Figure 1.
Etiology and pathophysiology of systemic lupus erythromatosus (SLE). Etiology of SLE includes genetic, epigenetic, hormonal, immunological and other external factors. These etiological factors act as a stimulus for inducing apoptosis of a normal cell, thereby breaking the dsDNA which in turn induces the production of interferons (Ifn-α) [
1,
10]. These interferons induce the activation of plasmacytoid dendritic cells. Further, the broken DNA acts as an antigen which is presented on dendritic cells (physiologically altered with FcγR). Meanwhile, T cells and B cells also interact via CD40 and CD40L interaction with the DNA antigen, thereby inducing the production of autoantibodies which further induce the interaction of plasmacytoid dendritic cells and T cells [
12,
13,
14]. This interaction upregulates the production of NFAT and NFκB, both of which inhibit the production of IL-2 (an immunosuppressive cytokine) and induce the production of BCL6, IL6, IL21 and IL23. These cytokines further upregulate the expression of STAT3 which aids in the co-stimulation of B cells and T cells, thereby leading to the production of autoantibodies [
13,
14,
15]. These autoantibodies induce SLE-related manifestations and a simultaneous signaling cascade also commences. Protein phosphatase 2 (PP2A) initiates a 3-tier phenomenon [
16], i.e.: mitochondrial hyperpolarization and the death of T cells [
17,
18,
19]; activation of Rho-associated protein kinase (ROCK) which further mediates the binding of IL17 transcription enhancer interferon regulatory factor 4 (IRF4) [
20]; dephosphorylation of cAMP-responsive element-binding protein 1 (CREB), resulting in suppression of IL2 transcription (mediated by downregulation of expression of MAPK—mitogen-activated protein kinase and DNMT1—DNA methyl transferase 1) [
21]. Further upregulation of IL17 and downregulation of IL2 production is mediated by calcium/calmodulin-dependent protein kinase IV (CaMKIV), which in turn increases the binding of cAMP response element modulator (CREMα) [
12,
13,
14,
15,
16,
17,
18]. Certain co-stimulatory signaling molecules such as ICOS (Inducible T cell co-stimulator), PI3K (phosphoinositide 3-kinase) and mTOR (mechanistic target of Rapamycin) also aid in similar interleukin regulation [
12].
Figure 1.
Etiology and pathophysiology of systemic lupus erythromatosus (SLE). Etiology of SLE includes genetic, epigenetic, hormonal, immunological and other external factors. These etiological factors act as a stimulus for inducing apoptosis of a normal cell, thereby breaking the dsDNA which in turn induces the production of interferons (Ifn-α) [
1,
10]. These interferons induce the activation of plasmacytoid dendritic cells. Further, the broken DNA acts as an antigen which is presented on dendritic cells (physiologically altered with FcγR). Meanwhile, T cells and B cells also interact via CD40 and CD40L interaction with the DNA antigen, thereby inducing the production of autoantibodies which further induce the interaction of plasmacytoid dendritic cells and T cells [
12,
13,
14]. This interaction upregulates the production of NFAT and NFκB, both of which inhibit the production of IL-2 (an immunosuppressive cytokine) and induce the production of BCL6, IL6, IL21 and IL23. These cytokines further upregulate the expression of STAT3 which aids in the co-stimulation of B cells and T cells, thereby leading to the production of autoantibodies [
13,
14,
15]. These autoantibodies induce SLE-related manifestations and a simultaneous signaling cascade also commences. Protein phosphatase 2 (PP2A) initiates a 3-tier phenomenon [
16], i.e.: mitochondrial hyperpolarization and the death of T cells [
17,
18,
19]; activation of Rho-associated protein kinase (ROCK) which further mediates the binding of IL17 transcription enhancer interferon regulatory factor 4 (IRF4) [
20]; dephosphorylation of cAMP-responsive element-binding protein 1 (CREB), resulting in suppression of IL2 transcription (mediated by downregulation of expression of MAPK—mitogen-activated protein kinase and DNMT1—DNA methyl transferase 1) [
21]. Further upregulation of IL17 and downregulation of IL2 production is mediated by calcium/calmodulin-dependent protein kinase IV (CaMKIV), which in turn increases the binding of cAMP response element modulator (CREMα) [
12,
13,
14,
15,
16,
17,
18]. Certain co-stimulatory signaling molecules such as ICOS (Inducible T cell co-stimulator), PI3K (phosphoinositide 3-kinase) and mTOR (mechanistic target of Rapamycin) also aid in similar interleukin regulation [
12].

Figure 2.
Clinical manifestations of systemic lupus erythromatosus along with therapeutic interventions. Systemic lupus erythromatosus is a chronic autoimmune disease targeting various systems of the human body including the cardiovascular, cerebrovascular, gastrointestinal, gynecological, hematological, hepatic, immunological, mucocutaneous, musculoskeletal, ocular, esophageal, pancreatic, pulmonary and renal systems. The treatment of SLE is centered upon formulating a regimen of topical and systemic therapies designed to reduce both disease severity and activity, wherein various treatment modalities are T1: dapsone and fingolimod; T2: lenalidomide; T3: thalidomide; T4: calcium channel blockers; T5: glucocorticoid prednisone; T6: azathioprine; T7: rifampin; T8: chaperonin 10; T9: mycophenolate mofetil; T10: misoprostol; T11: iron supplements; T12: vitamin B complex; T13: benzocaine; T14: salbutamol; T15: clofazimine; T16: IVIG (intravenous immunoglobulin); T17: cefuroxime; T18: quinacrine; T19: NSAIDs (non-steroidal anti-inflammatory drugs); T20: methylprednisolone; T21: ipatropium bromide; T22: ibuprofen; T23: aspirin; T24: corticosteroids; T25: aminosalicylate; and T26: methotrexate.
Figure 2.
Clinical manifestations of systemic lupus erythromatosus along with therapeutic interventions. Systemic lupus erythromatosus is a chronic autoimmune disease targeting various systems of the human body including the cardiovascular, cerebrovascular, gastrointestinal, gynecological, hematological, hepatic, immunological, mucocutaneous, musculoskeletal, ocular, esophageal, pancreatic, pulmonary and renal systems. The treatment of SLE is centered upon formulating a regimen of topical and systemic therapies designed to reduce both disease severity and activity, wherein various treatment modalities are T1: dapsone and fingolimod; T2: lenalidomide; T3: thalidomide; T4: calcium channel blockers; T5: glucocorticoid prednisone; T6: azathioprine; T7: rifampin; T8: chaperonin 10; T9: mycophenolate mofetil; T10: misoprostol; T11: iron supplements; T12: vitamin B complex; T13: benzocaine; T14: salbutamol; T15: clofazimine; T16: IVIG (intravenous immunoglobulin); T17: cefuroxime; T18: quinacrine; T19: NSAIDs (non-steroidal anti-inflammatory drugs); T20: methylprednisolone; T21: ipatropium bromide; T22: ibuprofen; T23: aspirin; T24: corticosteroids; T25: aminosalicylate; and T26: methotrexate.

Figure 3.
Pharmaco-mechanistic profile of phyto-metabolites in treating systemic lupus erythromatosus. Plant-derived phytoconstituents serve as (i) nitric oxide synthase (iNOS) inhibitors and promote the scavenging of free radicals, thereby preventing SLE associated DNA damage (alizarin, asperuloside, α-amyrin, β-amyrin, andrographolide, angelic acid, cadinol, isophytol, β-phellandrene, galic acid, kaempferol, limonene, lupeol, lectin, scrocaffeside A, salvianolic acid, mitraphylline); (ii) inhibitors of autoantibody production {linalool acetate, α-terpinyl acetate}; (iii) inhibitors of COX-2-mediated PGE2 production, thereby ameliorating inflammation and pain {andrographolide, isophytol, farnesene, cadinoleugenol, troptolide}; (iv) inhibitors of lymphocyte proliferation {limonene, carvacrol, terpinene, calycopterin}; (v) down-regulators of NFκB -mediated signaling {allicin, alliin-γ-glutamyl-S-allyl-L-cysteine, andrographolide, saikosaponin, epigallocatechin gallate, lupeol, taraxerol, friedelin, betulinic acid, linalool, pinene, terpinene, limonene, curcumin}; (vi) down-regulators of STAT3-mediated signalling {berbamine, curcumin}; (vii) inhibitors of production of proinflammatory cytokines {allicin, alliin-γ-glutamyl-S-allyl-L-cysteine, pinitol, theophylline, epigallocatechin gallate, curcumin, periplocoside E, triptolide}; (viii) down-regulators of the expression of Rho-associated protein kinase (ROCK) {curcumin}; (ix) inhibitors specifically of the production of IL-17 {curcumin, quinone, phenylpropanoids, steroids, periplocoside E}; (x) a topical remedy for butterfly shaped cutaneous lesions {ecdysterone, oleanolic acid, pyrocatechol, allicin, aloin, aloe emodin, β carotene, β sitosterol, azadirachtin, cynocobalamin, Plastoquinone, xanthone, coumarin, lycopenecurcubitacin, rosmarinic acid}; (xi) a pulmonary protectant remedy {bixin, ledol, ascaridole}; (xii) a cardioprotectant remedy {tyramine, pseudoephedrine, bufotenine, papaverine}; (xiii) a nephroprotectant remedy {cimicifugic acid, protocatechuic acidephedrineferulic acid, gallic acidchavicine, piperine}; (xiv) a hematopoietic remedy {cynocobalamin, folacin, flavolignans, β carotene, ginsenoside, etc.}.
Figure 3.
Pharmaco-mechanistic profile of phyto-metabolites in treating systemic lupus erythromatosus. Plant-derived phytoconstituents serve as (i) nitric oxide synthase (iNOS) inhibitors and promote the scavenging of free radicals, thereby preventing SLE associated DNA damage (alizarin, asperuloside, α-amyrin, β-amyrin, andrographolide, angelic acid, cadinol, isophytol, β-phellandrene, galic acid, kaempferol, limonene, lupeol, lectin, scrocaffeside A, salvianolic acid, mitraphylline); (ii) inhibitors of autoantibody production {linalool acetate, α-terpinyl acetate}; (iii) inhibitors of COX-2-mediated PGE2 production, thereby ameliorating inflammation and pain {andrographolide, isophytol, farnesene, cadinoleugenol, troptolide}; (iv) inhibitors of lymphocyte proliferation {limonene, carvacrol, terpinene, calycopterin}; (v) down-regulators of NFκB -mediated signaling {allicin, alliin-γ-glutamyl-S-allyl-L-cysteine, andrographolide, saikosaponin, epigallocatechin gallate, lupeol, taraxerol, friedelin, betulinic acid, linalool, pinene, terpinene, limonene, curcumin}; (vi) down-regulators of STAT3-mediated signalling {berbamine, curcumin}; (vii) inhibitors of production of proinflammatory cytokines {allicin, alliin-γ-glutamyl-S-allyl-L-cysteine, pinitol, theophylline, epigallocatechin gallate, curcumin, periplocoside E, triptolide}; (viii) down-regulators of the expression of Rho-associated protein kinase (ROCK) {curcumin}; (ix) inhibitors specifically of the production of IL-17 {curcumin, quinone, phenylpropanoids, steroids, periplocoside E}; (x) a topical remedy for butterfly shaped cutaneous lesions {ecdysterone, oleanolic acid, pyrocatechol, allicin, aloin, aloe emodin, β carotene, β sitosterol, azadirachtin, cynocobalamin, Plastoquinone, xanthone, coumarin, lycopenecurcubitacin, rosmarinic acid}; (xi) a pulmonary protectant remedy {bixin, ledol, ascaridole}; (xii) a cardioprotectant remedy {tyramine, pseudoephedrine, bufotenine, papaverine}; (xiii) a nephroprotectant remedy {cimicifugic acid, protocatechuic acidephedrineferulic acid, gallic acidchavicine, piperine}; (xiv) a hematopoietic remedy {cynocobalamin, folacin, flavolignans, β carotene, ginsenoside, etc.}.

Table 1.
Major phyto-metabolites along with their targeted utility as therapeutic potentials for systemic lupus erythromatosus.
Molecular Target | Probable Utility | Therapeutic Benefits | Source Plant | Active Metabolites # | Reference (s) |
---|
iNOS and COX | Decreasing the nitrite and PGE2 levels by inhibition of the iNOS and COX expression | Anti-inflammatory | Acacia farnesiana | Lectin, Lupeol, α-Amyrin, β-Amyrin | [23] |
Andrographis paniculata | Andrographolide | [24] |
Angelica glauca | Angelic acid, β-Phellandrene, Ligustilide, Limonene | [25] |
Arundo donax | N-acetyl-D-glucosamine lectin | [26] |
Malus domestica | Isophytol, Farnesene, Cadinol | [27] |
Ocimum gratissimum | Eugenol | [28] |
Paeonia lactiflora | Gallic acid, Kaempferol | [29] |
Picrorhiza scrophulariiflora | Caffeoyl glycosides, Phenylethanoid glycoside, Plantamajoside, Scrocaffeside A | [30] |
Salvia miltiorrhiza | Salvianolic acid, Dihydrotanshinone, Tanshinone | [31] |
Uncaria tomentosa | Mitraphylline | [32,33] |
NFκB | Inhibits T cell activation through the modulation of NFκB transcription factor; reducing the level of pro-inflammatory cytokines | Immunomodulator, Signaling Regulator | Allium sativum | Allicin, Alliin, γ-Glutamyl-S-allyl-L-cysteines | [34] |
Bupleurum falcatum | 3-O-Feruloyl 5-O-Caffeoylquinic acid, Saikosaponin | [35] |
Clerodendron trichotomum | Lupeol, Friedelin, Betulinic acid, Taraxerol | [35] |
Coriandrum sativum | Linalool, Terpinene, Pinene, Limonene, p-Cymene | [36] |
Th1/Th2 proinflammatory cytokines | Suppress inflammation, inhibit proliferation and pro-inflammatory cytokines, downregulation of Th1/Th2 cytokines expression | Immunomodulator | Argyrolobium roseum | Pinitol | [37] |
Camellia sinensis | Theophylline, Epigallocatechin gallate | [38] |
Tripterygium wilfordii | Triptolide | [35,39,40] |
STAT3 and ROCK | Downregulating the expression of STAT3 and ROCK | Signaling regulator | Berberis aristata | Berbamine | [15] |
Curcuma longa | Curcumin | [35,41] |
RAF1 and mTOR | Downregulating the expression of V-raf-leukemia viral oncogene 1 (RAF1), and mechanistic target of rapamycin (mTOR) mRNA | Signaling regulator | Morinda citrifolia | Alizarin, Asperuloside, Chrysophanol, Digoxin | [42] |