G-CSF attenuates neuroinflammation and neuronal apoptosis via the mTOR/p70SK6 signaling pathway in neonatal Hypoxia-Ischemia rat model

Dumbuya, John Sieh; Chen, Lu; Shu, Shijie; Ma, Lin; Luo, Wei; Li, Fēi; Wu, Jang‐Yen; Wang, Bin

doi:10.1016/j.brainres.2020.146817

Cited by 23 publications

(22 citation statements)

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“…Improved locomotion for the first 20 min was enhanced for a longer time period of 30 min at 7 days post BCAO This improved behavior at 7 days over 4 days indicates that the longer constitutive expression of the hG-CSF protein by the hG-CSF gene boosted protection, as reflected in improved behavior. In our previous study [ 81 ], we have demonstrated neuronal protection by G-CSF protein in hypoxia–ischemia animal model was in part due to its anti-inflammatory action since the expression levels of pro-inflammatory cytokines, TNF-α and IL-1ß were significantly decreased in the G-CSF protein treated group, while the anti-inflammatory cytokine, IL-10, expression level was increased. Our ongoing study of the mechanistic actions of hG-CSF gene therapy will include anti-inflammatory effect, pro-angiogenesis and pro-neurogenesis mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Granulocyte-colony stimulating factor gene therapy as a novel therapeutics for stroke in a mouse model

Menzie-Suderam

Modi

et al. 2020

J Biomed Sci

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Background Global ischemia is the resulting effect of a cardiopulmonary arrest (CPA). Presently there is no effective treatment to address neurological deficits in patients who survived a CPA. Granulocyte-colony stimulating factor is a growth factor (G-CSF) with a plethora of beneficial effects, including neuroprotection. Clinical application of human G-CSF (hG-CSF) is limited due to its plasma half-life of 4 h. Therefore, novel approaches need to be investigated that would (1) enable prolonged manifestation of hG-CSF and (2) demonstrate G-CSF efficacy from studying the underlying protective mechanisms of hG-CSF. In our previous work, we used the self-complementary adeno-associated virus (stereotype2: scAAV2) as a vector to transfect the hG-CSF gene into the global ischemic brain of a mouse. As an extension of that work, we now seek to elucidate the protective mechanisms of hG-CSF gene therapy against endoplasmic reticulum induced stress, mitochondrial dynamics and autophagy in global ischemia. Method A single drop of either AAV-CMV-hG-CSF or AAV-CMV-GFP was dropped into the conjunctival sac of the Swiss Webster mouse’s left eye, 30–60 min after bilateral common artery occlusion (BCAO). The efficacy of the expressed hG-CSF gene product was analyzed by monitoring the expression levels of endoplasmic reticulum stress (ER), mitochondrial dynamics and autophagic proteins over 4- and 7-days post-BCAO in vulnerable brain regions including the striatum, overlying cortex (frontal brain regions) and the hippocampus (middle brain regions). Statistical analysis was performed using mostly One-Way Analysis of variance (ANOVA), except for behavioral analysis, which used Repeated Measures Two-Way ANOVA, post hoc analysis was performed using the Tukey test. Results Several biomarkers that facilitated cellular death, including CHOP and GRP78 (ER stress) DRP1 (mitochondrial dynamics) and Beclin 1, p62 and LC3-ll (autophagy) were significantly downregulated by hG-CSF gene transfer. hG-CSF gene therapy also significantly upregulated antiapoptotic Bcl2 while downregulating pro-apoptotic Bax. The beneficial effects of hG-CSF gene therapy resulted in an overall improvement in functional behavior. Conclusion Taken together, this study has substantiated the approach of sustaining the protein expression of hG-CSF by eye drop administration of the hG-CSF gene. In addition, the study has validated the efficacy of using hG-CSF gene therapy against endoplasmic reticulum induced stress, mitochondrial dynamics and autophagy in global ischemia.

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Section: Discussionmentioning

confidence: 99%

Granulocyte-colony stimulating factor gene therapy as a novel therapeutics for stroke in a mouse model

Menzie-Suderam

Modi

et al. 2020

J Biomed Sci

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“…Nonetheless, after extensive liver injury, VEGF production is impaired throughout liver, as indicated by low plasma levels in people with ALF 15 . Similarly, G‐CSF facilitates the recruitment of stem/progenitor cells after hepatic growth‐arrest, 23 and contributes in tissue remodeling, for example, after partial hepatectomy, 45 Moreover, G‐CSF exerts anti‐inflammatory and cytoprotective effects through canonical JAK/STAT3 and noncanonical, mTOR or other pathways in multiple cells and tissues, for example, neurons 46 . Remarkably, after APAP toxicity human hepatocytes and mHep express GCSFR, which engages JAK/STAT3 signaling.…”

Section: Discussionmentioning

confidence: 99%

Transplanted hepatocytes rescue mice in acetaminophen‐induced acute liver failure through paracrine signals for hepatic ATM and STAT3 pathways

et al. 2021

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Acute liver failure constitutes a devastating condition that needs novel cell and molecular therapies. To elicit synergisms in cell types of therapeutic interest, we studied hepatocytes and liver sinusoidal endothelial in mice with acetaminophen-induced acute liver failure. The context of regenerative signals was examined by transplants in peritoneal cavity because it possesses considerable capacity and allows soluble signals to enter the systemic circulation. Whereas transplanted hepatocytes and liver sinusoidal endothelial cells engrafted in peritoneal cavity, only the former could rescue mice in liver failure by improving injury outcomes, activating hepatic DNA damage repair, and inducing liver regeneration. The cytokines secreted by donor hepatocytes or liver sinusoidal endothelial cells differed and in hepatocytes from mice undergoing acetaminophen toxicity major cytokines were even rendered deficient (eg, G-CSF, VEGF, and others). Significantly, recapitulating hepatotoxicity-related DNA damage response in cultured cells identified impairments in ATM and JAK/STAT3 intersections since replacing cytokines produced less from injured hepatocytes restored these pathways to avoid acetaminophen hepatotoxicity. Similarly, hepatocyte transplantation in acute liver failure restored ATM and JAK/STAT3 pathways to advance DNA damage/repair and liver regeneration. The unexpected identification of novel hepatic G-CSF receptor expression following injury allowed paradigmatic studies of G-CSF supplementation to confirm the centrality of this paracrine ATM and STAT3 intersection. Remarkably, DNA damage/repair and hepatic regeneration directed by G-CSF concerned rebalancing of regulatory gene networks overseeing inflammation, metabolism, and cell viability. We conclude that healthy donor hepatocytes offer 2 of 16 | VISWANATHAN eT Al.

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“…Most recently, Dumbuya et al (2020) demonstrated that G-CSF treatment in P7 HI rats reduced apoptosis and promoted the expression of IL-10. Simultaneously, G-CSF treatment also decreased infarct volume and tissue loss, and reduced expression of caspase-3, Bax, and Bcl-2.…”

Section: Experimental Hi Treatmentsmentioning

confidence: 99%

Current Therapies for Neonatal Hypoxic–Ischaemic and Infection-Sensitised Hypoxic–Ischaemic Brain Damage

Tetorou

Sisa

Iqbal

et al. 2021

Front. Synaptic Neurosci.

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Neonatal hypoxic–ischaemic brain damage is a leading cause of child mortality and morbidity, including cerebral palsy, epilepsy, and cognitive disabilities. The majority of neonatal hypoxic–ischaemic cases arise as a result of impaired cerebral perfusion to the foetus attributed to uterine, placental, or umbilical cord compromise prior to or during delivery. Bacterial infection is a factor contributing to the damage and is recorded in more than half of preterm births. Exposure to infection exacerbates neuronal hypoxic–ischaemic damage thus leading to a phenomenon called infection-sensitised hypoxic–ischaemic brain injury. Models of neonatal hypoxia–ischaemia (HI) have been developed in different animals. Both human and animal studies show that the developmental stage and the severity of the HI insult affect the selective regional vulnerability of the brain to damage, as well as the subsequent clinical manifestations. Therapeutic hypothermia (TH) is the only clinically approved treatment for neonatal HI. However, the number of HI infants needed to treat with TH for one to be saved from death or disability at age of 18–22 months, is approximately 6–7, which highlights the need for additional or alternative treatments to replace TH or increase its efficiency. In this review we discuss the mechanisms of HI injury to the immature brain and the new experimental treatments studied for neonatal HI and infection-sensitised neonatal HI.

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G-CSF attenuates neuroinflammation and neuronal apoptosis via the mTOR/p70SK6 signaling pathway in neonatal Hypoxia-Ischemia rat model

Cited by 23 publications

References 59 publications

Granulocyte-colony stimulating factor gene therapy as a novel therapeutics for stroke in a mouse model

Granulocyte-colony stimulating factor gene therapy as a novel therapeutics for stroke in a mouse model

Transplanted hepatocytes rescue mice in acetaminophen‐induced acute liver failure through paracrine signals for hepatic ATM and STAT3 pathways

Current Therapies for Neonatal Hypoxic–Ischaemic and Infection-Sensitised Hypoxic–Ischaemic Brain Damage

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