Lead is a toxin of great public health concern affecting the young and aging population. Several factors such as age, gender, lifestyle, dose, and genetic makeup result in interindividual variations to lead toxicity mainly due to variations in metabolic consequences. Hence, the present study aimed to examine dose-dependent lead-induced systemic changes in metabolism using rat model by administering specific doses of lead such as 10 (low lead; L-Pb), 50 (moderate lead; M-Pb), and 100 mg/kg (high lead; H-Pb) body weight for a period of one month. Biochemical and haematological analysis revealed that H-Pb was associated with low body weight and feed efficiency, low total protein levels (p ≤ 0.05), high blood lead (Pb-B) levels (p ≤ 0.001), low ALAD (δ-aminolevulinate dehydratase) activity (p ≤ 0.0001), high creatinine (p ≤ 0.0001) and blood urea nitrogen (BUN) (p ≤ 0.01) levels, elevated RBC and WBC counts, reduced haemoglobin and blood cell indices compared to control. Spatial learning and memory test revealed that H-Pb exposed animals presented high latency to the target quadrant and escape platform compared to other groups indicating H-Pb alters cognition function in rats. Histopathological changes were observed in liver and kidney as they are the main target organs of lead toxicity. LC-MS analysis further revealed that Butyryl-L-carnitine (p ≤ 0.01) and Ganglioside GD2 (d18:0/20:0) (p ≤ 0.05) levels were significantly reduced in H-Pb group compared to all groups. Further, pathway enrichment analysis revealed abundance and significantly modulated metabolites associated with oxidative stress pathways. The present study is the first in vivo model of dose-dependent lead exposure for serum metabolite profiling.
Epithelial-mesenchymal transition (EMT) is a critical process that occurs during the embryonic development, wound healing, organ fibrosis and the onset of malignancy. Emerging evidence suggests that the EMT is involved in the invasion and metastasis of cancers. The inflammatory reaction antecedent to fibrosis in the onset of oral submucous fibrosis (OSF) and the role of EMT in its malignant transformation indicates a hitherto unexplored involvement of EMT. This review focuses on the role of EMT markers which are regulators of the EMT mediated complex network of molecular mechanisms involved in the pathogenesis of OSF and OSCC. Further the gene enrichment analysis and pathway analysis supports the association of the upregulated and downregulated genes in various EMT regulating pathways.
Fibrosis is a pathological state characterized by excessive deposition of the extracellular matrix components leading to impaired tissue function in the affected organ. It results in scarring of the affected tissue akin to an over-healing wound as a consequence of chronic inflammation and repair in response to injury. Persistent trauma of susceptible oral mucosa due to habitual chewing of betel quid resulting in zealous healing of the mucosal tissue is one plausible explanation for the onset of oral submucous fibrosis (OSF). The irreversibility and resistance of collagen to degradation and its high potential to undergo malignant change are a major reason for morbidity in OSF. Hence, early diagnosis and timely treatment are crucial to prevent the progression of OSF to malignancy. This review focuses on the mechanistic insight into the role of collagen cross-links in advancing fibrosis and possible therapeutic targets that bring about a reversal of fibrosis. These options may be beneficial if attempted as a specific therapeutic modality in OSF as is in organ fibrosis. The upregulation of lysyl oxidase and lysyl hydroxylase has been shown to exhibit the higher levels of the hydroxylysine aldehyde-derived cross-links in fibrosis and tumor stroma promoting the tumor cell survival, resistance, and invasion. The in silico analysis highlights the potential drugs that may target the genes regulating collagen crosslinking.
Bisphenol A (BPA) mimics estrogen and consequently suspected to be detrimental to female reproductive system. Biomonitoring confirms the BPA burden in body leading to a complex condition called polycystic ovarian syndrome (PCOS) which is frequently attributed to female infertility. Due to unclear precise molecular pathomechanisms of BPA in PCOS, we intend to examine the molecular mechanisms of the reproductive, endocrine, mitochondrial features, and cellular senescence in BPA-treated rats. We analyzed vaginal smears and ovarian follicles using microscope, assessed sex hormones by ELISA, analyzed BPA target gene expression by semi-quantitative RT-PCR, assessed senescence induction by β-galactosidase staining and immunofluorescence in BPA-treated rats. Our data showed hormonal imbalance, impaired folliculogenesis, abnormal expression patterns of target genes, CDKN2A overexpression and enhanced ROS levels in BPA-treated rats. This study provides insights on the effects of BPA exposure on ovulatory, hormonal, mitochondrial dysfunction, and senescence that benefit in better understanding of PCOS induced by BPA.
Polycystic ovarian syndrome (PCOS) is a complicated endocrinopathy with an unclear etiology that afflicts fertility status in women. Although the underlying causes and pathophysiology of PCOS are not completely understood, it is suspected to be driven by environmental factors as well as genetic and epigenetic factors. Bisphenol A (BPA) is a weak estrogenic endocrine disruptor known to cause adverse reproductive outcomes in women. A growing relevance supports the notion that BPA may contribute to PCOS pathogenesis. Due to the indeterminate molecular mechanisms of BPA in PCOS endocrinopathy, we sought liquid chromatography with tandem mass spectrometry (LC-MS/MS), a metabolomics strategy that could generate a metabolic signature based on urinary BPA levels of PCOS and healthy individuals. Towards this, we examined urinary BPA levels in PCOS and healthy women by ELISA and performed univariate and chemometric analysis to distinguish metabolic patterns among high and low BPA in PCOS and healthy females, followed by pathway and biomarker analysis employing MetaboAnalyst 5.0. Our findings indicated aberrant levels of certain steroids, sphingolipids, and others, implying considerable disturbances in steroid hormone biosynthesis, linoleic, linolenic, sphingolipid metabolism, and various other pathways across target groups in comparison to healthy women with low BPA levels. Collectively, our findings provide insight into metabolic signatures of BPA-exposed PCOS women, which can potentially improve management strategies and precision medicine.