Applying GC-MS based serum metabolomic profiling to characterize two traditional Chinese medicine subtypes of diabetic foot gangrene.

Traditional Chinese medicine (TCM) has a long history and particular advantages in the diagnosis and treatment of diabetic foot gangrene (DFG). Patients with DFG are mainly divided into two subtypes, tendon lesion with edema (GT) and ischemic lesion without edema (GI), which are suitable for different medical strategies. Metabolomics has special significance in unravelling the complexities of multifactorial and multisystemic disorders. This study acquired the serum metabolomic profiles of two traditional Chinese medicine subtypes of DFG to explore potential molecular evidence for subtype characterization, which may contribute to the personalized treatment of DFG. A total of 70 participants were recruited, including 20 with DM and 50 with DFG (20 with GI and 30 with GT). Conventional gas chromatography-mass spectrometry (GC-MS) followed by orthogonal partial least-squares discriminant analysis (OPLS-DA) were used as untargeted metabolomics approaches to explore the serum metabolomic profiles. Kyoto encyclopedia of genes and genomes (KEGG) and MetaboAnalyst were used to identify the related metabolic pathways. Compared with DM patients, the levels of 14 metabolites were altered in the DFG group, which were also belonged to the differential metabolites of GI (13) and GT (7) subtypes, respectively. Among these, urea, α-D-mannose, cadaverine, glutamine, L-asparagine, D-gluconic acid, and indole could be regarded as specific potential metabolic markers for GI, as well as L-leucine for GT. In the GI subtype, D-gluconic acid and L-asparagine are positively correlated with activated partial thromboplastin time (APTT) and fibrinogen (FIB). In the GT subtype, L-leucine is positively correlated with the inflammatory marker C-reactive protein (CRP). Arginine and proline metabolism, glycine, serine and threonine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis are the most important metabolic pathways associated with GI. The main metabolic pathways related to GT include pyrimidine metabolism, glutathione metabolism, biosynthesis of valine, leucine, and isoleucine, as well as valine, serine, and isoleucine with metabolites. The results of this study indicate that patients with different DFG subtypes have distinct metabolic profiles, which reflect the pathological characteristics of each subtype respectively. These findings will help us explore therapeutic targets for DFG and develop precise treatment strategies.

The effects of CYP2C19 genotype polymorphism and clopidogrel resistance on ischemic event occurrence in patients with peripheral arterial disease undergoing revascularization: A prospective cohort study.

INTRODUCTION: Peripheral arterial disease (PAD) affects approximately 236 million people worldwide. Therefore, this study aimed to investigate the relationship between CYP2C19 genotype polymorphisms and clopidogrel resistance (CR) following revascularization in patients with PAD. MATERIALS AND METHODS: In total, 345 patients who underwent PAD revascularization were monitored for five years and risk factors for ischemic events were identified. Platelet reactivity and CYP2C19 genotypes were measured, and patients were classified as normal, intermediate, or poor metabolizers based on their genotypes. The study endpoint was defined as an ischemic event, that encompassed major adverse cardiovascular or limb events, or all-cause death. RESULTS: In this study, ischemic events following PAD revascularization were associated with patient age, prior minor amputation, the Rutherford category before revascularization, indications for revascularization, index ankle-branchial index before revascularization, CYP2C19 phenotypes, and CR. Intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients after PAD revascularization. Similarly, intermediate and poor metabolism, the Rutherford category before revascularization, and CR were independent risk factors for ischemic events in patients with PAD after revascularization within five years. Intermediate and poor metabolizers had a higher platelet reactivity and risk of CR than normal metabolizers. However, poor metabolizers had a higher platelet reactivity and risk of CR than intermediate metabolizers. Furthermore, the hazard ratio for ischemic events increased with platelet reactivity. This effect was more prevalent in intermediate and poor metabolizers than in normal metabolizers. CONCLUSIONS: Ischemic events in patients after PAD revascularization were affected by independent risk factors. Decreased clopidogrel metabolism increased the platelet reactivity and CR in patients after PAD revascularization. Furthermore, high platelet reactivity was associated with an increased risk of ischemic events in patients with intermediate and poor metabolism.

An effective treatment for diabetic foot necrosis with traditional Chinese and Western medicine: a case report.

Patients with diabetes who undergo a kidney transplant are at a great risk of undergoing amputations, usually associated with severe infection and necrosis. The treatment of severe diabetic foot necrosis is challenging in clinic, and the function of the limb is often hugely compromised. A 74-year-old male who had been diagnosed with severe post-renal transplant diabetic foot necrosis refused the option of below-knee amputation from previous surgeons, and requested to keep his left foot. The patient was treated with integrated traditional Chinese medicine (TCM) and Western medicine, with positive results. TCM therapeutic principles included 'clearing heat, removing toxicity, regulating Qi, resolving dampness, activating stagnant blood and nourishing yin as well as tonifying Qi and blood'. Treatment with Western medicine included wound debridement, internal fixation or joint fusion, and use of insulin, antibiotics and vasodilators. The patient was treated with a staged and diverse approach (i.e., a combination of TCM and Western medicine, surgical management and education for diabetic foot care), which ultimately helped the patient achieve limb salvage and regain normal function. A combination therapy of Western medicine and TCM may be a promising approach to heal diabetic foot ulcers.

Cutaneous nodular polyarteritis presenting as refractory ulcers on both lower extremities: A case report.

BACKGROUND: Cutaneous polyarteritis nodosa (cPAN) is a systemic disease that is limited to the skin. cPAN usually presents with cutaneous reticular cyanotic, erythematous and palpable nodules, and cutaneous ulcers.Research has indicated that the use of hormones and immunosuppressive drugs can delay ulcer healing and associated neuropathy, and also elevate the risk of disease recurrence upon their reduction or withdrawal. Therefore, it is a necessary to find a safe and effective approach that minimize hormone side effects in ulcer treatment. CASE PRESENTATION: The patient, a 48-year-old female of Han Chinese ethnicity, has suffered from recurrent erythema nodosum on both lower limbs for 8 years. The condition was aggravated by skin breakdown over the last 3 months. Despite multiple treatments, the patient's condition did not improve significantly, leading to the exploration of a combined approach of traditional Chinese and Western medicine. Following six months of combined traditional Chinese and Western medicine treatment, t the patient's newborn erythema and ulcers on both lower limbs did not reappear, and the ulcers gradually decreased in size and the erythema disappeared. The patient took the TCM regularly until April 15, 2023, when the ulcers were completely healed. Three months after the patient stopped taking TCM, the ulcers had completely healed with no recurrence, as observed during the follow-up visit on July 14th, 2023. CONCLUSION: Traditional Chinese Medicine Combined with Low-Dose Hormones May Effectively Treat Bilateral Lower Extremity Skin Ulcers Caused by Cutaneous Polyarteritis Nodosa.

Unraveling shared risk factors for diabetic foot ulcer: a comprehensive Mendelian randomization analysis.

INTRODUCTION: Diabetic foot ulcer (DFU) stands as a severe diabetic lower extremity complication, characterized by high amputation rates, mortality, and economic burden. We propose using Mendelian randomization studies to explore shared and distinct risk factors for diabetic lower extremity complications. RESEARCH DESIGN AND METHODS: We selected uncorrelated genetic variants associated with 85 phenotypes in five categories at the genome-wide significance level as instrumental variables. Genetic associations with DFU, diabetic polyneuropathy (DPN), and diabetic peripheral artery disease (DPAD) were obtained from the FinnGen and UK Biobank studies. RESULTS: Body mass index (BMI) emerged as the only significant risk factor for DPAD, DPN, and DFU, independent of type 2 diabetes, fasting glucose, fasting insulin, and HbA1c. Educational attainment stood out as the sole significant protective factor against DPAD, DPN, and DFU. Glycemic traits below the type 2 diabetes diagnosis threshold showed associations with DPAD and DPN. While smoking history exhibited suggestive associations with DFU, indicators of poor nutrition, particularly total protein, mean corpuscular hemoglobin, and mean corpuscular volume, may also signal potential DFU occurrence. CONCLUSIONS: Enhanced glycemic control and foot care are essential for the diabetic population with high BMI, limited education, smoking history, and indicators of poor nutrition. By focusing on these specific risk factors, healthcare interventions can be better tailored to prevent and manage DFU effectively.

Clopidogrel-Related High Residual Platelet Reactivity Associated with Estimated Glomerular Filtration Rate in Patients with Acute Ischemic Stroke.

INTRODUCTION: There are few studies on the relationship between the occurrence of clopidogrel-related high residual platelet reactivity (HRPR) and estimated glomerular filtration rate (eGFR) at admission in patients with ischemic stroke. The aim of this study was to investigate the possible relationship between the two. METHODS: Patients who were hospitalized and diagnosed with acute ischemic stroke were recruited from July 1, 2017, to June 30, 2018, at Shanghai TCM-Integrated Hospital. Renal function was measured within 24 h of enrollment and eGFR was calculated. Patients were tested for platelet reactivity using the VerifyNow system after 7 days of antiplatelet therapy with clopidogrel 75 mg/d alone, and patients with P2Y12 reaction unit values ≥230 were diagnosed with HRPR. The association between HRPR and eGFR was analyzed. RESULTS: A total of 274 patients were enrolled in the study, of whom 91 (33.21%) had HRPR. Multivariate logistic regression analysis suggested that an increased risk of HRPR was independently associated with female sex and reduced eGFR (female sex: OR = 2.24, 95% CI: 1.26-3.99, p = 0.006; mild chronic kidney disease [CKD]: OR = 2.95, 95% CI: 1.47-5.93, p = 0.002; moderate CKD: OR = 3.07, 95% CI: 1.08-8.75, p = 0.04). CONCLUSION: Decreased eGFR is an independent risk factor for the occurrence of HRPR in patients with ischemic stroke.

Itaconate: A promising precursor for treatment of neuroinflammation associated depression.

Neuroinflammation triggers the production of inflammatory factors, influences neuron generation and synaptic plasticity, thus playing an important role in the pathogenesis of depression and becoming an important direction of depression prevention and treatment. Itaconate is a metabolite secreted by macrophages in immunomodulatory responses, that has potent immunomodulatory effects and has been proven to exert anti-inflammatory effects in a variety of diseases. Microglia are mononuclear macrophages that reside in the central nervous system (CNS), and may be the source of endogenous itaconate in the brain. Itaconate can directly inhibit succinate dehydrogenase (SDH), reduce the production of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), activate nuclear factor erythroid-2 related factor 2 (Nrf2), and block glycolysis, and thereby improving the depressive symptoms associated with the above mechanisms. Notably, itaconate also indirectly ameliorates the depressive symptoms associated with some inflammatory diseases. With the optimization of the structure and the development of new delivery systems, the application value and therapeutic potential of itaconate have been significantly improved. Dimethyl itaconate (DI) and 4-octyl itaconate (4-OI), cell-permeable derivatives of itaconate, are more suitable for crossing the blood-brain barrier (BBB), exhibiting therapeutic effects in the research of multiple diseases. This article provides an overview of the immunomodulatory effects of itaconate and its potential therapeutic efficacy in inflammatory depression, focusing on the promising application of itaconate as a precursor of antidepressants.

Creutzfeldt-Jakob disease presenting as Korsakoff syndrome caused by E196A mutation in PRNP gene: A case report.

BACKGROUND: Prion diseases are a group of degenerative nerve diseases that are caused by infectious prion proteins or gene mutations. In humans, prion diseases result from mutations in the prion protein gene (PRNP). Only a limited number of cases involving a specific PRNP mutation at codon 196 (E196A) have been reported. The coexistence of Korsakoff syndrome in patients with Creutzfeldt-Jakob disease (CJD) caused by E196A mutation has not been documented in the existing literature. CASE SUMMARY: A 61-year-old Chinese man initially presented with Korsakoff syndrome, followed by rapid-onset dementia, visual hallucinations, akinetic mutism, myoclonus, and hyperthermia. The patient had no significant personal or familial medical history. Magnetic resonance imaging of the brain revealed extensive hyperintense signals in the cortex, while positron emission tomography/computed tomography showed a diffuse reduction in cerebral cortex metabolism. Routine biochemical and microorganism testing of the cerebrospinal fluid (CSF) yielded normal results. Tests for thyroid function, human immunodeficiency virus, syphilis, vitamin B1 and B12 levels, and autoimmune rheumatic disorders were normal. Blood and CSF tests for autoimmune encephalitis and autoantibody-associated paraneoplastic syndrome yielded negative results. A test for 14-3-3 protein in the CSF yielded negative results. Whole-genome sequencing revealed a disease-causing mutation in PRNP. The patient succumbed to the illness 11 months after the initial symptom onset. CONCLUSION: Korsakoff syndrome, typically associated with alcohol intoxication, also manifests in CJD patients. Individuals with CJD along with PRNP E196A mutation may present with Korsakoff syndrome.

Ruan Jian Qing Mai's Formula Promotes Bone Marrow-Derived Mesenchymal Stem Cell Migration and Proliferation.

Objective: To investigate the response of (BM-MSCs) to the Ruan Jian Qing Mai formula (RJQM) in the treatment of atherosclerotic occlusion (ASO), and consequently promoting the development of collateral circulation and angiogenesis. Method: 35 male rats were randomly assigned to 6 experimental groups and A control group. 0.9% NaCl solution and 2.7, 5.4, 10.8, 16.2, 21.6, and 27 g × kg-1 × d-1 of RJQM formula were gavaged to the experimental groups twice a day for 8 days. After the last administration, medicated serum was prepared from the blood collected from the abdominal aorta. The human BM-MSCs were divided into an experimental group and a control group. A blank group of cells was added with a complete medium without rat serum; an experimental group of cells was added with the prepared drug-containing serum. Under hypoxic conditions, the drug-containing serum was used to treat BM-MSCs and/or endothelial cells of human umbilical vein (HUVECs). A Cell counting kit (CCK8) was used to detect cell proliferation. Western blot (WB) and quantitative real-time PCR (qPCR) were used to identify related genes expression. Results: The results of this study showed that the purity of the BM-MSCs was >95%. The drug-containing serum significantly rise in CCND1 expression (encoding cyclin D1) and MYC, especially when the concentration of medicated serum was 10.8 g × kg-1 × d-1. Treatment of either BM-MSCs or HUVECs alone or both with medicated serum aids in the spread of mesenchymal stem cells from the bone marrow to HUVECs. qPCR results showed that the mRNA expression of CCL2, CCL3, CCL25, IL8, IGF1, and PDGFB increased dramatically after treatment with medicated serum. The expression of the corresponding receptors for these up-regulated chemokines was detected in BM-MSCs, and it was found that CXCR1, CXCR4, CXCR7, and PDGFRB were up-regulated. Conclusion: This study provides a preliminary understanding of the mechanism of RJQM in the treatment of ASO.

Exosomes: Potential key players towards novel therapeutic options in diabetic wounds.

Diabetic wounds are usually difficult to heal, and wounds in foot in particular are often aggravated by infection, trauma, diabetic neuropathy, peripheral vascular disease and other factors, resulting in serious foot ulcers. The pathogenesis and clinical manifestations of diabetic wounds are complicated, and there is still a lack of objective and in-depth laboratory diagnosis and classification standards. Exosomes are nanoscale vesicles containing DNA, mRNA, microRNA, cyclic RNA, metabolites, lipids, cytoplasm and cell surface proteins, etc., which are involved in intercellular communication and play a crucial role in vascular regeneration, tissue repair and inflammation regulation in the process of diabetic wound healing. Here, we discussed exosomes of different cellular origins, such as diabetic wound-related fibroblasts (DWAF), adipose stem cells (ASCs), mesenchymal stem cells (MSCs), immune cells, platelets, human amniotic epithelial cells (hAECs), epidermal stem cells (ESCs), and their various molecular components. They exhibit multiple therapeutic effects during diabetic wound healing, including promoting cell proliferation and migration associated with wound healing, regulating macrophage polarization to inhibit inflammatory responses, promoting nerve repair, and promoting vascular renewal and accelerating wound vascularization. In addition, exosomes can be designed to deliver different therapeutic loads and have the ability to deliver them to the desired target. Therefore, exosomes may become an innovative target for precision therapeutics in diabetic wounds. In this review, we summarize the latest research on the role of exosomes in the healing of diabetic wound by regulating the pathogenesis of diabetic wounds, and discuss their potential applications in the precision treatment of diabetic wounds.

Risk factor analysis for diabetic foot ulcer-related amputation including Controlling Nutritional Status score and neutrophil-to-lymphocyte ratio.

Diabetic foot ulcer often leads to amputation, and both nutritional status and immune function have been associated with this process. We aimed to investigate the risk factors of diabetic ulcer-related amputation including the Controlling Nutritional Status score and neutrophil-to-lymphocyte ratio biomarker. We evaluated data from hospital in patients with diabetic foot ulcer, performing univariate and multivariate analyses to screen for high-risk factors and Kaplan-Meier analysis to correlate high-risk factors with amputation-free survival. Overall, 389 patients underwent 247 amputations over the follow-up period. After correction to relevant variables, we identified five independent risk factors for diabetic ulcer-related amputation: ulcer severity, ulcer site, peripheral arterial disease, neutrophil-to-lymphocyte ratio and nutritional status. Amputation-free survival was lower for the moderate-to-severe versus mild cases, for the plantar forefoot versus hindfoot location, for the concomitant peripheral artery disease versus without and in the high versus low neutrophil-to-lymphocyte ratio (all p < 0.01). The results showed that ulcer severity (p < 0.01), ulcer site (p < 0.01), peripheral artery disease (p < 0.01), neutrophil-to-lymphocyte ratio (p < 0.01) and Controlling Nutritional Status score (p < 0.05) were independent risk factors for amputation in diabetic foot ulcer patients and have predictive values for diabetic foot ulcer progression to amputation.

San Huang Xiao Yan recipe modulates the HMGB1-mediated abnormal inflammatory microenvironment and ameliorates diabetic foot by activating the AMPK/Nrf2 signalling pathway.

BACKGROUND: Diabetic foot (DF) is one of the serious complications of diabetes and lacks of therapeutic drugs. Abnormal and chronic inflammation promoting foot infection and wound healing delay are the main pathogenesis of DF. The traditional prescription San Huang Xiao Yan Recipe (SHXY) has been used in the clinical treatment of DF for several decades as approved hospital experience prescription and showed remarkable therapeutic effect, but the mechanisms by which SHXY treats DF are still unclear. PURPOSE: Objectives of this study were to investigate SHXY anti-inflammatory effect on DF and explore the molecular mechanism for SHXY. METHODS: We detected the effects of SHXY on DF in C57 mouse and SD rat DF models. Animal blood glucose, weight and wound area were detected every week. Serum inflammatory factors were detected by ELISA. H&E and Masson's trichrome were used to observe tissue pathology. Single-cell sequencing data reanalysis revealed the role of M1 macrophages in DF. Venn analysis showed the co-target genes between DF M1 macrophages and compound-disease network pharmacology. Western blotting was used to explored target protein expression. Meanwhile, RAW264.7 cells were treated with drug-containing serum of SHXY to further unravel the roles of target proteins during high glucose-induced inflammation in vitro. The Nrf2 inhibitor ML385 was used on RAW 264.7 cells to further explore the relationship between Nrf2, AMPK and HMGB1. The main components of SHXY were analysed by HPLC. Finally, the treatment effect of SHXY on DF were detected on rat DF model. RESULTS: In vivo, SHXY can ameliorate inflammatory, accelerate wound healing and upregulate expression of Nrf2, AMPK and downregulate of HMGB1. Bioinformatic analysis showed that M1 macrophages were the main inflammatory cell population in DF. Moreover, the Nrf2 downstream proteins HO-1 and HMGB1 were potential DF therapeutic targets for SHXY. In vitro, we also found that SHXY increased AMPK and Nrf2 protein levels and downregulated HMGB1 expression in RAW264.7 cells. Inhibiting the expression of Nrf2 impaired the inhibition effect of SHXY on HMGB1. SHXY promoted Nrf2 translocation into the nucleus and increased the phosphorylation of Nrf2. SHXY also inhibited HMGB1 extracelluar release under high glucose. In rat DF models, SHXY also exhibited significant anti-inflammatory effect. CONCLUSION: The SHXY activated AMPK/Nrf2 pathway to suppress abnormal inflammation on DF via inhibiting HMGB1 expression. These findings provide novel insight into the mechanisms by which SHXY treats DF.

Novel strategies to reverse chemoresistance in colorectal cancer.

Colorectal cancer (CRC) is a common gastrointestinal malignancy with high morbidity and fatality. Chemotherapy, as traditional therapy for CRC, has exerted well antitumor effect and greatly improved the survival of CRC patients. Nevertheless, chemoresistance is one of the major problems during chemotherapy for CRC and significantly limits the efficacy of the treatment and influences the prognosis of patients. To overcome chemoresistance in CRC, many strategies are being investigated. Here, we review the common and novel measures to combat the resistance, including drug repurposing (nonsteroidal anti-inflammatory drugs, metformin, dichloroacetate, enalapril, ivermectin, bazedoxifene, melatonin, and S-adenosylmethionine), gene therapy (ribozymes, RNAi, CRISPR/Cas9, epigenetic therapy, antisense oligonucleotides, and noncoding RNAs), protein inhibitor (EFGR inhibitor, S1PR2 inhibitor, and DNA methyltransferase inhibitor), natural herbal compounds (polyphenols, terpenoids, quinones, alkaloids, and sterols), new drug delivery system (nanocarriers, liposomes, exosomes, and hydrogels), and combination therapy. These common or novel strategies for the reversal of chemoresistance promise to improve the treatment of CRC.

Wounds under diabetic milieu: The role of immune cellar components and signaling pathways.

A major challenge in the field of diabetic wound healing is to confirm the body's intrinsic mechanism that could sense the immune system damage promptly and protect the wound from non-healing. Accumulating literature indicates that macrophage, a contributor to prolonged inflammation occurring at the wound site, might play such a role in hindering wound healing. Likewise, other immune cell dysfunctions, such as persistent neutrophils and T cell infection, may also lead to persistent oxidative stress and inflammatory reaction during diabetic wound healing. In this article, we discuss recent advances in the immune cellular components in wounds under the diabetic milieu, and the role of key signaling mechanisms that compromise the function of immune cells leading to persistent wound non-healing.

Effect of the Ruan Jian Qing Mai Recipe on Wound Healing in Diabetic Mice and Prediction of its Potential Targets.

BACKGROUND: The "Ruan Jian Qing Mai (RJQM) recipe" is a traditional Chinese medicine (TCM), which has been found to have significant curative effects on diabetic ulcers in the clinic for a long time. Previous research has shown that RJQM can improve diabetic skin wound healing and promote angiogenesis. However, the active ingredients of the RJQM recipe and its pharmacological mechanism of treatment for diabetic skin wound healing still remain unclear.This study aims to investigate the effect of the RJQM recipe on diabetic wound healing, and to identify the possible active ingredients and their mechanism. METHODS: First, a skin injury model was established in diabetic mice, and wound healing was evaluated by hematoxylin-eosin (HE) staining, quantitative reverse transcription-polymerase chain reaction (RT-qPCR), and western blot analysis. Second, the chemical constituents of the RJQM recipe were analyzed and identified by ultra pressure liquid chromatography-mass spectrometry (UPLC-MS). Finally, the possible targets of drug treatment for diabetic skin injury were analyzed by network pharmacology and verified by in vitro experiments using cell culture. RESULTS: (1) In the full-thickness skin injury model, the skin wound healing rate and healing area were significantly increased in mice treated with the RJQM recipe compared with those of the model group. The results of immunofluorescence staining showed that the RJQM recipe could increase the expression of VEGF protein and promote the proliferation of vascular smooth muscle cells and the formation of microvessels, and RT-qPCR results found that the mRNA expression of angiogenesis-related factors in the RJQM recipe group was significantly higher than that in the model group. (2) A total of 25 compounds were identified by UPLC-MS. (3) According to the results of network pharmacology, the therapeutic effect of the RJQM recipe on diabetic skin injury may be related to S6 (quercetin), S1 (typhaneoside), S18 (isoliquiritigenin), protein kinase B-α (Akt1), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), insulin-like growth factor I receptor (IGF1R), vascular endothelial growth factor-a (VEGF-a), signal transducer and activator of transcription-3 (STAT3) and phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) signaling pathways. Based on the predictions by network pharmacology, we proved that the drug could treat diabetic skin damage by activating the PI3K-Akt-VEGF signaling pathway. CONCLUSION: The RJQM recipe promotes the formation of granulation tissue during the process of wound healing and exerts a good therapeutic effect on diabetic skin wound healing.

Exploring the potential mechanism of Simiao Yongan decoction in the treatment of diabetic peripheral vascular disease based on network pharmacology and molecular docking technology.

The study aims to investigate the potential action targets and molecular mechanisms of Simiao Yongan decoction (SMYAD) in treating diabetic peripheral vascular disease (DPVD) by utilizing network pharmacology analysis and molecular docking technology. The components and targets of SMYAD were screened using the TCMSP database, while DPVD-related genes were obtained from the GeneCards, OMIM, and Disgenet databases. After intersecting the gene sets, a Protein-Protein Interaction (PPI) network was established, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were carried out. The practical chemical components and core targets identified were molecularly docked using AutoDock software. A total of 126 active compounds were screened from which 25 main components included quercetin, rutoside, hesperidin, naringin, and ß-sitosterol were determined to be the active components most associated with the core targets. A total of 224 common target genes were obtained. Among them, JUN, AKT1, MAPK3, TP53, STAT3, RELA, MAPK1, FOS, and others are the expected core targets of traditional Chinese medicine. The top-ranked GO enrichment analysis results included 727 biological processes (BP), 153 molecular functions (MF), and 102 cellular components (CC). KEGG pathway enrichment analysis involved mainly 178 signaling pathways, such as cancer signaling pathway, AGE-RAGE signaling pathway, interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, endocrine resistance signaling pathway, cell aging signaling pathway, and so on. The molecular docking results demonstrate that the principal chemical components of SMYAD exhibit considerable potential for binding to the core targets. SMYAD has the potential to treat DPVD through various components, targets, and pathways. Its mechanism of action requires further experimental investigation.

Systematic review the efficacy and safety of cilostazol, pentoxifylline, beraprost in the treatment of intermittent claudication: A network meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of cilostazol, pentoxifylline, beraprost for intermittent claudication due to lower extremity arterial occlusive disease. METHODS: Randomized controlled clinical trials were identified from PubMed, Scopus, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, SinoMed, Wanfang and Chongqing VIP databases, from the database inception to 31/12/2021. The outcome measures were walking distance measured by treadmill (maximum and pain-free walking distance), ankle-brachial index and adverse events. The quality of included studies was assessed by the Cochrane bias risk assessment tool. A network meta-analysis was carried out with Stata 16.0 software. RESULTS: There were 29 RCTs included in the study, covering total 5352 patients. Cilostazol was ranked first for both maximum and pain-free walking distance, followed by beraprost and pentoxifylline. For cilostazol, pentoxifylline and beraprost, maximum walking distance increased by 62.93 95%CI(44.06, 81.79), 32.72 95%CI(13.51, 55.79) and 43.90 95%CI(2.10, 85.71) meters, respectively relative to placebo, and pain-free walking distance increased by 23.92 95%CI(11.24, 36.61), 15.16 95%CI(2.33, 27.99) and 19.78 95%CI(-3.07, 42.62) meters. For cilostazol, pentoxifylline, beraprost and cilostazol combined with beraprost, ankle-brachial index increased by 0.06 95%CI(0.04, 0.07), -0.01 95%CI(-0.08, 0.05), 0.18 95%CI(0.12, 0.23) and 0.23 95%CI(0.18, 0.27), respectively relative to placebo. The pentoxifylline and cilostazol was associated with a lower ratio of adverse events than beraprost and cilostazol combined with beraprost. CONCLUSION: Cilostazol, pentoxifylline and beraprost were all effective treatments for intermittent claudication; cilostazol with good tolerance was likely to be the most effective in walking distance, while beraprost and cilostazol combined with beraprost were more prominent in the ankle-brachial index.

Recent insights into the role of defensins in diabetic wound healing.

Diabetic wound, one of the most common serious complications of diabetic patients, is an important factor in disability and death. Much of the research on the pathophysiology of diabetic wound healing has long focused on mechanisms mediated by hyperglycemia, chronic inflammation, microcirculatory and macrocirculatory dysfunction. However, recent evidence suggests that defensins may play a crucial role in the development and perpetuation of diabetic wound healing. The available findings suggest that defensins exert a beneficial influence on diabetic wound healing through antimicrobial, immunomodulatory, angiogenic, tissue regenerator effects, and insulin resistance improvement. Therefore, summarizing the existing research progress on defensins in the diabetic wound may present a promising strategy for diabetic patients.

Oxidative stress-triggered pyroptosis mediates Candida albicans susceptibility in diabetic foot.

An accumulating trend of research demonstrates that diabetic patients are susceptible to skin infections with Candida albicans, but the mechanism still remains unclear. The intense oxidative stress (OS) responses were occurred in the lesion of diabetic mice footpads after C. albicans infection. Localised skin infections would lead to more severe complications while the severity of the condition worsens or the inadequate treatment. Notably, in this study, through the investigation of murine diabetic footpad C. albicans infection model and molecular biotechnology, including histopathological staining, immunofluorescence (IF) staining, quantitative real-time PCR (qPCR), western blot (WB), flow cytometry (FCM), sandwich enzyme-linked immunosorbent assay (ELISA) assays, we found that intense OS responses in the footpad tissue not only mediated the activation of NF-κB protein complex, but also triggered downstream pyroptosis and apoptosis through NLRP3 inflammasome, which is one of the potential reasons for the severe condition of infectious skin injuries in diabetic mice. Caspase-1, a classical signal pathway protein in pyroptosis, could promote pore formation on cell membranes and the release of the cytokine after NLRP3 inflammasome activation. With intense immune-inflammatory responses, the organism also stimulates immune organs such as the spleen and lymph nodes to produce negative feedback regulation and generate CD4+CD25+Foxp3+ Treg cells to rectify the process. Therefore, combined with the results of this work, it is possible to design and screen relevant drugs for NLRP3 inflammasomes as core targets to keep the OS response at a low level in the footpad tissues.

Characterization of inflammatory profiles and endothelial dysfunction in diabetic limb arterial occlusion.

Our study aims to detect the changes of adiponectin (APN), endothelin 1 (ET)-1, nitric oxide (NO), cystatin C (cysC) in diabetic limb arterial occlusion (DLAO) patients and unravel their associations with endothelial function. Total 240 type 2 diabetes mellitus (T2DM) patients were divided into a DM group (n = 80, ankle brachial index (ABI) ≥ 0.9) and a DLAO group (n = 160, ABI < 0.9). ABI, flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD), serum APN, ET-1, NO, and cysC were compared. There were significant increases in cysC and ET-1, and significant decreases in APN, NO, FMD and NMD of DLAO patients compared to T2DM patients. Serum APN and NO were positively correlated with ABI, while serum cysC and ET-1 were negatively correlated with ABI. cysC, ET-1 and diastolic blood pressure (DBP) were independent predictors of the severity of DLAO. Serum APN was positively correlated with FMD, NMD and NO, but was negatively correlated with ET-1 and cysC. FMD and NMD were positively correlated with APN and NO, and negatively correlated with ET-1 and cysC. Our study deciphers opposite roles of APN, NO, cysC and ET-1 in the development of DLAO and maintaining endothelial function.