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The Role Of Ceramides
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Pdf) Role Of Ceramides In Diabetic Foot Ulcers (review)
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Md. By Riyad Chowdhury. Riyad Chowdhury Skillit Preprints.org Google Scholar View Publications 1, 2, Hee Kyung Jin Hee Kyung Jin Skillit Preprints.org Google Scholar View Publications 1, 3, * and Jae-sung Bae Jae-sung Bae Preprints. org Google Scholar View Publications 1, 2, *
Submission received: 20 June 2022 / Revised: 31 July 2022 / Accepted: 2 August 2022 / Published: 12 August 2022
Japan’s #1 Ceramide Power
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and is associated with several pathophysiological features, including cellular dysfunction, neurotransmission failure, cognitive impairment, cell death, and other clinical consequences. Advanced research on the pathogenesis of AD has elucidated a mechanistic framework and revealed several therapeutic possibilities. Among the mechanisms, sphingolipids are mentioned as specific mediators associated with AD pathology. Reportedly, alterations in the metabolism of sphingolipids and their metabolites result in dysfunction of mitochondria, autophagy, amyloid beta regulation, and neuronal homeostasis, which exacerbates the progression of AD. Given the importance of sphingolipids, in this review, we discuss the role of ceramide, a bioactive sphingolipid metabolite, in the progression and pathogenesis of AD. Here, we describe its involvement in the dysregulation of the ceramide synthesis pathway and homeostasis, which ultimately leads to AD. In addition, this review refers to various therapeutics proposed to modulate the ceramide pathway to maintain ceramide levels and prevent disease progression.
Alzheimer’s disease (AD) is defined as a progressive cognitive impairment associated with the formation of senile plaques in the cerebral cortex and subcortical gray matter, consisting of amyloid beta (Aβ) and neurofibrillary tangles [ 1 ]. The World Health Organization has declared AD a “global public health priority” due to the lack of well-established treatments. To date, researchers have proposed various theories and hypotheses regarding the causes and targets of AD. Primarily, dementia is the cause of AD in people over 60 years of age, while about 50–75% of patients with dementia develop AD [2]. In addition, diabetes, hypertension and cardiovascular disease have also been identified as risk factors in the progression of AD [3]. Currently, therapeutic interventions based on proposed mechanisms in AD pathogenesis are being attempted. Some of these include antioxidant therapy, NSAIDs, cholinergic replacement therapy, hormone replacement therapy, memantine, and Aβ vaccines [4].
Sphingolipids are abundantly distributed in nerve cell membranes and the myelin sheath of nerve fibers [5]. Bioactive metabolites of sphingolipids, including ceramide, sphingomyelin, sphingosine, and sphingosine-1-phosphate (S1P) are synthesized by various enzymatic biosynthetic pathways [ 6 ]. In general, sphingolipids play a significant role in biological membranes, and their metabolism is involved in the regulation of various cell functions. Several reports have suggested that the metabolism of sphingolipids plays a key role in the pathogenesis of AD, and therefore it is considered as a potential treatment target [ 5 , 7 , 8 ]. Furthermore, small changes in sphingolipid metabolism can produce significant effects in age-related neurodegenerative diseases. In this context, several studies have shown that ceramides levels are significantly increased in the brain tissue of patients with AD compared to controls, while sphingomyelin and sphingosine-1-phosphate are decreased [5, 6, 7]. In addition, abnormal expression of enzymes in the sphingolipid synthesis pathway has also been described previously [9]. In addition, plasma sphingolipids are considered as potential biomarkers of neurodegenerative diseases [10]. In particular, one study showed that the levels of sphingomyelin and ceramide were altered in the plasma of patients with AD compared to the control group [ 11 ]. The study was further supported by another report, which showed increased sphingomyelin levels in the cerebrospinal fluid of patients with AD [12].
Different bioactive molecules of sphingolipids show several regulatory functions in cellular and tissue homeostasis, especially in aging, cell cycle, migration, proliferation, autophagy, inflammation and immune responses [6]. While these mediators are abundant in the central nervous system, any dysfunction of sphingolipids can contribute to neurodegenerative disorders. In particular, ceramide is one of the simplest sphingolipids widely distributed in animal tissues, while other sphingolipids are derivatives of ceramide [13]. Therefore, in this review, we aimed to discuss the effect of ceramide, a bioactive metabolite of sphingolipids, on the progression and pathogenesis of AD. In addition, this review mentions a list of therapeutics that have been suggested to mediate the ceramide synthesis pathway and prevent disease progression.
Pdf] Targeting Ceramide Synthesis To Reverse Insulin Resistance
Although the pathogenesis of AD is not clear, it is known that the disease involves several factors, including neurotransmitter, immune, genetic and environmental factors [14]. Currently, researchers have proposed various theories related to AD, namely, amyloid beta theory, tau theory, oxidative stress, mitochondrial dysfunction, inflammation, autophagy dysfunction, and nerve and blood vessel theory [2, 14]. Among these, the concept of Aβ-containing senile plaque formation has been previously described by several researchers. Aβ does not accumulate in the brain under normal conditions, as it is normally cleared by homeostatic clearance mechanisms. However, an imbalance in the rate of Aβ production and clearance results in the formation of amyloid plaques. A previous study found that Aβ deposition in the brain is associated with cognitive impairment in the elderly [ 15 ]. Therefore, preventing Aβ sedimentation may be a potential mechanism to ameliorate AD. Conversely, the development of neurofibrillary tangles by hyperphosphorylated tau protein is a fundamental neuropathological marker of AD [16]. Abundantly distributed in neurons, tau protein plays a role in maintaining the stability of cytoskeletal microtubules and axonal transport [ 17 ]. However, due to chemical inactivation in AD, tau tends to dissociate from micronubules and bind to other tau molecules to form tangles, which inhibit neuronal transport [ 18 ]. Consequently, disruption of synaptic communication between neurons promotes the progression and pathogenesis of AD. With regard to synapses, a previous report confirmed that synaptic plasticity is altered during AD and synapses are reduced in the brain [ 14 ]. Collectively, removal of Aβ, aggregation of tau protein, and synaptic loss cause neuronal injury and subsequent neuronal death and contribute to cognitive impairment.
Chemokines are a group of secreted proteins mostly known as regulators of cell migration, especially of leukocytes. Chemokines are associated with AD and are considered to be key factors in the pathology of AD due to their involvement in the regulation of inflammation or glial cells. A previous report suggested that the levels of chemokines in brain, cerebrospinal fluid and serum fluctuated continuously in patients with AD [14]. Due to their role in regulating proinflammatory and anti-inflammatory properties, chemokines cause neuroinflammation in the AD brain, subsequently leading to neuronal death. Microglia, a type of glial cell regulated by chemokines as an immune defense in the central nervous system. However, a previous study found that microglia are unable to remove waste and toxins from the brain, and their accumulation can lead to chronic neuroinflammation [18]. In addition, brain cells depend on mitochondrial oxidative phosphorylation for their energy. However, gene set enrichment analysis has shown significant downregulation of mitochondrial oxidative phosphorylation and disruption of mitochondrial import pathways in AD [19]. As such, mitochondrial dysfunction may also be associated with the pathogenesis of AD. In addition, autophagy is an important cell survival mechanism that facilitates bioenergetic homeostasis. Researchers have further discussed the involvement of autophagy dysfunction in the pathogenesis of AD, as increased autophagy causes the accumulation of Aβ in the brain [ 20 ].
Another key regulator of brain function is lipids, which are increasingly implicated in AD. It was previously observed that in AD patients, heterogeneous changes in lipid metabolism occur in different brain regions [ 21 ]. In particular, lipid composition in neurons is able to regulate the activity of membrane-bound proteins including BACE1, APP and presenilin thereby regulating amyloid beta levels [21]. Accordingly, Grimm et al. reported that membrane cholesterol and sphingomyelin levels can regulate γ-secretase activity [ 22 ]. Cholesterol also accumulates in nerve terminals and Aβ plaques in humans
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