GSH content. Further analysis revealed that NEDD4 knockdown promoted ferroptosis in ESCs by increasing the expression of prostaglandin-endoperoxide synthase 2 (PTGS2). As an E3 ubiquitin ligase, NEDD4 reduced PTGS2 protein levels by accelerating its ubiquitination and subsequent proteasomal degradation.

These findings suggest that inhibiting NEDD4 reduces ESC growth and invasion in EM by regulating PTGS2-dependent ferroptosis.

Currently, Medullary Thyroid Carcinoma (MTC) is considered a kind of rare neuroendocrine tumor, and molecular-targeted drugs have previously been used for MTC treatment.

However, the prognosis of MTC patients is still not significant. In the present work, we aimed to explore the antitumor activity of the molecularly targeted drug anlotinib in combination with radiofrequency ablation on MTC.

The targets of anlotinib were clearly expressed in MTC tissue specimens, and the expression level of these factors was much higher in MTC clinical specimens than in nontumor tissues. At the same time, anlotinib or Radiofrequency Ablation (RFA) showed clear antitumor activity against the MTC cell line TT (TT cells) and the tumor tissue it formed. Anlotinib, in combination with RFA, significantly increased the antitumor activity of RFA.

These results indicated that the combination of anlotinib with radiofrequency ablation could be a promising therapeutic strategy for MTC treatment.

High morbidity, high mortality and poor prognosis of esophageal squamous cell carcinoma (ESCC) highlights the urgent need for novel therapeutic strategies against ESCC. The current study addresses the precise role of M2-like macrophages-derived CCL17 in ESCC progression and to thoroughly elucidate the intrinsic molecular mechanisms.

In this work, for functional experiments, Eca109 cells cultivated in M2-CM were treated with anti-IgG (50 µg/ml) or anti-CCL17 (50 µg/ml) to expound the tumor-promoting effects of M2-like macrophage-derived CCL17 in ESCC. Moreover, for rescue experiments, Eca109 cells were treated with CCL17 (50 ng/ml) and/or CCR4 antagonist AZD2098 (20 µM) to probe whether CCL17 could influence the malignant behaviors including migration, invasion and stemness of ESCC cells via activating CCR4/ERK/PD-L1 pathway.

Markedly enhanced CCL17 secretion was observed in M2-like macrophages. CCL17 bound to CCR4 to activate ERK/PD-L1 signaling. M2-like macrophages-derived CCL17 facilitated ESCC cell migration and invasion and enhanced stemness characteristics of ESCC cells, which were partially reserved by AZD2098 treatment. The tumor-promoting effects of M2-like macrophages-derived CCL17 on ECSS was depended on the activation of CCR4/ERK/PD-L1 pathway.

To conclude, M2-like macrophages-derived CCL17 could facilitate ESCC cell migration and invasion and enhance stemness characteristics of ESCC cells via activating CCR4/ERK/PD-L1 signaling.