Flavonoids and PI3K/Akt/mTOR Signaling Cascade: A Potential Crosstalk in Anticancer Treatment.

Cancer is one of the leading causes of death worldwide. A slight decline in mortality has been noted, but the currently available treatment options did not give an expected outcome and are associated with several side effects resulting a substantial economic burden. The advent of plant-based treatment is rising because of its ease of use, ready availability, cost-effectiveness, and low/no toxicity. In recent years, flavonoids with their diverse physico-biological properties have gained the scientific community's attention for the treatment of various forms of cancer. Different flavonoids, especially, flavonols (quercetin, kaempferol, fisetin, and isorhamnetin), flavanones (hesperidin and naringin), and anthocyanins, have shown potent anticancer activities affecting various signaling cascades. Among those, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway is widely known to play a significant role in different physio-cellular activities, which triggers malignant transformation and is considered a key target for anticancer compounds. This pathway plays a vital role in regulating the cell cycle, metabolism, survival, and proliferation. The flavonoids exhibit their anticancer activity via different molecular pathways, including PI3K/Akt/mTOR. In the current piece of paper, our focus is to underpin the action of the above-mentioned flavonoids against different cancers, mainly covering in-vitro data, through PI3K/Akt/mTOR targeting.

Elucidating Treatment of Alzheimer's Disease via Different Receptors.

Alzheimer's disease (AD) is an irreversible multifaceted neurodegenerative disorder that gradually degrades neuronal cells. Presently, it is the most common reason for the memory loss and dementia in older individuals. It is patho-physiologically described by extracellular amyloid beta (Aß) deposition, intracellular neurofibrillary tangles (NFTs) retention, neuronal decline, and neurotransmitter system derangement. Various receptors such as nicotinic acetylcholine, N-methyl-D-aspartate, insulin, serotonin, adenosine, and histamine are actively involved in the physiological progression of AD. Till date memantine and only four other acetylcholinesterase inhibitors have been approved for the treatment of AD by US Food and Drug Administration (US-FDA). Hence, there is a critical need to explore and develop novel and helpful management systems which could specifically target different receptors involved in AD progression. We believe that these receptors targeting will either impede the disease onset or slow down its pathogenesis. In the present review, we tried to uncover some receptors that could be blocked by novel inhibitors and ultimately used for the therapeutic management of AD.

Neo-epitopes on crotonaldehyde modified DNA preferably recognize circulating autoantibodies in cancer patients.

DNA damage is one of the leading causes of various pathological conditions including carcinogenesis. Crotonaldehyde is a 4-carbon unsaturated bifunctional aldehyde which is found ubiquitously and produced both exogenously and endogenously. It reacts with deoxyguanosine and form adducts with DNA. These adducts were detected and found involved in tumor formation in rats treated with crotonaldehyde. In the present study, structural changes in DNA by crotonaldehyde were evaluated by Fourier transform infrared (FTIR) spectroscopy, differential scanning colorimetry (DSC), dynamic light scattering (DLS), high-performance liquid chromatography (HPLC), and atomic force microscopy (AFM). Enhanced binding was observed in cancer autoantibodies with the DNA modified by crotonaldehyde than the native counterpart. Immunological studies revealed enhanced binding of cancer autoantibodies with crotonaldehyde modified DNA, compared to the native form. Furthermore, lymphocyte DNA isolated from cancer patients demonstrated considerable recognition of anti-Cro-DNA IgG as compared to the DNA from healthy individuals. Therefore, we suggest that crotonaldehyde modified DNA presents unique epitopes, that may trigger autoantibody induction in cancer patients.

Preferential recognition of peroxynitrite-modified human serum albumin by circulating autoantibodies in cancer.

Peroxynitrite is a potent oxidizing and nitrating agent and has in vivo existence. Several studies have shown the damaging role of this molecule in biological system. Human serum albumin (HSA), being most abundant plasma protein, is easily targeted by different oxidizing and nitrating agents. Free radicals increase the onset of different cancers as evident by several researchers. In the present study, structural perturbations in HSA by peroxynitrite were observed by MALDI-MS, DSC and DLS. Immunological studies showed enhanced binding of peroxynitrite-modified HSA with cancer autoantibodies, compared to the native protein. A decline in the antioxidant property of peroxynitrite-modified HSA was also observed. Therefore, we may conclude that peroxynitrite exposure results in structural alteration and hence generation of neo-epitopes in HSA molecule along with the decrease in its antioxidant property. The possible role of peroxynitrite-modified HSA in carcinogenesis has been discussed.

Genotoxicity and immunogenicity of crotonaldehyde modified human DNA.

DNA damage plays an important role in mutagenesis, carcinogenesis, aging and several other pathophysiological conditions. Crotonaldehyde is a four carbon unsaturated bifunctional aldehyde produced both exogenously and endogenously. It reacts with deoxyguanosine in DNA to form adducts. In this study, crotonaldehyde induced modifications of human DNA were evaluated by various physicochemical techniques. Crosslinking of DNA was evident by agarose gel electrophoresis of S1 nuclease digested DNA, hydroxyapatite chromatography and comet assay. The crotonaldehyde modified DNA induced high titer antibodies in experimental animals which showed high specificity towards the immunogen. Spectroscopic studies revealed structural alterations in the DNA molecule upon crotonaldehyde treatment which result in the generation of neoepitopes and enhanced immunogenicity. The possible role of crotonaldehyde-modified DNA in cancer has been suggested.