Melatonin counteracts polyethylene microplastics induced adreno-cortical damage in male albino rats.

There are various substances that can disrupt the homeostatic mechanisms of the body, defined as endocrine-disrupting chemicals (EDCs). The persistent nature of microplastics (MPs) is a cause for concern due to their ability to accumulate in food chains and widespread use, making their toxic effects particularly alarming. The potential of MPs for disrupting the endocrine system was observed in multiple tissues. Moreover, the adrenal gland is known to be extremely sensitive to EDCs, while with the effect of MPs on the adrenal gland has not previously been studied. This study aimed to highlight the potential polyethylene microplastics (PE-MPs) induced adreno-toxic effects rather than exploring the implicated mechanisms and concluding if melatonin (Mel) can afford protection against PE-MPs induced adreno-toxicity. To fulfill the goal, six groups of rats were used; control, Mel, PE-MPs (3.75 mg/kg), PE-MPs (15 mg/kg), PE-MPs (3.75 mg/kg) +Mel, and PE-MPs (15 mg/kg) +Mel. PE-MPs induced toxic changes in the adrenal cortex, which was evident by increased adrenal weight, histopathological examination, and ultrastructural changes detected by electron microscope. A reduction in serum cortisol and an increase in serum adrenocorticotropic hormone resulted from the adreno-toxic effects of PE-MPs. Mechanisms may include the reduction of steroidogenesis-related genes, as PE-MPs drastically reduce mRNA levels of StAR, Nr0b1, Cyp11A1, as well as Cyp11B1. Also, oxidative stress that results from PE-MPs is associated with higher rates of lipid peroxidation and decreased superoxide dismutase and glutathione. PE-MPs inflammatory effect was illustrated by elevated expression of IL-1ß and NF-kB, detected by immunohistochemical staining, in addition to increased expression of caspase-3 and mRNA of Bax, markers of proapoptotic activity. The impacts of PE-MPs were relatively dose-related, with the higher dose showing more significant toxicity than the lower one. Mel treatment was associated with a substantial amelioration of PE-MPs-induced toxic changes. Collectively, this study fills the knowledge gap about the MPs-induced adrenal cortex and elucidates various related toxic mechanisms. It also supports Mel's potential protective activity through antioxidant, anti-inflammatory, anti-apoptotic, and gene transcription regulatory effects.

Epigenetic alterations of miR-155 and global DNA methylation as potential mediators of ochratoxin A cytotoxicity and carcinogenicity in human lung fibroblasts.

Ochratoxin A (OTA) is a well-known mycotoxin that adversely affects different human cells. Inhalational exposure to OTA and subsequent pulmonary diseases have been previously reported, yet its potential carcinogenicity and underlying molecular mechanisms have not been fully elucidated. This study aimed to evaluate the OTA-induced cytotoxicity and the epigenetic changes underlying its potential carcinogenicity in fetal lung fibroblast (WI-38) cells. OTA cytotoxicity was assessed by MTT assay; RT-qPCR was used to determine the expression of BAX, BCL-2, TP53, and miR-155, while ELISA was used for measuring 5-methyl cytosine percentage to assess global DNA methylation in OTA-treated versus control cells. WI-38 cells demonstrated sensitivity to OTA with IC50 at 22.38 µM. Though BAX and Bcl-2 were downregulated, with low BAX/BCL-2 ratio, and TP53 was upregulated, their fold changes showed decline trend with increasing OTA concentration. A significant dose-dependent miR-155 upregulation was observed, with dynamic time-related decline. Using subtoxic OTA concentrations, a significant global DNA hypermethylation with significant dose-dependent and dynamic alterations was identified. Global DNA hypermethylation and miR-155 upregulation are epigenetic mechanisms that mediate OTA toxicity on WI-38 cells. BAX downregulation, reduced BAX/BCL-2 ratio together with miR-155 upregulation indicated either the inhibition of TP53-dependent apoptosis or a tissue specific response to OTA exposure. The aforementioned OTA-induced variations present a new molecular evidence of OTA cytotoxicity and possible carcinogenicity in lung fibroblast cells.

Melatonin Alleviates Intestinal Barrier Damaging Effects Induced by Polyethylene Microplastics in Albino Rats.

There have been concerns about the potential health risks posed by microplastics (MP). The detection of MP in a variety of food products revealed that humans are ingesting MP. Nevertheless, there is a paucity of data about their impacts, as well as their uptake, on intestinal barrier integrity. This study examined the toxic effects of oral administration of two doses of polyethylene microplastics (PE-MP) (3.75 or 15 mg/kg/day for 5 weeks; mean particle size: 4.0-6.0 µm) on the intestinal barrier integrity in rats. Moreover, the effect of melatonin treatment with MP exposure was also assessed. The PE-MP particle uptake, histopathological changes, Alcian blue staining, Muc2 mRNA, proinflammatory cytokines (IL-1ß and TNF-α), and cleaved caspase-3, as well as tight junction proteins (claudin-1, myosin light-chain kinase (MLCK), occludin, and zonula occludens-1 (ZO-1)) were assessed. Oral administration of PE-MP resulted in apparent jejunal histopathological alterations; significantly decreased mucin secretion, occludin, ZO-1, and claudin-1 expression; and significantly upregulated MLCK mRNA, IL-1ß concentration, and cleaved caspase-3 expression. Melatonin reversed these altered parameters and improved the PE-MP-induced histopathological and ultrastructure changes. This study highlighted the PE-MP's toxic effect on intestinal barrier integrity and revealed the protective effect of melatonin.

Poly(ADP-ribose) polymerase inhibitors in the treatment landscape of triple-negative breast cancer (TNBC).

OBJECTIVE: Chemotherapy is the mainstay for triple-negative breast cancer (TNBC) patients. Over the years, the use of chemotherapy for these patients has demonstrated many adversities, including toxicity and resistance, which suggested the need to develop novel alternative therapeutic options, such as poly(ADP-ribose) polymerase inhibitors (PARPi). Herein, we provide an overview on PARPi, mechanisms of action and the role of biomarkers in PARPi sensitivity trials, clinical advances in PARPi therapy for TNBC patients based on the most recent studies and findings of clinical trials, and challenges that prevent PARP inhibitors from achieving high efficacy such as resistance and overlapping toxicities with other chemotherapies. DATA SOURCES: Searching for relevant articles was done using PubMed and Cochrane Library databases by using the keywords including TNBC; chemotherapy; PARPi; BRCA; homologous recombination repair (HRR). Studies had to be published in full-text in English in order to be considered. DATA SUMMARY: Although PARPi have been used in the treatment of local/metastatic breast malignancies that are HER2 negative and has a germline BRCA mutation, several questions are still to be answered in order to maximize the clinical benefit of PARP inhibitors in TNBC treatment, such as questions related to the optimal use in the neoadjuvant and metastatic settings as well as the best combinations with various chemotherapies. CONCLUSIONS: PARPi are emerging treatment options for patients with gBRCA1/2 mutations. Determining patients that are most likely to benefit from PARPi and identifying the optimal treatment combinations with high efficacy and fewer side effects are currently ongoing.

The Potential Effects of Quercetin-Loaded Nanoliposomes on Amoxicillin/Clavulanate-Induced Hepatic Damage: Targeting the SIRT1/Nrf2/NF-κB Signaling Pathway and Microbiota Modulation.

Amoxicillin/clavulanate (Co-Amox), a commonly used antibiotic for the treatment of bacterial infections, has been associated with drug-induced liver damage. Quercetin (QR), a naturally occurring flavonoid with pleiotropic biological activities, has poor water solubility and low bioavailability. The objective of this work was to produce a more bioavailable formulation of QR (liposomes) and to determine the effect of its intraperitoneal pretreatment on the amelioration of Co-Amox-induced liver damage in male rats. Four groups of rats were defined: control, QR liposomes (QR-lipo), Co-Amox, and Co-Amox and QR-lipo. Liver injury severity in rats was evaluated for all groups through measurement of serum liver enzymes, liver antioxidant status, proinflammatory mediators, and microbiota modulation. The results revealed that QR-lipo reduced the severity of Co-Amox-induced hepatic damage in rats, as indicated by a reduction in serum liver enzymes and total liver antioxidant capacity. In addition, QR-lipo upregulated antioxidant transcription factors SIRT1 and Nrf2 and downregulated liver proinflammatory signatures, including IL-6, IL-1ß, TNF-α, NF-κB, and iNOS, with upregulation in the anti-inflammatory one, IL10. QR-lipo also prevented Co-Amox-induced gut dysbiosis by favoring the colonization of Lactobacillus, Bifidobacterium, and Bacteroides over Clostridium and Enterobacteriaceae. These results suggested that QR-lipo ameliorates Co-Amox-induced liver damage by targeting SIRT1/Nrf2/NF-κB and modulating the microbiota.

Hematological consequences of polyethylene microplastics toxicity in male rats: Oxidative stress, genetic, and epigenetic links.

Microplastics (MPs) pollution is a newly emerging environmental issue. MPs can accumulate within animals and humans, which can pose a serious health threat. Petroleum-based polyethylene (PE) is one of the most popular plastics. Accordingly, its exposure rates have steadily increased over the years. This study aimed to analyze the effects of PE-MPs on the hematological system of albino rats and the epigenetic effect. Five groups of adult male eight-weeks-old rats received either distilled water, corn oil, 3.75 mg/kg PE-MPs, 15 mg/kg PE-MPs, or 60 mg/kg of PE-MPs, daily by oral gavage for 35 days. PE-MPs significantly increased the body weights of the rats and lipid peroxidation, with concomitant reduction of superoxide dismutase activity and depletion of reduced glutathione, thus adversely affecting oxidants/antioxidants balance. Moreover, PE-MPs increased the % of abnormal RBCs, irregular cells, tear drop cells, Schistocyte cells, and folded cells. The genotoxic effects on DNA were evident by increased DNA damage, confirmed by the comet assay, in addition to increased DNA methylation. The effects of PE-MPs have been shown to be dose correlated. In conclusion, this study provides evidence of dose-related PE-MPs-induced hematological, genotoxic, and epigenetic effects in mammals, and thus emphasizes the potentially hazardous health effects of environmental PE-MPs.

Exploiting Signal Joint T Cell Receptor Excision Circle to Investigate the Impact of COVID-19 and Autoimmune Diseases on Age Prediction and Immunosenescence.

Signal joint T cell receptor excision circles (sjTRECs) are a promising marker for age estimation and immunosenescence in different ethnic groups. Several limitations are expected to overshadow their use as accurate markers for age prediction. The current study was conducted to determine the influence of immunologic disorders, such as autoimmune diseases and COVID-19, on the accuracy of sjTRECs as molecular markers for age estimation and immunosenescence among living Egyptians. Peripheral blood sjTRECs level was measured by qPCR in 90 autoimmune patients, 58 COVID-19 patients, and 85 healthy controls. The mean dCt values were significantly (p = 0.0002) different between the three groups, with the highest values in healthy subjects, followed by autoimmune and COVID-19 patients. A significant negative correlation was identified between the sjTRECs levels and ages in all studied cases. There were significant positive correlations between chronological age and predicted age for healthy individuals, autoimmune, and COVID-19 patients with mean absolute deviations (MAD) of 9.40, 11.04, and 9.71, respectively. The two patients' groups exhibited early immunosenescence, which was more noticeable among the young adults with COVID-19 and autoimmune patients of age range (18-49 years). Autoimmunity may represent a critical factor impacting the accuracy of sjTRECs quantitation for age prediction.