TDP-43 as a therapeutic target in neurodegenerative diseases: Focusing on motor neuron disease and frontotemporal dementia.

A common feature of adult-onset neurodegenerative diseases is the presence of characteristic pathological accumulations of specific proteins. These pathological protein depositions can vary in their protein composition, cell-type distribution, and intracellular (or extracellular) location. For example, abnormal cytoplasmic protein deposits which consist of the TDP-43 protein are found within motor neurons in patients with amyotrophic lateral sclerosis (ALS, a common form of motor neuron disease) and frontotemporal dementia (FTD). The presence of these insoluble intracellular TDP-43 inclusions suggests that restoring TDP-43 homeostasis represents a potential therapeutical strategy, which has been demonstrated in alleviating neurodegenerative symptoms in cell and animal models of ALS/FTD. We have reviewed the mechanisms that lead to disrupted TDP-43 homeostasis and discussed how small molecule-based therapies could be applied in modulating these mechanisms. This review covers recent advancements and challenges in small molecule-based therapies that could be used to clear pathological forms of TDP-43 through various protein homeostasis mechanisms and advance the way towards finding effective therapeutical drug discoveries for neurodegenerative diseases characterized by TDP-43 proteinopathies, especially ALS and FTD. We also consider the wider insight of these therapeutic strategies for other neurodegenerative diseases.

Natural Bioactive Molecules as Neuromedicines for the Treatment/Prevention of Neurodegenerative Diseases.

The brain is vulnerable to different types of stresses, particularly oxidative stress as a result of oxygen requirements/utilization in the body. Large amounts of unsaturated fatty acids present in the brain increase this vulnerability. Neurodegenerative diseases (NDDs) are brain disorders that are characterized by the gradual loss of specific neurons and are attributed to broad evidence of cell-level oxidative stress. The accurate characterization of neurological disorders relies on several parameters along with genetics and environmental risk factors, making therapies less efficient to fight NDDs. On the way to tackle oxidative damage and discover efficient and safe therapies, bioactives are at the edge of NDD science. Naturally occurring bioactive compounds such as polyphenols, carotenoids, essential fatty acids, phytosterols, essential oils, etc. are particularly of interest owing to their potent antioxidant and anti-inflammatory activities, and they offer lots of brain-health-promoting features. This Review focuses on probing the neuroefficacy and bioefficacy of bioactives and their role in supporting relatively low antioxidative and low regenerative capacities of the brain, neurogenesis, neuroprotection, and ameliorating/treating NDDs.

Co-encapsulation of probiotics with prebiotics and their application in functional/synbiotic dairy products.

Oral administration of live probiotics along with prebiotics has been suggested with numerous beneficial effects for several conditions including certain infectious disorders, diarrheal illnesses, some inflammatory bowel diseases, and most recently, irritable bowel syndrome. Though, delivery of such viable bacteria to the host intestine is a major challenge, due to the poor survival of the ingested probiotic bacteria during the gastric transit, especially within the stomach where the pH is highly acidic. Although microencapsulation has been known as a promising approach for improving the viability of probiotics in the human digestive tract, the success rate is not satisfactory. For this reason, co-encapsulation of probiotics with probiotics has been practised as a novel alternative approach for further improvement of the oral delivery of viable probiotics toward their targeted release in the host intestine. This paper discusses the co-encapsulation technologies used for delivery of probiotics toward better stability and viability, as well the incorporation of co-encapsulated probiotics and prebiotics in functional/synbiotic dairy foods. The common encapsulation technologies (and the materials) used for this purpose, the stability and survival of co-encapsulated probiotics in the food, and the release behavior of the co-encapsulated probiotics in the gastrointestinal tract have also been explained. Most studies reported a significant improvement particularly in the viability of bacteria associated with the presence of prebiotics. Nevertheless, the previous research has mostly been carried out in the simulated digestion, meaning that future systematic research is to be carried out to investigate the efficacy of the co-encapsulation on the survival of the bacteria in the gut in vivo.

Nanovehicles for co-delivery of anticancer agents.

Effective cancer treatment remains a significant challenge in human healthcare. Although many different types of cancer therapy have been tested, scientists have now concluded that combinations of drugs, or drugs plus gene therapy, can target multiple pathways to fight cancer. Nanovehicles can increase drug uptake inside tumor cells, improve biodistribution and accumulation at tumor sites. The ability to deliver two or more anticancer drugs, genes, among others, at the same time and place will increase therapeutic effects while decreasing side effects and reducing the risk of multidrug resistance. This review discusses the advantages of nano-based co-delivery methods in cancer therapy, summarizes the common types of nanovehicles and their preparation methods, and covers some recent co-delivery studies in detail.

Nanocarrier-mediated brain delivery of bioactives for treatment/prevention of neurodegenerative diseases.

The treatment for brain disorders specifically neurodegenerative diseases (NDDs) has been a main challenge in the medical field. NDDs are progressive, disabling, and non-curable disorders that exhibit not only critical health issues on human sufferings but also the economic burden on the medicare systems. Due to the lack of efficient therapies to fight NDDs, it remains a challenging problem for physicians to find out new therapeutics to enhance the life quality of patients suffering from NDDs. In addition to genetics and environmental risk factors, high cell level oxidative stress has been stated as one of the most known etiologies in NDDs. Given the high anti-inflammatory and antioxidant potentials of naturally occurring bioactive compounds, they have been becoming interested therapeutics for brain disorders, which could provide ameliorating effects on different brain disorders. These substances can be involved in various neurodegeneration pathways to exhibit their health-promoting effects. Despite their health-promoting effects, they have a low bioavailability and poorly delivered into central nervous systems due to blood-central nervous system (CNS) barriers, which causes inefficient delivery of bioactives. A potential solution for tackling these obstacles lies in revolutionary nanoengineered platforms. Therefore, this review will focus on bioactive-loaded nanocarriers that can improve the efficiency of bioactive compounds including their blood circulation time, bioavailability, evade immune system, and transporting them to CNS to release their potential effects on treating and/or preventing neurodegeneration progress in NDDs.

Development of behenic acid-ethyl cellulose oleogel stabilized Pickering emulsions as low calorie fat replacer.

This study investigated the optimization of thermal, functional and rheological properties of Ethyl Cellulose (EC)-based oleogel considering different concentrations of Behenic Acid (BA) and stability of water in oleogel (w/og) emulsions. The results showed that the combination of EC and BA improved the oleogel properties at specific ratios (2:4 and 1:5 wt%). High strength (G' > 1000 mPa) with good thermo-responsive and viscoelastic behavior in the range of 45-60 °C and low loss of oil (<0.2%) were observed in these oleogel formulations. Polarized light microscopy images and XRD results showed the presence of crystals and high proportion of crystalline regions in the mentioned formulations. There were no significant differences among solid fat content (SFC) of EC contained oleogels. The FTIR results indicated new hydrogen bonds formation. The w/og stabilized emulsions with EC: BA (1:5 wt%) oleogel showed high physical stability even at high ratios of disperse phase (5 to 45 wt% of water). The particle size and polydispersity index (PDI) of emulsions were reduced significantly to 250 nm and 0.19, respectively by increasing the ratio of water phase to 45:55 w/og. The oleogel and developed Pickering w/og emulsion has good potential in the formulation of low calorie food products.

Zein-CMC-PEG Multiple Nanocolloidal Systems as a Novel Approach for Nutra-Pharmaceutical Applications.

Purpose: Hydrophobic nutraceuticals are suffering from water solubility and physicochemical stabilities once administered to the body or food matrixes. The present study depicts the successful formulation of a zein-carboxymethyl cellulose (CMC) complex to stabilize a water in oil (W/O) emulsion to protect them from environmental and gastrointestinal conditions. The formulated water in oil in water (W/O/W) system was used for nanoencapsulating of hydrophobic nutraceutical, rutin, via protein-polysaccharide complexes. Methods: Zein nano particles smaller than 100 nm were produced using poly ethylene glycol (PEG 400) and Tween 80, which eliminates the use of ethanolic solutions in preparation of zein nanoparticles (ZN). CMC was then added to the ZN under magnetic stirrer to provide zein-CMC complex. A concentration of 20% CMC showed the smallest particle size (<100 nm). Rutin was dispersed in water in oil in water (W/O/W) emulsion stabilized by zein-CMC complex. A set of experiments such as encapsulation efficiency (EE%), encapsulation stability (ES%), and releasing rate of rutin were measured during 30 days of storage at 4°C. Results: Results showed that, produced multiple emulsion prepared with lower concentrations of Tween 80 (0.5%), ethanol: PEG: water ratio of 0:80:20 showed smaller size (89.8±4.2 nm). ES% at pH values of 1.2, 6.8, and 7.4 were 86.63±6.19, 91.54±3.89, and 97.13±2.39 respectively, indicating high pH tolerability of formulated W/O/W emulsions. Conclusion: These findings could pave a new approach in stabilizing W/O/W emulsions for encapsulating and controlling the release of water insoluble nutraceuticals/drugs.

Nano-Phytosome: A Developing Platform for Herbal Anti-Cancer Agents in Cancer Therapy.

BACKGROUND: Cancer is one of the main causes of death in the world. It has not yet been cured in an efficient manner and has remained a major challenge for current chemotherapy. OBJECTIVE: This review summarizes the latest investigations regarding the possible application of phytosome complexes for cancer therapy, their formulation techniques, and mechanism of transportation through phytosome. RESULTS: Nanotechnology opened a pioneer field in cancer therapy by modifying significant properties of drugs and their carriers. Nanotechnology utilizes various nanostructures to transport anti-cancer agents to the site of action. The greater stability of nanophytosomes is due to formation of chemical links between phospholipid molecules and phytoactive agents. Among several new drug delivery systems, phytosomes depict an advanced technology to deliver phytoactive compounds to the target site of action, and at present, several phytosome formulations are in clinical use. CONCLUSION: Potential anti-cancer properties of phytoconstituents are enhanced by phytosomal formulations.