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Diabetic peripheral neuropathy (DPN) is the most prevalent microvascular complication of diabetes and Huangqi Guizhi Wuwu Decoction (HGWD) is frequently employed in classical Chinese medicine for treating DPN. This study aims to investigate the potential therapeutic targets and mechanisms of HGWD for treating DPN using network pharmacology and molecular docking methodologies. The intersection targets of DPN and HGWD were retrieved from the databases, with the resulting intersection targets being imported into the STRING database to construct the protein-protein interaction (PPI) network. Cytoscape 3.9.1 was used to screen the core targets and plot the herb-active ingredient-target (H-A-T) network. To identify the pivotal signaling pathways, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on intersection targets. Molecular docking was subsequently conducted with AutoDock Vina to validate the binding energy between the core active ingredients and the core targets. 91 potential targets of HGWD were identified for the treatment of DPN. Topological analysis revealed core targets, including AKT1, TNF, PPARG, NFKB1, TP53, STAT3, PTGS2, HIF1A, ESR1, and GSK3B, alongside core active ingredients such as protoporphyrin, jaranol, kaempferol, quercetin, and isorhamnetin. GO and KEGG analyses indicated that PI3K/AKT, HIF-1, and AGE/RAGE signaling pathways could be crucial in treating DPN using HGWD. Furthermore, molecular docking results demonstrated robust binding activities between the active ingredients in HGWD and the identified core targets. The above results indicated that HGWD may exerting an anti-DPN effect by modulating the PI3K/AKT, HIF-1, and AGE/RAGE signaling pathways., Competing Interests: Declarations. Ethical approval: Not applicable. This article does not contain any studies with human participants or animals performed by any of the authors. Consent to participate: Not applicable. Consent to publish: All the authors listed have approved the manuscript that is enclosed. Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Diabetes is a multifunctional chronic disease that affects both the central and/or peripheral nervous systems. This study assessed whether nicotinamide (NAm) or conjugate of nicotinic acid with gamma-aminobutyric acid (N-GABA) could be potential neuroprotective agents against type 1 diabetes (T1D)-induced nervous system impairments in rats. After six weeks of T1D, induced by streptozotocin, nonlinear male Wistar rats were treated for two weeks with NAm (100 mg/kg, i. p.) or N-GABA (55 mg/kg, i. p.). Expression levels of myelin basic protein (MBP) were analyzed by immunoblotting. Polyol pathway parameters of the sciatic nerves were assessed spectrophotometrically, and their structure was examined histologically. NAm had no effect on blood glucose or body weight in T1D, while N-GABA reduced glucose by 1.5-fold. N-GABA also increased MBP expression by 1.48-fold, enhancing neuronal myelination, while NAm showed no such effect. Activation of the polyol pathway was observed in the T1D sciatic nerves. Both compounds decreased sorbitol content and aldose reductase activity, thereby alleviating changes similar to primary degeneration in the sciatic nerves and preventing peripheral neuropathy development. These results demonstrate that NAm and, more notably, N-GABA may exert neuroprotective effects against T1D-induced nervous system impairments by increasing MBP expression levels, improving myelination processes in the brain, inhibiting the polyol pathway, and partially restoring morphometric parameters in the sciatic nerves. This suggests their potential therapeutic efficacy as promising agents for the prevention of T1D-induced nervous system alterations., Competing Interests: Declarations Ethical Approval All animal experiments were carried out in accordance with the Directive 2010/63/ EU and approved by the Animal Care and Use Committee of Palladin Institute of Biochemistry, NAS of Ukraine. Competing Interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We investigated the potential role of hydrogen sulfide (H 2 S) as a novel therapy for diabetic peripheral neuropathy in diabetic rats. A single dose of streptozotocin (60 mg/kg) was applied to the rats for the diabetic rat models. Sodium bisulfide (50 μmol/kg/d) was injected intraperitoneally daily for 2 weeks as H 2 S treatment. Electromyogram, haematoxylin eosin staining, transmission electron microscopy, western blotting and enzyme-linked immunosorbent assay were then performed. H 2 S treatment did not affect body weights, blood glucose levels or liver function of diabetic rats, while the creatine levels of the H 2 S-treated diabetic rats decreased compared with the diabetic control rats. H 2 S treatment for 2 weeks did not affect the sciatic nerve conduction velocity of the diabetic rats. However, H 2 S treatment relieved neurons loss and cell atrophy of dorsal root ganglion, and axon degeneration of sciatic nerve in diabetic rats. Serum super oxide dismutase (SOD) levels and SOD2 levels in the sciatic nerve of diabetic rats were lower than the non-diabetic rats but were restored after H 2 S treatment. Serum and sciatic nerve homogenate malondialdehyde and aldose reductase expression were higher in diabetic rats but decreased significantly after H 2 S treatment. Our study revealed that H 2 S alleviates neural degeneration in diabetic rats probably by reducing oxidative stress and downregulating aldose reductase expression., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Diabetic neuropathy is one of the challenging complications of diabetes and is characterized by peripheral nerve damage due to hyperglycemia in diabetes. Mitochondrial dysfunction has been reported as one of the key pathophysiological factor contributing to nerve damage in diabetic neuropathy, clinically manifesting as neurodegenerative changes like functional and sensorimotor deficits. Accumulating evidence suggests a clear correlation between mitochondrial dysfunction and NLRP3 inflammasome activation. Unraveling deeper molecular aspects of mitochondrial dysfunction may provide safer and effective therapeutic alternatives. This review links mitochondrial dysfunction and appraises its role in the pathophysiology of diabetic neuropathy. We have also tried to delineate the role of mitophagy in NLRP3 inflammasome activation in experimental diabetic neuropathy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Aims: The pathophysiological of diabetic distal symmetric polyneuropathy (DSPN) remains to be elucidated and there are no diagnostic or prognostic biomarkers for the condition. In this explorative proteomic study, metabolic proteome profiling of serum in patients with/without DSPN was analyzed. We aimed to discover proteins with different abundance ranges through proximity extension assay (PEA) technology., Methods: Temperature quantitative sensory testing (QST) and electromyography (EMG) were used to access the small- and large-fiber function of all participants, respectively. The metabolic proteome profile of serum was analyzed using PEA technology (Olink Target 96 METABOLISM panel)., Results: We evaluated serum from patients without DSPN (n = 27), with small-fiber neuropathy (SFN, n = 25) and with mixed small- and large-fiber neuropathy (MSLFN, n = 24). Fifteen proteins, which were especially related to immune response, insulin resistance, and lipid metabolism, were significantly different between patients without DSPN and with MSLFN. Besides, seven proteins, especially related to extracellular structure organization, were significantly different between serum from patients with SFN and with MSLFN. What's more, serum from patients without DSPN showed that three proteins, related to immune response, altered significantly compared to serum from patients with SFN., Conclusions: This was the first study that characterized the metabolic proteomic profile of serum in DSPN patients by analyzing a panel of 92 metabolic proteins using PEA technology., (© 2024 Wiley‐VCH GmbH.)

A substantial proportion of diabetic patients suffer a debilitating and persistent pain state, known as peripheral painful neuropathy that necessitates improved therapy or antidote. Decursin, a major active ingredient from Angelica gigas Nakai, has been reported to possess antidepressant activity in preclinical studies. As antidepressants have been typically used as standard agents against persistent neuropathic pain, this study aimed to probe the effect of decursin on neuropathic pain associated with streptozotocin-induced type 1 diabetes in male C57BL6J mice. The Hargreaves test and the von Frey test were used to assess pain-like behaviors, shown as heat hyperalgesia and mechanical allodynia respectively. Chronic treatment of diabetic mice with decursin not only ameliorated the established symptoms of heat hyperalgesia and mechanical allodynia, but also arrested the development of these pain states given preemptively at low doses. Although decursin treatment hardly impacted on metabolic disturbance in diabetic mice, it ameliorated exacerbated oxidative stress in pain-associated tissues, improved mitochondrial bioenergetics in dorsal root ganglion neurons, and restored nerve conduction velocity and blood flow in sciatic nerves. Notably, the analgesic actions of decursin were modified by pharmacologically manipulating redox status and mitochondrial bioenergetics. These findings unveil the analgesic activity of decursin, an effect that is causally associated with its bioenergetics-enhancing and antioxidant effects, in mice with type 1 diabetes., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetes causes macrovascular and microvascular complications such as peripheral neuropathy. Glutamate regulates insulin secretion in pancreatic β-cells, and its increased activity in the central nervous system is associated with peripheral neuropathy in animal models of diabetes. One strategy to modulate glutamatergic activity consists in the pharmacological manipulation of metabotropic glutamate receptors (mGluRs), which, compared to the ionotropic receptors, allow for a fine-tuning of neurotransmission that is compatible with therapeutic interventions. mGluRs are a family of eight G-protein coupled receptors classified into three groups (I-III) based on sequence homology, transduction mechanisms, and pharmacology. Activation of group II and III or inhibition of group I represents a strategy to counteract the glutamatergic hyperactivity associated with diabetic neuropathy. In this review article, we will discuss the role of glutamate receptors in the release of insulin and the development/treatment of diabetic neuropathy, with particular emphasis on their manipulation to prevent the glutamatergic hyperactivity associated with diabetic neuropathy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, financial or otherwise., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Diabetic neuropathy is one of the most serious and common complications of diabetes with a wide spectrum, affecting 30-50% of diabetic patients. However, the current treatments of this disorder, mainly based on controlling blood glucose level, show an inadequate clinical outcome. Better approaches are needed. In this fashion, it is noted that promoting nerve regeneration and preventing nerve degeneration should be focused on equally and appropriately. In this mini review, how more effective approaches are in targeting PI3K/AKT and MEK/ERK pathways in the treatment of peripheral diabetic neuropathy is discussed. Future treatment of peripheral diabetic neuropathy should consider these approaches., (© 2024 The Author(s). Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Ethnopharmacological Relevance: Jinmaitong (JMT) is a prescription of Traditional Chinese Medicine that is composed of 12 crude drugs. It has been used in the treatment of diabetic neuropathic pain (DNP) for more than 30 years., Aim of Study: Microglia are thought to play an important role in neuropathic pain. This study aimed to evaluate the protective effect of JMT against DNP and to investigate the underlying mechanisms in which the microglia and JAK2/STAT3 signaling pathway were mainly involved., Materials and Methods: The chemical composition of JMT was analyzed using liquid chromatography tandem mass spectrometry. The diabetes model was constructed using 11 to 12-week-old male Zucker diabetic fatty (ZDF) rat (fa/fa). The model rats were divided into 5 groups and were given JMT at three dosages (11.6, 23.2, and 46.4 g/kg, respectively, calculated as the crude drug materials), JAK inhibitor AG490 (positive drug, 10 μg/day), and placebo (deionized water), respectively, for eight weeks (n = 6). Meanwhile, Zucker lean controls (fa/+) were given a placebo (n = 6). Body weight was tested weekly and blood glucose was monitored every 2 weeks. The mechanical allodynia and heat hyperalgesia were assessed using mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests. After treatment, the microglia activation marker Iba-1, CD11B, CD68, neuroinflammatory mediators, and mediators of the JAK2/STAT3 signaling pathway were compared between different groups. The mRNA and protein levels of target genes were assessed by quantitative real-time PCR and Western Blot, respectively., Results: We found that JMT significantly inhibited the overactivation of microglia in spinal cords, and suppressed neuroinflammation of DNP model rats, thereby ameliorating neurological dysfunction and injuries. Furthermore, these effects of JMT could be attributed to the inhibition of the JAK2/STAT3 signaling pathway., Conclusions: Our findings suggested that JMT effectively ameliorated DNP by modulating microglia activation via inhibition of the JAK2/STAT3 signaling pathway. The present study provided a basis for further research on the therapeutic strategies of DNP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Research has shown that obesity is a low-grade inflammatory disease that is often associated with comorbidities, such as diabetes and chronic pain. Recent data have indicated that chemokines may play a role in these conditions due to their pronociceptive and chemotactic properties, which promote hypersensitivity and inflammation. Accumulating evidence suggests that CCR2, CCR5, and their ligands (CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11 CCL12, and/or CCL13) play a role in rodent models of pain and obesity, as well as in patients with diabetes and obesity. It was proven that the blockade of CCR2 and CCR5, including the simultaneous blockade of both receptors by dual antagonists, effectively reduces hypersensitivity to thermal and mechanical stimuli in chronic pain states, including diabetic neuropathy. The present review discusses these chemokine receptors and the role of their ligands in diabetes and obesity, as well as their involvement in diabetic neuropathy and obesity-induced hypersensitivity.

Diabetic neuropathy (DN) is a common complication of long-lasting type 1 and type 2 diabetes, with no curative treatment available. Here, we tested the effect of the incretin mimetic liraglutide in DN in mice with early-stage type 1 diabetes bred in a standard laboratory or enriched environment. With a single i.p. injection of streptozotocin 150 mg/kg, we induced murine diabetes. Liraglutide (0.4 mg/kg once daily, i.p. for ten days since the eighth post-streptozotocin day) failed to decrease the glycemia in the diabetic mice; however, it alleviated their antinociceptive behavior, as tested with formalin. The second phase of the formalin test had significantly lower results in liraglutide-treated mice reared in the enriched environment vs. liraglutide-treated mice under standard conditions [2.00 (0.00-11.00) vs. 29.00 (2.25-41.50) s, p = 0.016]. Liraglutide treatment, however, decreased the threshold of reactivity in the von Fray test. A significantly higher neopterin level was demonstrated in the diabetic control group compared to treatment-naïve controls and the liraglutide-treated diabetic mice ( p < 0.001). The glutamine/glutamate ratio in both liraglutide-treated groups, either reared under standard conditions ( p = 0.003) or an enriched environment ( p = 0.002), was significantly higher than in the diabetic controls. This study demonstrates an early liraglutide effect on pain sensation in two streptozotocin-induced diabetes mouse models by reducing some inflammatory and oxidative stress parameters.

Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes that affects a significant proportion of diabetic patients worldwide. Although the pathogenesis of DPN involves axonal atrophy and demyelination, the exact mechanisms remain elusive. Current research has predominantly focused on neuronal damage, overlooking the potential contributions of Schwann cells, which are the predominant glial cells in the peripheral nervous system. Schwann cells play a critical role in neurodevelopment, neurophysiology, and nerve regeneration. This review highlights the emerging understanding of the involvement of Schwann cells in DPN pathogenesis. This review explores the potential role of Schwann cell plasticity as an underlying cellular and molecular mechanism in the development of DPN. Understanding the interplay between Schwann cell plasticity and diabetes could reveal novel strategies for the treatment and management of DPN.

Chronic pain remains a significant medical challenge with complex underlying mechanisms, and an urgent need for new treatments. Our research built and utilized the iPain single-cell atlas to study chronic pain progression in dorsal root and trigeminal ganglia. We discovered that senescence of a small subset of pain-sensing neurons may be a driver of chronic pain. This mechanism was observed in animal models after nerve injury and in human patients diagnosed with chronic pain or diabetic painful neuropathy. Notably, treatment with senolytics, drugs that remove senescent cells, reversed pain symptoms in mice post-injury. These findings highlight the role of cellular senescence in chronic pain development, demonstrate the therapeutic potential of senolytic treatments, and underscore the value of the iPain atlas for future pain research., (© 2024. The Author(s).)

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical allodynia. The role of skin mechanoreceptors in the development of mechanical allodynia is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aβ axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin-keratinocyte specific BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Mitophagy, the cellular process of selectively eliminating damaged mitochondria, plays a crucial role in maintaining metabolic balance and preventing insulin resistance, both key factors in type 2 diabetes mellitus (T2DM) development. When mitophagy malfunctions in diabetic neuropathy, it triggers a cascade of metabolic disruptions, including reduced energy production, increased oxidative stress, and cell death, ultimately leading to various complications. Thus, targeting mitophagy to enhance the process may have emerged as a promising therapeutic strategy for T2DM and its complications. Notably, plant-derived compounds with β-cell protective and mitophagy-stimulating properties offer potential as novel therapeutic agents. This review highlights the intricate mechanisms linking mitophagy dysfunction to T2DM and its complications, particularly neuropathy, elucidating potential therapeutic interventions for this debilitating disease., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Diabetes-induced hyperglycemia leads to excessive production of oxygen free radicals, inflammatory cytokines, and oxidative stress, which initiates diabetic peripheral neuropathy (DPN). Currently, this condition affects 20% of adults with diabetes. Despite significant advances in the treatment of diabetes, the incidence of its complications, including DPN, is still high. Thus, there is a growing research interest in developing more effective and treatment approaches with less side effects for diabetes and its complications. Nigella sativa L. (NS) has received much research attention as an antioxidant, anti-yperglycemic factor, and anti-inflammatory agent. This natural compound demonstrates its antidiabetic neuropathy effect through various pathways, including the reduction of lipid peroxidation, the enhancement of catalase and superoxide dismutase enzyme activity, and the decrease in inflammatory cytokine levels. The present review focuses on the bioactive and nutraceutical components of black cumin (Nigella sativa L.) and their effects on DPN. In addition, we have also summarized the findings obtained from several experimental and clinical studies regarding the antidiabetic neuropathy effect of NS in animal models and human subjects., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: The study aimed to investigate brain metabolites in type 1 diabetes and the associations with disease characteristics. We explored the metabolic profiles predicting different neuropathic phenotypes using multiple linear regression analyses., Methods: We compared brain metabolites in 55 adults with type 1 diabetes (including painful diabetic peripheral neuropathy (DPN), painless DPN, without DPN) with 20 healthy controls. Proton magnetic resonance spectroscopy measurements (N-acetylaspartate (NAA), glutamate (glu), myo-inositol (mI), and glycerophosphocholine (GPC) were obtained in ratios to creatine (cre)) from the parietal region, anterior cingulate cortex and thalamus., Results: The overall diabetes group revealed decreased parietal NAA/cre compared to healthy controls (1.41 ± 0.12 vs. 1.55 ± 0.13,p < 0.001) and increased mI/cre (parietal: 0.62 ± 0.08 vs. 0.57 ± 0.07,p = 0.025, cingulate: 0.65 ± 0.08 vs. 0.60 ± 0.08,p = 0.033). Reduced NAA/cre was associated with more severe DPN (all p ≤ 0.04) whereas increased mI/cre was associated with higher hemoglobin A 1c (HbA 1c ) (p = 0.02). Diabetes was predicted from decreased parietal NAA/cre, increased parietal ml/cre, and decreased thalamic glu/cre. DPN was predicted from decreased parietal NAA/cre and increased GPC/cre. Painful DPN was predicted from increased parietal GPC/cre and thalamic glu/cre., Conclusions: Specific metabolic brain profiles were linked to the different phenotypes of diabetes, DPN and painful DPN., Significance: Assessment of metabolic profiles could be relevant for detailed understanding of central neuropathy in diabetes., Competing Interests: Declarations of interest None., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

There is an increasing prevalence of diabetes mellitus (DM), particularly type 2 DM (T2DM), and its associated complications. T2DM is linked to insulin resistance, chronic inflammation, and oxidative stress, which can lead to both macrovascular and microvascular complications, including peripheral diabetic neuropathy (PDN). Inflammatory processes play a key role in the development and progression of T2DM and its complications, with specific markers like C-reactive protein (CRP), interleukins (ILs), and tumor necrosis factor (TNF)-α being associated with increased risk. Other key inflammatory markers such as nuclear factor kappa B (NF-κB) are activated under hyperglycemic and oxidative stress conditions and contribute to the aggravation of PDN by regulating inflammatory gene expression and enhancing endothelial dysfunction. Other important roles in the inflammatory processes are played by Toll-like receptors (TLRs), caveolin 1 (CAV1), and monocyte chemoattractant protein 1 (MCP1). There is a relationship between vitamin D deficiency and PDN, highlighting the critical role of vitamin D in regulating inflammation and immune responses. The involvement of macrophages in PDN is also suspected, emphasizing their role in chronic inflammation and nerve damage in diabetic patients. Vitamin D supplementation has been found to reduce neuropathy severity, decrease inflammatory markers, and improve glycemic control. These findings suggest that addressing vitamin D deficiency could offer therapeutic benefits for PDN. These molecular pathways are critical in understanding the pathogenesis of DM complications and may offer potential biomarkers or therapeutic targets including anti-inflammatory treatments, vitamin D supplementation, macrophage phenotype modulation, and lifestyle modifications, aimed at reducing inflammation and preventing PDN. Ongoing and more extensive clinical trials with the aim of investigating anti-inflammatory agents, TNF-α inhibitors, and antioxidants are needed to advance deeper into the understanding and treatment of painful diabetic neuropathy.

Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25-75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A substantial proportion of diabetic patients suffer a debilitating and persistent pain state, known as peripheral painful neuropathy that necessitates improved therapy or antidote. Purpurin, a natural anthraquinone compound from Rubia tinctorum L., has been reported to possess antidepressant activity in preclinical studies. As antidepressants have been typically used as standard agents against persistent neuropathic pain, this study aimed to probe the effect of purpurin on neuropathic pain associated with streptozotocin-induced type 1 diabetes in male C57BL6J mice. The Hargreaves test and the von Frey test were used to assess the pain-like behaviors, shown as heat hyperalgesia and mechanical allodynia respectively. Chronic treatment of diabetic mice with purpurin not only ameliorated the established symptoms of heat hyperalgesia and mechanical allodynia, but also arrested the development of these pain states given preemptively at low doses. Although purpurin treatment hardly impacted on metabolic disturbance in diabetic mice, it ameliorated exacerbated oxidative stress in pain-associated tissues, improved mitochondrial bioenergetics in dorsal root ganglion neurons and restored nerve conduction velocity in sciatic nerves. Notably, the analgesic actions of purpurin were modified by pharmacologically manipulating redox status and mitochondrial bioenergetics. These findings unveil the analgesic activity of purpurin, an effect that is causally associated with its bioenergetics-enhancing and antioxidant effects, in mice with type 1 diabetes., Competing Interests: Declaration of Competing interest The authors declare no conflicts of interest in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Diabetes mellitus has emerged as a pressing global concern, with a notable increase in recent years. Despite advancements in treatment, existing medications struggle to halt the progression of diabetes and its associated complications. Increasing evidence underscores inflammation as a significant driver in the onset of diabetes mellitus. Therefore, perspectives on new therapies must consider shifting focus from metabolic stress to inflammation. High mobility group box (HMGB-1), a nuclear protein regulating gene expression, gained attention as an endogenous danger signal capable of sparking inflammatory responses upon release into the extracellular environment in the late 1990s., Purpose: Given the parallels between inflammatory responses and type 2 diabetes (T2D) development, this review paper explores HMGB-1's potential involvement in onset and progression of diabetes complications. Specifically, we will review and update the understanding of HMGB-1 and its inflammatory pathways in insulin resistance, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy., Conclusions: HMGB-1 and its receptors i.e. receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs) present promising targets for antidiabetic interventions. Ongoing and future projects in this realm hold promise for innovative approaches targeting HMGB-1-mediated inflammation to ameliorate diabetes and its complications., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Diabetic neuropathic pain (DNP), one of the most common complications of diabetes, is characterized by bilateral symmetrical distal limb pain and substantial morbidity. To compare the differences  is aimed at serum metabolite levels between 81 DNP and 73 T2DM patients without neuropathy and found that the levels of branched-chain amino acids (BCAA) are significantly lower in DNP patients than in T2DM patients. In high-fat diet/low-dose streptozotocin (HFD/STZ)-induced T2DM and leptin receptor-deficient diabetic (db/db) mouse models, it is verified that BCAA deficiency aggravated, whereas BCAA supplementation alleviated DNP symptoms. Mechanistically, using a combination of RNA sequencing of mouse dorsal root ganglion (DRG) tissues and label-free quantitative proteomic analysis of cultured cells, it is found that BCAA deficiency activated the expression of L-type amino acid transporter 1 (LAT1) through ATF4, which is reversed by BCAA supplementation. Abnormally upregulated LAT1 reduced Kv1.2 localization to the cell membrane, and inhibited Kv1.2 channels, thereby increasing neuronal excitability and causing neuropathy. Furthermore, intraperitoneal injection of the LAT1 inhibitor, BCH, alleviated DNP symptoms in mice, confirming that BCAA-deficiency-induced LAT1 activation contributes to the onset of DNP. These findings provide fresh insights into the metabolic differences between DNP and T2DM, and the development of approaches for the management of DNP., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Accumulation of advanced glycation end-products (AGEs) in the brain contributes significantly to cognitive impairment in patients with diabetes by disrupting the post-mitotic state of neuronal cells, thereby triggering ectopic cell cycle re-entry (CCR) and subsequent neuronal apoptosis. Cinnamaldehyde (CINA), a potential mitigator of cognitive impairment due to its blood glucose-lowering properties, warrants exploration for its role in counteracting diabetes-related neurological damage. In this study, we examined the neuroprotective effect of CINA on AGE-damaged SH-SY5Y human neuroblastoma cells differentiated in vitro. We investigated the impact of CINA on AGE-induced neuronal CCR and apoptosis, finding that it substantially suppressed aberrant DNA replication, precluded cells from entering the mitotic preparatory phase, and diminished apoptosis. Additionally, CINA inhibited the expression of eIF4E without altering S6K1 phosphorylation. These findings indicate that CINA safeguards neuronal cells from AGE-related damage by preventing abnormal CCR, preserving the post-mitotic state of neuronal cells, and reducing AGE-induced apoptosis, potentially through the inhibition of eIF4E-controlled cell proliferation. Our results highlight the prospective utility of CINA in managing diabetic neuropathy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

The transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) has multifarious action with its target genes having redox-regulating functions and being involved in inflammation control, proteostasis, autophagy, and metabolic pathways. Therefore, the genes controlled by NRF2 are involved in the pathogenesis of myriad diseases, such as cardiovascular diseases, metabolic syndrome, neurodegenerative diseases, autoimmune disorders, and cancer. Amidst this large array of diseases, diabetic neuropathy (DN) occurs in half of patients diagnosed with diabetes and appears as an injury inflicted upon peripheral and autonomic nervous systems. As a complex effector factor, NRF2 has entered the spotlight during the search of new biomarkers and/or new therapy targets in DN. Due to the growing attention for NRF2 as a modulating factor in several diseases, including DN, this paper aims to update the recently discovered regulatory pathways of NRF2 in oxidative stress, inflammation and immunity. It presents the animal models that further facilitated the human studies in regard to NRF2 modulation and the possibilities of using NRF2 as DN biomarker and/or as target therapy., (© 2024 The Author(s). Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Diabetic peripheral neuropathy (DPN) is a significant and frequent complication of diabetes. Bu-Yang-Huan-Wu Decoction (BHD) is a classic traditional Chinese herbal prescription that is commonly used in modern clinical practice for the effective treatment of DPN, but the underlying mechanism is not yet clearly defined. The chemical constituents of BHD were characterized by UPLC-Q-Orbitrap HR MS/MS, and a total of 101 chemical components were identified, including 30 components absorbed into blood. An interaction network of "compound-target-disease" interactions was constructed based on the compounds detected absorbed in blood and their corresponding targets of diabetic neuropathy acquired from disease gene databases, and the possible biological targets and potential signalling pathways of BHD were predicted via network pharmacology analysis. Subsequently, methylglyoxal-induced (MGO-induced) Schwann cells (SCs) were used to identify the active ingredients in blood components of BHD and verify the molecular mechanisms of BHD. Through network topological analysis, 30 shared targets strongly implicated in the anti-DPN effects of BHD were identifed. Combined network pharmacology and in vitro cellular analysis, we found that the active ingredient of BHD may treat DPN by modulating the AGEs/RAGE pathway. This study provides valuable evidence for future mechanistic studies and potential therapeutic applications for patients with DPN., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Diabetic peripheral neuropathy (DPN) is caused by several factors, including reactive free oxygen radicals (ROS)-induced excessive Ca 2+ influx. Transient receptor potential (TRP) vanilloid 4 (TRPV4) is a member of the Ca 2+ -permeable TRP superfamily. Resveratrol (RESV) has been extensively utilized in TRP channel regulation due to its pharmacological properties, which include antioxidant and TRP inhibitory effects. The protective function of RESV and the contribution of TRPV4 to streptozotocin (STZ)-induced neuropathic pain in mice are still unclear. Here, we evaluated the effects of RESV through the modulation of TRPV4 on Ca 2+ influx, ROS-mediated pain, apoptosis, and oxidative damage in the mouse dorsal root ganglion (DRGs). From the 32 mice, four groups were induced: control, RESV, STZ, and STZ + RESV. We found that the injection of RESV reduced the changes caused by the STZ-induced stimulation of TRPV4, which in turn increased mechanical/thermal neuropathic pain, cytosolic Ca 2+ influx, TRPV4 current density, oxidants (lipid peroxidation, mitochondrial ROS, and cytosolic ROS), and apoptotic markers (caspase-3, -8, and -9). The RESV injection also increased the STZ-mediated reduction of viability of DRG and the amounts of glutathione, glutathione peroxidase, vitamin A, β-carotene, and vitamin E in the brain, erythrocytes, plasma, liver, and kidney. All of these findings suggest that TRPV4 stimulation generates oxidative neurotoxicity, neuropathic pain, and apoptosis in the STZ-induced diabetic mice. On the other hand, neurotoxicity and apoptosis were reduced due to the downregulation of TRPV4 carried out through the RESV injection., (© 2024. The Author(s).)

Ethnopharmacological Relevance: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, mainly manifested as paresthesia. Tangzu granule (TZG) is derived from famous traditional Chinese medicine decoctions and optimized by long-term temporary practice. TZG has good efficacy in improving numbness, pain and pruritus of the lower extremities of DPN patients. However, the overall regulatory mechanisms underlying its effects on DPN remain unclear., Aim of the Study: This study aims to explore the potential mechanism of TZG for treating DPN., Materials and Methods: Sprague-Dawley (SD) rats were used to establish an in vivo model of DPN with streptozotocin (STZ) injection and high-fat diet (HFD) feeding. Additionally, sciatic glial RSC96 cells were induced with high glucose in vitro. SD rats in intervention group received TZG treatment for 12 weeks. After 12 weeks of treatment, sciatic nerve function was evaluated by intelligent hot plate meter and neuro electrophysiology detector. The morphological changes of sciatic nerve cells were observed by hematoxylin-eosin staining and transmission electron microscope. IL-1β, IL-18 inflammatory cytokines, pyroptosis and P2X7R/NLRP3 signaling pathway were observed by Western blotting, immunofluorescence staining and ELISA., Results: TZG improved nerve conduction velocity and sciatic neuropathy rational structural changes in DPN rats. It also inhibited RSC96 inflammatory response and cell death that induced by high glucose. This may be related to TZG inhibiting P2X7R, decreasing the activation of NLRP3 inflammasomes, down-regulating the levels of pyroptosis proteins such as caspase-1, cleaved caspase-1, gasdermin D (GSDMD), and GSDMD-N, and inhibiting the release of interleuki (IL)-18 and IL-1β inflammatory cytokines., Conclusions: TZG inhibited pyroptosis through P2X7R/NLRP3 signaling pathway, alleviated neuroinflammation, and showed protective effect in the treatment of DPN., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The present review aimed to provide an update on the scientific progress of the role of epigenetic modifications on diabetic peripheral neuropathic pain (DPNP). DPNP is a devastating and troublesome complication of diabetes mellitus (DM), which affects one third of patients with DM and causes severe hyperalgesia and allodynia, leading to challenges in the treatment of these patients. The pathophysiology of DPNP is multifactorial and is not yet fully understood and treatment options for this disease are currently unsatisfactory. The underlying mechanisms and pathophysiology of DPNP have largely been explored in animal models and a mechanism‑derived approach might offer a potential therapeutic‑target for attenuating certain phenotypes of DPNP. Altered gene expression levels within the peripheral or central nervous systems (CNS) are a crucial mechanism of DPNP, however, the transcriptional mechanisms of these genes have not been fully elucidated. Epigenetic modifications, such as DNA methylation and histone modifications (methylation, acetylation, or phosphorylation), can alter gene expression levels via chromatin remodeling. Moreover, it has been reported that altering gene expression via epigenetic modifications within the peripheral or CNS, contributes to the changes in both pain sensitivity and pharmacological efficacy in DPNP. Therefore, the present review summarized the findings of relevant literature on the epigenetic alterations in DPNP and the therapeutic potential for targeting these alterations in the future treatment of this disease.

Diabetic peripheral neuropathy (DPN) is a common nerve-damaging complication of diabetes mellitus. Effective treatments are needed to alleviate and reverse diabetes-associated damage to the peripheral nerves. Curcumin is an effective neuroprotectant that plays a protective role in DPN promoted by Schwann cells (SCs) lesions. However, the potential molecular mechanism of curcumin remains unclear. Therefore, our aim is to study the detailed molecular mechanism of curcumin-mediated SCs repair in order to improve the efficacy of curcumin in the clinical treatment of DPN. First, candidate target genes of curcumin in rat SC line RSC96 cells stimulated by high glucose were identified by RNA sequencing and bioinformatic analyses. Enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) was carried out by Metascape, followed by 8 algorithms on Cytoscape to determine 4 hub genes, namly Hmox1, Pten, Vegfa and Myc. Next, gene set enrichment analysis (GSEA) and Pearson function showed that Hmox1 was significantly correlated with apoptosis. Subsequently, qRT-PCR, MTT assay, flow cytometry, caspase-3 activity detection and westernblot showed that curcumin treatment increased RSC96 cell viability, reduced cell apoptosis, increased Hmox1, Pten, Vegfa and Myc expression, and up-regulated Akt phosphorylation level under high glucose environment. Finally, molecular docking predicted the binding site of curcumin to Hmox1. These results suggest that curcumin can reduce the apoptosis of SCs induced by high glucose, and Hmox1 is a potential target for curcumin. Our findings provide new insights about the mechanism of action of curcumin on SC as a potential treatment in DPN., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Diabetic peripheral neuropathy (DPN) is a primary complication observed in diabetes that severely affects quality of life. Recent evidence suggests that photobiomodulation (PBM) is a promising therapy against painful conditions and nerve damage. However, the effects of PBM on DPN remains mostly unknown. In the present study, we investigated the efficacy of PBM therapy in modulating proinflammatory cytokine expression in both central and peripheral nervous systems of rats with Streptozotocin (STZ)-induced type 1 diabetes. Male Wistar rats were allocated into control (naïve), diabetic (STZ), and treatment (STZ + PBM) groups. A single intraperitoneal (i.p.) injection of STZ (85 mg/kg) was administered for the induction of diabetes. Animals were subjected to 10 treatment sessions, every other day. The results herein presented indicate that PBM treatment diminishes Receptor for Advanced Glycation End-products (RAGE) and Nuclear Factor Kappa B (NF-ϰB) expression in peripheral nervous system and suppresses TNF-α expression in central nervous system tissues. Furthermore, PBM-therapy in diabetic rats also induces increased levels of the anti-inflammatory protein IL-10 in both peripheral and central nervous system. Collectively, our findings demonstrate compelling evidence that PBM-therapy modulates cytokine dynamics and influences RAGE/NF-ϰB axis in a STZ-induced model of type 1 diabetes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Diabetic neuropathic pain (DNP) is a diabetic complication that causes severe pain and deeply impacts the quality of the sufferer's daily life. Currently, contemporary clinical treatments for DNP generally exhibit a deficiency in effectiveness. Electroacupuncture (EA) is recognized as a highly effective and safe treatment for DNP with few side effects. Regrettably, the processes via which EA alleviates DNP are still poorly characterized. Transient receptor potential vanilloid 1 (TRPV1) and phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) are overexpressed on spinal cord dorsal horn (SCDH) in DNP rats, and co-localization is observed between them. Capsazepine, a TRPV1 antagonist, effectively reduced nociceptive hypersensitivity and downregulated the overexpression of phosphorylated CaMKIIα in rats with DNP. Conversely, the CaMKII inhibitor KN-93 did not have any impact on TRPV1. EA alleviated heightened sensitivity to pain caused by nociceptive stimuli and downregulated the level of TRPV1, p-CaMKIIα, and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) in DNP rats. Intrathecal injection of capsaicin, on the other hand, reversed the above effects of EA. These findings indicated that the CaMKII/CREB pathway on SCDH is located downstream of TRPV1 and is affected by TRPV1. EA alleviates DNP through the TRPV1-mediated CaMKII/CREB pathway., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Individuals suffering from diabetic polyneuropathy (DPN) experience debilitating symptoms such as pain, paranesthesia, and sensory disturbances, prompting a quest for effective treatments. Dipeptidyl-peptidase (DPP)-4 inhibitors, recognized for their potential in ameliorating DPN, have sparked interest, yet the precise mechanism underlying their neurotrophic impact on the peripheral nerve system (PNS) remains elusive. Our study delves into the neurotrophic effects of DPP-4 inhibitors, including Diprotin A, linagliptin, and sitagliptin, alongside pituitary adenylate cyclase-activating polypeptide (PACAP), Neuropeptide Y (NPY), and Stromal cell-derived factor (SDF)-1a-known DPP-4 substrates with neurotrophic properties. Utilizing primary culture dorsal root ganglia (DRG) neurons, we meticulously evaluated neurite outgrowth in response to these agents. Remarkably, all DPP-4 inhibitors and PACAP demonstrated a significant elongation of neurite length in DRG neurons (PACAP 0.1 μM: 2221 ± 466 μm, control: 1379 ± 420, p < 0.0001), underscoring their potential in nerve regeneration. Conversely, NPY and SDF-1a failed to induce neurite elongation, accentuating the unique neurotrophic properties of DPP-4 inhibition and PACAP. Our findings suggest that the upregulation of PACAP, facilitated by DPP-4 inhibition, plays a pivotal role in promoting neurite elongation within the PNS, presenting a promising avenue for the development of novel DPN therapies with enhanced neurodegenerative capabilities.

Diabetic peripheral neuropathy (DPN) is a complication of diabetes mellitus that lacks specific treatment, its high prevalence and disabling neuropathic pain greatly affects patients' physical and mental health. Schwann cells (SCs) are the major glial cells of the peripheral nervous system, which play an important role in various inflammatory and metabolic neuropathies by providing nutritional support, wrapping axons and promoting repair and regeneration. Increasingly, high glucose (HG) has been found to promote the progression of DPN pathogenesis by targeting SCs death regulation, thus revealing the specific molecular process of programmed cell death (PCD) in which SCs are disrupted is an important link to gain insight into the pathogenesis of DPN. This paper is the first to review the recent progress of HG studies on apoptosis, autophagy, pyroptosis, ferroptosis and necroptosis pathways in SCs, and points out the crosstalk between various PCDs and the related therapeutic perspectives, with the aim of providing new perspectives for a deeper understanding of the mechanisms of DPN and the exploration of effective therapeutic targets., Competing Interests: The authors declare that the study was conducted in the absence of any business or financial relationship that could be interpreted as a potential conflict of interest., (Copyright © 2024 Wu, Wang, Luo, Zhang, Zhao and Chen.)

Objective: Diabetic neuropathic pain (DNP) is one of the most prevalent symptoms of diabetes. The alteration of proteins in the spinal cord dorsal horn (SCDH) plays a significant role in the genesis and the development of DNP. Our previous study has shown electroacupuncture could effectively relieve DNP. However, the potential mechanism inducing DNP's genesis and development remains unclear and needs further research., Methods: This study established DNP model rats by intraperitoneally injecting a single high-dose streptozotocin; 2 Hz electroacupuncture was used to stimulate Zusanli (ST36) and Kunlun (BL60) of DNP rats daily from day 15 to day 21 after streptozotocin injection. Behavioral assay, quantitative PCR, immunofluorescence staining, and western blotting were used to study the analgesic mechanism of electroacupuncture., Results: The bradykinin B1 receptor (B1R) mRNA, nuclear factor-κB p65 (p65), substance P, and calcitonin gene-related peptide (CGRP) protein expression were significantly enhanced in SCDH of DNP rats. The paw withdrawal threshold was increased while body weight and fasting blood glucose did not change in DNP rats after the electroacupuncture treatment. The expression of B1R, p65, substance P, and CGRP in SCDH of DNP rats was also inhibited after the electroacupuncture treatment., Conclusion: This work suggests that the potential mechanisms inducing the allodynia of DNP rats were possibly related to the increased expression of B1R, p65, substance P, and CGRP in SCDH. Downregulating B1R, p65, substance P, and CGRP expression levels in SCDH may achieve the analgesic effect of 2 Hz electroacupuncture treatment., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The dynamics of nephropathy development in rats with type 2 diabetes mellitus, caused by a high-fat diet and the streptozotocin administration (25 mg/kg), and metabolic syndrome, caused by addition of 20% fructose solution to the diet, was evaluated during the experiment. Models with moderate severity of metabolic changes without significant changes in body weight were obtained after 24 weeks. To study neuropathy severity, the method of electroneuromyography was used; the velocities of motor and sensory excitation propagation along the caudal nerve fibers were measured. In modeled diabetes mellitus against the background of hyperglycemia, a marked decrease in motor and sensory propagation rates was observed, and an increase in the response durations was noted from week 12 to week 24, indicating pronounced neuropathy. In the fructose model, the motor response duration increased from week 12, which possibly indicates the development of peripheral neuropathy., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

In this paper we investigated lipid and metabolite changes in diabetic neuropathy, using untargeted lipidomics and metabolomics analyses of the spinal cords from streptozotocin-treated diabetic rats.170 metabolites and 45 lipids were dysregulated in the painful diabetic neuropathy (PDN) phase. Pathway enrichment analysis revealed perturbations in starch and sucrose, tryptophan, pyrimidine, cysteine and methionine, thiamine, tyrosine, and nucleotides. The disturbance of tyrosine, tryptophan, methionine, triacylglycerol, and phosphatidylethanolamine metabolism indicated that pathological mechanisms in the PDN involved energy metabolism, oxidative stress, and neural reparative regeneration. These revelations offered potential biomarkers for PDN and enriched the comprehension of the complex molecular mechanisms characterizing PDN, establishing a solid foundation for subsequent inquiries into neural convalescence and recovery after PDN., (© 2024. The Author(s).)

Background: Silibinin (SBN), a sirtuin 1 (SIRT1) activator, has been evaluated for its anti-inflammatory activity in many inflammatory diseases. However, its role in diabetes-induced peripheral neuropathy (DPN) remains unknown. The SIRT1 activation convalesces nerve functions by improving mitochondrial biogenesis and mitophagy., Methods: DPN was induced by streptozotocin (STZ) at a dose of 55 mg/kg, i.p. in the male SD rats whereas neurotoxicity was induced in Neuro2A cells by 30 mM (high glucose) glucose. Neurobehavioural (nerve conduction velocity and nerve blood flow) western blot, immunohistochemistry, and immunocytochemistry were performed to evaluate the protein expression and their cellular localisation., Results: Two-week SBN treatment improved neurobehavioural symptoms, SIRT1, PGC-1α, and TFAM expression in the sciatic nerve and HG insulted N2A cells. It has also maintained the mitophagy by up-regulating PARL, PINK1, PGAM5, LC3 level and provided antioxidant defence by upregulating Nrf2., Conclusion: SBN has shown neuroprotective potential in DPN through SIRT1 activation and antioxidant mechanism.

Background: Hyperglycemia-induced neuroinflammation significantly contributes to diabetic neuropathic pain (DNP), but the underlying mechanisms remain unclear., Objective: To investigate the role of Sirt3, a mitochondrial deacetylase, in hyperglycemia-induced neuroinflammation and DNP and to explore potential therapeutic interventions., Method and Results: Here, we found that Sirt3 was downregulated in spinal dorsal horn (SDH) of diabetic mice by RNA-sequencing, which was further confirmed at the mRNA and protein level. Sirt3 deficiency exacerbated hyperglycemia-induced neuroinflammation and DNP by enhancing microglial aerobic glycolysis in vivo and in vitro. Overexpression of Sirt3 in microglia alleviated inflammation by reducing aerobic glycolysis. Mechanistically, high-glucose stimulation activated Akt, which phosphorylates and inactivates FoxO1. The inactivation of FoxO1 diminished the transcription of Sirt3. Besides that, we also found that hyperglycemia induced Sirt3 degradation via the mitophagy-lysosomal pathway. Blocking Akt activation by GSK69093 or metformin rescued the degradation of Sirt3 protein and transcription inhibition of Sirt3 mRNA, which substantially diminished hyperglycemia-induced inflammation. Metformin in vivo treatment alleviated neuroinflammation and diabetic neuropathic pain by rescuing hyperglycemia-induced Sirt3 downregulation., Conclusion: Hyperglycemia induces metabolic reprogramming and inflammatory activation in microglia through the regulation of Sirt3 transcription and degradation. This novel mechanism identifies Sirt3 as a potential drug target for treating DNP., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Aims: This study aims to explore the potential role of vascular endothelial growth factor-B (VEGF-B) in the pathogenesis of diabetic peripheral neuropathy (DPN). The expression of VEGFRs were reanalysed by using gene arrays of peripheral nerve samples from mouse models of DPN retrieved from the GEO database. 213 T2D patients as well as 31 healthy individuals were recruited. The serum VEGF-B was detected and its relationship with DPN was analysed. The elevated VEGFR1 was the only change of VEGFR gene expression in the peripheral nerve from mouse models of DPN. The level of serum VEGF-B in T2D patients with DPN was higher than that in T2D patients without DPN and healthy people. Analysis of correlation and binary logistic regression confirmed that the increased serum VEGF-B level was an independent risk factor of DPN in T2D patients. VEGF-B-VEGFR1 signaling pathway may be involved in the development of DPN.

Alterations in the structure, function, and microcirculation of the thalamus, a key brain region involved in pain pathways, have previously been demonstrated in patients with painless and painful diabetic peripheral neuropathy (DPN). However, thalamic neurotransmitter levels including γ-aminobutyric acid (GABA) (inhibitory neurotransmitter) and glutamate (excitatory neurotransmitter) in different DPN phenotypes are not known. We performed a magnetic resonance spectroscopy study and quantified GABA and glutamate levels within the thalamus, in a carefully characterized cohort of participants with painless and painful DPN. Participants with DPN (painful and painless combined) had a significantly lower GABA:H2O ratio compared with those without DPN (healthy volunteers [HV] and participants with diabetes without DPN [no DPN]). Participants with painless DPN had the lowest GABA:H2O ratio, which reached significance compared with HV and no DPN, but not painful DPN. There was no difference in GABA:H2O in painful DPN compared with all other groups. A significant correlation with GABA:H2O and neuropathy severity was also seen. This study demonstrates that lower levels of thalamic GABA in participants with painless DPN may reflect neuroplasticity due to reduced afferent pain impulses, whereas partially preserved levels of GABA in painful DPN may indicate that central GABAergic pathways are involved in the mechanisms of neuropathic pain in diabetes., (© 2024 by the American Diabetes Association.)

Diabetic peripheral neuropathy (DPN) is a common complication associated with diabetes, and can affect quality of life considerably. Dorsal root ganglion (DRG) plays an important role in the development of DPN. However, the relationship between DRG and the pathogenesis of DPN still lacks a thorough exploration. Besides, a more in-depth understanding of the cell type composition of DRG, and the roles of different cell types in mediating DPN are needed. Here we conducted single-cell RNA-seq (scRNA-seq) for DRG tissues isolated from healthy control and DPN rats. Our results demonstrated DRG includes eight cell-type populations (e.g., neurons, satellite glial cells (SGCs), Schwann cells (SCs), endothelial cells, fibroblasts). In the heterogeneity analyses of cells, six neuron sub-types, three SGC sub-types and three SC sub-types were identified, additionally, biological functions related to cell sub-types were further revealed. Cell communication analysis showed dynamic interactions between neurons, SGCs and SCs. We also found that the aberrantly expressed transcripts in sub-types of neurons, SGCs and SCs with DPN were associated with diabetic neuropathic pain, cell apoptosis, oxidative stress, etc. In conclusion, this study provides a systematic perspective of the cellular composition and interactions of DRG tissues, and suggests that neurons, SGCs and SCs play vital roles in the progression of DPN. Our data may provide a valuable resource for future studies regarding the pathophysiological effect of particular cell type in DPN., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Guo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Diabetic neuropathy (DN) is a common complication of diabetes, affecting over 50% of patients, leading to significant pain and a burden. Currently, there are no effective treatments available. Cell death is considered a key factor in promoting the progression of DN. This article reviews how cell death is initiated in DN, emphasizing the critical roles of oxidative stress, mitochondrial dysfunction, inflammation, endoplasmic reticulum stress, and autophagy. Additionally, we thoroughly summarize the mechanisms of cell death that may be involved in the pathogenesis of DN, including apoptosis, autophagy, pyroptosis, and ferroptosis, among others, as well as potential therapeutic targets offered by these death mechanisms. This provides potential pathways for the prevention and treatment of diabetic neuropathy in the future.

Anethole is a terpenoid with antioxidant, anti-inflammatory, and neuronal blockade effects, and the present work was undertaken to study the neuroprotective activity of anethole against diabetes mellitus (DM)-induced neuropathy. Streptozotocin-induced DM rats were used to investigate the effects of anethole treatment on morphological, electrophysiological, and biochemical alterations of the sciatic nerve (SN). Anethole partially prevented the mechanical hyposensitivity caused by DM and fully prevented the DM-induced decrease in the cross-sectional area of the SN. In relation to electrophysiological properties of SN fibers, DM reduced the frequency of occurrence of the 3rd component of the compound action potential (CAP) by 15%. It also significantly reduced the conduction velocity of the 1st and 2nd CAP components from 104.6 ± 3.47 and 39.8 ± 1.02 to 89.9 ± 3.03 and 35.4 ± 1.56 m/s, respectively, and increased the duration of the 2nd CAP component from 0.66 ± 0.04 to 0.82 ± 0.09 ms. DM also increases oxidative stress in the SN, altering values related to thiol, TBARS, SOD, and CAT activities. Anethole was capable of fully preventing all these DM electrophysiological and biochemical alterations in the nerve. Thus, the magnitude of the DM-induced neural effects seen in this work, and the prevention afforded by anethole treatment, place this compound in a very favorable position as a potential therapeutic agent for treating diabetic peripheral neuropathy.

Pulsed electromagnetic fields (PEMFs) are recognized for their potential in regenerative medicine, offering a non-invasive avenue for tissue rejuvenation. While prior research has mainly focused on their effects on bone and dermo-epidermal tissues, the impact of PEMFs on nervous tissue, particularly in the context of neuropathy associated with the diabetic foot, remains relatively unexplored. Addressing this gap, our preliminary in vitro study investigates the effects of complex magnetic fields (CMFs) on glial-like cells derived from mesenchymal cell differentiation, serving as a model for neuropathy of the diabetic foot. Through assessments of cellular proliferation, hemocompatibility, mutagenicity, and mitochondrial membrane potential, we have established the safety profile of the system. Furthermore, the analysis of microRNAs (miRNAs) suggests that CMFs may exert beneficial effects on cell cycle regulation, as evidenced by the upregulation of the miRNAs within the 121, 127, and 142 families, which are known to be associated with mitochondrial function and cell cycle control. This exploration holds promise for potential applications in mitigating neuropathic complications in diabetic foot conditions.

Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε-3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes., (© 2024. The Author(s).)

Introduction: Diabetic peripheral neuropathy (DPN) impacts patient quality of life. In such patients, increased expression of mer tyrosine kinase (MerTK) has been demonstrated; however, its mechanism of action remains unclear. In this study, type 2 diabetes mellitus (T2DM) and DPN models were established in Sprague Dawley rats via low-dose streptozotocin and a high-fat diet and the mode of action of MerTK was examined., Methods: MerTK-specific inhibitors were administered by gavage once daily for 2 weeks. Sciatic nerve conduction velocity and nerve structure were measured. The levels of MerTK, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and relevant biochemical indexes were detected., Results: The study revealed upregulation of MerTK expression in T2DM and more so in DPN groups. Inhibiting MerTK led to reduced nerve conduction velocity and further deterioration of sciatic nerve structure, as evidenced by structural morphology. Concurrently, serum levels of total cholesterol, glycated hemoglobin, and triglyceride significantly increased. Moreover, levels of NF-κB increased in both serum and nerve tissue, alongside a significant rise in TNF-α and IL-1β expressions. MerTK could bind to the inhibitor of kappa B kinase beta (Ikbkb) in Schwann cells, establishing Ikbkb as a precursor to NF-κB activation., Discussion: Inhibition of MerTK exacerbates neuropathy, indicating its protective role in DPN by suppressing the NF-κB pathway, highlighting a potential new target for its diagnosis and treatment., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Diabetic peripheral neuropathy (DPN) is a common complication of type 2 diabetes mellitus (T2DM) that causes peripheral and autonomic nervous system dysfunction. Dysregulation of miRNAs plays a crucial role in DPN development. However, the role of miR-503-5p in DPN remains unknown. Herein, T2DM mice (db/db) were used as a DPN model in vivo, and astrocytes isolated from db/db mice were induced with high glucose levels as a DPN model in vitro. MiR-503-5p expression was analyzed using qRT-PCR. GFAP, MCP-1, and SEPT9 protein levels were analyzed using western blotting and immunofluorescence. Luciferase assays were performed to investigate the interaction between miR-503-5p and SEPT9. We found that miR-503-5p expression decreased in the spinal cord of DPN model mice and astrocytes treated with high glucose (HG). The db/db mice displayed higher body weight and blood glucose, lower mechanical withdrawal threshold and thermal withdrawal latency, and higher GFAP and MCP-1 protein levels than db/m mice. However, tail vein injection of agomiR-503-5p remarkably reversed these parameters, whereas antigomiR-503-5p enhanced them. HG markedly facilitated GFAP and MCP-1 protein expression in astrocytes, whereas miR-503-5p mimic or inhibitor transfection markedly blocked or elevated GFAP and MCP-1 protein expression, respectively, in astrocytes with HG. SEPT9 was a target of miR-503-5p. In addition, SEPT9 protein levels were found to be elevated in db/db mice and astrocytes treated with HG. Treatment with agomiR-503-5p and miR-503-5p mimic was able to reduce SEPT9 protein levels, whereas treatment with antigomiR-503-5p and miR-503-5p inhibitor led to inhibition of the protein. Furthermore, SEPT9 overexpression suppressed the depressing effect of miR-503-5p overexpression in astrocytes subjected to HG doses. In conclusion, miR-503-5p was found to alleviate peripheral neuropathy-induced neuropathic pain in T2DM mice by regulating SEPT9 expression., (© 2024. The Author(s).)

The exact mechanism by which diabetic neuropathy develops is still not fully known, despite our advances in medical knowledge. Progressing neuropathy may occur with a persistently favorable metabolic status in some patients with diabetes mellitus, while, in others, though seldom, a persistently unfavorable metabolic status is not associated with significant neuropathy. This might be significantly due to genetic differences. While recent years have brought compelling progress in the understanding of the pathogenetic background-in particular, accelerated progress is being made in understanding molecular biological mechanisms-some aspects are still not fully understood. A comparatively small amount of information is accessible on this matter; therefore, by summarizing the available data, in this review, we aim to provide a clearer picture of the current state of knowledge, identify gaps in the previous studies, and possibly suggest directions for future studies. This could help in developing more personalized approaches to the prevention and treatment of diabetic neuropathy, while also taking into account individual genetic profiles.

Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral fenofibrate, a peroxisome proliferator-activated receptor-α agonist, on the amelioration of DCN using diabetic mice (n = 120). Ocular surface assessments, corneal nerve and cell imaging analysis, tear proteomics and its associated biological pathways, immuno-histochemistry and western blot on PPARα expression, were studied before and 12 weeks after treatment. At 12 weeks, PPARα expression markedly restored after topical and oral fenofibrate. Topical fenofibrate significantly improved corneal nerve fibre density (CNFD) and tortuosity coefficient. Likewise, oral fenofibrate significantly improved CNFD. Both topical and oral forms significantly improved corneal sensitivity. Additionally, topical and oral fenofibrate significantly alleviated diabetic keratopathy, with fenofibrate eye drops demonstrating earlier therapeutic effects. Both topical and oral fenofibrate significantly increased corneal β-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased β-III-tubulin and reduced CDC42 mRNA expression in trigeminal ganglions. Proteomic analysis showed that neurotrophin signalling and anti-inflammation reactions were significantly up-regulated after fenofibrate treatment, whether applied topically or orally. This study concluded that both topical and oral fenofibrate ameliorate DCN, while topical fenofibrate significantly reduces neuroinflammation., (© 2024. The Author(s).)

Purpose: Diabetic neuropathy (DN) is a notable complication of diabetes mellitus. The potential involvement of miR-146a in DN regulation is presently under investigation. Metformin, a commonly prescribed medication for diabetes, is the primary therapeutic intervention. This study aimed to unveil the potential protective effects of metformin on diabetic neuropathy and explore the mechanisms underlying its action., Method: Six-weeks male Sprague Dawley rats (n = 40) were randomly divided into 5 groups. The rat model of diabetic neuropathy (DN) was established by administering streptozotocin (STZ). To investigate the effects on the sciatic nerve and resident Schwann cells (RSCs), metformin and miR-146a mimics were administered, and our research explored the potential underlying mechanism., Result: The sciatic nerve samples obtained from diabetic rats exhibited noticeable morphological damage, accompanied by decreased miR-146a expression (2.61 ± 0.11 vs 5.0 ± 0.3, p < 0.01) and increased inflammation levels (p65: 1.89 ± 0.04 vs 0.82 ± 0.05, p < 0.01; TNF-α: 0.93 ± 0.03 vs 0.33 ± 0.03, p < 0.01). Notably, the administration of metformin effectively ameliorated the structural alterations in the sciatic nerve by suppressing the inflammatory pathway (p65: 1.15 ± 0.05 vs 1.89 ± 0.04, p < 0.01; TNF-α: 0.67 ± 0.04 vs 0.93 ± 0.03, p < 0.01) and reducing oxidative stress (NO: 0.062 ± 0.004 vs 0.154 ± 0.004umol/mg, p < 0.01; SOD: 3.08 ± 0.09 vs 2.46 ± 0.09 U/mg, p < 0.01). The miR-146a mimics intervention group exhibited comparable findings., Conclusion: This study's findings implied that metformin can potentially mitigate diabetic neuropathy in rats through the modulation of miR-146a expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)