1. Introduction

2. Introduction

1.1. Sphingolipid Metabolism

In thNume anabrolic pathway, sphingolipids synthesis begins in the endoplasmic reticulum with the condensation of L-serine and palmitoyl coenzyme A (CoA) to form 3-ketous human studies have shown that, in cardiovascular, renal, and metabolic diseases, the profiles of sphinganine by serine palmitoyltransferasomyelin [1–4] and its metabolites ceramide. Subsequently [5–11], 3-ketosphinganine reductase is responsible for reducing 3-ketoosine [12], and sphinganine to sphinganine, which can be acylated to form dihydroceramide by ceramide synthase. Finally, dihydroceramide is oxidized by a desaturase, which results in ceramide formationosine-1-phosphate (S1P) [13,14] are altered (reduction or elevation) in the plasma, organs (liver and heart), and tissues (skeletal muscle and ^[1][2][3]. Ceramide is transported from the endoplasmic reticulum to the Golgi apparatus and is converted into sphingomyelin by sphingomyelin synthase or glycosphingolipids byipose). Most of these studies focused on the determination of ceramide glucosyltransferasa. Sphingomyelin and complex glycosphingolipids can be transported to the plasma membrane (Figure 1) ^[3][4].

Iin plasma. However, it is necessary to perform preclinical the plasma membrane and other cell compartments, thestudies to determine the content of sphingomyelin can 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 generateand its bioactive metabolites in plasma and organs such as the brain, liver, heart, and kidney, because the sphingosine-1-phosphate (S1P) (Figure 1) ^{[3][5][6][7][8][9]}. S1P clipid metabolism imbalan bce cleavaged by the S1P lyase to a fatty aldehyde and phosphoethanolaminean be affected directly ^[10].or Alterinatively, S1P can be dephosphorylateddirectly in various organs.

On back to sphingosine by phosphataseshe other ^[11]. S1P chand, act as an intracellular second messenger or an extracellular ligand ^[12][13].

1.2. Classification of Sphingolipid Catabolism Enzymes

Accordchanges in the expression or activingty to the optimal pH for their activity, SMases are classified into acid, neutral, and alkaline. aSMase can be subclassified based oof the enzymes that participate in sphingolipid metabolism may explain the alterations in their cellular locatioprofile.

In into lysosomal aSMase (L-SMase) and secretory aSMase (S-SMase) ^[5][6]. Ceramhe anabolic pathway, the synthesidases also have been classified according to their optimal pH in acid, neutral, and alkaline ^[7][8]. Twof sphingolipids stars by the condensation of serine and palmitoyl-CoA isoforms of nto 3-ketosphingosine kinases (SKs) have been identified, sphingosine kinase-1 and sphingosine kinase-2anine by the enzyme serine palmitoyl transferase, ^[9].

1.3. Genetic Diseases of Sphingolipid Catabolism Enzymes

Types A and B Niemann Pick disease is caust is followed by aSMase deficiency, which leads to organ dysfunction due to the accumulation of reduction yielding sphinganine. The sphingomyelin in various organs. Niemann Pick disease is inherited as recessive traits ^[14]. Faanine is acylate by ceramide synthase resulting dihydrbocer disease is a lysosomal storage disorder, it is causamides. Finally, ceramide is formed by mutations in the gene that encodes to aCDase, which lead to decreased aCDase activity and in turn, to the dehydrogenation of dihydroceramide by dihydroceramide accumulation and various pathological manifestations. Farber disease is inheridesaturase. The ceramide is converted in an autosomal recessive manner ^[15].

1.4. Sphingolipid Catabolism Enzymes as Therapeutic Targets in Cardiovascular Diseases

Nuto sphingomyerous human studies have shown that, in cardiovascular, renal, and metabolic diseases, the profiles of lin by sphingomyelin synthase or glycosphingomyelin ^{[16][17][18][19]} anlipid its metabolitesy ceramide ^{[20][21][22][23][24][25][26]}, sphingosine ^[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 determination of ceramide in plasma. However, it is necessary to perform preclinical studies to determine the content ofosyltransferase. In the catabolic pathway, sphingomyelinases (SMases) hydrolyzes sphingomyelin and its bioactive metabolites in plasma and organs such as the brain, liver, heart, and kidney, because theto release ceramide, which is hydrolyzed into sphingolipid metabolism imbalance can be affected directly or indirectly in various organs.

Csine and S1P by ceramidase (CDase) and sphainges in the expression or activity of the enzymes that participate in sphingolipid metabolism may explain the alterations in their profileosine kinase (SK), respectively (Figure 1) [15].

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 ^[30][31][16,17].

Regarding enzyme activity, secretory SMase activity increased in the serum of patients with type 2 diabetes, chronic heart failure, or acute coronary syndromes ^[32][33][34][18–20]. 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 ^[22][7].

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 Theprefore, 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.

Reseavious study, we demonstrated that in the isolated perfused rat kidney of diabetic rchers evaluated the sphingomyelin content and its metabolites in two experimental models: diabetic and hypertensive rats. The results show thatts, the vasoconstriction produced by S1P increases [21]. Additionally, in the plasma and liver of diabetic rats, sphingomyelin is increased; in the heart,isolated perfused rat kidney, angiotensin II (Ang II) stimulates ceramide; and in the kidney, S1P formation via the activation of nSMase(Figure 2) [22]. Mo

3. Applications

Therefover, increased sphingomyelin was observed in the plasma and all evaluated organs of hypertensive rats, as well as increased ceramide and sphingosine in the heart, and increased S1P in the plasma, kidneyre, drugs that modify the expression or activity of the enzymes involved in sphingolipid metabolism are attractive candidates for the treatment of cardiovascular, renal, and heart (Figure 2)metabolic disease.

TheOur results suggest that empagliflozin downregulates the interaction of the de novo pathway and the catabolic pathway of sphingolipid metabolism in the diabetes, whereas, in Ang II-dependent hypertension, it only downregulates the sphingolipid catabolic pathway (Figure 3Figure 2).

2. Applications 

2.1. Pharmacologic IFunhibitors of Sphingolipidding: Catabolism Enzymes

The uise of pharmacologic inhibitors has been critical for the study of sphingolipid catabolism enzymes as a potential therapeutic approach in respiratory (chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis), neurodegenerative (Alzheimer’s disease), metabolic (obesity, diabetes), and cardiovascular disease (Table 1) ^{[35][36][37][38]}.

          Table 1. Pharmacologic inhibitors of sphingolipid metabolism enzymes.

1. 227
2. , 550–557, https://doi.org/10.1002/jcp.22745.
3. Lopez, X.; Goldfine, A.; Holland, W.L.; Gordillo, R.; Scherer, P.E. Plasma ceramides are elevated in female children and adolescents with type 2 diabetes.
4. Pediatr. Endocrinol. Metab.
5. 2013
6. ,
7. 26, 995–998, https://doi.org/10.1515/jpem-2012-0407.
8. Mitsnefes, M.; Scherer, P.E.; Friedman, L.A.; Gordillo, R.; Furth, S.; A Warady, B.; CKiD Study Group; the CKiD study group Ceramides and cardiac function in children with chronic kidney disease. Nephrol.2014, 29, 415–422,https://doi.org/10.1007/s00467-013-2642-1.
9. Klein, R.L.; Hammad, S.M.; Baker, N.L.; Hunt, K.J.; Al Gadban, M.M.; Cleary, P.A.; Virella, G.; Lopes-Virella, M.F. Decreased plasma levels of select very long chain ceramide species Are associated with the development of nephropathy in type 1 diabetes. Metabolism2014, 63, 1287–1295https://doi.org/10.1016/j.metabol.2014.07.001.
10. de la Maza, M.P.;Rodriguez, J.M.; Hirsch, S.; Leiva, L.; Barrera, G.; Bunout, D. Skeletalmuscleceramidespecies in menwith abdominal obesity. Nutr. Health Aging2015, 19, 389–396.
11. Górska, M.; Dobrzyn, A.; Baranowski, M. Concentrations of sphingosine and sphinganine in plasma of patients with type 2 diabetes. Med Sci. Monit.2005, 11, CR35–CR38.
12. Deutschman, D.H.; Carstens, J.S.; Klepper, R.L.; Smith, W.S.; Page, M.; Young, T.R.; A Gleason, L.; Nakajima, N.; A Sabbadini, R. Predicting obstructive coronary artery disease with serum sphingosine-1-phosphate. Hear. J.2003, 146, 62–68,https://doi.org/10.1016/s0002-8703(03)00118-2.
13. Kowalski, G.M.; Carey, A.L.; Selathurai, A.; Kingwell, B.A.; Bruce, C.R. Plasma Sphingosine-1-Phosphate Is Elevated in Obesity. PLoS ONE2013, 8, e72449, https://doi.org/10.1371/journal.pone.0072449.
14. Hannun, Y.A.; Luberto, C.; Argraves, K.M. Enzymes of Sphingolipid Metabolism: From Modular to Integrative Signaling. Biochemistry2001, 40, 4893–4903, https://doi.org/10.1021/bi002836k.
15. Baranowski, M.; Blachnio-Zabielska, A.; Hirnle, T.; Harasiuk, D.; Matlak, K.; Knapp, M.; Zabielski, P.; Górski, J. Myocardium of type 2 diabetic and obese patients is characterized by alterations in sphingolipid metabolic enzymes but not by accumulation of ceramide. Lipid Res.2010, 51, 74–80, https://doi.org/10.1194/jlr.m900002-jlr200.
16. Kolak, M.; Gertow, J.; Westerbacka, J.; Summers, A.S.; Liska, J.; Franco-Cereceda, A.; Orešič, M.; Yki-Järvinen, H.; Eriksson, P.; Fisher, R.M. Expression of ceramide-metabolising enzymes in subcutaneous and intra-abdominal human adipose tissue. Lipids Heal. Dis.2012, 11, 115–115, https://doi.org/10.1186/1476-511x-11-115.
17. Górska, M.; Barańczuk, E.; Dobrzyń, A. Secretory Zn2+-dependent Sphingomyelinase Activity in the Serum of Patients with Type 2 Diabetes is Elevated. Metab. Res.2003, 35, 506–507, https://doi.org/10.1055/s-2003-41810.
18. Doehner, W.; Bunck, A.C.; Rauchhaus, M.; von Haehling, S.; Brunkhorst, F.M.; Cicoira, M.; Tschope, C.; Ponikowski, P.; Claus, R.A.; Anker, S.D. Secretory sphingomyelinase is upregulated in chronic heart failure: a second messenger system of immune activation relates to body composition, muscular functional capacity, and peripheral blood flow. Heart J. 2007, 28, 821–828.
19. Pan, W.; Yu, J.; Shi, R.; Yan, L.; Yang, T.; Li, Y.; Zhang, Z.; Yu, G.; Bai, Y.; Schuchman, H.; et al. Elevation of ceramide and activation of secretory acid sphingomyelinase in patients with acute coronary syndromes. Coron Artery Dis. 2014; 25(3):230-5, https://doi.org/10.1097/mca.0000000000000079.
20. Bautista-Pérez, R.; Arellano, A.; Franco, M.; Osorio, H.; Coronel, I. Sphingosine-1-phosphate induced vasoconstriction is increased in the isolated perfused kidneys of diabetic rats. Diabetes Res. Clin. Pr.2011, 94, e8–e11, https://doi.org/10.1016/j.diabres.2011.06.023.
21. Bautista-Pérez, R.; Del Valle-Mondragón, L.; Cano-Martínez, A.; Pérez-Méndez, O.; Escalante, B.; Franco, M. Involvement of neutral sphingomyelinase in theangiotensin II signalingpathway. J. Physiol. Physiol.2015, 308, F1178–F1187, https:// doi.org/10.1152/ajprenal.00079.2014.

2.2. Sphingosine 1-Phosphate and its Receptors as Drug Targets

One of the biologic project was supported by Mexican Council of Science al applications of S1P has emerged with the discovery 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 id Technology (CONACyT) “Project supported by the s a potent agonist of four S1P receptors: S1P₁, S1P_3-5 ^[40][41].

2.3. Sphingomyelin and its Metabolites as Potential Therapeutic Targets of COVID-19 Disease

In the serum of pctoratientsl with COVID-19 increased the concentration of serine palmitoyltransferase and acid sphingomyelinase (aSMase). Also, increased the concentration of dihydrosphingosine, dihydroceramide, ceramide, and sphingosine, and decrease sphingosine-1-phosphateresearch fund for education” ^[42][43]. Symptomatic COVID-19 patiRents exhibited a decrease in their serum sphingosine levels compared to asymptomatic patients levels ^[44]. Interestingly, sphingosine binds to angiotensinearch Grant A1-S-converting9870 enzyme 2 (ACE2) and prevents its interaction with the viral spike protein of SARS CoV 2 in human nasal epithelial cells ^[45]. Infect(to Rocion of human epithelial cells and different human cell lines with SARS-CoV-2 is reduced by treatment with amitriptyline and other antidepressantsBautista-Pérez). In addition, th

Re administration of anticeramide antibodies or neutral ceramidaerencese also protects against SARS-CoV-2 infections ^[46].

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