Original Article (Clinical Toxicology)


The Main Targets of Okadaic Acid Toxin in Human Intestinal Caco-2 Cells: An Investigation of Biological Systems

Reza M Robati, Zahra Razzaghi, Babak Arjmand, Mostafa Rezaei Tavirani, Mohammad Rostami Nejad, Mitra Rezaei, Mona Zamanian Azodi

International Journal of Medical Toxicology and Forensic Medicine, Vol. 13 No. 4 (2023), 14 Azar 2023,
https://doi.org/10.32598/ijmtfm.v13i4.42997

Background: Okadaic acid (OA) is a toxin of polluted shellfish. Consuming the contaminated shellfish is accompanied by diarrhea and paralytic and amnesic disorders. There is a correlation between diarrhea and the consumed OA. Determining the critical targeted genes by OA was the aim of this study.
Methods: The transcriptomic data about the effect of OA on human intestinal caco-2 cells were extracted from gene expression omnibus (GEO) and evaluated via the GEO2R program. The significant differentially expressed genes (DEGs) were included in a protein-protein interaction (PPI) network and the central nodes were enriched via gene ontology to find the crucial affected biological terms.
Results: Among the 178 significant DEGs plus 50 added first neighbors, four hub-bottleneck genes (ALB, FOS, JUN, and MYC) were determined. Twenty-eight critical biological terms were identified as the dysregulated individuals in response to the presence of OA. “ERK1/2-activator protein-1 (AP-1) complex binds KDM6B promoter” was highlighted as the major class of biological terms.
Conclusion: It can be concluded that down-regulation of ALB as a potent central gene leads to impairment of blood homeostasis in the presence of OA. Up-regulation of the other three central genes (JUN, FOS, and MYC) grossly affects the vital pathways in the human body.

The Potential Anti-inflammatory Effect of Spirulina Platensis on an in Vitro Model of Celiac Disease

Somayeh Jahani-Sherafat, Samira Alipour, Ensiyeh Olamafar, Mahtab Jahdkaran, Mona Zamanian Azodi, Mahmood Khodadoost, Mohammad Rostami-Nejad

International Journal of Medical Toxicology and Forensic Medicine, Vol. 13 No. 4 (2023), 14 Azar 2023,
https://doi.org/10.32598/ijmtfm.v13i4.42998

Background: Celiac disease (CD) is a prevalent autoimmune enteropathy triggered by the ingestion of gluten. The management of CD involves adhering to a gluten-free diet (GFD). Recent studies have been actively exploring potential supplementary or alternative therapies for individuals with CD. The primary objective of the present study was to assess the effectiveness of Spirulina platensis in regulating the intestinal barrier-related gene expression and alleviating inflammation and oxidative stress associated with CD in PT-gliadin-triggered Caco-2 cells.
Methods: S. platensis extracts and a pepsin/trypsin (PT) digest of gliadin were prepared and exposed to the human colon carcinoma Caco-2 cell line. Cell viability was assessed. Total RNA was extracted from Caco-2 cells and cDNA synthesis was performed. A quantitative real-time polymerase chain reaction (qRT-PCR) assay was conducted to evaluate the mRNA levels of interleukin (IL)-6, transforming growth factor beta (TGF-β), COX-2, nuclear factor kappa B (NF-κB), ZO-1, and occludin.
Results: Treating Caco-2 cells with S. platensis alone (P=0.01 for both) or in combination with PT-gliadin (P=0.004 and P=0.02, respectively) resulted in decreased IL-6 expression and increased occludin mRNA expression. Additionally, S. platensis extract enhanced Zo-1 mRNA levels (P=0.002) and reduced NF-κB mRNA expression (P=0.02). The combination of gliadin and S. platensis led to decreased mRNA expression of COX-2 (P=0.03) and NF-κB (P=0.04). No significant differences were observed in TGF-β mRNA expression between the studied groups (P>0.05).
Conclusion: Additional investigation is needed to examine the influence of interactions between S. platensis and gliadin regarding the comprehensive response of CD to gliadin, encompassing the activation of gluten-sensitive immune cells.

Original Article (General Medicine)


Investigating the Mechanism of Arsenic-induced Ferroptosis in the Skin

Mehdi Koushki, Nasrin Amiri-Dashatan, Mitra Rezaei, Fatemeh Montazer, Abdolrahim Nikzamir, Reza Vafaee, Vahid Mansouri, Masoumeh Farahani

International Journal of Medical Toxicology and Forensic Medicine, Vol. 13 No. 4 (2023), 14 Azar 2023,
https://doi.org/10.32598/ijmtfm.v13i4.43485

Background: Ferroptosis, an oxidative and iron-dependent cell death, is a new type of regulated cell death. There are few studies on the mechanisms of ferroptosis in the skin and related diseases. Arsenic is shown to induce ferroptosis cell death. This study aimed to decipher the relationship between arsenic exposure and ferroptosis cell death in the skin.
Methods: Arsenic-gene interactions were obtained. Then, skin-specific arsenic-gene interactions were screened. Ferroptosis-related genes were identified. Analysis of functional and biological interactions was performed to identify possible mechanisms.
Results: The arsenic-gene interactions and the ferroptosis-related genes showed an overlap of 59 genes. Functional enrichment, protein-protein interaction, and transcription factor (TF)/miRNA target gene interaction analyses were used to look into the mechanism of arsenic-induced ferroptosis in the skin. ACTB, CTNNB1, HSPA8, SRC, RACK1, CD44, and SQSTM1 were identified as key proteins. Gene ontology analysis of these proteins indicated the mitochondrial morphology and functionality changes following arsenic-induced ferroptosis in the skin. HIF1A and SP1 TFs regulate a large number of genes compared to other TFs. Ten miRNAs with high interaction with ferroptosis-associated genes were identified.
Conclusion: This work investigated the mechanism of arsenic-induced ferroptosis in the skin and identified key genes and regulators, and functional analysis highlighted the role of mitochondria in this skin exposure.

Investigation the effect of Scrophularia striata hydroalcoholic Extract On Cell Death and Migration in Cervical Cancer Cell Line

Jaber Zafari, Elham Rajabbeigi, Leila Mohaghegh Shalmani, Seyedeh Zohreh Azarshin, Fatemeh Javani Jouni, Vahid Mansouri, Hamid Mohaghegh Shalmani, Hamideh Moravej Farshi

International Journal of Medical Toxicology and Forensic Medicine, Vol. 13 No. 4 (2023), 14 Azar 2023,
https://doi.org/10.32598/ijmtfm.v13i4.42601

Background: With the growing interest in plant-derived chemotherapeutic agents, there has been a significant rise in research exploring a broad range of plants in recent years. Scrophularia striata has gained attention due to its extensive medical applications. This study aimed to investigate the effect of S. striata extract on HeLa cervical cancer cells, specifically their migration, apoptosis, and necrosis.
Methods: We first cultured HeLa cells in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% FBS and 1% penicillin/streptomycin. We then examined the cytotoxicity of S. striata extract at varying concentrations (0, 1, 10, 100, 500, and 1000 μg/mL) using the MTT assay after 24 hours. We evaluated the extent of wound healing using a scratch assay and analyzed the apoptosis activity of the extract using flow cytometry.
Results: Our results showed that S. striata extract (IC50: 433.8 μg/mL) significantly enhances wound healing (P≤0.01) in cervical cancer and promotes apoptosis and necrosis of HeLa cells.
Conclusion: Our findings suggest that S. striata may serve as an effective treatment for cervical cancer by inducing cell death and reducing migration.

Review Article


Potential Molecular Mechanisms of Bisphenol A in Obesity Development

Nasrin Amiri-Dashatan, Zahra Taheri, Niosha Asadi, Farnaz Jahangiri , Nikoo Mozafari, Marzieh Ramandi, Mitra Rezaei , Abdolrahim Nikzamir, Somayeh Jahani Sherafat, Mehdi Koushki

International Journal of Medical Toxicology and Forensic Medicine, Vol. 13 No. 4 (2023), 14 Azar 2023,
https://doi.org/10.32598/ijmtfm.v13i4.43484

Bisphenol A (BPA), an endocrine disruptor, is associated with metabolic disorders. However, several studies have suggested that exposure to BPA can cause obesity. It has recently got more attention from scientists as a risk factor for obesity due to its ability to mimic natural estrogens and bind to their receptors. Nonetheless, the molecular mechanism underpinning the environmental etiology of metabolic disorders has not been not fully clarified. In this regard, BPA exposure directly disrupts endocrine regulation, neuroimmune and signaling pathways, and gut microbes, resulting in obesity. In addition, epidemiological studies have revealed a significant relationship between BPA exposure and the development of obesity, although conflicting results have been reported. Therefore, this review summarized the possible role and molecular mechanisms associated with BPA exposure that may lead to obesity based on in vivo and in vivo studies.

The Potential of Algae in Treating Celiac Disease

Nastaran Asri, Mohammad Rostami-Nejad, Mona Zamanian Azodi, Mitra Rezaei, Reza M Robati

International Journal of Medical Toxicology and Forensic Medicine, Vol. 13 No. 4 (2023), 14 Azar 2023,
https://doi.org/10.32598/ijmtfm.v13i4.43127

Compounds found in algae, such as bioactive substances, sulfated polysaccharides, and polyunsaturated fatty acids, have been found to have positive effects on the immune system. Previous research has shown that algae can also benefit digestive system disorders. They possess antioxidant and anti-inflammatory properties and can influence the balance of gut microbiota and maintain the integrity of the intestinal lining. Celiac disease (CD), a disorder caused by an abnormal immune response to gluten, results in inflammation and damage to the intestinal lining, leading to problems with nutrient absorption. Although a lifelong gluten-free diet is the only treatment option for this disease, it is challenging to adhere to. Therefore, recent studies have focused on finding supplementary or alternative therapies for celiac disease patients. Traditional medical treatments, like anti-inflammatory and biological drugs, are associated with significant side effects and are not suitable for supplementary therapy for this group of patients. Algae shows promise as a potential research area for treating CD; however, their specific effects on this condition have not been widely studied. The aim of this study was to gather current information and draw attention to the potential use of algae extracts in treating CD to encourage further research in this field.

Overcoming Cisplatin’s Challenges: A Promising Future in Cancer Care; A Comprehensive Review

Najmeh Abedini Nazari, Behnam Omidi Sarajar, Seyedeh Zohreh Azarshin, Fatemeh Javani Jouni, Zahra Razzaghi, Jaber Zafari

International Journal of Medical Toxicology and Forensic Medicine, Vol. 13 No. 4 (2023), 14 Azar 2023,
https://doi.org/10.32598/ijmtfm.v13i4.43478

Background: Cisplatin’s common use as an anti-neoplastic drug poses significant challenges due to its adverse effects, including renal disorders, neuropathies, hearing impairment, and gastrointestinal issues.
Methods: A comprehensive search was done across major bibliographic databases, including PubMed, Embase, Web of Science, Google Scholar, and Scopus on cisplatin’s application in various cancer treatments. A manual examination of article reference lists was conducted, collecting data from 1990 to October 2023 for up-to-date research analysis.
Results: Cisplatin primarily acts by binding to DNA in the cell nucleus and disrupting DNA transcription and replication, leading to cytotoxicity and malignant cell destruction. Mechanisms of resistance included altered drug absorption, increased efflux and detoxification, modified targets, and increased DNA repair. Interactions with matrix proteins, pH changes, and food affect cisplatin effectiveness. Cisplatin-induced DNA damage mainly forms DNA adducts, causing intra- and inter-strand cross-links. Despite its therapeutic benefits, inevitable adverse effects, like nephrotoxicity, ototoxicity, gastrointestinal diseases, hepatotoxicity, cardiovascular issues, and neuropathy exist. Strategies to mitigate these include hydration therapy, thiol-containing agents, antioxidants, and modulators. Combination therapy enhances cisplatin efficacy.
Conclusion: Cisplatin is a potent anticancer tool marked by challenges from adverse effects and emerging resistance. Ongoing research focuses on combined therapeutic approaches and supports interventions to enhance efficacy and reduce adverse effects, fostering optimism for better cancer treatments.

Toxicology and Metabolic Effects of Methanol and Formaldehyde on the Brain, a Review Article

Vahid Mansouri, Mostafa Rezaei-Taviran, Alireza Ahmadzadeh, Shahin Shadnia, Babak Mostafazadeh, Reza M Robati, Zahra Razaghi

International Journal of Medical Toxicology and Forensic Medicine, Vol. 13 No. 4 (2023), 14 Azar 2023,
https://doi.org/10.32598/ijmtfm.v13i4.42894

Background: Methanol is a toxic alcohol for the human body. The molecular biology of methanol metabolites affecting different organs, such as the brain, is under investigation. This systematic review aimed to consider methanol toxic molecular biology, based on the original articles obtained from data banks to figure out recent achievements.
Methods: Scientific articles regarding the toxic effects and metabolites of methanol on the central nervous system (CNS) were collected from valid databases and classified based on their validity. Exclusion criteria were articles with duplicates, no available full text, review articles, case reports, and letters.
Results: Current metabolic reactions were addressed in the development of CNS diseases, such as optic neuropathy, basal ganglia lesions, and Alzheimer’s disease. However, proteomic investigations introduced new metabolic changes, and serum proteins regarding blood coagulation, vitamin A metabolism, and immune responses were suggested for early detection of toxicity.
Conclusion: Besides CNS disorders introduced for methanol toxicity, there is no exact proteomic serum marker to diagnose toxicity soon; however, the interleukin-1 beta system is suggested as a candidate, and more investigation is required to improve its competency.