Regulation of glycolysis and the Warburg effect in wound healing

Vinaik, Roohi; Barayan, Dalia; Auger, Christopher; Abdullahi, Abdikarim; Jeschke, Marc G.

doi:10.1172/jci.insight.138949

Cited by 55 publications

(49 citation statements)

References 34 publications

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“…Furthermore, shikonin treatment led to a reduction in IL-1β production in an experimental model of atherosclerotic coronary artery disease [ 225 ]. These anti-inflammatory effects of shikonin-mediated inhibition of PKM2 were further confirmed in several experimental models of human inflammatory diseases [ 226 , 227 , 228 , 229 ] ( Figure 4 A ). For instance, shikonin treatment promoted wound healing and alleviated burn-induced inflammation in rodents [ 229 ], preserved redox homeostasis and abrogated IL-1β-induced expression of ICAM1 and VCAM1 in human endothelial cells, and protected against vascular oxidative stress in apolipoprotein E-deficient (ApoE −/− ) mice subjected to partial ligation of the left carotid artery and fed a cholesterol-rich diet.…”

Section: Emerging Areas Of Research Involving Pkm2supporting

confidence: 53%

“…These anti-inflammatory effects of shikonin-mediated inhibition of PKM2 were further confirmed in several experimental models of human inflammatory diseases [ 226 , 227 , 228 , 229 ] ( Figure 4 A ). For instance, shikonin treatment promoted wound healing and alleviated burn-induced inflammation in rodents [ 229 ], preserved redox homeostasis and abrogated IL-1β-induced expression of ICAM1 and VCAM1 in human endothelial cells, and protected against vascular oxidative stress in apolipoprotein E-deficient (ApoE −/− ) mice subjected to partial ligation of the left carotid artery and fed a cholesterol-rich diet. Additionally, shikonin reduced macrophage infiltration into the carotid arteries of ApoE −/− mice [ 230 ], alleviated UUO-induced mouse renal fibrosis and TGF-β1-stimulated myofibroblast activation [ 231 ], and inhibited the proliferation of fibroblasts from the pulmonary hypertensive vessel (PH-Fibs) and the subsequent activation of macrophages [ 226 ].…”

Section: Emerging Areas Of Research Involving Pkm2supporting

confidence: 53%

“…Future efforts towards uncovering the anti-inflammatory potential of shikonin may prove significant. Further promoting the importance of future investigations, shikonin has shown significant promise as an antimicrobial and antiviral agent, as well as a wound healing promoter [ 224 , 229 , 237 , 238 , 239 , 240 , 241 , 242 ] ( Figure 4 B ). Nevertheless, it remains to be determined whether these beneficial properties of shikonin are mediated through modulation of PKM2 activity.…”

Section: Emerging Areas Of Research Involving Pkm2mentioning

confidence: 99%

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The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

Puckett

Alquraishi

Chowanadisai

et al. 2021

IJMS

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Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.

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Section: Emerging Areas Of Research Involving Pkm2supporting

confidence: 53%

Section: Emerging Areas Of Research Involving Pkm2supporting

confidence: 53%

Section: Emerging Areas Of Research Involving Pkm2mentioning

confidence: 99%

See 1 more Smart Citation

The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

Puckett

Alquraishi

Chowanadisai

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…For instance, altered metabolism is observed in immune cells [ 7 ], LPS-activated macrophages [ 8 ], pulmonary hypertension [ 9 ], sepsis [ 10 ] and metabolic disorders [ 11 ]. Additionally, several studies reported that keloid is an aberrant scarring featuring metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis [ 12 , 13 ]. Annette reported that compared to normal fibroblasts (NFB), cultured KFB exhibit increased glucose uptake and lactate accumulation and higher hexokinase, glyceraldehyde-3-phosphate dehydrogenase, and lactate dehydrogenase activities [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…Annette reported that compared to normal fibroblasts (NFB), cultured KFB exhibit increased glucose uptake and lactate accumulation and higher hexokinase, glyceraldehyde-3-phosphate dehydrogenase, and lactate dehydrogenase activities [ 12 ]. Vinaik [ 13 ] demonstrated the upregulation of GLUT1 and enhanced expression of several glycolytic enzymes such as HK1, HK2, PFK1, PFK2, PDK1 and PKM2 in keloid tissues compared with normal skin tissues. Our previous studies [ 14 , 15 ] indicated that KFB exhibit increased glycolysis and compromised mitochondrial functions.…”

Section: Introductionmentioning

confidence: 99%

Altered glucose metabolism and cell function in keloid fibroblasts under hypoxia

Wang

Qin

et al. 2021

Redox Biology

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Keloids exhibit metabolic reprogramming including enhanced glycolysis and attenuated oxidative phosphorylation. Hypoxia induces a series of protective responses in mammalian cells. However, the metabolic phenotype of keloid fibroblasts under hypoxic conditions remains to be elucidated. The present study aimed to investigate glycolytic activity, mitochondrial function and morphology, and the HIF1α and PI3K/AKT signaling pathways in keloid fibroblasts (KFB) under hypoxic conditions. Our results showed that hypoxia promoted proliferation, migration invasion and collagen synthesis and inhibited apoptosis in KFB. The mRNA levels, protein expressions and enzyme activities of glycolytic enzymes in KFB were higher than those in normal skin fibroblasts (NFB) under normoxia. Moreover, hypoxia remarkedly upregulated glycolysis in KFB. Decreased activities of mitochondrial complexes and abnormal mitochondria were detected in KFB under normoxic conditions and the damage was aggravated by hypoxia. An intracellular metabolic profile assay suggested hypoxia increased glycolytic parameters except glycolytic reserve but inhibited the key parameters of mitochondrial function apart from H + leak. Protein levels of HIF1α and phosphorylation levels of the PI3K/AKT signaling pathway were upregulated in the context of 3% oxygen. Enhanced total reactive oxygen species (ROS), mitochondrial ROS (mitoROS) and antioxidant activities of KFB were observed in response to hypoxia. Additionally, autophagy was induced by hypoxia. Our data collectively demonstrated potentiated glycolysis and attenuated mitochondrial function under hypoxia, indicating that altered glucose metabolism regulated by hypoxia could be a therapeutic target for keloids.

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A Pellino‐2 variant is associated with constitutive NLRP3 inflammasome activation in a family with ocular pterygium–digital keloid dysplasia

et al. 2023

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Edited by Wilfried EllmeierOcular pterygium-digital keloid dysplasia (OPDKD) is a rare hereditary disease characterized by corneal ingrowth of vascularized conjunctival tissue early in life. Later, patients develop keloids on fingers and toes but are otherwise healthy. In a recently described family with OPDKD, we report the presence of a de novo c.770C > T, p.(Thr257Ile) variant in PELI2 in the affected individual. PELI2 encodes for the E3 ubiquitin ligase Pellino-2. In transgenic U87MG cells overexpressing Pellino-2 with the p.(Thr257Ile) amino acid substitution, constitutive activation of the NLRP3 inflammasome was observed. However, the Thr257Ile variant did not affect Pellino-2 intracellular localization, its binding to known interaction partners, nor its stability. Our findings indicate that constitutive autoactivation of the NLRP3 inflammasome contributes to the development of PELI2-associated OPDKD.

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Regulation of glycolysis and the Warburg effect in wound healing

Cited by 55 publications

References 34 publications

The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

Altered glucose metabolism and cell function in keloid fibroblasts under hypoxia

A Pellino‐2 variant is associated with constitutive NLRP3 inflammasome activation in a family with ocular pterygium–digital keloid dysplasia

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