Oxidative Stress and Natural Antioxidants: Back and Forth in the Neurological Mechanisms of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD.

Therapeutic Targeting of Mitochondrial Plasticity and Redox Control to Overcome Cancer Chemoresistance.

Significance: Mitochondria are subcellular organelles performing essential metabolic functions contributing to cellular bioenergetics and regulation of cell growth or death. The basic mitochondrial function in fulfilling the need for cell growth and vitality is evidenced whereby cancer cells with depleted mitochondrial DNA (rho zero, p0 cells) no longer form tumors until newly recruited mitochondria are internalized into the rho zero cells. Herein lies the absolute dependency on mitochondria for tumor growth. Hence, mitochondria are key regulators of cell death (by apoptosis, necroptosis, or other forms of cell death) and are, therefore, important targets for anticancer therapy. Recent Advances: Mitochondrial plasticity regulating their state of fusion or fission is key to the chemoresistance properties of cancer cells by promoting pro-survival pathways, enabling the mitochondria to mitigate against the cellular stresses and extreme conditions within the tumor microenvironment caused by chemotherapy, hypoxia, or oxidative stress. Critical Issues: This review discusses many characteristics of mitochondria, the processes and pathways controlling the dynamic changes occurring in the morphology of mitochondria, the roles of reactive oxygen species, and their relationship with mitochondrial fission or fusion. It also examines the relationship of redox to mitophagy when mitochondria become compromised and its effect on cancer cell survival, stemness, and the changes accompanying malignant progression from primary tumors to metastatic disease. Future Directions: A challenging question that arises is whether the changes in mitochondrial dynamics and their regulation can provide opportunities for improving drug targeting during cancer treatment and enhancing survival outcomes. Antioxid. Redox Signal. 39, 591-619.

Targeting the redox imbalance in mitochondria: A novel mode for cancer therapy.

Changes in reactive oxygen species (ROS) levels affect many aspects of cell behavior. During carcinogenesis, moderate ROS production modifies gene expression to alter cell function, elevating metabolic activity and ROS. To avoid extreme ROS-activated death, cancer cells increase antioxidative capacity, regulating sustained ROS levels that promote growth. Anticancer therapies are exploring inducing supranormal, cytotoxic oxidative stress levels either inhibiting antioxidative capacity or promoting excess ROS to selectively destroy cancer cells, triggering mechanisms such as apoptosis, autophagy, necrosis, or ferroptosis. This review exemplifies pro-oxidants (natural/synthetic/repurposed drugs) and their clinical significance as cancer therapies providing revolutionary approaches.

Molecular docking and simulation studies of phytocompounds derived from Centella asiatica and Andrographis paniculata against hexokinase II as mitocan agents.

Hexokinase II (HK2), a glycolytic enzyme is commonly overexpressed in most cancer types. The overexpression of HK2 is reported to promote the survival of cancer cells by facilitating the constant ATP generation and protecting the cancer cell against apoptotic cell death. Hence, HK2 is considered as potential target of many mitochondria targeting anticancerous agents (referred to as mitocans). Most of the existing mitocans are synthetic and hence such compounds are observed to exhibit adverse effects, witnessed through many experimental outcomes. These limitations necessitates hunting for an alternative source of mitocans with minimum/no side effects. The need for an alternative therapy points towards the ethnomedicinal herbs, known for their minimal side effects and effectiveness. Henceforth recent studies have put forth the effort to utilize anticancer herbs in formulating naturally derived mitocans as an add-on to improve cancer therapeutics. So, our study aims to explore the HK2 targeting potential of phytocompounds from the selected anticancerous herbs Andrographis paniculata (AP) and Centella asiatica (CA). 60 phytocompounds collectively from CA and AP were docked against HK2 and drug-likeness prediction of the selected phytocompounds was performed to screen the best possible ligand for HK2. Furthermore, the docked complexes were subjected to molecular dynamics simulations (MDS) to analyse the molecular mechanism of protein-ligand interactions. The results of the study suggest that the natural compounds asiatic acid and bayogenin (from CA) and andrographolide (from AP) can bepotential natural mitocans by targeting HK2. Further experimental studies (in-vitro and in-vivo) are required to validate the results.

Mitochondrial defects: An emerging theranostic avenue towards Alzheimer's associated dysregulations.

Mitochondria play a crucial role in expediting the energy homeostasis under varying environmental conditions. As mitochondria are controllers of both energy production and apoptotic pathways, they are also distinctively involved in controlling the neuronal cell survival and/or death. Numerous factors are responsible for mitochondria to get degraded with aging and huge functional failures in mitochondria are also found to be associated with the commencement of numerous neurodegenerative conditions, including Alzheimer's disease (AD). A large number of existing literatures promote the pivotal role of mitochondrial damage and oxidative impairment in the pathogenesis of AD. Numerous mitochondria associated processes such as mitochondrial biogenesis, fission, fusion, mitophagy, transportation and bioenergetics are crucial for proper functioning of mitochondria but are reported to be defective in AD patients. Though, the knowledge on the precise and in-depth mechanisms of these actions is still in infancy. Based upon the outcome of various significant studies, mitochondria are also being considered as therapeutic targets for AD. Here, we review the current status of mitochondrial defects in AD and also summarize the possible role of these defects in the pathogenesis of AD. The various approaches for developing the mitochondria-targeted therapies are also discussed here in detail. Consequently, it is suggested that improving mitochondrial activity via pharmacological and/or non-pharmacological interventions could postpone the onset and slow the development of AD. Further research and consequences of ongoing clinical trials should extend our understanding and help to validate conclusions regarding the causation of AD.

Nanotherapeutic approaches to target mitochondria in cancer.

Treatment of cancer cells exemplifies a difficult test in the light of challenges associated with the nature of cancer cells and the severe side effects too. After making a large number of trials using both traditional and advanced therapies (immunotherapy and hormone therapy), approaches to design new therapies have reached a saturation level. However, nanotechnology-based approaches exhibit higher efficacy and great potential to bypass many of such therapeutic limitations. Because of their higher target specificity, the use of nanoparticles offers incredible potential in cancer therapeutics. Mitochondria, acting as a factory of energy production in cells, reveal an important role in the death as well as the survival of cells. Because of its significant involvement in the proliferation of cancer cells, it is being regarded as an important target for cancer therapeutics. Numerous studies reveal that nanotechnology-based approaches to directly target the mitochondria may help in improving the survival rate of cancer patients. In the current study, we have detailed the significance of mitochondria in the development of cancer phenotype, as well as indicated it as the potential targets for cancer therapy. Our study further highlights the importance of different nanoparticle-based approaches to target mitochondria of cancer cells and the associated outcomes of different studies. Though, nanotechnology-based approaches to target mitochondria of cancer cells demonstrate a potential and efficient way in cancer therapeutics. Yet, further study is needed to overcome the linked limitations.

Mitophagy impairment in neurodegenerative diseases: Pathogenesis and therapeutic interventions.

Neurons are specialized cells, requiring a lot of energy for its proper functioning. Mitochondria are the key cellular organelles and produce most of the energy in the form of ATP, required for all the crucial functions of neurons. Hence, the regulation of mitochondrial biogenesis and quality control is important for maintaining neuronal health. As a part of mitochondrial quality control, the aged and damaged mitochondria are removed through a selective mode of autophagy called mitophagy. However, in different pathological conditions, this process is impaired in neuronal cells and lead to a variety of neurodegenerative disease (NDD). Various studies indicate that specific protein aggregates, the characteristics of different NDDs, affect this process of mitophagy, adding to the severity and progression of diseases. Though, the detailed process of this association is yet to be explored. In light of the significant role of impaired mitophagy in NDDs, further studies have also investigated a large number of therapeutic strategies to target mitophagy in these diseases. Our current review summarizes the abnormalities in different mitophagy pathways and their association with different NDDs. We have also elaborated upon various novel therapeutic strategies and their limitations to enhance mitophagy in NDDs that may help in the management of symptoms and increasing the life expectancy of NDD patients. Thus, our study provides an overview of mitophagy in NDDs and emphasizes the need to elucidate the mechanism of impaired mitophagy prevalent across different NDDs in future research. This will help designing better treatment options with high efficacy and specificity.

Targeted Delivery for Neurodegenerative Disorders Using Gene Therapy Vectors: Gene Next Therapeutic Goals.

The technique of gene therapy, ever since its advent nearly fifty years ago, has been utilized by scientists as a potential treatment option for various disorders. This review discusses some of the major neurodegenerative diseases (NDDs) like Alzheimer's disease (AD), Parkinson's Disease (PD), Motor neuron diseases (MND), Spinal Muscular Atrophy (SMA), Huntington's Disease (HD), Multiple Sclerosis (MS), etc. and their underlying genetic mechanisms along with the role that gene therapy can play in combating them. The pathogenesis and the molecular mechanisms specifying the altered gene expression of each of these NDDs have also been discussed in elaboration. The use of gene therapy vectors can prove to be an effective tool in the field of curative modern medicine for the generations to come. Therefore, consistent efforts and progressive research towards its implementation can provide us with powerful treatment options for disease conditions that have so far been considered as incurable.

Natural Agents Targeting Mitochondria in Cancer.

Mitochondria are the key energy provider to highly proliferating cancer cells, and are subsequently considered one of the critical targets in cancer therapeutics. Several compounds have been studied for their mitochondria-targeting ability in cancer cells. These studies' outcomes have led to the invention of "mitocans", a category of drug known to precisely target the cancer cells' mitochondria. Based upon their mode of action, mitocans have been divided into eight classes. To date, different synthetic compounds have been suggested to be potential mitocans, but unfortunately, they are observed to exert adverse effects. Many studies have been published justifying the medicinal significance of large numbers of natural agents for their mitochondria-targeting ability and anticancer activities with minimal or no side effects. However, these natural agents have never been critically analyzed for their mitochondria-targeting activity. This review aims to evaluate the various natural agents affecting mitochondria and categorize them in different classes. Henceforth, our study may further support the potential mitocan behavior of various natural agents and highlight their significance in formulating novel potential anticancer therapeutics.