Current Molecular Medicine - Volume 25, Issue 7, 2025

Several studies have indicated an association between cadmium (Cd) exposure and the induction of thyroid dysfunction in animal models.

There are inconsistent findings on the effect of Cd on the thyroid gland. Therefore, this systematic study was designed to determine the association between changes in thyroid function markers and Cd exposure in animals.

The search was performed on Scopus, PubMed, Web of Science and databases, and Google Scholar until May 2023. Studies on the relationship between Cd exposure and fish's thyroid function were conducted on rodents and fish.

In total, 171 articles were obtained from the main databases using the search strategy mentioned in this study. Finally, 24 articles were selected according to our inclusion criteria for systematic studies. The findings indicated an increase/decrease or no change in triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) levels in rodents, fish, and animals exposed to Cd.

Our findings indicated an association between Cd exposure and thyroid dysfunction in rodents, fish, and other animals. However, the association between urinary and blood Cd levels and thyroid function remains unclear in humans because of controversial findings and a lack of strong mechanistic evidence. We perform large cohort human studies to the answer to this question.

Ferroptosis of keratinocytes is closely associated with amplification of skin inflammation in psoriasis. This study focuses on unlocking the role of caffeic acid (CA), a polyphenol compound, in keratinocyte ferroptosis and understanding the underlying mechanistic basis.

The interaction between early growth response protein 1 (EGR1) and chac glutathione specific γ-glutamylcyclotransferase 1 (CHAC1) was predicted by bioinformatics and validated via chromatin immunoprecipitation and dual-luciferase reported assays. Their expressions in primary human epidermal keratinocytes were altered by transfection of EGR1/CHAC1 overexpression or knockdown plasmids, and then keratinocytes were followed by CA treatment and Erastin (ferroptosis inducer). Keratinocyte viability was determined by CCK-8 assay, and the ferroptotic effect was evaluated using colorimetric assay and flow cytometry. Proinflammatory cytokine secretion by keratinocytes was detected via ELISA. Expressions of EGR1 and CHAC1 in keratinocytes were analyzed by qRT-PCR or Western blot.

Increased expressions of EGR1 and CHAC1 were detected in keratinocytes with Erastin treatment. CA (100 μM) antagonized Erastin (10 µM)-induced decrease in viability, increases in EGR1 and CHAC1 expressions, upregulation of MDA, ROS, and Fe²⁺, downregulation of GSH and SOD, and secretion of proinflammatory cytokines from keratinocytes. EGR1 overexpression potentiated Erastin-induced effects. Moreover, EGR1 overexpression and CA mutually counteracted their effects on Erastin-induced keratinocytes. EGR1 transcriptionally activated and positively regulated CHAC1. The above Erastin-induced effects were neutralized by EGR1 knockdown but potentiated by CHAC1 overexpression. Moreover, EGR1 knockdown and CHAC1 overexpression reversed each other's effects.

CA reduces ferroptosis by inhibiting EGR1-induced activation of CHAC1 to dampen inflammation of keratinocytes in psoriasis. This study providing new compounds and candidate targets for the clinical treatment of psoriasis.

Podocyte injury is the most important pathological hallmark of kidney diseases. Autophagy is a critical factor that involves podocyte injury. Here, we sought to determine whether Astragaloside IV (AS-IV) was able to improve renal function and reverse podocyte injury through the regulation of autophagy.

Using the Adriamycin (ADR) mice model, cultured immortalized mouse podocytes were exposed to AS-IV. Western blotting, immunofluorescence, and histochemistry were used to analyze markers of autophagy, mitochondrial dysfunction, podocyte apoptosis, and glomerulopathy in the progression of focal segmental glomerular sclerosis.

We observed that AS-IV can inhibit podocyte apoptosis, increased reactive oxygen species (ROS) generation, mitochondrial fragmentation, and dysfunction by inducing the Mfn2/Pink1/Parkin mitophagy pathway both in vivo and in vitro. Over-expression of Mfn2 reduced puromycin aminonucleoside (PAN)-induced podocyte injury, while downregulation of Mfn2 expression limited the renal protective effect of AS-IV by regulating mitophagy.

AS-IV ameliorates renal function and renal pathological changes in ADR mice and inhibits PAN-induced podocyte injury by directly enhancing Mfn2/Pink1/Parkin-associated autophagy.

Restructuring of dermal microcapillaries is one of the hallmarks of plaque psoriasis. To control the proliferation of vascular endothelial cells, vascular endothelial growth factor (VEGF) promotes the remodeling of the existing blood vessels and angiogenesis.

This study aimed to explain the lowering protein and mRNA levels of VEGF in lesional skin of patients with severe psoriasis (the Psoriasis Area and Severity Index, PASI > 25).

Using the method of qPCR, we assessed the expression of VEGF mRNA in lesional and nonlesional psoriatic skin. Using ELISA, we also compared the levels of VEGF in skin homogenates of psoriasis patients and healthy volunteers.

We found that the exacerbation of psoriasis induced VEGF on mRNA and protein levels 12 and 20 times, respectively. We also confirmed a strong correlation between VEGF and PASI score in patients with PASI < 25. In addition, we showed that several factors, namely HGF, HNRPD, and sFLT1 interfere with the biosynthesis of VEGF in skin lesions of patients with PASI > 25%.

Thus, using VEGF as a biomarker to monitor the disease shall be done cautiously in patients with severe psoriasis.

Increased expression of MRP 1 in AML patients results in the efflux of drugs from the cells, preventing the patient from achieving remission or potentially leading to relapse. Several studies have demonstrated that early identification of ABC transporter may yield favorable outcomes.

The objectives of the study were to investigate the correlation between MRP 1 gene expression and MRP 1 protein levels and the response to remission induction in AML patients.

A total of 40 AML patients were recruited from March 2021 to June 2022. Peripheral blood was collected in two tubes (yellow and purple top) to assess the MRP 1 gene and protein. For MRP 1 gene assessment, RNA was isolated from blood samples, cDNA was prepared, and qRT-PCR was performed to analyze gene expression. The relationship between the gene and complete remission was determined. Identification of MRP 1 protein was conducted using ELISA, and the relationship between protein levels and complete remission (CR) was explored.

Most of the patients were aged between 25 and 39 years, encompassing both males and females. This study observed a clinical correlation between MRP 1 gene expression and complete remission. The findings revealed that 69.2 percent of patients with high gene expression failed to achieve complete remission, whereas the analysis of MRP 1 protein in relation to complete remission showed no statistical significance. The MRP1 gene showed high expression (66.7%) in patients with FLT3 mutation, whereas low expression of MRP1 was associated with a high occurrence (60%) of NMP1 mutation.

Further comprehensive multicenter studies with larger sample sizes are required to validate the findings of this study. It is recommended to pinpoint the mechanism and regulation of MRP 1 and its interaction with other molecular pathways.

Osteosarcoma (OS) is a common malignancy among adolescents and children, characterized by a high propensity for metastasis and resistance to chemotherapy.

This study aimed to investigate the role of COL12A1, a gene often overexpressed in various cancers and associated with poor prognosis, in the progression of OS and explore the underlying mechanisms.

The expression pattern and potential function of COL12A1 in OS were evaluated using bioinformatics analyses, clinical sample examination, and OS cell lines. Various assays, including transwell, CCK-8, flow cytometry, and wound healing, were performed to assess the impact of COL12A1 on OS cell growth, cell cycle progression, apoptosis, invasion, and migration. Western blot analysis was conducted to investigate markers associated with the FAK/PI3K/AKT/mTOR pathway.

COL12A1 expression was significantly elevated in OS tissues and cells. Upregulation of COL12A1 promoted cell growth, accelerated cell cycle progression, and enhanced migration and invasion while inhibiting apoptosis. Conversely, the knockdown of COL12A1 had the opposite effect. Additionally, COL12A1 over-expression increased the phosphorylation of components in the FAK/PI3K/AKT/mTOR pathway. The FAK inhibitor Y15 mitigated the effects of COL12A1 overexpression on cell apoptosis, invasion, proliferation, and the FAK/PI3K/AKT/mTOR pathway in OS.

Our findings indicated that COL12A1 enhanced OS development by activating the FAK/PI3K/AKT/mTOR pathway, suggesting that COL12A1 could serve as a valuable biomarker for the prediction and identification of OS patients.

To clarify the roles of PAR-2 (protease-activated receptor 2) in Crohn's disease-associated colonic fibrosis.

G protein-coupled receptor, termed PAR-2, is triggered after serine proteases. Through activating genes encoding extracellular matrix proteins and proinflammatory cytokines, PAR-2 triggering promotes inflammatory / pro-fibrotic pathways. Although PAR-2 is highly expressed within the digestive system, its significance within colonic fibrosis (CF) has not yet been probed.

To assess the roles and mechanisms of PAR-2 in Crohn's disease-associated colonic fibrosis.

PAR-2 expression was assessed variably in the colon of human and model mice. Immunofluorescence assay was used to analyze the phenotypic changes of fibroblasts after PAR-2 activation in the lamina propria. In in vitro assays, we explored the roles of PAR-2 in CCD-18Co fibroblasts treated with PAR-2 inhibitor ENMD-1068 and PAR-2 agonist SLIGRL-NH2.

PAR-2 was highly expressed in the subepithelial layer surrounding colonic crypts of CD patients or murine fibrosis cohort. Colonic PAR-2 expression was consistent with collagen deposition. Decreasing PAR-2 in experimental colon fibrosis caused a decrease in the amount of colonic collagen and histological fibrosis, followed by a reduction in colonic fibroblast activation. PAR-2 activation enhanced CF by showing a profibrogenic phenotype and collagen synthesis within CCD-18Co fibroblasts.

Our results show that PAR-2 activation could upregulate extracellular matrix (ECM) proteomic levels, encourage CF, and cause a pro-fibrogenic phenotype within human colonic myofibroblasts.

Primary Aldosteronism (PA) is the most common cause of secondary hypertension. Immunohistochemical analysis of PA is based on specific monoclonal antibodies targeting CYP11B1 and CYP11B2, which are enzymes responsible for the aldosterone production in the adrenal cortex. The recently proposed HISTALDO classification introduced CYP11B2 immunohistochemistry to define clinically relevant diagnostic categories. We aimed to investigate the relationship between clinical characteristics and immunohistochemistry of CYP11B2 in PA and also evaluate staining in cortisol-producing cells by comparing patients with Cushing’s Syndrome (CS). Consecutive patients diagnosed with PA (n=21) and CS (n=20) were included between 2015-2022. All of them underwent unilateral adrenalectomy in our tertiary center.

Following hematoxylin and eosin (H&E) staining of the pathological specimens, all slides were re-evaluated and immunostained for CYP11B2. A semiquantitative H-score was assessed for each patient and compared with staining intensity. Patients with PA were grouped and classified according to the HISTALDO classification.

The mean size of adenoma in patients with PA was much smaller compared to patients with CS (p=0.001). An increase in the immunohistochemical H-score of the patients with PA (121.36 ±81.04 vs 73.94±57.70, p=0.045) was observed in comparison to the patients with CS. When comparing the patients with PA according to HISTALDO criteria, the H-score of the patients with Aldosterone Producing Adenoma (APA, n=10) was 136.6±78.86 compared to the non-APA group, which was 86.81±85.3 (n=11, p=0.05). Moreover, mean preoperative aldosterone levels (p=0.06) and aldosterone-to-renin ratio (ARR, p=0.03) were higher in patients with APA compared to non-APA patients. Response to surgical therapy was more favorable in patients with APA than the patients with non-APA.

CYP11B2 is a key enzyme responsible for the synthesis of aldosterone. CYP11B2 expression, as assessed by immunostaining, was associated with the clinical characteristics, severity of PA, and response to the treatment. Hence, immunohistochemical analysis of CYP11B2 should be incorporated into the routine clinical workup to better localize aldosterone-producing cells.