An in situ slow-releasing H2S donor depot with long-term therapeutic effects for treating ischemic diseases

Hsieh, Meng-Hsuan; Tsai, Hung‐Wen; Lin, Kun‐Ju; Wu, Zhenzhou; Hu, Hsin-Yi; Chang, Yen; Wei, Hao-Ji; Sung, Hsing‐Wen

doi:10.1016/j.msec.2019.109954

“…For example, it is suggested that DATS could be used for the treatment of I/R injury in brain tissues for its inhibitory effects on oxidative stress through Nrf2 activation ( Silva-Islas et al, 2019 ). Besides, DATS is also believed to own the ability for the promotion of angiogenesis ( Hayashida et al, 2017 ), which can be utilized for the protection of ischemic tissue in diabetic mice ( Yang et al, 2018 ) as well as the salvation of the ischemic limb ( Hsieh et al, 2019 ). In addition, there is a report suggesting that DATS is involved in the interruption of cell apoptosis through the induction of autophagy ( Chu et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Diallyl Trisulfide Enhances the Survival of Multiterritory Perforator Skin Flaps

Dong

¹

,

Chen

²

,

Zhu

³

et al. 2022

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The multiterritory perforator flap is one of the widest flap patterns used to repair tissue defects. However, flap necrosis of the distal part is still a challenging issue for plastic surgeons. Diallyl trisulfide (DATS) is an efficient ingredient extracted from garlic, exerting many important effects on different diseases. Our experiment aims to reveal whether DATS has a beneficial effect on the survival of perforator flaps and to explore its mechanism of action. The results showed that DATS enhanced angiogenesis and autophagy and reduced cell apoptosis and oxidative stress, thereby improving the survival rate of skin flaps. After co-administration with autophagy inhibitor 3-methyladenine (3MA), perforator flap survival was further improved. Mechanistically, we showed that PI3K/Akt and AMPK-HIF-1α signaling pathways in flap were activated under DATS treatment. All in all, DATS promoted the survival of multiterritory perforator flaps via the synergistic regulation of PI3K/Akt and AMPK-HIF-1α signaling pathways, and inhibition of DATS-induced autophagy further improves flap survival.

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“…Genetic ablation of NRF2 suppresses the proliferation and angiogenic function of endothelial cells in vitro and in vivo [43]. Furthermore, in the preclinical model of ischemic retinopathy, cerebral ischemia, and HLI, knockdown of NRF2 limits the effectiveness of angiogenesis therapy [72][73][74]. Importantly, the activation of NRF2 could promote the expression of angiogenic genes in wound biopsies in diabetic patients [75].…”

Section: Discussionmentioning

confidence: 99%

Buyang Huanwu Decoction Enhances Revascularization via Akt/GSK3β/NRF2 Pathway in Diabetic Hindlimb Ischemia

Bao

¹

,

Deng

²

,

Huang

³

et al. 2021

Oxidative Medicine and Cellular Longevity

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Background. Peripheral arterial disease (PAD) is a typical disease of atherosclerosis, most commonly influencing the lower extremities. In patients with PAD, revascularization remains a preferred treatment strategy. Buyang Huanwu decoction (BHD) is a popular Chinese herbal prescription which has showed effects of cardiovascular protection through conducting antioxidant, antiapoptotic, and anti-inflammatory effects. Here, we intend to study the effect of BHD on promoting revascularization via the Akt/GSK3β/NRF2 pathway in diabetic hindlimb ischemia (HLI) model of mice. Materials and Methods. All db/db mice ( n = 60 ) were randomly divided into 6 groups by table of random number. (1) Sham group ( N = 10 ): 7-0 suture thread passed through the underneath of the femoral artery and vein without occlusion. The remaining 5 groups were treated differently on the basis of the HLI (the femoral artery and vein from the inguinal ligament to the knee joint were transected and the vascular stump was ligated with 7-0 silk sutures) model: (2) HLI+NS group ( N = 15 ): 0.2 ml NS was gavaged daily for 3 days before modeling and 14 days after occlusion; (3) HLI+BHD group ( N = 15 ): 0.2 ml BHD (20 g/kg/day) was gavaged daily for 3 days before modeling and 14 days after occlusion; (4) HLI+BHD+sh-NC group ( N = 8 ): local injection of adenovirus vector carrying the nonsense shRNA (Ad-GFP) in the hindlimbs of mice before treatment; (5) HLI+BHD+sh-NRF2 group ( N = 8 ): knockdown of NRF2 in the hindlimbs of mice by local intramuscular injection of adenovirus vector carrying NRF2 shRNA (Ad-NRF2-shRNA) before treatment; and (6) HLI+BHD+LY294002 group ( N = 4 ): intravenous injection of LY294002 (1.5 mg/kg) once a day for 14 days on the basis of the HLI+BHD group. Laser Doppler examination, vascular cast, and immunofluorescence staining were applied to detect the revascularization of lower limbs in mice. Western blot analysis was used to detect the expression of vascular endothelial growth factor (VEGF), interleukin-1beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor- (TNF-) α, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone-1 (NQO-1), catalase (CAT), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphorylated protein kinase B (p-AKT), and phosphorylated glycogen synthase kinase-3 beta (p-GSK3β). HE staining was used to assess the level of muscle tissue damage and inflammation in the lower extremities. Local multipoint injection of Ad-NRF2-shRNA was used to knock down NRF2, and qPCR was applied to detect the mRNA level of NRF2. The blood glucose, triglyceride, cholesterol, MDA, and SOD levels of mice were tested using corresponding kits. The SPSS 20.0 software and GraphPad Prism 6.05 were used to do all statistics. Values of P < 0.05 were considered as statistically significant. Results and Conclusions. BHD could enhance the revascularization of lower limbs in HLI mice, while BHD has no effect on blood glucose and lipid level in db/db mice ( P > 0.05 ). BHD could elevate the protein expression of VEGF, HO-1, NQO-1, and CAT ( P < 0.05 ) and decrease the expression of IL-1β, IL-6, and TNF-α ( P < 0.05 ) in HLI mice. Meanwhile, BHD could activate NRF2 and promote the phosphorylation of AKT/GSK3β during revascularization ( P < 0.05 ). In contrast, knockdown of NRF2 impaired the protective effects of BHD on HLI ( P < 0.05 ). LY294002 inhibited the upregulation of NRF2 activated by BHD through inhibiting the phosphorylation of the AKT/GSK3β pathway ( P < 0.05 ). The present study demonstrated that BHD could promote revascularization on db/db mice with HLI through targeting antioxidation, anti-inflammation, and angiogenesis via the AKT/GSK3β/NRF2 pathway.

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“…H 2 S has shown the abilities to relieve oxidative stress [ 177 ], promote angiogenesis [ 16 ], and inhibit cellular apoptosis [ 178 ], which are benefit for treating ischemia. In an attempt to treat limb ischemia, Sung et al prepared DATS loaded H 2 S releasing PLGA microparticles (DATS@MPs) through an oil-in-water single emulsion method [ 68 ]. Compared with free DATS, DATS@MPs enabled prolonged intracellular H 2 S generation, favoring long-lasting therapeutic effects.…”

Section: Therapeutic Applications Of Intelligent Polymeric H ...mentioning

confidence: 99%

Intelligent polymeric hydrogen sulfide delivery systems for therapeutic applications

Rong

¹

,

Wang

²

,

Zhou

³

et al. 2023

Bioactive Materials

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An in situ slow-releasing H2S donor depot with long-term therapeutic effects for treating ischemic diseases

Cited by 18 publications

References 44 publications

Diallyl Trisulfide Enhances the Survival of Multiterritory Perforator Skin Flaps

Diallyl Trisulfide Enhances the Survival of Multiterritory Perforator Skin Flaps

Buyang Huanwu Decoction Enhances Revascularization via Akt/GSK3β/NRF2 Pathway in Diabetic Hindlimb Ischemia

Intelligent polymeric hydrogen sulfide delivery systems for therapeutic applications

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