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T2DM is a complex metabolic disorder characterized by hyperglycemia and glucose intolerance. It is recognized as one of the most common metabolic disorders and its prevalence continues to raise major concerns in healthcare globally. Alzheimer's disease (AD) is a gradual neurodegenerative brain disorder characterized by the chronic loss of cognitive and behavioral function. Recent research suggests a link between the two diseases. Considering the shared characteristics of both diseases, common therapeutic and preventive agents are effective. Certain bioactive compounds such as polyphenols, vitamins, and minerals found in vegetables and fruits can have antioxidant and anti-inflammatory effects that allow for preventative or potential treatment options for T2DM and AD. Recently, it has been estimated that up to one-third of patients with diabetes use some form of complementary and alternative medicine. Increasing evidence from cell or animal models suggests that bioactive compounds may have a direct effect on reducing hyperglycemia, amplifying insulin secretion, and blocking the formation of amyloid plaques. One plant that has received substantial recognition for its numerous bioactive properties is Momordica charantia (M. charantia) , otherwise known as bitter melon, bitter gourd, karela, and balsam pear. M. charantia is utilized for its glucose-lowering effects and is often used as a treatment for diabetes and related metabolic conditions amongst the indigenous populations of Asia, South America, India, and East Africa. Several pre-clinical studies have documented the beneficial effects of M. charantia through various postulated mechanisms. Throughout this review, the underlying molecular mechanisms of the bioactive components of M. charantia will be highlighted. More studies will be necessary to establish the clinical efficacy of the bioactive compounds within M. charantia to effectively determine its pertinence in the treatment of metabolic disorders and neurodegenerative diseases, such as T2DM and AD.

Skeletal muscle atrophy is prevalent in a myriad of pathological conditions, such as diabetes, denervation, long-term immobility, malnutrition, sarcopenia, obesity, Alzheimer's disease, and cachexia. This is a critically important topic that has significance in the health of the current society, particularly older adults. The most damaging effect of muscle atrophy is the decreased quality of life from functional disability, increased risk of fractures, decreased basal metabolic rate, and reduced bone mineral density. Most skeletal muscle in humans contains slow oxidative, fast oxidative, and fast glycolytic muscle fiber types. Depending on the pathological condition, either oxidative or glycolytic muscle type may be affected to a greater extent. This review article discusses the prevalence of skeletal muscle atrophy and several mechanisms, with an emphasis on high-fat, high-sugar diet patterns, obesity, and diabetes, but including other conditions such as sarcopenia, Alzheimer's disease, cancer cachexia, and heart failure.

Neurodegenerative diseases are caused by the progressive loss of function or structure of nerve cells in the central nervous system. The most common neurodegenerative diseases include Alzheimer's disease, Huntington's disease, motor neuron disease, and Parkinson's disease. Although the physical or mental symptoms of neurodegenerative disease may be relieved by various treatment combinations, there are currently no strategies to directly slow or prevent neurodegeneration. Given the demographic evidence of a rapidly growing aging population and the associated prevalence of these common neurodegenerative diseases, it is paramount to develop safe and effective ways to protect against neurodegenerative diseases. Most neurodegenerative diseases share some common etiologies such as oxidative stress, neuroinflammation, and mitochondrial dysfunction. Genistein is an isoflavone found in soy products that have been shown to exhibit antioxidant, anti-inflammation, and estrogenic properties. Increasing evidence indicates the protective potential of genistein in neurodegenerative disorders. In this review, we aim to provide an overview of the role that genistein plays in delaying the development of neurodegenerative disease. PRACTICAL APPLICATIONS: Genistein is a naturally occurring isoflavone found mainly in soybean, but also green peas, legumes, and peanuts. Genistein is found to pass through the blood-brain barrier and possess a neuroprotective effect. In this review, we discuss studies in support of these actions and the underlying biological mechanisms. Together, these data indicate that genistein may hold neuroprotective effects in either delaying the onset or relieving the symptoms of neurodegenerative disease., (© 2022 Wiley Periodicals LLC.)

Diabetes and Alzheimer's disease are common chronic illnesses in the United States and lack clearly demonstrated therapeutics. Mitochondria, the "powerhouse of the cell", is involved in the homeostatic regulation of glucose, energy, and reduction/oxidation reactions. The mitochondria has been associated with the etiology of metabolic and neurological disorders through a dysfunction of regulation of reactive oxygen species. Mitochondria-targeted chemicals, such as the Szeto-Schiller-31 peptide, have advanced therapeutic potential through the inhibition of oxidative stress and the restoration of normal mitochondrial function as compared to traditional antioxidants, such as vitamin E. In this article, we summarize the pathophysiological relevance of the mitochondria and the beneficial effects of Szeto-Schiller-31 peptide in the treatment of Diabetes and Alzheimer's disease., (Copyright © 2021. Published by Elsevier Ltd.)

To date, there is no cure or effective treatment for Alzheimer's disease (AD), a chronic neurodegenerative condition that affects memory, language, and behavior. AD is characterized by neuroinflammation, accumulation of brain amyloid-beta (Aβ) oligomers and neurofibrillary tangles, increased neuronal apoptosis, and loss of synaptic function. Promoting regular exercise and a diet containing polyphenols are effective non-pharmacological approaches that prevent the progression of neurodegenerative diseases. In this study, we measured various conformational toxic species of Aβ and markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection after 5 months of exercise training (ET), resveratrol (Resv) treatment, or combination treatment in the 3xTg-AD mouse model of AD. Our main results indicate that Resv decreased neuroinflammation and accumulation of Aβ oligomers, increased levels of neurotrophins, synaptic markers, silent information regulator, and decreased markers of apoptosis, autophagy, endolysosomal degradation and ubiquitination in the brains of 3xTg-AD mice. ET improved some markers related to neuroprotection, but when combined with Resv treatment, the benefits achieved were as effective as Resv treatment alone. Our results show that the neuroprotective effects of Resv, ET or Resv and ET are associated with reduced toxicity of Aβ oligomers, suppression of neuronal autophagy, decreased apoptosis, and upregulation of key growth-related proteins.

As the population ages, obesity and metabolic complications as well as neurological disorders are becoming more prevalent, with huge economic burdens on both societies and families. New therapeutics are urgently needed. Nerve growth factor (NGF), first discovered in 1950s, is a neurotrophic factor involved in regulating cell proliferation, growth, survival, and apoptosis in both central and peripheral nervous systems. NGF and its precursor, proNGF, bind to TrkA and p75 receptors and initiate protein phosphorylation cascades, resulting in changes of cellular functions, and are associated with obesity, diabetes and its complications, and Alzheimer's disease. In this article, we summarize changes in NGF levels in metabolic and neuronal disorders, the signal transduction initiated by NGF and proNGF, the physiological and pathophysiological relevance, and therapeutic potential in treating chronic metabolic diseases and cognitive decline., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest with this manuscript., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Type 2 diabetes mellitus is a complicated metabolic disorder characterized by hyperglycemia and glucose intolerance. Alzheimer's disease is a progressive brain disorder characterized by a chronic loss of cognitive and behavioral function. Considering the shared characteristics of both diseases, common therapeutic and preventive agents may be effective. Bioactive compounds such as polyphenols, vitamins, and carotenoids found in vegetables and fruits can have antioxidant and anti-inflammatory effects. These effects make them suitable candidates for the prevention or treatment of diabetes and Alzheimer's disease. Increasing evidence from cell or animal models suggest that bioactive compounds may have direct effects on decreasing hyperglycemia, enhancing insulin secretion, and preventing formation of amyloid plaques. The possible underlying molecular mechanisms are described in this review. More studies are needed to establish the clinical effects of bioactive compounds.

High fat diet-induced obesity is associated with insulin resistance (IR) and other chronic, diet related illnesses, including dementia. Alzheimer disease is the most common form of dementia, and is characterized by the presence of amyloid plaques and neurofibrillary tangles in brain. This study was designed to determine whether diet-induced changes in peripheral insulin sensitivity could contribute to alterations in brain insulin signaling and cognitive functions. Six week old, male C57BL/6NHsd mice were randomly assigned a high fat diet (40% energy from fat) with 42g/L liquid sugar (HFS) added to the drinking water or a normal chow diet (12% energy from fat) for 14weeks. Metabolic phenotypes were characterized for energy expenditure, physical activity, and food intake, and glucose and insulin tolerance tests. In addition, we examined the changes in protein expression related to brain insulin signaling and cognitive function. Mice fed HFS exhibited a statistically significant increase in obesity, and lower glucose and insulin tolerance as compared to animals fed the normal chow diet. In brain, HFS elicited IR as evidenced by a significant decrease in tyrosine phosphorylation of insulin receptor and an increase serine phosphorylation of IRS-1. These changes were accompanied by inflammatory (NFκB, JNK) and stress responses (p38 MAPK, CHOP) in whole brain lysate. In addition, HFS mouse brain exhibited biochemical changes related to increased amyloid beta deposition and neurofibrillary tangle formation, and decreased synaptic plasticity. These results suggested changes in insulin sensitivity might contribute to cognitive impairment associated with the HFS diet in mice., (Copyright © 2016. Published by Elsevier B.V.)

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting elderly individuals at an alarming rate. It has become a global health crisis imposing tremendous social and economic burden on society. Although there is no cure for AD, it is important to identify and implement preventive strategies that may delay or prevent the symptoms, limit the burden, and improve the quality of life of those afflicted. Adequate nutrition and physical activity are the two potential lifestyle modifiable factors that have gained considerable interest for their potential in the prevention or management of this challenging disease. In this review, we discuss the beneficial effects of physical activity and adequate nutrition on minimizing the risk of developing AD., Methods: The research question was initially formulated in a structured and explicit way. Relevant studies were identified using a wide range of scientific databases. Their potential relevance was based on the criteria for inclusion and exclusion. The quality of selected studies was subjected to a more precise quality assessment using standard tools. A detailed description of the implemented intervention and how it differed from what the control group received was outlined. The effects of intervention on measurable outcomes for the study sample were applied., Results: One hundred and sixty-four references were included in the review comprising of epidemiological, longitudinal, cross-sectional, intervention and randomized controlled studies. This review highlighted the effect of various nutrient diet supplements on cognitive performance in humans as well as animals with AD and mild cognitive impairment (MCI). Moreover, the effect of physical exercise on the cognitive function in animal models with AD was outlined., Conclusion: The findings of this review highlight the therapeutic potential of combination of nutritionally adequate diet and physical activity in preventing or delaying the symptoms associated with AD pathology.

Amyloid beta (Aβ) protein is the primary proteinaceous deposit found in the brains of patients with Alzheimer's disease (AD). Evidence suggests that Aβ plays a central role in the development of AD pathology. Here, we show in PC12 cells, Aβ impairs tropomyosin receptor kinase A (TrkA) ubiquitination, phosphorylation, and its association with p75(NTR), p62, and TRAF6 induced by nerve growth factor. The ubiquitination and tyrosine phosphorylation of TrkA was also found to be impaired in postmortem human AD hippocampus compared to control. Interestingly, the nitrotyrosylation of TrkA was increased in AD hippocampus and this explains why the phosphotyrosylation and ubiquitination of TrkA was impaired. In AD brain, the production of matrix metalloproteinase-7 (MMP-7), which cleaves proNGF, was reduced, thereby leading to the accumulation of pro-NGF and a decrease in the level of active NGF. TrkA signaling events, including Ras/MAPK and phosphatidylinositol 3-kinase (PI3K)/Akt pathways, are deactivated with Aβ and in the human AD hippocampus. Findings show that Aβ blocks the TrkA ubiquitination and downstream signaling similar to AD hippocampus. Cell survival and differentiation are essential for living organisms. We propose that under normal conditions, nerve growth factor (NGF) leads to Tropomyosin receptor kinase A (TrkA) phosphorylation, ubiquitination and its association with p75(NTR), p62 and TRAF6, thereby promoting cell survival and differentiation. In diseased conditions such as Alzheimer's, proNGF leads to nitrotyrosylation of TrkA, thereby impairing its ubiquitination and downstream signaling which results in apoptosis. TRAF6 = tumor necrosis factor receptor-associated factor 6; Ub = ubiquitin., (© 2015 International Society for Neurochemistry.)

Epidemiological and observational studies indicate a positive correlation between type 2 diabetes (T2DM) and dementia, with an increased risk of dementia and Alzheimer's disease (AD) associated with insulin-treated diabetes patients. The purpose of this review is to reveal the molecular mechanisms that connect physiological and pathological processes commonly observed in T2DM and AD. Conformational modifications in peptide residues, such as amyloid-β peptide in AD and amylin in T2DM have been shown to instigate formation of insoluble protein aggregates that get deposited in extracellular spaces of brain and pancreatic tissue thus disrupting their normal function. Impaired insulin signaling plays a critical role in AD pathogenesis by reducing IRS-associated PI3 kinase activity and increasing GSK-3β activity. GSK-3β has been suggested to be a component of the γ-secretase complex and is involved in amyloid-β protein precursor processing. GSK-3β along with CDK5 is responsible for hyperphosphorylation of tau leading to the formation of neurofibrillary tangles. In summary, there is evidence to believe that a molecular link connects AD and T2DM and has potential for further investigation toward development of an effective therapeutic target.

The cellular mechanism of neuronal apoptosis in Alzheimer's disease (AD) is poorly understood. Many hypotheses have been put fourth to explain the underlying reason for neuro-degeneration in AD. Here, it is demonstrated that all neurotrophins that activated p75, without co-activation of the relevant Trk co-receptor, mediated apoptosis in hippocampal neurons. Thus, proneurotrophins and amyloid beta peptides (Abeta) can induce p75-mediated apoptosis in hippocampal neurons since they do not bind or activate Trk receptors. Based on the combined effects of aging, proneurotrophins, neurotrophins, and Abeta, a novel model of pathogenesis in AD is proposed. This mini-review explores the ligand and cell type based signaling pathways of the neurotrophin receptor p75 relating to Alzheimer's disease.