Investigation of Neuropathology after Nerve Release in Chronic Constriction Injury of Rat Sciatic Nerve

Chen, Szu Han; Wu, Chia Ching; Lin, Shao Chieh; Tseng, Wan Ling; Huang, Tsui-Chin; Yadav, Anjali; Lu, Fu I.; Liu, Ya-Hsin; Lin, Shau Ping; Hsueh, Yuan Yu

doi:10.3390/ijms22094746

Cited by 16 publications

(19 citation statements)

References 48 publications

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“…Activation of the PI3K/Akt/eNOS pathway is a crucial process in the stimulation of angiogenesis, including HUVECs viability and tube formation [ 55 ]. Nitric oxide (NO) is a vessel active substance secreted by the vascular endothelial system and plays a crucial role in maintaining vascular homeostasis [ 56 ]. NO is generated by the endothelial nitric oxide synthase (eNOS).…”

Section: Discussionmentioning

confidence: 99%

Exosomes derived from pioglitazone-pretreated MSCs accelerate diabetic wound healing through enhancing angiogenesis

et al. 2021

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Background Enhanced angiogenesis can promote diabetic wound healing. Mesenchymal stem cells (MSCs)-derived exosomes, which are cell-free therapeutics, are promising candidates for the treatment of diabetic wound healing. The present study aimed to investigate the effect of exosomes derived from MSCs pretreated with pioglitazone (PGZ-Exos) on diabetic wound healing. Results We isolated PGZ-Exos from the supernatants of pioglitazone-treated BMSCs and found that PGZ-Exos significantly promote the cell viability and proliferation of Human Umbilical Vein Vascular Endothelial Cells (HUVECs) injured by high glucose (HG). PGZ-Exos enhanced the biological functions of HUVECs, including migration, tube formation, wound repair and VEGF expression in vitro. In addition, PGZ-Exos promoted the protein expression of p-AKT, p-PI3K and p-eNOS and suppressed that of PTEN. LY294002 inhibited the biological function of HUVECs through inhibition of the PI3K/AKT/eNOS pathway. In vivo modeling in diabetic rat wounds showed that pioglitazone pretreatment enhanced the therapeutic efficacy of MSCs-derived exosomes and accelerated diabetic wound healing via enhanced angiogenesis. In addition, PGZ-Exos promoted collagen deposition, ECM remodeling and VEGF and CD31 expression, indicating adequate angiogenesis in diabetic wound healing. Conclusions PGZ-Exos accelerated diabetic wound healing by promoting the angiogenic function of HUVECs through activation of the PI3K/AKT/eNOS pathway. This offers a promising novel cell-free therapy for treating diabetic wound healing. Graphic abstract

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Section: Discussionmentioning

confidence: 99%

Exosomes derived from pioglitazone-pretreated MSCs accelerate diabetic wound healing through enhancing angiogenesis

et al. 2021

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“…Immune mediators, such as IL-1β, are only required during the WD process and are cleared prior to the initiation of nerve reinnervation, which implies that these factors play temporal roles during distinct stages of the process [ 6 ]. The balanced expression of TNFα has been shown to promote axonal regeneration, based on the observed effects of TNFα inhibition by the intraperitoneal and epineurial administration of a TNFα antagonist (etanercept) at the time of a crush injury [ 7 , 8 ]. By contrast, chronic and prolonged inflammation caused by peripheral nerve injury can lead to complications, such as neuropathic pain [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NFκB to promote axonal regeneration and remyelination

Yadav

Huang

Chen

et al. 2021

J Neuroinflammation

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Background Epigenetic regulation by histone deacetylases (HDACs) in Schwann cells (SCs) after injury facilitates them to undergo de- and redifferentiation processes necessary to support various stages of nerve repair. Although de-differentiation activates the synthesis and secretion of inflammatory cytokines by SCs to initiate an immune response during nerve repair, changes in either the timing or duration of prolonged inflammation mediated by SCs can affect later processes associated with repair and regeneration. Limited studies have investigated the regulatory processes through which HDACs in SCs control inflammatory cytokines to provide a favorable environment for peripheral nerve regeneration. Methods We employed the HDAC inhibitor (HDACi) sodium phenylbutyrate (PBA) to address this question in an in vitro RT4 SC inflammation model and an in vivo sciatic nerve transection injury model to examine the effects of HDAC inhibition on the expression of pro-inflammatory cytokines. Furthermore, we assessed the outcomes of suppression of extended inflammation on the regenerative potential of nerves by assessing axonal regeneration, remyelination, and reinnervation. Results Significant reductions in lipopolysaccharide (LPS)-induced pro-inflammatory cytokine (tumor necrosis factor-α [TNFα]) expression and secretion were observed in vitro following PBA treatment. PBA treatment also affected the transient changes in nuclear factor κB (NFκB)-p65 phosphorylation and translocation in response to LPS induction in RT4 SCs. Similarly, PBA mediated long-term suppressive effects on HDAC3 expression and activity. PBA administration resulted in marked inhibition of pro-inflammatory cytokine secretion at the site of transection injury when compared with that in the hydrogel control group at 6-week post-injury. A conducive microenvironment for axonal regrowth and remyelination was generated by increasing expression levels of protein gene product 9.5 (PGP9.5) and myelin basic protein (MBP) in regenerating nerve tissues. PBA administration increased the relative gastrocnemius muscle weight percentage and maintained the intactness of muscle bundles when compared with those in the hydrogel control group. Conclusions Suppressing the lengthened state of inflammation using PBA treatment favors axonal regrowth and remyelination following nerve transection injury. PBA treatment also regulates pro-inflammatory cytokine expression by inhibiting the transcriptional activation of NFκB-p65 and HDAC3 in SCs in vitro.

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“…Previous studies reported that in the CCI-induced neuropathy model, the TNF-α, IL-1β signals, and infiltration of CD68+ inflammatory cells induced a partial decrease after nerve release [ 207 , 208 ]. Our study showed that TNF-α signaling was an essential feature of PNS autoimmunity [ 209 ], since TNF-α expression limitation protected against PIN [ 210 , 211 ].…”

Section: Resultsmentioning

confidence: 99%

Sustainable Release of Propranolol Hydrochloride Laden with Biconjugated-Ufasomes Chitosan Hydrogel Attenuates Cisplatin-Induced Sciatic Nerve Damage in In Vitro/In Vivo Evaluation

et al. 2022

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Peripheral nerve injuries significantly impact patients’ quality of life and poor functional recovery. Chitosan–ufasomes (CTS–UFAs) exhibit biomimetic features, making them a viable choice for developing novel transdermal delivery for neural repair. This study aimed to investigate the role of CTS–UFAs loaded with the propranolol HCl (PRO) as a model drug in enhancing sciatica in cisplatin-induced sciatic nerve damage in rats. Hence, PRO–UFAs were primed, embedding either span 20 or 60 together with oleic acid and cholesterol using a thin-film hydration process based on full factorial design (24). The influence of formulation factors on UFAs’ physicochemical characteristics and the optimum formulation selection were investigated using Design-Expert® software. Based on the optimal UFA formulation, PRO–CTS–UFAs were constructed and characterized using transmission electron microscopy, stability studies, and ex vivo permeation. In vivo trials on rats with a sciatic nerve injury tested the efficacy of PRO–CTS–UFA and PRO–UFA transdermal hydrogels, PRO solution, compared to normal rats. Additionally, oxidative stress and specific apoptotic biomarkers were assessed, supported by a sciatic nerve histopathological study. PRO–UFAs and PRO–CTS–UFAs disclosed entrapment efficiency of 82.72 ± 2.33% and 85.32 ± 2.65%, a particle size of 317.22 ± 6.43 and 336.12 ± 4.9 nm, ζ potential of −62.06 ± 0.07 and 65.24 ± 0.10 mV, and accumulatively released 70.95 ± 8.14% and 64.03 ± 1.9% PRO within 6 h, respectively. Moreover, PRO–CTS–UFAs significantly restored sciatic nerve structure, inhibited the cisplatin-dependent increase in peripheral myelin 22 gene expression and MDA levels, and further re-established sciatic nerve GSH and CAT content. Furthermore, they elicited MBP re-expression, BCL-2 mild expression, and inhibited TNF-α expression. Briefly, our findings proposed that CTS–UFAs are promising to enhance PRO transdermal delivery to manage sciatic nerve damage.

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Investigation of Neuropathology after Nerve Release in Chronic Constriction Injury of Rat Sciatic Nerve

Cited by 16 publications

References 48 publications

Exosomes derived from pioglitazone-pretreated MSCs accelerate diabetic wound healing through enhancing angiogenesis

Exosomes derived from pioglitazone-pretreated MSCs accelerate diabetic wound healing through enhancing angiogenesis

Sodium phenylbutyrate inhibits Schwann cell inflammation via HDAC and NFκB to promote axonal regeneration and remyelination

Sustainable Release of Propranolol Hydrochloride Laden with Biconjugated-Ufasomes Chitosan Hydrogel Attenuates Cisplatin-Induced Sciatic Nerve Damage in In Vitro/In Vivo Evaluation

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