Mechanism of the JAK2/STAT3-CAV-1-NR2B signaling pathway in painful diabetic neuropathy

Chuanda, LI; Zhao, Jiayi; Chen, Jiali; Lü, Jing; Zhang, Mao‐Biao; Huang, Qi; Cao, Yannan; Ge, Jia; Tao, Yuan‐Xiang; Li, Jun; Cao, Hong

doi:10.1007/s12020-019-01880-6

Cited by 37 publications

(24 citation statements)

References 41 publications

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“…44,52 A rapidly growing body of evidence showed that microglial cells are critical components for hyperpathia and coexistence of STAT3 with microglia. 53,54 Our current immunofluorescence results showed that p-JAK2 and p-STAT3 were activated by BCP colocalized with astrocytes, microglial cells, and neurons in spinal dorsal horn. Vast majority of these proteins were located on the neurons, which may in turn cause hyperexcitability of neurons.…”

Section: Discussionmentioning

confidence: 70%

B14 ameliorates bone cancer pain through downregulating spinal interleukin-1β via suppressing neuron JAK2/STAT3 pathway

et al. 2019

Mol Pain

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Curcumin has several pharmacological properties such as anti-inflammatory, antioxidant, and neuroprotective activities. B14 is a curcumin analogue and is considered to be a more potent compound with preserved pharmacodynamic activities. Based on the previous research studies, janus-activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway plays a remarkable role in inflammation, chronic pain, and even contributes to the pathogenesis of neuropathic pain. Pro-inflammatory cytokines interleukin-1b is a downstream factor of JAK2/STAT3 signal transition pathway, which participates in neuron injury and inflammation. We hypothesized that this signal transition pathway played an indispensable role in bone cancer pain. We herein established a bone cancer pain model to monitor the variation of JAK2/STAT3 signal transduction pathway and measured the effect of B14. The results in bone cancer pain model showed that (i) the levels of interleukin-1b were elevated, and the ratios of p-JAK2/JAK2 and p-STAT3/STAT3 were increased; (ii) double immunostaining showed that p-JAK2, p-STAT3, and interleukin-1b were colocalized primarily with neurons, rather than with astrocytes or microglial cells; (iii) B14 injection (intraperitoneally) markedly eased bone cancer pain; (iv) Western blotting showed that B14 injection lowered p-JAK2, p-STAT3, and interleukin-1b levels, meanwhile the ratios of p-JAK2/ JAK2 and p-STAT3/STAT3 was reduced; (v) immunofluorescence results also confirmed decreased levels of p-JAK2, p-STAT3, and interleukin-1b in B14 treatment group. These findings suggested that B14 injection attenuated bone cancer pain in rats. This intervention inhibited JAK2/STAT3 cascade activation, downregulating interleukin-1b expression in spinal dorsal horn.

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Section: Discussionmentioning

confidence: 70%

B14 ameliorates bone cancer pain through downregulating spinal interleukin-1β via suppressing neuron JAK2/STAT3 pathway

et al. 2019

Mol Pain

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“…It was further demonstrated that the CAV1-NR2B pathway is activated by microglial JAK2-STAT3 signaling (Janus kinase 2-signal transducer and activator of transcription 3), which contributes to diabetic neuropathic pain. Pain was also relieved by administering AG490 (JAK2 inhibitor) to the rats [193]. Collectively these data render promising DPN therapies based on the JAK2-STAT3-CAV1-NR2B signaling pathway.…”

Section: Role Of Caveolin-1 In Oxidative Stressmentioning

confidence: 85%

Role of Caveolin-1 in Diabetes and Its Complications

Haddad

Madhoun

Nizam

et al. 2020

Oxidative Medicine and Cellular Longevity

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It is estimated that in 2017 there were 451 million people with diabetes worldwide. These figures are expected to increase to 693 million by 2045; thus, innovative preventative programs and treatments are a necessity to fight this escalating pandemic disorder. Caveolin-1 (CAV1), an integral membrane protein, is the principal component of caveolae in membranes and is involved in multiple cellular functions such as endocytosis, cholesterol homeostasis, signal transduction, and mechanoprotection. Previous studies demonstrated that CAV1 is critical for insulin receptor-mediated signaling, insulin secretion, and potentially the development of insulin resistance. Here, we summarize the recent progress on the role of CAV1 in diabetes and diabetic complications.

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“…Furthermore, the cytokines further activate glial cells and neurons to release more activating substances, such as ATP, pro-inflammatory factors and reactive oxygen species ( 42 ). These activating substances further enhance pain and may transform acute pain into chronic pain ( 43 ). In the present study, the expression levels of the inflammatory factors IL-6 and TNF-α not only increased in the DRG, but also in the tissues surrounding incision after noxious injury, which provided evidence towards the aforementioned hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Role of caveolin‑1 in chronic postsurgical pain in rats

et al. 2021

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Chronic postsurgical pain (CPSP) has a high incidence, but the underlying mechanisms remain elusive. Previous studies have indicated that caveolin-1 (Cav-1) plays a notable role in pain modulation. To study the role of Cav-1 in CPSP in the present study, a rat model of skin/muscle incision and retraction (SMIR) was established. Under anesthesia, skin and superficial muscle of the medial thigh were incised and a small pair of retractors inserted. It was revealed that SMIR increased the expression of Cav-1 in the dorsal root ganglion (DRG) and the injured tissue around the incision. Furthermore, the infiltration of endothelial cells and macrophages in the injured tissue around the incision increased constantly, and the vascular permeability increased due to the destruction of the vascular endothelial barrier function around the injured tissue. Cav-1 was mainly expressed by CD68-positive macrophages and CD34-positive endothelial cells in the injured tissues around the incision, while it was also primarily localized in the medium and large neurofilament 200-positive neurons and a small number of calcitonin gene-related peptide- and isolectin B4-positive small and medium-sized neurons in the DRG. The results demonstrated that the sustained high expression levels of Cav-1 in the injured tissue around the incision could lead to the dysfunction of the vascular endothelial barrier and, thus, could induce the inflammatory response through the lipoprotein transport of endothelial cells, thereby resulting in peripheral sensitization. In addition, the sustained high expression levels of Cav-1 in the DRG could sensitize large-sized neurons and change the transmission mode of noxious stimuli. The findings of the present study indicated that a Cav-1-mediated process could participate in neuronal transmission pathways associated with pain modulation.

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Mechanism of the JAK2/STAT3-CAV-1-NR2B signaling pathway in painful diabetic neuropathy

Cited by 37 publications

References 41 publications

B14 ameliorates bone cancer pain through downregulating spinal interleukin-1β via suppressing neuron JAK2/STAT3 pathway

B14 ameliorates bone cancer pain through downregulating spinal interleukin-1β via suppressing neuron JAK2/STAT3 pathway

Role of Caveolin-1 in Diabetes and Its Complications

Role of caveolin‑1 in chronic postsurgical pain in rats

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