Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications.

Mitophagy, a specialised form of autophagy, selectively targeting damaged or dysfunctional mitochondria, and is crucial for maintaining cellular homeostasis and mitochondrial quality control. Dysregulation of mitophagy contributes to various pathological conditions, including cancer, neurodegenerative and cardiovascular diseases. This review presents a comprehensive analysis of the molecular mechanisms, regulatory pathways, and interplay with other cellular processes governing mitophagy, emphasizing its importance in physiological and pathological contexts. We explore the PINK1/Parkin-mediated and receptor-mediated mitophagy pathways, encompassing BNIP3/NIX, FUNDC1, and Bcl2-L-13. Additionally, we discuss post-translational modifications and cellular signalling pathways modulating mitophagy, as well as the connection between mitophagy and ageing, highlighting the decline in mitophagy efficiency and its impact on age-related pathologies. The review also investigates mitophagy's role in human diseases such as cancer, myocardial ischemia-reperfusion injury, Parkinson's, and Alzheimer's disease. We assess the potential of mitophagy-targeting therapeutic strategies, focusing on the development of dietary therapies, small molecules, drugs, and gene therapy approaches that modulate mitophagy levels and efficiency for treating these diseases and dysfunctions commonly observed in ageing individuals. In summary, this review offers an extensive overview of the molecular mechanisms and regulatory networks involved in mitophagy, its association with autophagy, and implications in human health and disease. By examining the potential of mitophagy-modulating therapies in disease and non-disease settings, we aim to inspire further research to develop innovative treatment strategies for various pathological conditions linked to mitochondrial dysfunction and to ageing.

A review of biologically active flavonoids as inducers of autophagy and apoptosis in neoplastic cells and as cytoprotective agents in non-neoplastic cells.

Phytochemicals are a diverse group of compounds found in various fruits, vegetables, nuts, and legumes. Many phytochemicals have been observed to possess health benefits. Some have been found to be chemoprotective or can act as chemotherapeutics by inducing autophagy, apoptosis, or otherwise regulating the cell cycle. Many also act as potent antioxidants. Flavonoids are a subclass of bioactive phytochemicals consisting of two phenolic benzene rings, joined together by a heterocyclic pyran or pyrone. It has been observed in multiple studies that there is a correlation between diets rich in flavonoids and a reduction in cancer levels, heart disease, neurodegenerative diseases, and other pathologies. As foods containing flavonoids are widely consumed, and their mechanisms of action are still only partially understood, this review was compiled to compare the effects and mechanisms of action of some of the most widely characterized and publicized flavonoids. The flavonoids silibinin, quercetin, isorhamnetin, luteolin, curcumin genkwanin, and acacetin, together with flavonoid extracts from papaw and Tephroseris kirilowii (Turcz) Holub, a member of the Daisy family, were found to be potent regulators of the cell cycle. The decision to overview these specific flavonoids was based on their therapeutic effects, and/or their potential effects. The sparsity of data comparing these flavonoids was also a key consideration. These flavonoids all modulated to some extent the pathways of autophagy and/or apoptosis and regulated the cell cycle, inflammation, and free radical levels. This explains why they are protective of healthy or moderately damaged cells, but toxic to neoplastic or pre-cancerous cells.

A novel combined resveratrol/berberine phytochemotheraputic using the HePG2 cell line as a model for the treatment of hepatocarcinoma.

The results presented herein show that at clinically relevant concentrations (0-30 µM), the well-tolerated phytochemical berberine (BER) induces cell death in cultured human hepatocarcinoma (HepG2) cells as a model for liver cancer, primarily via apoptosis. Similar, relatively low-concentration single treatments using the structurally related phytochemical resveratrol (RSV), had little or no effect on cell viability but inhibited the cell cycle, while simultaneously increasing the strength of cellular adhesion. When used in combination, an RSV/BER cotreatment appeared to retain the ability of a single RSV treatment to increase cellular adhesion, but also induced a massive loss in hepatocarcinoma cellular viability, inducing cell death in more than 90% of cells. This model, therefore, suggests that it may be possible to use RSV to stabilise hepatocarcinomas against metastasis while using cotreatment with BER to simultaneously induce cell death. By measuring the changes in the activity of the pleiotropic enzyme transglutaminase 2 (TGM2), which is known to be overexpressed in hepatocarcinoma and many other tumours, we hypothesise a role for this enzyme in the activities of these two phytochemicals, and propose the potential use of this RSV/BER cotreatment as a chemotherapeutic in TGM2+ hepatocarcinomas.

Cell death: a review of the major forms of apoptosis, necrosis and autophagy.

Cell death was once believed to be the result of one of two distinct processes, apoptosis (also known as programmed cell death) or necrosis (uncontrolled cell death); in recent years, however, several other forms of cell death have been discovered highlighting that a cell can die via a number of differing pathways. Apoptosis is characterised by a number of characteristic morphological changes in the structure of the cell, together with a number of enzyme-dependent biochemical processes. The result being the clearance of cells from the body, with minimal damage to surrounding tissues. Necrosis, however, is generally characterised to be the uncontrolled death of the cell, usually following a severe insult, resulting in spillage of the contents of the cell into surrounding tissues and subsequent damage thereof. Failure of apoptosis and the resultant accumulation of damaged cells in the body can result in various forms of cancer. An understanding of the pathways is therefore important in developing efficient chemotherapeutics. It has recently become clear that there exists a number of subtypes of apoptosis and that there is an overlap between apoptosis, necrosis and autophagy. The goal of this review is to provide a general overview of the current knowledge relating to the various forms of cell death, including apoptosis, necrosis, oncosis, pyroptosis and autophagy. This will provide researchers with a summary of the major forms of cell death and allow them to compare and contrast between them.