1. Introduction

2. Introduction

         Sphingolipid metabolism

Num      In therous human studies have shown that, in cardiovascular, renal, and metabolic diseases, the profiles of anabolic pathway, sphingolipids synthesis begins in the endoplasmic reticulum with the condensation of L-serine and palmitoyl coenzyme A (CoA) to form 3-ketosphingomyelinanine by serine ^[1][2][3][4] pand lmits metabolites ceramidetoyltransferase. ^{[5][6][7][8][9][10][11]}Subsequently, 3-ketosphingosinanine reductase is responsible ^[12],for areducind g 3-ketosphingosine-1-phosphate (S1P)anine to sphinganine, which ^[13][14]can arbe altered (reduction or elevation) in the plasma, organs (liver and heart), and tissues (skeletal muscle and adipose). Most of these studies focused on the determination ofcylated to form dihydroceramide by ceramide synthase. Finally, dihydroceramide is oxidized by a desaturase, which results in ceramide formation [1-3]. Ceramide is transported from the endoplasmic reticulum to the Golgi apparatus and is converted into sphingomyelin by sphingomyelin synthase or glycosphingolipids by ceramide in plasma. However, it is necessary to perform precliglucosyltransferasa. Sphingomyelin and complex glycosphingolipids can be transported to the plasma membrane (Figure 1) [3-4].

      Inical studies to determine the content ofthe plasma membrane and other cell compartments, the sphingomyelin and its bioactive metabolites in plasma and organs such as the brain, liver, heart, and kidney, because thcan be hydrolyzed by sphingomyelinases (SMases) and release ceramide.  Ceramide can be hydrolyzed by ceramidases (CDases) to form sphingosine, which can be phosphorylated by sphingosine kinase (SK) to generate sphingolipid metabolism imbalsine-1-phosphate (S1P) (Figure 1) [3, 5-9]. S1P canc be can be affected directly or indirectly in various organs.

Oleavaged by the S1P lyase to a fatty aldehyde and phosphoethanolamine [10]. Alternatively, S1P can be dephosphorylated back to sphingosine the other hand, changes in the expression or activby phosphatases [11]. S1P can act as an intracellular second messenger or an extracellular ligand [12, 13].  

      Classification of sphingolipid catabolism enzymes

      According ty of the enzymes that participate in sphingolipid metabolism may explain the alterations in their profile.

Ino the optimal pH for their activity, SMases are classified into acid, neutral, and alkaline. aSMase can be subclassified based on their cellular location into lysosomal aSMase th(L-SMase anabolic pathway, the synthesis of sphingolipids stars by the condensation of serine and palmitoyl-CoA into 3-keto) and secretory aSMase (S-SMase) [5,6]. Ceramidases also have been classified according to their optimal pH in acid, neutral, and alkaline [7, 8]. Two isoforms of sphinganine by the enzyme serine palmitoyl transfosine kinases (SKs) have been identified, sphingosine kinase-1 and sphingosine kinase-2 [9].

      Genetic diseases of sphingolipid catabolism enzymes

     Typerase, and it is follow A and B Niemann Pick disease is caused by a reduction yielding sphinganine. The aSMase deficiency, which leads to organ dysfunction due to the accumulation of sphinganine is acylate by ceramide synthase resulting dihydroceramides. Finally, ceramide is formomyelin in various organs. Niemann Pick disease is inherited as recessive traits [14]. Farber disease is a lysosomal storage disorder, it is caused by the dehydrogenation of dihydroceramide by dihydromutations in the gene that encodes to aCDase, which lead to decreased aCDase activity and in turn, to ceramide desaturase. The ceraccumulation and various pathological manifestations. Farber disease is inherited in an autosomal recessive manner [15].

      Sphingolipid catabolism enzymes as therapeutic targets in cardiovascular diseases

     Numerous humamn studide is converted into es have shown that, in cardiovascular, renal, and metabolic diseases, the profiles of sphingomyelin by[16–19] and its metabolites ceramide [20-26], sphingomysinelin synthase or glycosphingolipid by ceramide glucosyltransferase. I [27], and sphingosine-1-phosphate (S1P) [28,29] are altered (reduction or elevation) in the plasma, organs (liver and heart), and tissues (skeletal muscle and adipose). Most of these studies focused on the catabolic pathway, sphingomyelinases (SMases) hydrolyzesdetermination of ceramide in plasma. However, it is necessary to perform preclinical studies to determine the content of sphingomyelin to release ceramide, which is hydrolyzed intoand its bioactive metabolites in plasma and organs such as the brain, liver, heart, and kidney, because the sphingosine and S1P by ceramidase (CDase) and splipid metabolism imbalance can be affected directly or indirectly in various organs.

Chiangosine kinase (SK), respectively (Figure 1)es in the expression or activity of the enzymes that participate in sphingolipid metabolism may explain the alterations in their ^[15]profile.

Concerning the expression at the mRNA level of the enzymes involved in the synthesis (serine palmitoyltransferase) and degradation of ceramide (SMase, CDase, and SK-1), the levels of these enzymes were increased in intra-abdominal adipose tissue and the myocardium of obese patients with or without type 2 diabetes ^[16][17][30,31].

Regarding enzyme activity, secretory SMase activity increased in the serum of patients with type 2 diabetes, chronic heart failure, or acute coronary syndromes ^[18][19][20][32-34]. In the adipose tissue of obese non-diabetic or diabetic patients, the activity of serine palmitoyltransferase, neutral and acid CDase (nCDase and aCDase) was increased, while the aSMase activity was decreased ^[7][22].

Changes in the profiles of sphingomyelin and its metabolites ceramide, sphingosine, and sphingosine-1-phosphate (S1P) can result in a pathological condition triggered by accumulation or by altering cell signaling.

In a pTherevious study, researchers demonstrated that in the isofore, drugs that modify the expression or activity of the enzymes involved in sphingolipid metabolism are attractive candidates for the treatment of cardiovascular, renal, and metabolic diseases.

We evaluated perfused rat kidney ofthe sphingomyelin content and its metabolites in two experimental models: diabetic ratsand hypertensive rats. Our results show that, in the vasoconstriction produced by S1P plasma and liver of diabetic rats, sphingomyelin is increased; in the heart, ceramide; and in the kidney, S1P. Moreover, increases ^[21]. Addd sphitngomyelionally,n was observed in the isolated perfused rat kidney, angiotensin II (Ang II)plasma and all evaluated organs of hypertensive rats, as well as increased ceramide and sphingosine in the heart, and increased S1P in the plasma, kidney, and heart (Figure 2).

Our restimults suggest that empagliflozin downregulates ceramide formation via the activation of nSMase the interaction of the de novo pathway and the catabolic pathway of sphingolipid metabolism in diabetes, whereas, in Ang II-dependent hypertension, it only downregulates the sphingolipid catabolic pathway (FFigure 3).

3. Applications

     Pharmacologic inhibigutore 2) ^[22].

2.s of Aspplihingolipid cataboliosm enzymes

Therefore, drugs that modify the expression or activity of the enzymes involved in use of pharmacologic inhibitors has been critical for the study of sphingolipid mecatabolism are attraenzymes as a potential therapeutic approach in respiratory (chronic obstructive candidates for the treatment ofpulmonary disease, idiopathic pulmonary fibrosis), neurodegenerative (Alzheimer’s disease), metabolic (obesity, diabetes), and cardiovascular, renal, a disease (Table 1) [35-38].

Sphingosine 1-phosphate and its receptors as drug targets

Onde of metabolic disease.

Tthe biological applications of S1P has emerged with the discoveresults suggest that empagliflozin downregy of the immunosuppressant drug.  FTY720 acts as an S1P agonist when it is phosphorylated to FTY720-P.  FTY720 can be phosphorylated by both SK1 and SK2, but SK2 has more affinity for the drug than SK1 [39]. FTY720-P is a potent agonist of four S1P receptors: S1P₁, S1P_3-5 [40, 41].  

Sphingomyelin and its metabolites as potential therapeutic targets of COVID-19 disease

In the serulm of pates the interacients with COVID-19 increased the concentration of the de novo pathway and the catabolic pathway ofserine palmitoyltransferase and acid sphingomyelinase (aSMase).   Also, increased the concentration of dihydrosphingosine, dihydroceramide, ceramide, and sphingosine, and decrease sphingosine-1-phosphate [42, 43].   Symptomatic COVID-19 patients exhibited a decrease in their serum sphingolipid metabolism in the diabetes, whereas in Ang II-dependent hypertension, it only downregulates the sphingolipid catabolic pathway (Figusine levels compared to asymptomatic patients levels [44]. Interestingly, sphingosine binds to angiotensin-converting enzyme 2 (ACE2) and prevents its interaction with the viral spike protein of SARS CoV 2 in human nasal epithelial cells [45]. Infection of human epithelial cells and different human cell lines with SARS-CoV-2 is reduced by treatment with amitriptyline and other antidepressants. In addition, the administration of anticeramide antibodies or neutral ceramidase also protects against SARS-CoV-2 infections [46].

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