Treatment Of Diabetic Peripheral Neuropathy Research Articles

The Analgesic Effects of Baclofen 5% Topical Cream for Treatment of Diabetic Peripheral Neuropathy: a Placebo-Control and Double-Blinded Clinical Trial

The Analgesic Effects of Baclofen 5% Topical Cream for Treatment of Diabetic Peripheral Neuropathy: a Placebo-Control and Double-Blinded Clinical Trial

Is Nerve Electrophysiology a Robust Primary Endpoint in Clinical Trials of Treatments for Diabetic Peripheral Neuropathy?

There is currently no FDA-approved disease-modifying therapy for diabetic peripheral neuropathy (DPN). Nerve conduction velocity (NCV) is an established primary endpoint of disease-modifying therapies in DPN and clinical trials have been powered with an assumed decline of 0.5 m/s/year. This paper sought to establish the time-dependent change in NCV associated with a placebo, compared to that observed in the active intervention group. A literature search identified twenty-one double-blind, randomised controlled trials in DPN of ≥1 year duration conducted between 1971 and 2021. We evaluated changes in neurophysiology, with a focus on peroneal motor and sural sensory NCV and amplitude in the placebo and treatment groups. There was significant variability in the change and direction of change (reduction/increase) in NCV in the placebo arm, as well as variability influenced by the anatomical site of neurophysiological measurement within a given clinical trial. A critical re-evaluation of efficacy trials should consider placebo-adjusted effects and present the placebo-subtracted change in NCV rather than assume a universal annual decline of 0.5 m/s/year. Importantly, endpoints such as corneal confocal microscopy (CCM) have demonstrated early nerve repair, whilst symptoms and NCV have not changed, and should thus be considered as a viable alternative.

Regulatory Effects of Astragaloside IV on Hyperglycemia-Induced Mitophagy in Schwann Cells.

Objective This study aimed to observe the regulatory effects of astragaloside IV (AS-IV) on hyperglycemia-induced mitochondrial damage and mitophagy in Schwann cells and to provide references for clinical trials on AS-IV in the treatment of diabetic peripheral neuropathy. Methods Schwann cells were grown in a high-glucose medium to construct an autophagy model; the cells were then treated with AS-IV and N-acetylcysteine (control) to observe the regulatory effects of AS-IV on oxidative stress and mitophagy. Results AS-IV exhibited antioxidant activity and inhibited the overactivation of autophagy in Schwann cells, significantly reducing the level of reactive oxygen species and downregulating the expression of autophagy-related proteins (LC3, PINK, and Parkin) under hyperglycemic conditions, thereby exerting a protective effect on mitochondrial morphology and membrane potential. Conclusion AS-IV can maintain the mitochondrial function of Schwann cells under hyperglycemic conditions by effectively alleviating oxidative stress and overactivation of mitophagy. The evidence from this study supports an AS-IV-based therapeutic strategy against diabetic peripheral neuropathy.

Research Progress of Buyang Huanwu Decoction in the Treatment of Diabetic Peripheral Neuropathy

Diabetes peripheral neuropathy is a complication aused by diabetes, involving peripheral nerves. The onset of DPN is occult and the process is slow, and the late stage of the disease will lead to severe nerve damage. With the change of modern people's lifestyle, the number of obese people is increasing, which leads to the increasing number of DPN patients. Common hypoglycemic drugs can not control blood sugar well and can not interfere with the process of DPN. Opioid analgesics and antiepileptic drugs are often used to relieve neuropathic pain and other symptoms in clinic. However, these drugs can only relieve the pain at that time, treat the symptoms but not the root cause, and have great toxic and side effects on human body. Therefore, the research and development of DPN specialty drugs has attracted wide attention around the world. Unfortunately, most of the drugs under research have failed due to safety problems. Therefore, there is an urgent need for safe and effective drugs to treat DPN. Therefore, it is necessary to treat this disease by means of traditional Chinese medicine. The Buyang Huanwu Decoction recorded in the medical forest correcting mistakes is a famous prescription for supplementing qi and activating blood circulation, which has the pathogenesis of DN. The research shows that the effect of Buyang Huanwu Decoction on DPN is accurate, but the effective substances and the mechanism of action in Buyang Huanwu Decoction are not clear. This subject takes Buyang Huanwu decoction as the research object to explore its mechanism of action and the research progress of clinical application, so as to lay a solid foundation for the treatment of diabetes peripheral neuropathy by traditional Chinese medicine. The Buyang Huanwu Decoction recorded in the medical forest correcting mistakes is a famous prescription for supplementing qi and activating blood circulation, which has the pathogenesis of DN. The research shows that the effect of Buyang Huanwu Decoction on DPN is accurate, but the effective substances and the mechanism of action in Buyang Huanwu Decoction are not clear. This subject takes Buyang Huanwu decoction as the research object to explore its mechanism of action and the research progress of clinical application, so as to lay a solid foundation for the treatment of diabetes peripheral neuropathy by traditional Chinese medicine.

Network Pharmacology Study on the Mechanism of Qiang Huo-Yinchen Treating Diabetic Peripheral Neuropathy

Objective: To explore the mechanism of Qiang huo-Yin chen in the treatment of diabetic peripheral neuropathy (DPN) based on network pharmacology. Methods Using traditional Chinese medicine system pharmacology analysis platform (TCMSP), oral bioavailability (OB) ≥30 %, drug-like (DL)≥0.18 as screening conditions, notopterygium-Yinchen compounds and related targets were obtained. DNP-related genes were obtained from the human gene database (GeneCards) and the online human Mendel genetic database (OMIM). The intersection genes between candidate compounds and DNP were obtained by online Wayne diagram analysis. The interaction network of intersection proteins was constructed by STRING 10.0 database. Gene ontology (GO) analysis and signal pathway enrichment analysis based on Kyoto Encyclopedia of Genes and Genes (KEGG) were performed on the intersection proteins through DAVID database. Cytoscape 3.8.2 software was used to construct the component-target-signaling pathway network of Radix Astragali- Radix Angelicae Sinensis in the treatment of diabetic nephropathy. Results: The constructed component-target network contained 23 active components, including cnidilin, quercetin, beta-sitosterol, isorhamnetin, and areapillin. HSP90AA1, BLC2, CASP3 among 63 targets, KEGG involves 28 pathways such as lipid and atherosclerosis, AGE-RAGE in diabetic complications, apoptosis, pathway signaling pathways of neurodegenerative diseases. Conclusion: Qianghuo-yinchen pair may act on HSP90AA1, BLC2, CASP3 and other targets through multiple components such as quercetin and β-sitosterol, and regulate multiple signaling pathways such as lipid, apoptosis, and neurodegenerative diseases, thereby playing a role in the treatment of DNP.

Alterations in plantar vessel blood flow in patients with mild diabetic peripheral neuropathy

IntroductionEarly identification and treatment of diabetic peripheral neuropathy (DPN) are crucial. Presently, the mechanism of DPN is not very clear, and there are inconclusive conclusions about the influencing factors of...

Diabetic Peripheral Neuropathy.

Diabetic painless and painful peripheral neuropathy remains the most frequent complication of diabetes mellitus, but the pathophysiology remains undescribed, there are no robust clinical endpoints and no efficient treatment exists. This hampers good clinical practice, fruitful clinical research and successful pharmacological trials, necessary for the development of early detection, prevention and treatment. This chapter supplies an update on background and treatment of diabetic peripheral neuropathy. Goals and perspectives for future clinical and scientific approaches are also described.

Efficacy and safety of acupuncture combined Chinese herbal medicine for diabetic peripheral neuropathy: A protocol for systematic review and meta-analysis.

Background:Acupuncture combined with Chinese herbal medicine has been widely utilized for pain management in patients with diabetic peripheral neuropathy (DPN). However, its results are still inconsistent, and no systematic review has specifically addressed this issue. Thus, this systematic review will comprehensively and systematically investigate the effectiveness and safety of acupuncture combined with Chinese herbal medicine for pain relief in DPN.Methods:Randomized controlled trials on acupuncture combined with Chinese herbal medicine treatment of DPN published before September of 2021 will be searched in 9 databases including Medline, Web of Science, PubMed, Cochrane Library, Excerpta Medica Database, Sinomed, China National Knowledge Infrastructure, WanFang, and China Science and Technology Journal Database. The methodological assessment performed using the risk of bias assessment tool of Cochrane, and the level of evidence quality for the main results will be evaluated by a recommended grading, evaluation, formulation, and evaluation system approach. Bayesian network meta-analysis will be conducted using STATA V.14.0 and WinBUGS V.1.4.3.Results:This study will provide a high-quality comprehensive evaluation of the safety of acupuncture combined with Chinese herbal medicine for treating DPN.Conclusion:This systematic review will evaluate the efficacy and safety of Chinese herbal medicine combined with acupuncture in the treatment of DPN, and provide the latest evidence for clinical application.Ethics and dissemination:The protocol of the systematic review does not require ethical approval because it does not involve humans. This article will be published in peer-reviewed journals and presented at relevant conferences.Registration number: INPLASY2021100004.

Clinical comprehensive evaluation of Mudan Granules in treatment of diabetic peripheral neuropathy with Qi-deficiency and collateral stagnation syndrome

This study explored the clinical comprehensive evaluation of Mudan Granules, aiming to promote the safe, effective and rational use of Mudan Granules, reflect its clinical value and provide a basis for medical decision-making. The safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine of Mudan Granules were combed, and the multi-criteria decision analysis(MCDA) model was used to carry out comprehensive evaluation on each dimension. In terms of safety, multiple sources of evidence showed that the adverse reactions of Mudan Granules mainly involved gastrointestinal system, with controllable safety risk rated as grade B. In terms of effectiveness, Mudan Granules can significantly alleviate the diabetic peripheral neuropathy(Qi-deficiency and collateral stagnation syndrome), limb and trunk numbness, pain and sensory abnormalities and other clinical symptoms, exhibiting positive curative effect rated as grade A. In terms of economy, Mudan Granules combined with Mecobalamin and other conventional western medicines is economical compared with the western medicine alone group, which is supported by sufficient evidence and clear results, rated as grade B. In terms of innovation, Mudan Granules is the only Chinese patent medicine with the indication of benefiting Qi for activating blood circulation and dredging collaterals in the Medicine Catalogue for National Basic Medical Insurance, Industrial Injury Insurance, and Maternity Insurance. It has important clinical innovation and is evaluated as grade A. In the aspect of suitability, Mudan Granules has good suitability in ADR treatment, drug characteristics and usage, and is rated as grade B. In terms of accessibility, Mudan Granules has the price level comparable to that of similar drugs, with good affordability. The resources of medicinal materials for the preparation of Mudan Granules are abundant and available, which is rated grade B. Moreover, Mudan Granules, as a hospital preparation with both functions of tonification and purgation, reflects the combination between syndrome differentiation and disease differentiation as well as the combination between overall and local characteristics, and has prominent Chinese medicine features. According to the above dimensions, we suggest to classify Mudan Granules as a class A preparation which can be directly included the policy results of basic clinical drug administration.

Efficacy and Safety of Gabapentine and Duloxetine in Diabetic Peripheral Neuropathic Pain

Introduction: Diabetic peripheral neuropathy (DPNP) is not uncommon now a days. As the pathophysiology is not completely understood, symptoms relief is still the main goal of treatment. Gabapentine and Duloxetine are being using around the world for this purpose. But clinical data regarding its efficacy and safety are not sufficiently available. Materials and Methods: This prospective comparative clinical study conducted in Sylhet MAG Osmani Medical College and Sylhet Diabetic Hospital, Bangladesh from January 2013 to December 2013. Diagnosis of DPNP confirmed by Michigan Neuropathy Screening Instrument (MNSI) and Douleur Neuropathic en-4 (DN4). Patients were treated by Gabapentine (Group-A) and Duloxetine (Group-B); and followed up at 4th, 8th and 12th week of treatment using 11-point numerical pain rating scale (NRS), clinical global impression of change (CGIC) score and patient’s global impression of change (PGIC) score. Results: A total of 72 patients with DPNP were recruited. Final comparison was done in 64 patients – 33 in Group-A and 31 in Group-B. Changes in NRS (p = <0.001), CGIC (p = <0.001) and PGIC (p = <0.001) were statistically significant during the course of treatment. However, inter-group variation of NRS, CGIC and PGIC were not statistically significant at the beginning and 4th, 8th and 12th week of treatment. Insignificant adverse effects were noted between the groups in this study except constipation (p = 0.022) and nausea-vomiting (p = 0.01) of Duloxetine taking group. Conclusion: Gabapentine and Duloxetine are equally effective in the treatment of DPNP with good safety profile. Medicine Today 2021 Vol.33(2): 108-113

Quercetin reduces inflammation in a rat model of diabetic peripheral neuropathy by regulating the TLR4/MyD88/NF-κB signalling pathway

Neuroinflammation contributes significantly to the pathogenesis of diabetic peripheral neuropathy (DPN). Quercetin reportedly exerts neuroprotective effects in DPN. Here, we aimed to evaluate the potential anti-inflammatory effects of quercetin in a DPN rat model. Eight weeks after streptozotocin administration, diabetic rats were treated with quercetin (30 and 60 mg/kg/day orally) for 6 weeks. We assessed the mechanical withdrawal threshold (MWT), nerve conduction velocity (NCV) and morphological changes in sciatic nerves. Additionally, we measured the levels of tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6 by ELISA and the expression of TLR4, MyD88, and NF-κB in sciatic nerves by western blotting and immunohistochemical assays. Our results revealed that blood glucose levels and body weight were unaltered following quercetin treatment. However, quercetin improved MWT (p < 0.05), NCV (p < 0.05), and pathological changes in the sciatic nerves of DPN rats. Quercetin significantly alleviated the increased expression of TNF-α (p < 0.05) and IL-1β (p < 0.001). Furthermore, high-dose quercetin administration significantly downregulated the expression of TLR4 (p < 0.001), MyD88 (p < 0.001), and NF-κB (p < 0.001) in sciatic nerves of DPN rats. Our findings revealed that quercetin could reduce the levels of inflammatory factors in DPN rats, possibly mediated via the downregulation of the TLR4/MyD88/NF-κB signalling pathway. Collectively, these results suggest that although quercetin did not decreased blood glucose levels or reversed the reduced body weight, it showed anti-inflammatory and neuroprotective effects, which was beneficial for the treatment of DPN.

Genetic loss-of-function of activating transcription factor 3 but not C-type lectin member 5A prevents diabetic peripheral neuropathy

We investigated the mediating roles of activating transcription factor 3 (ATF3), an injury marker, or C-type lectin member 5A (CLEC5A), an inflammatory response molecule, in the induction of endoplasmic reticulum (ER) stress and neuroinflammation in diabetic peripheral neuropathy in ATF3 and CLEC5A genetic knockout (aft3−/− and clec5a−/−, respectively) mice. ATF3 was expressed intranuclearly and was upregulated in mice with diabetic peripheral neuropathy (DN) and clec5a−/− mice. The DN and clec5a−/− groups also exhibited neuropathic behavior, but not in the aft3−/− group. The upregulation profiles of cytoplasmic polyadenylation element-binding protein, a protein translation–regulating molecule, and the ER stress-related molecules of inositol-requiring enzyme 1α and phosphorylated eukaryotic initiation factor 2α in the DN and clec5a−/− groups were correlated with neuropathic behavior. Ultrastructural evidence confirmed ER stress induction and neuroinflammation, including microglial enlargement and proinflammatory cytokine release, in the DN and clec5a−/− mice. By contrast, the induction of ER stress and neuroinflammation did not occur in the aft3−/− mice. Furthermore, the mRNA of reactive oxygen species–removing enzymes such as superoxide dismutase, heme oxygenase-1, and catalase were downregulated in the DN and clec5a−/− groups but were not changed in the aft3−/− group. Taken together, the results indicate that intraneuronal ATF3, but not CLEC5A, mediates the induction of ER stress and neuroinflammation associated with diabetic neuropathy.Neuroinflammation and endoplasmic reticulum stress is a critical process that leads to diabetic peripheral neuropathy (DPN). Activating transcription factor 3 (ATF3) is a susceptible molecule, and loss-of-function of ATF3, but not C-type lectin member 5A (CLEC5A), prevents the development of neuroinflammation and ER stress. Functional blockade of ATF3 may be a potential treatment for diabetic peripheral neuropathy by inhibiting neuroinflammation and cellular stress-induced ER stress.

Astragaloside IV alleviates Schwann cell injury in diabetic peripheral neuropathy by regulating microRNA-155-mediated autophagy

BackgroundMicroRNA-155(miR-155) is closely associated with diabetic peripheral neuropathy (DPN). Astragaloside IV (AST) is a significant extract of Astragalus membranaceus, which has been found to be effective in the treatment of DPN. However, whether astragaloside IV alleviate DPN via regulating miR-155-mediated autophagy remains unclear. PurposeThis study was designed to evaluate the effects of AST on DPN myelin Schwann cells injury and explore the mechanism of AST in treating DPN for the first time. MethodsGK rats fed with high-fat diet and RSC96 cells cultured in high glucose were used to establish DPN Schwann cells injury in vivo and in vitro model. The effects of AST on DPN were explored through blood glucose detection, nerve function detection, pathological detection and the expression of Neuritin detected by immunohistochemical. To study the effect of AST on the DPN Schwann cells autophagy and the upstream PI3K/Akt/mTOR pathway, the expressions of beclin-1 and LC3 were detected by western blot (WB) in sciatic nerves and by immunofluorescence (IFC) in RSC96 cells. The real-time polymerase chain reaction (RT-PCR) was applied to detect the expressions of miR-155, ATG5, ATG12 both in vivo and in vitro. The binding effect of miR-155 and target gene PI3KCA was verified by luciferase reporter gene assay. The expressions of PI3K, p-Akt/Akt, p-mTOR/mTOR were detected by WB and the expressions of PI3KCA were detected by RT-PCR in vitro. The apoptosis was detected by flow cytometry. Meanwhile, the influence of miR-155 overexpression and knocked down on the above indicators was also detected in RSC96 cells. At last, further mechanism experiments were conducted to verify the mechanism of AST regulating the autophagy and apoptosis of RSC96 cells. ResultsAST reduced blood glucose levels, alleviated peripheral nerve myelin sheath injury, and improved neurological function in DPN rats. In addition, AST enhanced the autophagy activity and alleviated the apoptosis in RSC96 cell. Mechanism study shown that AST promote autophagy via regulating miR-155-mediated PI3K/Akt/mTOR signaling pathways. AST reduced RSC96 cells apoptosis by promoting autophagy. ConclusionAST alleviate the myelin sheath injury of DPN caused by the apoptosis of Schwann cells via enhancing autophagy, which was attributed to inhibiting the activation of the PI3K/Akt/mTOR signaling pathway by upregulating miR-155 expression.

Lipin1 Alleviates Autophagy Disorder in Sciatic Nerve and Improves Diabetic Peripheral Neuropathy.

Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes, and its neural mechanisms underlying the pathogenesis remain unclear. Autophagy plays an important role in neurodegenerative diseases and nerve tissue injury. Lipin1 is a phosphatidic acid phosphatase enzyme that converts phosphatidic acid (PA) into diacylglycerol (DAG), a precursor of triacylglycerol and phospholipids which plays an important role in maintaining normal peripheral nerve conduction function. However, whether Lipin1 involved in the pathogenesis of DPN via regulation of autophagy is not elucidated. Here, we show that the Lipin1 expression was downregulated in streptozotocin (STZ)-induced DPN rat model. Interestingly, STZ prevented DAG synthesis, and resulted in autophagic hyperactivity, effects which may increase the apoptosis of Schwann cells and lead to demyelination in sciatic nerve in DPN rats. More importantly, upregulation of lipin1 in the DPN rats ameliorated autophagy disorders and pathological changes of the sciatic nerve, which associated with the increase of the motor nerve conductive velocity (MNCV) in DPN rats. In contrast, knockdown of lipin1 exacerbates neuronal abnormalities and facilitates the genesis of DPN phenotypes in rats. In addition, overexpression of lipin1 in RSC96 cells also significantly decreased the autophagic hyperactivity and apoptosis induced by hyperglycemia. These results suggest that lipin1 may exert neuroprotection within the sciatic nerve anomalies and may serve as a potential therapeutic target for the treatment of DPN.

Targeting Neuroimmune Interactions in Diabetic Neuropathy with Nanomedicine.

Significance: Diabetes is a major source of neuropathy and neuropathic pain that is set to continue growing in prevalence. Diabetic peripheral neuropathy (DPN) and pain associated with diabetes are not adequately managed by current treatment regimens. Perhaps the greatest difficulty in treating DPN is the complex pathophysiology, which involves aspects of metabolic disruption and neurotrophic deficits, along with neuroimmune interactions. There is, therefore, an urgent need to pursue novel therapeutic options targeting the key cellular and molecular players. Recent Advances: To that end, cellular targeting becomes an increasingly compelling drug delivery option as our knowledge of neuroimmune interactions continues to mount. These nanomedicine-based approaches afford a potentially unparalleled specificity and longevity of drug targeting, using novel or established compounds, all while minimizing off-target effects. Critical Issues: The DPN therapeutics directly targeted at the nervous system make up the bulk of currently available treatment options. However, there are significant opportunities based on the targeting of non-neuronal cells and neuroimmune interactions in DPN. Future Directions: Nanomedicine-based agents represent an exciting opportunity for the treatment of DPN with the goals of improving the efficacy and safety profile of analgesia, as well as restoring peripheral neuroregenerative capacity. Antioxid. Redox Signal. 36, 122-143.

Using corneal confocal microscopy to compare Mecobalamin intramuscular injections vs oral tablets in treating diabetic peripheral neuropathy: a RCT

This randomized controlled study used corneal confocal microscopy (CCM) to compare the efficacy of Mecobalamin intramuscular injections vs oral tablets in treating mild to moderate diabetic peripheral neuropathy (DPN) by detecting early nerve fiber repair. Enrolled patients were randomized approximately 1:1 to receive Mecobalamin intramuscular injections (0.5 mg/day, 3 times/week) or Mecobalamin oral tablets (1.5 mg/day) for 8 weeks. Primary outcome was change of inferior whorl length (IWL) from baseline. Secondary outcomes included changes of corneal nerve fibre length (CNFL), corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and the Survey of Autonomic Symptoms (SAS). 15 (93.75%) patients in the injection group and 17 (89.47%) patients in the tablet group completed the study. The injection treatment significantly improved patients’ IWL from baseline (21.64 ± 3.00 mm/mm2 vs 17.64 ± 4.83 mm/mm2, P < 0.01) while the tablet treatment didn’t. Additionally, the injection treatment led to significantly improved CNFL, CNBD and SAS from baseline (all P < 0.05) while the tablet treatment did not. No patient experienced any adverse events. In conclusion, CCM is sensitive enough to detect the superior efficacy of 8-week Mecobalamin intramuscular injection treatment for DPN compared to the oral tablet treatment.ClinicalTrials.gov registration number: NCT04372316 (30/04/2020).

Electroacupuncture Alleviates Diabetic Peripheral Neuropathy by Regulating Glycolipid-Related GLO/AGEs/RAGE Axis.

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes mellitus (DM) and affects over one-third of all patients. Neuropathic pain and nerve dysfunction induced by DM is related to the increase of advanced glycation end products (AGEs) produced by reactive dicarbonyl compounds in a hyperglycemia environment. AGEs induce the expression of pro-inflammatory cytokines via the main receptor (RAGE), which has been documented to play a crucial role in the pathogenesis of diabetic peripheral neuropathy. Electroacupuncture (EA) has been reported to have a positive effect on paralgesia caused by various diseases, but the mechanism is unclear. In this study, we used high-fat-fed low-dose streptozotocin-induced rats as a model of type 2 diabetes (T2DM). Persistent metabolic disorder led to mechanical and thermal hyperalgesia, as well as intraepidermal nerve fiber density reduction and nerve demyelination. EA improved neurological hyperalgesia, decreased the pro-inflammatory cytokines, reduced the generation of AGEs and RAGE, and regulated the glyoxalase system in the EA group. Taken together, our study suggested that EA plays a role in the treatment of T2DM-induced DPN, and is probably related to the regulation of metabolism and the secondary influence on the GLO/AGE/RAGE axis.

Systematic Elucidation of the Mechanism of Sappan Lignum in the Treatment of Diabetic Peripheral Neuropathy Based on Network Pharmacology.

Background Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes, which seriously affects the physical and mental health of patients. Sappan Lignum (SL) is effective in treating DPN. Previous reports have shown that SL has a clear hypoglycemic and anti-inflammatory effect. However, the study of SL in the treatment of DPN is still limited and rare. Objective To investigate the mechanism of SL in the treatment of DPN based on network pharmacology. Methods The active ingredients of SL were screened by related databases. The compound targets were collected by the target prediction platforms. The DPN-related targets were gathered through disease databases. The intersection targets were obtained by uploading the compound targets and disease targets to Venny 2.1.0, and a compound-target network was constructed by Cytoscape3.7.2. The protein-protein interaction (PPI) relationships were obtained by the STRING11.0 database. Genome Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the DAVID6.8 database. Molecular docking of key compounds and core targets was performed by DockThor. Results A total of 29 compounds and 51 intersection targets with potential therapeutic effects on DPN were obtained. The compound-target network construction resulted in four key compounds: protostemonine, 3-deoxysappanchalcone, 7,3′,4′-trihydroxy-3-benzyl-2H-chromene, and o-12′-methylergocornine. PPI network analysis yielded 10 core targets: AKT1, MAPK3, CXCL8, TNF, OPRM1, MTOR, STAT3, MAPK8, SIRT1, and HSP90AA1. KEGG analysis resulted in 82 signaling pathways (P < 0.05), including insulin resistance, HIF-1 signaling pathway, and type II diabetes. The docking results indicated that the main active compounds could stably bind to core targets. Conclusion SL had the mechanism of multiple ingredients, multiple targets, and multiple pathways in the treatment of DPN. This study provided a scientific basis for further research on the treatment of DPN with SL and its extracts.

Tuina for diabetic peripheral neuropathy: A protocol for a systematic review and meta-analysis.

Background:Diabetic peripheral neuropathy (DPN) is one of the most common microvascular complications of diabetes mellitus, with an incidence ranging from 60% to 90%. With the change in modern dietary structure, the incidence of diabetes is increasing year by year, and DPN is also on the rise. Tuina therapy has been widely used in the treatment of DPN, but there is no systematic review on the treatment of DPN. Therefore, this study aimed to conduct a meta-analysis of Tuina in the treatment of DPN to clarify its efficacy.Methods:The following electronic databases will be searched: PubMed, the Cochrane Library, Embase, Web of Science, Medline, CNKI, Chinese Biomedical Literature Database, VIP, and Wan Fang databases. We will consider articles published between database initiation and May 2021. We will use Review Manager 5.4, provided by the Cochrane Collaborative Network for statistical analysis. Clinical randomized controlled trials related to Tuina for diabetic peripheral neuropathy were included in this study. Language is limited to both Chinese and English. Research selection, data extraction, and research quality assessments were independently completed by two researchers. We then assessed the quality and risk of the included studies and observed the outcome measures.Results:This study provides a high-quality synthesis to assess the effectiveness and safety of Tuina for treating diabetic peripheral neuropathy.Conclusion:This systematic review will provide evidence to determine whether Tuina is an effective and safe intervention for patients with diabetic peripheral neuropathy.Ethics and dissemination:The protocol of the systematic review does not require ethical approval because it does not involve humans. This article will be published in peer-reviewed journals and presented at relevant conferences.Registration number:INPLASY202150027.

Network Pharmacology and Molecular Docking Study on the Potential Mechanism of Yi-Qi-Huo-Xue-Tong-Luo Formula in Treating Diabetic Peripheral Neuropathy.

Objective To investigate the potential mechanism of action of Yi-Qi-Huo-Xue-Tong-Luo formula (YQHXTLF) in the treatment of diabetic peripheral neuropathy (DPN). Methods Network pharmacology and molecular docking techniques were used in this study. Firstly, the active ingredients and the corresponding targets of YQHXTLF were retrieved using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) platform; subsequently, the targets related to DPN were retrieved using GeneCards, Online Mendelian Inheritance in Man (OMIM), Pharmgkb, Therapeutic Target Database (TTD) and Drugbank databases; the common targets of YQHXTLF and DPN were obtained by Venn diagram; afterwards, the “YQHXTLF Pharmacodynamic Component-DPN Target” regulatory network was visualized using Cytoscape 3.6.1 software, and Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the potential targets using R 3.6.3 software. Finally, molecular docking of the main chemical components in the PPI network with the core targets was verified by Autodock Vina software. Results A total of 86 active ingredients and 229 targets in YQHXTLF were screened, and 81 active ingredients and 110 targets were identified to be closely related to diabetic peripheral neuropathy disease. PPI network mapping identified TP53, MAPK1, JUN, and STAT3 as possible core targets. KEGG pathway analysis showed that these targets are mostly involved in AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, and MAPK signaling pathway. The molecular docking results showed that the main chemical components of YQHXTLF have a stable binding activity to the core pivotal targets. Conclusion YQHXTLF may act on TP53, MAPK1, JUN, and STAT3 to regulate inflammatory response, apoptosis, or proliferation as a molecular mechanism for the treatment of diabetic peripheral neuropathy, reflecting its multitarget and multipathway action, and providing new ideas to further uncover its pharmacological basis and mechanism of action.