Acrylamide (Acr) is a widely encountered environmental and dietary toxicant known to induce oxidative stress and disrupt male reproductive function. Leydig cells, due to their high metabolic activity and mitochondrial dependence, are particularly vulnerable to redox imbalance. N-acetylcysteine (Nac), a thiol-containing antioxidant and glutathione precursor, has been extensively studied for its cytoprotective properties. However, its modulatory effects on Acr-induced toxicity in Leydig cells and its pharmacodynamic interaction profile remain incompletely characterized. In this study, TM3 Leydig cells were exposed to Acr in the presence or absence of Nac. Cell viability was assessed by MTT assay, and chemical interaction profiles were evaluated using ZIP, Bliss, and Chou-Talalay combination index analyses. Oxidative stress parameters, including intracellular reactive oxygen species (ROS), lipid peroxidation, antioxidant enzyme activities (SOD, CAT, GPx), and glutathione levels, were measured. Apoptotic responses were analyzed through double fluorescence staining, RT-qPCR of apoptosis-related genes (Bax, Bcl2, Casp3, Trp53), and Western blot analysis of CASP3 protein expression. Acr exposure significantly reduced cell viability, increased ROS and lipid peroxidation levels, suppressed antioxidant defenses, and activated the mitochondrial apoptotic pathway. Nac treatment markedly improved cell viability, restored antioxidant capacity, reduced oxidative stress markers, and suppressed p53/Bax/Casp3-mediated apoptotic signaling. Combination analyses revealed an antagonistic interaction profile, indicating that Nac biologically limits Acr-induced cytotoxicity. Collectively, these findings demonstrate that Nac exerts protective effects in Leydig cells by modulating redox homeostasis and mitochondrial apoptosis, suggesting its potential as a protective regulator against Acr-induced reproductive toxicity.
This study investigated the protective effects of epicatechin against cypermethrin-induced oxidative stress and genotoxicity in PC-12 cells. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay following exposure to cypermethrin (1-300 μM). The IC50 concentration was determined and subsequently used to induce toxicity. PC-12 cells were treated with epicatechin (50, 100, 150, and 200 μM) in the presence of cypermethrin. Intracellular reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and DNA damage were evaluated using 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) assay, biochemical assays, and alkaline comet assay, respectively. Cypermethrin induced concentration-dependent cytotoxicity, reducing cell viability from 107.5% at 1 μM to 40.29% at 300 μM, with an IC50 value of 238.5 ± 6.9 μM. Cypermethrin significantly increased ROS production (83.55%), depleted intracellular GSH (93.00 ± 1.73 to 50.33 ± 1.53 nmol/mg protein), and elevated MDA levels (22.67 ± 2.52 to 81.00 ± 2.00 nmol/mg protein) compared with the control group (p < 0.05). Epicatechin treatment dose-dependently attenuated oxidative stress, restoring GSH levels to 74.67 ± 1.53 nmol/mg protein, reducing MDA levels to 51.00 ± 2.65 nmol/mg protein, and decreasing ROS production to 53.43% at 200 μM. Comet assay analysis demonstrated that cypermethrin significantly increased tail length, percentage DNA in tail, and tail moment, whereas epicatechin (200 μM) markedly reduced all genotoxicity parameters and comet tail formation. Epicatechin protects PC-12 cells from cypermethrin-induced oxidative and genotoxic injury by enhancing antioxidant defenses, limiting lipid peroxidation, and reducing DNA damage. Further in vivo studies are required to confirm its neuroprotective potential and define optimal dosing.
Oxidative stress has a key role in paraquat (PQ)-mediated hepatic failure. Considering the known antioxidant and anti-inflammatory properties of nonselective phosphodiesterase inhibitors, this study investigated the potential of pentoxifylline (PTX) to counteract acute PQ-induced liver damage. The molecular interactions of PQ and PTX with key oxidative stress enzymes (NADPH oxidase, xanthine oxidase) were investigated by molecular docking using AutoDock 4.2.6. For in vivo studies, thirty-six mice were randomized into six groups: a normal saline control, a PQ-intoxicated group (20 mg/kg, single dose), a PTX control group (100 mg/kg for 3 days), and three treatment groups that received PTX (25, 50, or 100 mg/kg) for three consecutive days, starting one hour after PQ administration. Blood and liver tissues were collected 24 hours after the final dose for biochemical and histological analysis. The PQ administration resulted in a significant increase in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), hepatic lipid peroxidation (LPO), and nitric oxide (NO) levels, while concurrently decreasing antioxidant capacity (TAC), total thiol molecule (TTM), and superoxide dismutase (SOD) activity in liver tissue. PTX treatment effectively improved serum hepatic enzymes, LPO, TTM, and SOD levels, as corroborated by histological findings. Moreover, molecular docking analysis suggests that PTX may reduce PQ-induced oxidative stress by competitively inhibiting the FAD-binding site of xanthine oxidase, and by engaging a non-active-site region of NADPH oxidase. This study indicates PTX administration may prevent PQ-induced hepatic damage in mice, potentially by inhibiting free radical formation. Further research is needed to validate the proposed enzymes inhibition mechanisms and assess PTX's potential in acute PQ poisoning.
Microplastics (MPs) are emerging environmental pollutants that have received increasing attention in recent years. However, data on their potential risks to mammalian species remain limited. In this study, female rats were exposed via oral gavage to pristine (PPS) and fluorescent polystyrene (FPS) particles (5 μm diameter) over four estrous cycles. FPS-MPs were detected in hepatic tissue (133 ± 35 particles), confirming their translocation. Exposure to PPS-MPs increased superoxide dismutase (SOD) (2.58-fold) and catalase (CAT) activity (1.36-fold), while reducing protein sulfhydryl levels (PSH) (0.35-fold), indicating oxidative stress. Histological analysis and quantitative assessment revealed significant alterations, including significant decrease in glycogen content (2.4- fold). Immunofluorescence analysis showed a pronounced increase in α-tubulin and a decrease in DAAM-1 signals, a formin protein essential for actin filament assembly and cytoskeletal organization, suggesting impaired cytoskeletal dynamics. These observations were further supported by molecular analyses, which showed α-tubulin overexpression (3.35-fold) and reduced DAAM-1 expression (0.5-fold). Our findings indicate that exposure to environmentally relevant concentrations of MPs induces early hepatocellular alterations, suggesting that oxidative stress and cytoskeletal remodeling may be central mechanisms underlying MP-induced hepatotoxicity. These findings should be interpreted with caution, as the study used only female rats, a single dose, particle size, and polymer type, with a short exposure duration, and it should be noted that FPS-MPs were used only to track distribution, whereas toxicity assessments were performed with non-fluorescent particles.
Plastics are ubiquitous in the environment and are widely used in food packaging, medicine, agriculture, construction and other sectors. However, the plasticizers they contain pose a substantial threat to environmental safety and human health. Phthalates represent the most important class of plasticizers and are classified as endocrine-disrupting chemicals (EDCs), capable of causing adverse effects even at very low exposure levels. Extensive in vitro and in vivo studies have demonstrated that phthalates and their metabolites exhibit reproductive toxicity, leading to reduced sperm motility and count, hormonal dysregulation, ovarian failure, preterm birth and other detrimental outcomes. This review synthesizes current evidence on the association between phthalate exposure and various reproductive system disorders. Epidemiological studies show that phthalate exposure is linked to impaired sperm quality, prostate disease and erectile dysfunction in males, suggesting a contributing role in the pathogenesis of infertility. However, the association with shortened anogenital distance remains unclear. In females, phthalate exposure has been associated with endometriosis, polycystic ovary syndrome, premature ovarian failure, infertility and miscarriage, although the epidemiological evidence is inconsistent. In conclusion, paying attention to the reproductive health risks posed by phthalate exposure is of critical importance, particularly for vulnerable groups including women of childbearing age, pregnant women, and children.
Forskolin and pinitol are bioactive dietary compounds studied for several pharmacological properties. Considering their widespread therapeutic application and the limited information available regarding their genotoxic and/or antigenotoxic properties, the present study investigated whether commercially available forskolin and pinitol can induce DNA damage and/or protect DNA against damage induced by ethyl methanesulfonate (EMS). The sex-linked recessive lethal (SLRL) test in germline and the alkaline comet assay in somatic cells were performed in Drosophila melanogaster to assess in vivo genotoxicity and DNA-protective effects against EMS-induced DNA damage. The SLRL assay demonstrated that neither forskolin nor pinitol induced genotoxic effects in D. melanogaster males. Both compounds significantly reduced EMS-induced sex-linked recessive lethal mutations, indicating a marked DNA-protective effect in germline cells. In the comet assay, no significant increase in DNA damage was observed following forskolin treatment, whereas pinitol induced moderate increases in the total comet score only at the highest concentration compared with the negative control, with values statistically significantly lower than those of the positive control. The greatest DNA-protective effect against EMS was observed following co-treatment with 0.5 mg/mL of forskolin or pinitol, resulting in percentage reductions of 94.2% and 80.5%, respectively. The findings suggest that forskolin and pinitol possess protective effects against EMS-induced DNA damage. Their DNA-protective capacity at non-genotoxic concentrations indicates potential chemopreventive properties and supports further investigation of their biological effects. These findings support further investigation into the molecular mechanisms underlying their protective effects and their potential application in the prevention and management of diseases associated with genomic instability.
Hypoxia is a defining feature of the tumor microenvironment and a key driver of malignant progression through transcriptional reprogramming of metabolic, angiogenic, and survival pathways. In this study, hypoxia-induced molecular responses were investigated in human hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cells using cobalt(II) chloride (CoCl2) as a hypoxia mimetic. Cell viability profiling was performed to determine the optimal experimental concentration, followed by quantitative PCR analysis of hypoxia-related genes and miRNA-gene interaction network analysis. Cell viability profiling identified 100 µM CoCl2 as the optimal condition for downstream analyses. Quantitative PCR revealed robust induction of HIF-1α in both cell lines, indicating activation of hypoxic signaling. However, downstream responses differed markedly between cell types. MCF-7 cells exhibited significant upregulation of SLC2A1 and increased VEGFA and NFKB1 expression, consistent with activation of glycolytic and pro-angiogenic pathways. In contrast, HepG2 cells showed limited downstream transcriptional engagement despite elevated HIF1A expression. Furthermore, miRNA-gene interaction analysis revealed a dense regulatory network in MCF-7 cells, whereas HepG2 cells displayed a more restricted, VEGFA-centered miRNA profile. These findings demonstrate that chemical hypoxia induces cell-type-specific transcriptional and post-transcriptional responses in breast and liver cancer cells. The results suggest that miRNA-mediated regulation may contribute to differential tumor adaptation to hypoxic stress and highlight the importance of cellular context in hypoxia-associated signaling pathways.
Bisphenol A (BPA), a ubiquitous plasticizer, has been implicated in lipid metabolic imbalance, yet its contribution to nonalcoholic fatty liver disease (NAFLD) remains incompletely understood. Here, we combined NHANES data analysis, network toxicology, microarray profiling, molecular docking and dynamics simulations, and LO2 hepatocyte experiments to investigate the association between BPA exposure and NAFLD and its underlying mechanisms. Epidemiologically, urinary BPA levels were positively associated with NAFLD prevalence. In vitro, low-dose BPA induced hepatocellular triglyceride and cholesterol accumulation and impaired cell function. Mechanistic investigations highlighted inflammatory, steroidogenic, and lipid metabolic pathways. Network pharmacology and gene expression profiling pinpointed MMP9, PTGS2, MMP2, NOS3, and PLAU as key BPA-responsive genes, and experimental validation confirmed upregulation of MMP9, PTGS2, and PLAU transcripts and proteins alongside increased MMP2 protein. These findings integrate population-level, computational, and hepatocyte evidence, suggesting that matrix remodeling, inflammation, and lipid metabolism may underlie the link between BPA exposure and NAFLD.
Schouwia purpurea (Family: Brassicaceae) S. purpurea is a wild medicinal plant traditionally used for treating gastrointestinal, inflammatory, and infectious disorders in arid regions of North Africa. Despite its ethnomedicinal importance, little is known about its systemic safety profile. This study aimed to evaluate the 14-day repeated dose oral toxicity of the aqueous-ethanolic extract of (SPE) S. purpurea in female albino Wistar mice. Thirty mice were randomly assigned into five groups (n = 6): control (distilled water), and extract-treated groups receiving 200, 500, 1000, and 2000 mg/kg of S. purpurea via oral gavage for 14 consecutive days. Animals were observed daily for mortality, behavioral changes, and clinical signs of toxicity. Blood samples were collected for biochemical analysis of liver and kidney function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea, and creatinine. No deaths were recorded in any group. Groups receiving 200 and 500 mg/kg showed no significant changes in biochemical markers. However, a significant dose-dependent elevation in ALT, AST, urea, and creatinine was observed at 1000 and 2000 mg/kg. Additionally, mice in the 2000 mg/kg group exhibited mild lethargy and transient convulsions during the second week, suggesting potential neurotoxic effects, without mortality. These results indicate that the SPE is biochemically and clinically safe at doses up to 500 mg/kg. However, due to the presence of mild histopathological alterations in the liver and kidneys at 500 mg/kg, the dose of 200 mg/kg is established as the no-observed-adverse-effect level (NOAEL), while 500 mg/kg is identified as the lowest-observed-adverse-effect level (LOAEL). Higher doses of SPE may induce dose-dependent hepatic, renal, and neurobehavioral stress.
Construction dust is a major source of air pollution and easily causes intractable respiratory diseases such as pneumoconiosis. Dust suppressants are effective for dust control, yet most existing studies only focus on dust suppression performance, lacking systematic toxicological assessments, especially data on extrapulmonary multi-organ toxicity. In this study, SPF male C57BL/6 mice were used to establish three subchronic inhalation exposure groups: dust alone, dust suppressant alone, and co-exposure of dust and suppressant. Indicators including body weight, organ coefficients, blood routine, serum cytokines, and liver, kidney, and heart pathological lesions were detected to investigate the extrapulmonary multi-organ toxicity of an eco-friendly composite dust suppressant. The suppressant had little effect on mouse body weight. At appropriate concentrations (4-20 mg/m3), it inhibited dust-induced inflammatory responses and alleviated liver and kidney injuries. When the concentration reached 100 mg/m3, the suppressant interacted with dust to increase DNA oxidative damage markers, indicating potential genotoxic risks. This study fills the gap in extrapulmonary toxicological research of dust suppressants, provides references for toxicology evaluation and experimental basis for determining safe application concentrations on construction sites.
Glutamate-induced excitotoxicity, characterized by oxidative stress and genomic instability, is a hallmark of neurodegenerative disorders. This study investigated the protective effects of curcumin against glutamate-induced excitotoxicity in SH-SY5Y cells, focusing on oxidative balance and DNA integrity. SH-SY5Y cells were exposed to 40 mM L-glutamate to induce excitotoxicity. Cells were concurrently treated with curcumin (2.5-15 µM). Cell viability was assessed via XTT assay. Oxidative status was evaluated by measuring Total Antioxidant Status (TAS) and Total Oxidant Status (TOS). Genomic integrity was analyzed using the Comet assay (Tail DNA%). Exposure to 40 mM glutamate caused ∼50% cell death, significantly increased TOS levels, and induced extensive DNA damage (increased Tail DNA%). Co-treatment with 10 and 15 µM curcumin significantly restored cell viability in a dose-dependent manner. Notably, 10 µM curcumin ameliorated glutamate-induced TAS depletion and significantly reduced DNA fragmentation, restoring genomic stability to near-baseline levels. Curcumin alone exhibited no pro-oxidant or genotoxic effects. Curcumin exerts a significant cytoprotective effect against glutamate excitotoxicity in SH-SY5Y cells. This protection is primarily mediated through the restoration of the cellular antioxidant pool and the preservation of genomic integrity, suggesting curcumin as a promising therapeutic agent for mitigating excitotoxic neuronal damage.
ABSTARCTAmikacin (AK), a potent aminoglycoside antibiotic, is known to induce nephrotoxicity. This study evaluated the renoprotective effects of ROF, a selective PDE4 inhibitor, against AK-induced renal injury in Wistar rats. Forty male rats were divided into four groups (n = 10): Control (saline), ROF-only (1.5 mg/kg/day orally for 6 days), AK-only (single intraperitoneal injection of 1.2 g/kg on day 3), and AK+ROF (co-treatment). Renal function was assessed via serum creatinine and BUN. Oxidative stress was evaluated by measuring MDA and the antioxidants GSH, SOD, and CAT. The expression of key proteins in the Nrf2/HO-1, NF-κB, and apoptotic pathways was analyzed using ELISA and IHC. Kidney histopathology was examined using H&E, PAS, and Masson's trichrome staining. AK administration significantly elevated serum creatinine and BUN levels, increased lipid peroxidation, and suppressed antioxidant enzymes (SOD, CAT, and GSH). It also upregulated NF-κB along with TNF-α, IL-1β, and IL-6, and enhanced apoptotic markers (caspase-3, Bax) while reducing Bcl-2 expression. Histopathological analysis revealed severe tubular degeneration and inflammatory infiltration in the AK group. The most prominent finding was that ROF co-treatment robustly activated the Nrf2/HO-1 antioxidant pathway, leading to a comprehensive protective effect. ROF significantly ameliorated renal dysfunction, restored antioxidant enzyme activities, and reduced lipid peroxidation. It concurrently suppressed the NF-κB inflammatory cascade and modulated apoptotic signaling. These biochemical improvements were corroborated by marked histopathological recovery. In conclusion, ROF demonstrated potent renoprotection against AK-induced injury primarily through Nrf2/HO-1 pathway activation, which underpinned its synergistic antioxidant, anti-inflammatory, and anti-apoptotic actions, supporting its potential as a therapeutic strategy to mitigate aminoglycoside nephrotoxicity.
Bisphenol A (BPA) impairs chronic wound healing via immune dysregulation, yet its mechanisms in diabetic foot ulcers (DFU) remain unclear. This study explores BPA's molecular mechanisms in DFU and screens for antagonists. BPA targets and DFU DEGs (from GEO) were intersected to identify common targets. PPI network construction, functional enrichment, and immune infiltration analyses were conducted. Single-cell sequencing and molecular docking validated target expression and BPA binding. Drug enrichment analysis predicted therapeutic compounds. A total of 51 common targets between BPA and DFU were screened. Functional enrichment analysis showed that these targets were mainly enriched in inflammatory responses, extracellular matrix remodeling, angiogenesis, and signaling pathways such as PI3K-Akt and MAPK. Three core targets were identified through network analysis: BCL2, EGFR, and MMP9. Single-cell analysis revealed that BCL2 was highly expressed in B cells, MMP9 was specifically expressed in macrophages, and EGFR was mainly expressed in fibroblasts and epithelial cells. Molecular docking confirmed that BPA had good binding activity with these three core targets (binding energy < -5.0 kcal/mol). Drug enrichment analysis screened multiple potential antagonists, including the marketed drugs enoxaparin and sulfasalazine. This study reveals BPA drives DFU via BCL2/EGFR/MMP9 targets, disrupting PPAR pathways and immune microenvironment, offering insights into pollutant-mediated wound healing and therapeutic targets for DFU.
Chlorpyrifos (CPF), a widely used organophosphorus pesticide, poses potential nephrotoxicity risks, yet its molecular mechanisms remain incompletely elucidated. This study integrated network toxicology, molecular docking, molecular dynamics (MD) simulations, and in vitro experiments to systematically explore CPF-induced renal injury mechanisms. ADMET and toxicity predictions indicated CPF's potential nephrotoxic risk. Through cross-database screening, 33 overlapping targets were identified, and seven core targets, MPO, XDH, TLR4, NFE2L2, NOS2, NOS3, and SOD2, were further selected via protein-protein interaction network analysis. Enrichment analysis revealed significant involvement in oxidative stress, inflammatory response, and HIF-1 signaling pathways. Molecular docking and 100 ns MD simulations demonstrated stable binding of CPF and its metabolites to core targets. In vitro experiments using HK‑2 cells confirmed that CPF upregulated MPO expression and induced oxidative damage and inflammatory responses, which were attenuated upon MPO knockdown. This multi-level strategy reveals that CPF may trigger nephrotoxicity via oxidative stress and inflammatory activation, providing new insights into its toxicological mechanisms.
Prenatal valproic acid (VPA) exposure is strongly linked to developmental cardiotoxicity, yet no targeted pharmacological countermeasure exists. Converging mechanistic evidence indicates that VPA cardiotoxicity centers on AMPK/PGC-1α suppression, positioning the AMPK activator metformin (MET) as a rational candidate for in vivo protection. We examined MET's protective effects against VPA-induced developmental cardiotoxicity in zebrafish embryos. Embryos were randomly allocated to four groups (Control, VPA 0.1 mM, MET 10 mM, VPA + MET) immediately after fertilization and chronically exposed until 96 hpf. Oxidative stress biomarkers (MDA, NO, SOD, GSH) and the expression of cardiac (nkx2.5, vmhc, amhc), AMPK (prkaa2, acaca), and mitochondrial/energy-related genes (ppargc1a, cpt1b, pck1, atp5pb, mt-nd1) were quantified. Compared with controls, VPA reduced nkx2.5 (p < 0.01) and elevated amhc (p < 0.05), triggered pericardial edema (p < 0.0001), suppressed prkaa2, ppargc1a, and atp5pb (p < 0.05, p < 0.001, and p < 0.0001, respectively), upregulated acaca (p < 0.0001), increased MDA and NO (p < 0.0001), and lowered SOD and GSH (p < 0.0001 and p < 0.001, respectively). Relative to the VPA group, MET co-treatment restored nkx2.5 expression (p < 0.001), attenuated pericardial edema (p < 0.0001), increased prkaa2 (p < 0.05), ppargc1a (p < 0.01), and atp5pb (p < 0.0001), suppressed acaca (p < 0.0001), and normalized MDA (p < 0.05), NO (p < 0.0001), SOD, and GSH (both p < 0.0001). The restoration of prkaa2/ppargc1a, mitochondrial, and antioxidant capacity by MET suggests that the AMPK/PGC-1α axis may serve as a central target in VPA cardiotoxicity.
Paclitaxel (PAX) is an effective chemotherapeutic agent for treating various cancers but is associated with side effects such as hepatotoxicity, neurotoxicity, and myelosuppression. To mitigate these toxicities, adjunct therapies like salicylic acid (SA), a plant-derived compound with anti-inflammatory, antioxidant, and cytoprotective properties, have been explored. This study investigates SA's potential to counteract PAX's cytotoxic effects, focusing on hepatic tissue. Thirty-five BALB/cJ mice were treated with PAX and SA, either individually or in combination (low and high doses), for 14 days. Post-treatment, biochemical and histological analyses were performed. ELISA assays measured serum levels of inflammatory markers IL-1β, IL-6, and TNF-α, while caspase-3/7 activity was evaluated to assess apoptosis. qPCR assessed gene expression related to apoptosis (CASP1, CASP3, Bcl-2). Results showed that PAX significantly increased serum levels of inflammatory markers, which were reduced by SA treatment. PAX also elevated caspase-3/7 activity, but co-treatment with SA suppressed this effect. Histological analysis revealed that low-dose SA alleviated PAX-induced necrosis and inflammation in the liver, kidney, and spleen. Moreover, PAX alone significantly upregulated CASP1 and CASP3 expression, while co-treatment with SA significantly downregulated these genes. These findings highlight the protective role of SA in reducing PAX-induced toxicity, particularly in hepatic tissues, suggesting that SA could be a potential adjunct therapy for minimizing chemotherapy-related side effects.
Extensive safety measures for food additives focus primarily on target organ toxicity, neglecting the potential effects on oxidative stress and inflammation-related disruptions in the immune system. This study evaluated the effects of four common food additives-monosodium glutamate (MSG), sodium nitrate (SN), sodium sulfite (SS), and butylated hydroxyanisole (BHA)-on splenic inflammation and oxidative stress markers in naïve female mice. The results showed that oral administration of MSG, SN, SS, and BHA-alone or in combination-for 4 weeks induced immune-suppressive effects and chronic antioxidative stress, via inflammatory responses in spleen. This was accompanied by overexpression of interferon-γ (IFN-γ), immunoglobulin G (IgG), tumor growth factor-β (TGF-β), catalase (CAT), and superoxide dismutase (SOD), and increased proportions of B regulatory (CD19+ CD24+) and T regulatory (CD4+ CD25+) cells, which may contribute to the downregulation of C-reactive protein (CRP), interleukin-1β (IL-1β), IL-6, IL-10, and malondialdehyde (MDA) in the spleen. Also, higher percentages of necrosis and late apoptosis in splenocytes were noted. In conclusion, exposure to dietary additives MSG, SN, SS, and BHA-alone or in combination-modulated markers of inflammation and oxidative stress and affected the expression of regulatory T and B cells, resulting in the immune system's dysfunctions. BHA showed the greatest negative impact, followed by MSG, with SS and SN having lesser effects. Because these additives are common in commercially packaged foods, they should be used sparingly, and more research is needed to understand their systemic and long-term toxic effects on different organs, particularly due to the rising use of new compounds at varying exposure levels.
The latest episode of cough syrup-associated pediatric deaths in India linked to the reported diethylene glycol (DEG) contamination reverberates a long-standing catastrophic history from the Elixir Sulfanilamide disaster in the USA to the similar incidents in Haiti, Panama, and Gambia. Such recurring preventable tragedies highlight continuing concerns on global pharmaceutical regulation enforcement, toxicological implications on public health, and drug safety, particularly in low- and middle-income countries. In spite of clearly established pharmacopeial limits of diethylene glycol and other excipients used in pharmaceutical industry, probable gaps in excipient verification, insufficient quality control measures, and patchy regulatory monitoring have continued to be discussed in relation to contaminated drug formulations reaching global markets. Existing conventional strategies to combat reoccurrences, such as mandatory analytical testing of excipients and final drug products, vendor qualification, and strict pharmacovigilance programs, are necessary but not sufficient. This article describes the toxicological aspects of diethylene glycol poisoning, provides a brief overview of the historical events, and critically examines the reasons behind recurrence of DEG-related poisonings. Further, it provides specific recommendations to eradicate such catastrophes by employing futuristic strategies using block chain technology and artificial intelligence-based solutions.
