Exosomes/microvesicles target SARS-CoV-2 via innate and RNA-induced immunity with PIWI-piRNA system.

Murine neural stem cells (NSCs) were recently shown to release piRNA-containing exosomes/microvesicles (Ex/Mv) for exerting antiviral immunity, but it remains unknown if these Ex/Mv could target SARS-CoV-2 and whether the PIWI-piRNA system is important for these antiviral actions. Here, using in vitro infection models, we show that hypothalamic NSCs (htNSCs) Ex/Mv provided an innate immunity protection against SARS-CoV-2. Importantly, enhanced antiviral actions were achieved by using induced Ex/Mv that were derived from induced htNSCs through twice being exposed to several RNA fragments of SARS-CoV-2 genome, a process that was designed not to involve protein translation of these RNA fragments. The increased antiviral effects of these induced Ex/Mv were associated with increased expression of piRNA species some of which could predictably target SARS-CoV-2 genome. Knockout of piRNA-interacting protein PIWIL2 in htNSCs led to reductions in both innate and induced antiviral effects of Ex/Mv in targeting SARS-CoV-2. Taken together, this study demonstrates a case suggesting Ex/Mv from certain cell types have innate and adaptive immunity against SARS-CoV-2, and the PIWI-piRNA system is important for these antiviral actions.

In vitro study to evaluate the cytotoxicity of BPA analogues based on their oxidative and genotoxic potential using human peripheral blood cells.

Although Bisphenol-A (BPA) has been found to exhibit toxicological properties such as genotoxicity and oxidative stress, yet there is very little data available on its analogues. Since the replacement of BPA by its analogues, their presence has been found to increase in the environment leading to increased human exposure that makes it essential to investigate their toxic effects. Therefore, we explored the genotoxic and oxidative potential of two common BPA analogues, Bisphenol-B (BPB) and Bisphenol-F (BPF). Both analogues were found to induce cytotoxicity in human peripheral blood cells. They also caused an increase in reactive oxygen species levels leading to a decrease in GSH and an increase in LPO levels. Comet assay also suggested them to be genotoxic. Therefore, bisphenols were found capable of inducing cytotoxicity via oxidative stress and genotoxicity.

Occurrence, toxicity and endocrine disrupting potential of Bisphenol-B and Bisphenol-F: A mini-review.

Recent imposition of restriction on the use of Bisphenol-A (BPA) paved the way for entry of its analogues in the market. Bisphenol-B and Bisphenol-F are the major analogues of commercial value. Thus, their increasing production and application make them vulnerable to human exposure. Since these analogues have been recently reported to show toxic properties similar to BPA, so they have attracted remarkable scientific attention. This mini-review summarizes the recent reports on the occurrence, toxicity and endocrine disruption of these two BPA analogues.

Computational study suggesting reconsideration of BPA analogues based on their endocrine disrupting potential estimated by binding affinities to nuclear receptors.

Due to its endocrine disrupting nature Bisphenol-A (BPA), a chemical used in the plastic industry was placed under a ban which provided an incentive for its replacement by bisphenol and non-bisphenol based plasticizers. The use of bisphenol replacements in industry is increasing day by day. Therefore, it becomes prudent to put them under scrutiny. We studied the direct interaction of 45 BPA replacements and BPA with 12 nuclear receptors using an endocrine disruptome docking program (Kolsek et al., 2014b). Infact, the mechanism which could involve a direct interaction of ligands with nuclear receptors was taken into consideration. We found that the replacements, which were analogues of BPA, easily interacted with nuclear receptors due to the presence of phenyl moiety and their hydrophobic nature probably crucial for their endocrine disrupting potential. We therefore, strongly recommend reconsideration of BPA analogues in industries.

Comparative study of the interactions between bisphenol-A and its endocrine disrupting analogues with bovine serum albumin using multi-spectroscopic and molecular docking studies.

Interaction studies of bisphenol analogues; biphenol-A (BPA), bisphenol-B (BPB), and bisphenol-F (BPF) with bovine serum albumin (BSA) were performed using multi-spectroscopic and molecular docking studies at the protein level. The mechanism of binding of bisphenols with BSA was dynamic in nature. SDS refolding experiments demonstrated no stabilization of BSA structure denatured by BPB, however, BSA denatured by BPA and BPF was found to get stabilized. Also, CD spectra and molecular docking studies revealed that BPB bound more strongly and induced more conformational changes in BSA in comparison to BPA. Hence, this study throws light on the replacement of BPA by its analogues and whether the replacement is associated with a possible risk, raising a doubt that perhaps BPB is not a good substitute of BPA.

Binding of Bisphenol-F, a bisphenol analogue, to calf thymus DNA by multi-spectroscopic and molecular docking studies.

BPF (Bisphenol-F), a member of the bisphenol family, having a wide range of industrial applications is gradually replacing Bisphenol-A. It is a recognized endocrine disrupting chemical (EDC). EDCs have been implicated in increased incidences of breast, prostate and testis cancers besides diabetes, obesity and decreased fertility. Due to the adverse effects of EDCs on human health, attempts have been directed towards their mechanism of toxicity especially at the molecular level. Hence, to understand the mechanism at the DNA level, interaction of BPF with calf thymus DNA was studied employing multi-spectroscopic, voltammetric and molecular docking techniques. Fluorescence spectra, cyclic voltammetry (CV), circular dichroism (CD) and molecular docking studies of BPF with DNA were suggestive of minor groove binding of BPF. UV-visible absorption and fluorescence spectra suggested static quenching due to complex formation between BPF and ctDNA. Hoechst 33258 (HO) and ethidium bromide (EB) displacement studies further confirmed such mode of BPF interaction. Thermodynamic and molecular docking parameters revealed the mechanism of binding of BPF with ctDNA to be favorable and spontaneous due to negative ΔG and occurring through hydrogen bonds and van der waals interactions. BPF induced DNA cleavage under in vitro conditions by plasmid nicking assay suggested it to be genotoxic.

Computational study involving identification of endocrine disrupting potential of herbicides: Its implication in TDS and cancer progression in CRPC patients.

Several environmental pollutants, including herbicides, act as endocrine disrupting chemicals (EDCs). They can cause cancer, diabetes, obesity, metabolic diseases and developmental problems. Present study was conducted to screen 608 herbicides for evaluating their endocrine disrupting potential. The screening was carried out with the help of endocrine disruptome docking program, http://endocrinedisruptome.ki.si (Kolsek et al., 2013). This program screens the binding affinity of test ligands to 12 major nuclear receptors. As high as 252 compounds were capable of binding to at least three receptors wherein 10 of them showed affinity with at-least six receptors based on this approach. The latter were ranked as potent EDCs. Majority of the screened herbicides were acting as antagonists of human androgen receptor (hAR). A homology modeling approach was used to construct the three dimensional structure of hAR to understand their binding mechanism. Docking results reveal that the most potent antiandrogenic herbicides would bind to hydrophobic cavity of modeled hAR and may lead to testicular dysgenesis syndrome (TDS) on fetal exposure. However, on binding to T877 mutant AR they seem to act as agonists in castration-resistant prostate cancer (CRPC) patients.

From BPA to its analogues: Is it a safe journey?

Bisphenol-A (BPA) is one of the most abundant synthetic chemicals in the world due to its uses in plastics. Its widespread exposure vis-a-vis low dose effects led to a reduction in its safety dose and imposition of ban on its use in infant feeding bottles. This restriction paved the way for the gradual market entry of its analogues. However, their structural similarity to BPA has put them under surveillance for endocrine disrupting potential. The application of these analogues is increasing and so are the studies reporting their toxicity. This review highlights the reasons which led to the ban of BPA and also reports the exposure and toxicological data available on its analogues. Hence, this compilation is expected to answer in a better way whether the replacement of BPA by these analogues is safer or more harmful?