Convergent Molecular Pathways in Type 2 Diabetes Mellitus and Parkinson’s Disease: Insights into Mechanisms and Pathological Consequences

Xxxx, Sandeep; Ahmad, Mir Hilal; Rani, Linchi; Mondal, Amal Chandra

doi:10.1007/s12035-022-02867-7

Cited by 5 publications

(5 citation statements)

References 170 publications

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“…Recent evidence has shown a correlation between energy metabolism and neurodegeneration, with T2DM increasing the risk of Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. [20][21][22] DEGs were found to be enriched in the following items according to the KEGG analysis: CGMP-PKG signaling pathway, AMPK signaling pathway, Thyroid hormone signaling pathway, Insulin signaling pathway, Adipocytokine signaling pathway. AMPK signaling has been found to enhance insulin sensitivity, offering potential treatment options for diabetic patients.…”

Section: Discussionmentioning

confidence: 99%

Analyzing Immune Cell Infiltration and Copper Metabolism in Diabetic Foot Ulcers

Yi,

Yuan,

Bao

et al. 2024

JIR

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Background Diabetes impairs wound healing, notably in diabetic foot ulcers (DFU). Stress, marked by the accumulation of lipoylated mitochondrial enzymes and the depletion of Fe–S cluster proteins, triggers cuproptosis—a distinct form of cell death. The involvement of copper in the pathophysiology of DFU has been recognized, and currently, a copper-based therapeutic strategy is emerging as a viable option for enhancing ulcer healing. This study investigates genes linked to copper metabolism in DFU, aiming to uncover potential targets for therapeutic intervention. Methods Two diabetic wound Gene Expression Omnibus (GEO) datasets were analyzed to study immune cell dysregulation in diabetic wounds. Differentially expressed genes related to copper metabolism were identified and analyzed using machine learning methods. Gene ontology, pathway enrichment, and immune infiltration analyses were performed using DFU samples. The expression of identified genes was validated using qRT-PCR and single-cell RNA sequencing. Results Ten genes associated with copper metabolism were identified. Among these, SLC31A1 and ADNP were found to be significantly differentially expressed in DFU. Notably, SLC31A1 exhibited higher expression in macrophages, whereas ADNP was found to be highly expressed in fibroblasts and chondrocytes. Conclusion The study indicates a close link between copper metabolism, the infiltration of immune cells, and DFU. It proposes that copper metabolism could influence the progression of DFU through the activation of immune responses. These observations offer fresh perspectives on the underlying mechanisms of DFU and identify potential targets for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Analyzing Immune Cell Infiltration and Copper Metabolism in Diabetic Foot Ulcers

Yi,

Yuan,

Bao

et al. 2024

JIR

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“…Therefore, the inhibition of miR-34a via SRG can not only increase the expression of SIRT1 to induce the activity of autophagy but also strengthen the ability of cells to resist apoptosis, anti-aging, and promote regeneration. Furthermore, PD is associated with chronic inflammation [ 63 ] and diabetes [ 64 ]. The downregulation of miR-34a via SRG can further improve the effects of chronic inflammation and diabetes on the progression of PD.…”

Section: Discussionmentioning

confidence: 99%

Syringin Prevents 6-Hydroxydopamine Neurotoxicity by Mediating the MiR-34a/SIRT1/Beclin-1 Pathway and Activating Autophagy in SH-SY5Y Cells and the Caenorhabditis elegans Model

Fu,

Hong,

Chen

2023

Cells

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Defective autophagy is one of the cellular hallmarks of Parkinson’s disease (PD). Therefore, a therapeutic strategy could be a modest enhancement of autophagic activity in dopamine (DA) neurons to deal with the clearance of damaged mitochondria and abnormal protein aggregates. Syringin (SRG) is a phenolic glycoside derived from the root of Acanthopanax senticosus. It has antioxidant, anti-apoptotic, and anti-inflammatory properties. However, whether it has a preventive effect on PD remains unclear. The present study found that SRG reversed the increase in intracellular ROS-caused apoptosis in SH-SY5Y cells induced by neurotoxin 6-OHDA exposure. Likewise, in C. elegans, degeneration of DA neurons, DA-related food-sensitive behaviors, longevity, and accumulation of α-synuclein were also improved. Studies of neuroprotective mechanisms have shown that SRG can reverse the suppressed expression of SIRT1, Beclin-1, and other autophagy markers in 6-OHDA-exposed cells. Thus, these enhanced the formation of autophagic vacuoles and autophagy activity. This protective effect can be blocked by pretreatment with wortmannin (an autophagosome formation blocker) and bafilomycin A1 (an autophagosome–lysosome fusion blocker). In addition, 6-OHDA increases the acetylation of Beclin-1, leading to its inactivation. SRG can induce the expression of SIRT1 and promote the deacetylation of Beclin-1. Finally, we found that SRG reduced the 6-OHDA-induced expression of miR-34a targeting SIRT1. The overexpression of miR-34a mimic abolishes the neuroprotective ability of SRG. In conclusion, SRG induces autophagy via partially regulating the miR-34a/SIRT1/Beclin-1 axis to prevent 6-OHDA-induced apoptosis and α-synuclein accumulation. SRG has the opportunity to be established as a candidate agent for the prevention and cure of PD.

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“…Besides, astrocytes and microglia are activated in response to α‐synuclein‐induced inflammation leading to the generation of ROS and pro‐inflammatory cytokines in a vicious cycle 132 . Higher oxidative stress and inflammation in T2DM promotes the peripheral and local activation of the NF‐κB and the NLRP3 inflammasome leading to neuroinflammation which involved in PD neuropathology 133 …”

Section: Nf‐κb/nlrp3 Inflammasome Axismentioning

confidence: 99%

“… 132 Higher oxidative stress and inflammation in T2DM promotes the peripheral and local activation of the NF‐κB and the NLRP3 inflammasome leading to neuroinflammation which involved in PD neuropathology. 133 …”

Section: Nf‐κb / Nlrp3 Inflammasome Axismentioning

confidence: 99%

NF‐κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective

Alrouji

Al-Kuraishy

Al-Gareeb

et al. 2023

J Cellular Molecular Medi

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Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). Genetic predisposition and immune dysfunction are involved in the pathogenesis of PD. Notably, peripheral inflammatory disorders and neuroinflammation are associated with PD neuropathology. Type 2 diabetes mellitus (T2DM) is associated with inflammatory disorders due to hyperglycaemia-induced oxidative stress and the release of pro-inflammatory cytokines. Particularly, insulin resistance (IR) in T2DM promotes the degeneration of dopaminergic neurons in the substantia nigra (SN). Thus, T2DM-induced inflammatory disorders predispose to the development and progression of PD, and their targeting may reduce PD risk in T2DM.

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Convergent Molecular Pathways in Type 2 Diabetes Mellitus and Parkinson’s Disease: Insights into Mechanisms and Pathological Consequences

Cited by 5 publications

References 170 publications

Analyzing Immune Cell Infiltration and Copper Metabolism in Diabetic Foot Ulcers

Analyzing Immune Cell Infiltration and Copper Metabolism in Diabetic Foot Ulcers

Syringin Prevents 6-Hydroxydopamine Neurotoxicity by Mediating the MiR-34a/SIRT1/Beclin-1 Pathway and Activating Autophagy in SH-SY5Y Cells and the Caenorhabditis elegans Model

NF‐κB/NLRP3 inflammasome axis and risk of Parkinson's disease in Type 2 diabetes mellitus: A narrative review and new perspective

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