Targeting sirtuins in diabetic retinopathy: Differential roles in inflammation and mitochondrial dysfunction

Table 1 Natural compounds targeting sirtuins

Natural products	SIRT	Possible signaling pathways	Function	Clinical evidence/status
Ginsenoside Rd	SIRT1	GPR30-PKA-LKB1-AMPK, AMPK/SIRT1	(1) Activation of AMPK increases the NAD+/NADH ratio, promotes LKB1 deacetylation, thereby enhancing the AMPK/SIRT1 interaction and restoring FAO; (2) Through IDH2, mitochondrial NADPH regeneration is maintained, thereby suppressing high glucose-induced NOX2 activation, oxidative stress, mitochondrial dysfunction, and endothelial cell death; and (3) Upregulation of SIRT1 expression increases mitochondrial DNA copy number and enhances the activity of antioxidant enzymes SOD and CAT	Many clinical studies have proved the role of ginsenoside RD in ischemic stroke[168,169]. The direct evidence in DR is still mainly preclinical research[128]
Ginsenoside Rb1	SIRT1	NAD-PARP-SIRT1	Alleviated high glucose-induced oxidative damage	A randomized, placebo-controlled study (early chronic kidney disease)[167]. The direct evidence in DR is still mainly preclinical research[102]
Ginsenoside Rg1	SIRT3	lncRNA SNHG7/miR-2116-5p/SIRT3	Attenuated the pathological processes in retinal endothelial cells induced by high glucose, including proliferation, migration, and angiogenesis	At present, there is no latest evidence of clinical research. The direct evidence in DR is still mainly preclinical research[128]
Resveratrol	SIRT1	SIRT1/HMGB1	(1) Activation of AMPK, prevention of SIRT1 inactivation, and reduction of NF-κB phosphorylation; (2) Inhibition of high glucose-induced ROS production and apoptosis through the AMPK/SIRT1/PGC-1α pathway; and (3) Upregulation of SIRT1 expression suppresses HMGB1 upregulation, modulates ferroptosis, and reduces oxidative stress, thereby protecting the BRB	Have completed a number of randomized controlled trials for diabetes and its complications, which confirmed that it can improve endothelial function, reduce oxidative stress and inflammatory markers, and promote the expression of SIRT1[160,161]. The direct evidence in DR is still mainly preclinical research[130]
Carnosic acid	SIRT1	SIRT1/p53/SLC7A11, AMPK pathway	Reduces intracellular Fe2+ and total iron content via the SIRT1/p53/SLC7A11 axis, alleviates ferroptosis-related molecular abnormalities, and inhibits iron deposition	At present, there is no latest evidence of clinical research. The direct evidence in DR is still mainly preclinical research[136]
Arbutin	SIRT1	SIRT1/NF-κB pathway	Elevates SIRT1 protein expression, thereby mitigating high glucose-induced damage in RPE cells	Existing human clinical trials (skin pigmentation)[166]. The direct evidence in DR is still mainly preclinical research[144]
Hawthorn polyphenols	SIRT1	MiR-34a/SIRT1, AMPK/SIRT1/NF-κB, miR-34a/SIRT1/p53	(1) Modulate the miR-34a/SIRT1 axis, reduces acetylation levels and inhibits high glucose-induced inflammation and apoptosis; and (2) Inhibited the AMPK/SIRT1/NF-κB and miR-34a/SIRT1/p53 pathways, it lowers ROS production and attenuates apoptotic cell death	A randomized, double-blind, placebo-controlled, crossover study (hypertension)[161]. The direct evidence in DR is still mainly preclinical research[140]
Polydatin	SIRT1	SIRT1/NLRP3 pathway	Exerts a protective effect on Müller cells through the SIRT1/NLRP3 inflammasome pathway	A multicentric randomized controlled trial (irritable bowel syndrome)[164]. The direct evidence in DR is still mainly preclinical research[88]
Baicalein	SIRT3	Endoplasmic reticulum stress	By activating SIRT3 and modulating endoplasmic reticulum stress, it ameliorates functional impairment in retinal microvascular endothelial cells under	Phase I clinical trial (influenza virus)[163]. The direct evidence in DR is still mainly preclinical research[147]
Honokiol	SIRT3	Mitochondrial fusion	Protects against diabetic retinal microvascular injury by promoting SIRT3-dependent mitochondrial fusion	At present, there is no latest evidence of clinical research. The direct evidence in DR is still mainly preclinical research[149]
Rhein	SIRT1	AMPK/SIRT1/PGC-1α	Ameliorate HG-induced inflammation, oxidative stress, apoptosis and protect against mitochondrial dysfunction by the activation of the AMPK/SIRT1/PGC-1α signaling pathway	The direct evidence in DR is still mainly preclinical research[159]
Astragalus polysaccharide	SIRT1	MiR-204/SIRT1	(1) Reversed the sustained up-regulation of miR-204 induced by metabolic memory, thereby alleviating its suppression of the protective protein SIRT1; and (2) The subsequent up-regulation of SIRT1 significantly mitigated endoplasmic reticulum stress and ultimately inhibited the ensuing apoptotic process	Randomized, placebo-controlled, phase 2 study (adjuvant chemotherapy-induced)[171]. The direct evidence in DR is still mainly preclinical research[156]
Gastrodin	SIRT1	SIRT1/TLR4/NF-κBp65	(1) Upregulate SIRT1 expression, which subsequently inhibits the activation TLR4 and the phosphorylation of NF-κBp65; and (2) Alleviates HG-induced oxidative stress and cell apoptosis	Randomized double-blind placebo-controlled trial (delirium after cardiac surgery)[162]. The direct evidence in DR is still mainly preclinical research[154]
Artesunate	SIRT1	AMPK/SIRT1-dependent autophagy pathway	Increased beclin-1 expression and elevated LC3II/I ratio, thereby inhibiting microglial activation	Approved drug (antimalarial)[170]. The direct evidence in DR is still mainly preclinical research[133]

SIRT: Sirtuin; GPR30: G protein-coupled receptor 30; PKA: Protein kinase A; LKB1: Liver kinase B1; AMPK: AMP-activated protein kinase; NAD+/NADH: Nicotinamide adenine dinucleotide; FAO: Fatty acid oxidation; IDH2: Isocitrate dehydrogenase 2; NADP+/NADPH: Nicotinamide adenine dinucleotide phosphate; NOX2: Nicotinamide adenine dinucleotide phosphate oxidase 2; CAT: Catalase; SOD: Superoxide dismutase; DR: Diabetic retinopathy; PARP: Poly(ADP-ribose) polymerase; lncRNA: Long non-coding RNA; HMGB1: High mobility group box 1; NF-κB: Nuclear factor-κB; ROS: Reactive oxygen species; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator-1α; BRB, blood-retinal barrier; SLC7A11: Solute carrier family 7 member 11; RPE: Retinal pigment epithelium; miR-34a: MicroRNA-34a; NLRP3: NLR family pyrin domain-containing 3; HG: High glucose; miR-204: MicroRNA-204; TLR4: Toll-like receptor 4; LC3I/LC3II: Microtubule-associated protein 1A/1B-light chain 3; SNHG7: Small nucleolar RNA host gene 7; miR-2116-5p: MicroRNA-2116-5p.