Bibliometric and visualization analyses of cancer-related fatigue research published worldwide from 2001 to 2023.

Objective: Cancer seriously endangers human health and represents a global public health issue. Cancer-related fatigue (CRF) is a distressing and persistent sense of exhaustion caused by cancer or cancer treatment, widely prevalent among cancer patients. This study aims to summarize emerging trends and provide directions for future research of CRF through bibliometric and visualization analyses. Methods: A systematic search in the Web of Science Core Collection database from 2001-01-01 to 2023-05-18 were conducted. Only reviews and articles written in English were considered. CiteSpace and the R were used for bibliometric and visualization analyses. Results: The analysis revealed that 2,566 studies on CRF have been published by 1,041 institutions in 70 countries so far. The number of articles published and cited annually have been steadily increasing. Eduardo Bruera published the most articles, and Julienne E Bower is the most co-cited author. The University of Texas System is the leading institution in cancer-related fatigue research. The United States and China have the largest number of publications. Supportive Care in Cancer published the most articles, and Journal of Clinical Oncology is the most co-cited journal. "Comparison of Pharmaceutical, Psychological, and Exercise Treatments for Cancer-Related Fatigue: A Meta-analysis", authored by Mustian KM et al. and published in JAMA Oncology was the most co-cited document. Keyword analysis indicated that research focus had shifted from "epoetin alpha" and "anemia" to "risk factors", "systematic review", "acupuncture", "anxiety", "traditional Chinese medicine" and "guidelines". Conclusion: In conclusion, this analysis provides comprehensive research trends and knowledge network maps of CRF. Clinical physicians should concurrently focus on the anemia, insomnia, anxiety, and depression status of patients when assessing or managing CRF. Improvements in related risk factors also contribute to alleviating fatigue. Furthermore, it is essential to pay attention to authoritative CRF guidelines. Acupuncture and traditional Chinese medicine also have therapeutic potential, which merits further investigation. Researchers should draw attention to the crucial roles of inflammation, hypoxia, and mitochondrial dysfunction, which could be the frontiers.

A novel conductive microtubule hydrogel for electrical stimulation of chronic wounds based on biological electrical wires.

Electrical stimulation (ES) is considered a promising therapy for chronic wounds via conductive dressing. However, the lack of a clinically suitable conductive dressing is a serious challenge. In this study, a suitable conductive biomaterial with favorable biocompatibility and conductivity was screened by means of an inherent structure derived from the body based on electrical conduction in vivo. Ions condensed around the surface of the microtubules (MTs) derived from the cell's cytoskeleton are allowed to flow in the presence of potential differences, effectively forming a network of biological electrical wires, which is essential to the bioelectrical communication of cells. We hypothesized that MT dressing could improve chronic wound healing via the conductivity of MTs applied by ES. We first developed an MT-MAA hydrogel by a double cross-linking method using UV and calcium chloride to improve chronic wound healing by ES. In vitro studies showed good conductivity, mechanical properties, biocompatibility, and biodegradability of the MT-MAA hydrogel, as well as an elevated secretion of growth factors with enhanced cell proliferation and migration ability in response to ES. The in vivo experimental results from a full-thickness diabetic wound model revealed rapid wound closure within 7d in C57BL/6J mice, and the wound bed dressed by the MT-MAA hydrogel was shown to have promoted re-epithelization, enhanced angiogenesis, accelerated nerve growth, limited inflammation phases, and improved antibacterial effect under the ES treatment. These preclinical findings suggest that the MT-MAA hydrogel may be an ideal conductive dressing for chronic wound healing. Furthermore, biomaterials based on MTs may be also promising for treating other diseases.

PROS1 is a crucial gene in the macrophage efferocytosis of diabetic foot ulcers: a concerted analytical approach through the prisms of computer analysis.

BACKGROUND: Diabetic foot ulcers (DFUs) pose a serious long-term threat because of elevated mortality and disability risks. Research on its biomarkers is still, however, very limited. In this paper, we have effectively identified biomarkers linked with macrophage excretion in diabetic foot ulcers through the application of bioinformatics and machine learning methodologies. These findings were subsequently validated using external datasets and animal experiments. Such discoveries are anticipated to offer novel insights and approaches for the early diagnosis and treatment of DFU. METHODS: In this work, we used the Gene Expression Omnibus (GEO) database's datasets GSE68183 and GSE80178 as the training dataset to build a gene model using machine learning methods. After that, we used the training and validation sets to validate the model (GSE134431). On the model genes, we performed enrichment analysis using both gene set variant analysis (GSVA) and gene set enrichment analysis (GSEA). Additionally, the model genes were subjected to immunological association and immune function analyses. RESULTS: In this study, PROS1 was identified as a potential key target associated with macrophage efflux in DFU by machine learning and bioinformatics approaches. Subsequently, the key biomarker status of PROS1 in DFU was also confirmed by external datasets. In addition, PROS1 also plays a key role in macrophage exudation in DFU. This gene may be associated with macrophage M1, CD4 memory T cells, naïve B cells, and macrophage M2, and affects IL-17, Rap1, hedgehog, and JAK-STAT signaling pathways. CONCLUSIONS: PROS1 was identified and validated as a biomarker for DFU. This finding has the potential to provide a target for macrophage clearance of DFU.

Effect of total astragalosides on diabetic non-healing wound by regulating immune microenvironment.

Aim: The aim of the research was to analyse the regulatory effect of astragaloside (AST) on the immune microenvironment of diabetic non-healing wound (DNHW), and to analyse the clinical efficacy and mechanism of wound repair in multiple layers. Material and methods: Ninety adult male Wistar rats, which were kept healthy (SPF) under natural infection, were randomly divided into three groups, namely, blank, control and observation groups, with 30 rats in each group. After adaptive feeding for 7 days, the diabetes model was established. After the model was formed, the wounds were uniformly prepared, and then the blank group only was shaved. Both the control group and the observation group were treated with moist exposure therapy. The control group was covered with physiological saline gauze, while the observation group was covered with AST gauze. The healing status of the wounds in both groups was observed and recorded on the 1st, 7th, and 14th days after formation. And the levels of α-smooth muscle actin (α-SMA) and collagen I (COL-1) in the wound tissue were measured. Results: On the 1st day after wound formation, the wound healing area, α-SMA, and COL-1 levels in the three groups were consistent (p > 0.05). On the 7th and 14th days after wound formation, the wound healing area in the three groups increased compared within the group, but only the control and observation groups had significantly higher wound healing area than on the 1st day after wound formation (p < 0.05). In addition, the blank group had lower levels of α-SMA and COL-1, while the control and observation groups had higher levels of α-SMA and COL-1 (p < 0.05). In the comparison between groups, the wound healing area, α-SMA, and COL-1 levels in the control and observation groups were higher than those in the blank group, while the wound healing area, α-SMA, and COL-1 levels in the observation group were higher than those in the control group (p < 0.05). Conclusions: AST can regulate the immune microenvironment of DNHW, improve α-SMA and COL-1, and accelerate the wound healing of DNHW.

Extracellular vesicles secreted by bone marrow stem cells mediate angiogenesis for the treatment of diabetic ulcers: A systematic review and meta-analysis of preclinical studies.

Background: Diabetic ulcers (DUs) typically occur in patients with vascular diseases and diabetes. Extracellular vesicles secreted by bone marrow-derived stem cells (BMSC-EVs) represent a cell-free therapy that has emerged as a promising alternative for treating DU, especially due to significant advancements in the understanding of their role in promoting angiogenesis; however, their application in DU treatment remains in the preclinical stage, and their effectiveness is still uncertain. Therefore, we conducted this meta-analysis to evaluate the therapeutic efficacy of BMSC-EVs in treating DU and to expedite the clinical translation of BMSC-EV therapy for DU. Methods: We conducted a comprehensive search of PubMed, Cochrane Library, MEDLINE, EMBASE, China National Knowledge Infrastructure (CNKI), Wanfang Database, VIP Database, and our self-constructed database of Chinese Biomedical Literature up to May 2023 to identify preclinical studies related to the therapeutic use of extracellular vesicles secreted by bone marrow-derived stem cells for treating diabetic ulcers. Outcome measures included wound healing rate, neovascularization density, a-sma, and CD31. RevMan 5 software was employed for all statistical analyses. Results: In this meta-analysis, a total of 11 studies involving 103 animals were identified. The pooled analysis indicated that BMSC-EV treatment showed a superior wound healing rate compared to that of the control group (SMD = 1.06, 95% CI [0.52, 1.60], P = 0.0001). In the subgroup analysis, EV combined with new materials or drug therapy performed better than the sole injection of extracellular vesicles (SMD = 1.85, 95% CI [0.87, 2.82], P < 0.00001). BMSC-EV treatment also resulted in a higher number of neovascular structures compared to the control group(SMD = 5.80, 95% CI[0.89,10.71], P = 0.006). In the subgroup analysis, EV combined therapy showed a significant difference in the number of blood vessels compared to the sole injection of extracellular vesicles (SMD = 4.90, 95% CI[2.64,7.15], P < 0.00001). However, BMSCs-EV treatment did not demonstrate any statistically significant difference in the angiogenesis-related indicators CD31 and α-SMA compared to the control group (SMD = 1.61, 95% CI[-0.51,3.74], P = 0.14). Conclusion: According to the current meta-analysis, BMSC-EV therapy can enhance the healing of diabetic ulcers and promote wound angiogenesis, particularly when used in combination with novel dressings or other drugs, which further accelerates the healing process of diabetic ulcers. To establish the most effective parameters for EV treatment in diabetic ulcers, future research should promptly progress into clinical trials.

Genetic support of the causal association between gut microbiota and peripheral artery disease: a bidirectional Mendelian randomization study.

BACKGROUND: The causal relationship between gut microbiota and peripheral artery disease (PAD) is still not clear. In this research, we employed the Mendelian randomization (MR) technique to explore the potential causal connection between 211 gut microbiota species and PAD. We also investigated whether the causal effects operate in both directions. METHODS: We used Genome-wide Association Studies (GWAS) summary statistics data from the MiBioGen and FinnGen consortia to conduct a two-sample MR analysis to explore the causal link between gut microbiota and PAD. Sensitivity analysis is conducted to assess the robustness of the MR results. In addition to that, reverse MR analysis was performed to examine the inverse causal relationship. RESULTS: The inverse variance weighted (IVW) method provided evidence supporting a causal relationship between 9 specific gut microbiota taxa and PAD. The study findings indicated that family Family XI (OR=1.11, CI 1.00-1.24, P=0.048), genus Lachnoclostridium (OR=1.24, 1.02-1.50, P=0.033), and genus Lachnospiraceae UCG001 (OR=1.17, 1.01-1.35, P=0.031) are risk factors associated with PAD. class Actinobacteria (OR=0.84, 0.72-0.99, P=0.034), family Acidaminococcaceae (OR=0.80, 0.66-0.98, P=0.029), genus Coprococcus2 (OR=0.79, 0.64-0.98, P=0.029), genus Ruminococcaceae UCG004 (OR=0.84, 0.72-0.99, P=0.032), genus Ruminococcaceae UCG010 (OR=0.74, 0.58-0.96, P=0.022), and order NB1n (OR=0.88, 0.79-0.98, P=0.02) may be associated with the risk factors of PAD. Moreover, our analysis did not uncover any evidence of a reverse causal relationship between PAD and the nine specific gut microbiota taxa investigated. CONCLUSIONS: Our MR research has confirmed the potential causal relationship between gut microbiota and PAD while also identifying specific gut bacterial communities associated with PAD.

A novel diabetic foot ulcer diagnostic model: identification and analysis of genes related to glutamine metabolism and immune infiltration.

BACKGROUND: Diabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes, with vascular changes, neuropathy, and infections being the primary pathological mechanisms. Glutamine (Gln) metabolism has been found to play a crucial role in diabetes complications. This study aims to identify and validate potential Gln metabolism biomarkers associated with DFU through bioinformatics and machine learning analysis. METHODS: We downloaded two microarray datasets related to DFU patients from the Gene Expression Omnibus (GEO) database, namely GSE134431, GSE68183, and GSE80178. From the GSE134431 dataset, we obtained differentially expressed Gln-metabolism related genes (deGlnMRGs) between DFU and normal controls. We analyzed the correlation between deGlnMRGs and immune cell infiltration status. We also explored the relationship between GlnMRGs molecular clusters and immune cell infiltration status. Notably, WGCNA to identify differentially expressed genes (DEGs) within specific clusters. Additionally, we conducted GSVA to annotate enriched genes. Subsequently, we constructed and screened the best machine learning model. Finally, we validated the predictions' accuracy using a nomogram, calibration curves, decision curve analysis (DCA), and the GSE134431, GSE68183, and GSE80178 dataset. RESULTS: In both the DFU and normal control groups, we confirmed the presence of deGlnMRGs and an activated immune response. From the GSE134431 dataset, we obtained 20 deGlnMRGs, including CTPS1, NAGS, SLC7A11, GGT1, GCLM, RIMKLA, ARG2, ASL, ASNS, ASNSD1, PPAT, GLS2, GLUD1, MECP2, ASS1, PRODH, CTPS2, ALDH5A1, DGLUCY, and SLC25A12. Furthermore, two clusters were identified in DFU. Immune infiltration analysis indicated the presence of immune heterogeneity in these two clusters. Additionally, we established a Support Vector Machine (SVM) model based on 5 genes (R3HCC1, ZNF562, MFN1, DRAM1, and PTGDS), which exhibited excellent performance on the external validation datasetGSE134431, GSE68183, and GSE80178 (AUC = 0.929). CONCLUSION: This study has identified five Gln metabolism genes associated with DFU, revealing potential novel biomarkers and therapeutic targets for DFU. Additionally, the infiltration of immune-inflammatory cells plays a crucial role in the progression of DFU.

Research progress and challenges in stem cell therapy for diabetic foot: Bibliometric analysis and perspectives.

BACKGROUND: Stem cell therapy has shown great potential for treating diabetic foot (DF). AIM: To conduct a bibliometric analysis of studies on the use of stem cell therapy for DF over the past two decades, with the aim of depicting the current global research landscape, identifying the most influential research hotspots, and providing insights for future research directions. METHODS: We searched the Web of Science Core Collection database for all relevant studies on the use of stem cell therapy in DF. Bibliometric analysis was carried out using CiteSpace, VOSviewer, and R (4.3.1) to identify the most notable studies. RESULTS: A search was conducted to identify publications related to the use of stem cells for DF treatment. A total of 542 articles published from 2000 to 2023 were identified. The United States had published the most papers on this subject. In this field, Iran's Shahid Beheshti University Medical Sciences demonstrated the highest productivity. Furthermore, Dr. Bayat from the same university has been an outstanding researcher in this field. Stem Cell Research & Therapy is the journal with the highest number of publications in this field. The main keywords were "diabetic foot ulcers," "wound healing," and "angiogenesis." CONCLUSION: This study systematically illustrated the advances in the use of stem cell therapy to treat DF over the past 23 years. Current research findings suggested that the hotspots in this field include stem cell dressings, exosomes, wound healing, and adipose-derived stem cells. Future research should also focus on the clinical translation of stem cell therapies for DF.

Stem Cell Therapy for Diabetic Foot: An Umbrella Review of Systematic Reviews and Meta-Analyses.

Objective: This umbrella review aims to summarize and evaluate the evidence from current systematic reviews/meta-analyses (SRs/MAs) on the effectiveness of stem cell therapy for diabetic foot (DF). Approach: We conducted a comprehensive search in four databases for SRs/MAs that included randomized controlled trials (RCTs) on stem cell therapy for DF. Two separate researchers independently evaluated the methodological quality and evidence quality of the SRs/MAs that were included in the study. We conducted a quantitative synthesis of all RCTs included in the SRs/MAs to obtain objective and updated conclusions. Egger's test and sensitivity analysis are used to examine the reliability of the results. Results: This umbrella review includes eight SRs/MAs, and their methodological quality and evidence quality were all deemed unsatisfactory. Out of the 8 SRs/MAs, 26 RCTs were included, with a total corrected covered area of 21.4%, indicating a high degree of overlap. The test of super-significance did not yield any significant results. Our updated meta-analysis suggests that DF patients can benefit from stem cell therapy, as indicated by effectiveness in measures, including healing rate, amputation rate, ankle-brachial index, transcutaneous oxygen pressure, ulcer size reduction, complete healing time, pain-free walking distance, rest pain score, and new angiogenesis rate. Innovation: This study conducted a comprehensive evaluation and reanalysis of the current evidence regarding the effectiveness and safety of stem cell therapy for DF, which is the first of its kind. Conclusion: Based on the existing evidence, stem cell therapy is effective and safe for patients with DF.

Identifying and Validating GSTM5 as an Immunogenic Gene in Diabetic Foot Ulcer Using Bioinformatics and Machine Learning.

Background: A diabetic foot ulcer (DFU) is a serious, long-term condition associated with a significant risk of disability and mortality. However, research on its biomarkers is still limited. This study utilizes bioinformatics and machine learning methods to identify immune-related biomarkers for DFU and validates them through external datasets and animal experiments. Methods: This study used bioinformatics and machine learning to analyze microarray data from the Gene Expression Omnibus (GEO) database to identify key genes associated with DFU. Animal experiments were conducted to validate these findings. This research employs the datasets GSE68183 and GSE80178 retrieved from the GEO database as the training dataset for building a gene machine learning model, and after conducting differential analysis on the data, this study used package glmnet and package e1071 to construct LASSO and SVM-RFE machine learning models, respectively. Subsequently, we validated the model using the training set and validation set (GSE134431). We conducted enrichment analysis, including GSEA and GSVA, on the model genes. We also performed immune functional analysis and immune-related analysis on the model genes. Finally, we conducted immunohistochemistry (IHC) validation on the model genes. Results: This study identifies GSTM5 as a potential immune-related key target in DFU using machine learning and bioinformatics methods. Subsequent validation through external datasets and IHC experiments also confirms GSTM5 as a critical biomarker for DFU. The gene may be associated with T cells regulatory (Tregs) and T cells follicular helper, and it influences the NF-κB, GnRH, and MAPK signaling pathway. Conclusion: This study identified and validated GSTM5 as a biomarker for DFU. This finding may potentially provide a target for immune therapy for DFU.

An umbrella review of the evidence to guide decision-making in acupuncture therapies for chemotherapy-induced peripheral neuropathy.

BACKGROUND: Acupuncture therapy is believed to have therapeutic potential for patients suffering from chemotherapy-induced peripheral neuropathy (CIPN). This umbrella review aims to summarize and evaluate the evidence from current systematic reviews/meta-analyses (SRs/MAs) on the effectiveness of acupuncture treatment for CIPN. METHODS: We conducted a comprehensive search in eight electronic databases for SRs/MAs that included RCTs on acupuncture treatment for CIPN. Two separate researchers independently evaluated the methodological quality, reporting quality, and evidence quality of the SRs/MAs that were included in the study. Additionally, we examined the extent of overlap among the included RCTs by calculating the corrected covered area (CCA). Furthermore, we assessed the dependability of the effect sizes by conducting excess significance tests. We conducted a quantitative synthesis of all RCTs included in the SRs/MAs to obtain objective and updated conclusions. Furthermore, we also conducted an analysis of the acupuncture points used in RCTs. RESULTS: This umbrella review includes 9 SRs/MAs, and their methodological quality, risk of bias, reporting quality, and evidence quality were all deemed unsatisfactory. Out of the 9 SRs/MAs, 28 RCTs were included, with a total CCA of 25.4%, indicating a high degree of overlap. The test of super-significance did not yield any significant results. Our updated meta-analysis suggests that CIPN patients can benefit from acupuncture therapy, as indicated by effectiveness in measures including BPI-SF, VAS, FACT-NTX, NRS, SCV, and NCI-CTCAE. Egger's test and sensitivity analysis demonstrate the reliability and stability of this conclusion. The commonly used acupuncture points in the current RCTs include ST36, LI11, LI4, LR3, and SP6. CONCLUSION: Based on the existing evidence, acupuncture is effective and safe for patients with CIPN, as it can significantly improve effective rate, pain symptoms, quality of life, and nerve conduction velocity. However, given the low quality of current evidence, we should be cautious in interpreting this conclusion.

Preclinical study of diabetic foot ulcers: From pathogenesis to vivo/vitro models and clinical therapeutic transformation.

Diabetic foot ulcer (DFU), a common intractable chronic complication of diabetes mellitus (DM), has a prevalence of up to 25%, with more than 17% of the affected patients at risk of amputation or even death. Vascular risk factors, including vascular stenosis or occlusion, dyslipidemia, impaired neurosensory and motor function, and skin infection caused by trauma, all increase the risk of DFU in patients with diabetes. Therefore, diabetic foot is not a single pathogenesis. Preclinical studies have contributed greatly to the pathogenesis determination and efficacy evaluation of DFU. Many therapeutic tools are currently being investigated using DFU animal models for effective clinical translation. However, preclinical animal models that completely mimic the pathogenesis of DFU remain unexplored. Therefore, in this review, the preparation methods and evaluation criteria of DFU animal models with three major pathological mechanisms: neuropathy, angiopathy and DFU infection were discussed in detail. And the advantages and disadvantages of various DFU animal models for clinical sign simulation. Furthermore, the current status of vitro models of DFU and some preclinical studies have been transformed into clinical treatment programs, such as medical dressings, growth factor therapy, 3D bioprinting and pre-vascularization, Traditional Chinese Medicine treatment. However, because of the complexity of the pathological mechanism of DFU, the clinical transformation of DFU model still faces many challenges. We need to further optimize the existing preclinical studies of DFU to provide an effective animal platform for the future study of pathophysiology and clinical treatment of DFU.

Uncovering the pharmacological mechanisms of Zizhu ointment against diabetic ulcer by integrating network analysis and experimental evaluation in vivo and in vitro.

Diabetic ulcer (DU) has been recognized as one of the most prevalent and serious complications of diabetes. However, the clinical efficacy of standard treatments for DU remains poor. Traditional Chinese medicine (TCM) shows a positive therapeutic effect on DU. Specifically, Zizhu ointment (ZZO) has been widely used to treat DU in long-term clinical practice, but the exact mechanism by which it promotes DU wound healing remains unknown. In this study, network analysis and high-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) were conducted to identify the active compounds of ZZO. We detected isovalerylshikonin (ISO), mandenol, daidzein, kaempferol, and formononetin in both network analysis and UPLC-HRMS. Moreover, ZZO could ameliorate DU by regulating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and inflammation signaling pathways, according to the results of KEGG analysis. We established a DU mouse model with a high-fat diet and streptozotocin injection in vivo to evaluate the network analysis result. The experimental results showed that ZZO could inhibit inflammation, remodel fibrous tissue, and promote angiogenesis in the DU area, facilitating wound healing in DU mice. Moreover, the PI3K/AKT signaling pathway was indeed activated by ZZO treatment, promoting macrophage M2 polarization. In addition, we used molecular docking technology to evaluate the binding sites between ZZO and the PI3K/AKT pathway. The results showed that ISO has a good binding interaction with AKT. Moreover, ISO promoted M2 polarization in macrophages in a dose-dependent manner in vitro. Our study found that ZZO could promote DU wound healing by inhibiting inflammation, which was achieved by macrophage M2 polarization through activating the PI3K/AKT pathway. Further studies have demonstrated that ISO plays major role in the above process. These findings provide a theoretical basis for further preclinical evaluation and lay a foundation for nano-gel compound treatment with ZZO.

Zizhu Ointment Accelerates Wound-Healing of Diabetic Ulcers through Promoting M2 Macrophage Polarization via Downregulating the Notch4 Signaling Pathway.

Objective: The long-term clinical practice shows that Zizhu ointment (ZZO) is an empirical formula for the treatment of diabetic ulcers (DUs). In this study, we investigated the underlying mechanism of ZZO in the treatment of DU mice. Methods: Through streptozotocin induction and high-fat diet, a DU mouse model was established and ZZO was given for treatment. The activation of Notch4 signaling was examined by immunofluorescence staining, RT-PCR, as well as Western blotting. Flow cytometry was performed to detect the counts of F4/80+ cells, M1 and M2 macrophages, as well as the expression of CD11c, CD206, etc. The role of Notch4 in wound healing in diabetic mice was verified by Notch4 inhibitors and agonists. Results: Accelerated wound healing and decreased expression levels of Notch4 and its target genes and ligands were observed in diabetic mice treated with ZZO. ZZO promoted M2 macrophage polarization, downregulated the expression of proinflammatory factors, and upregulated the levels of anti-inflammatory factors. The same tendency was observed in diabetic mice after treatment with Notch4 inhibitors. Knockout of Notch4 accelerated the wound healing rate as well. Conclusions: ZZO accelerates wound healing of diabetic mice through inhibiting the activation of Notch4 signaling, promoting M2 macrophage polarization, and alleviating inflammation.

ß-acetoxyisovaleryl alkannin (AAN-II) from Alkanna tinctoria promotes the healing of pressure-induced venous ulcers in a rabbit model through the activation of TGF-ß/Smad3 signaling.

Alkannin-based pharmaceutical formulations for improving wound healing have been on the market for several years. However, detailed molecular mechanisms of their action have yet to be elucidated. Here, we investigated the potential roles of AAN-II in improving the healing of pressure-induced venous ulcers using a rabbit model generated by combining deep vein thrombosis with a local skin defect/local skin defect. The extent of healing was evaluated using hematoxylin and eosin (HE) or vimentin staining. Rabbit skin fibroblasts were cultured for AAN-II treatment or TGFB1-sgRNA lentivirus transfection. ELISA was used to evaluate the levels of various cytokines, including IL-1ß, IL-4, IL-6, TNF-α, VEGF, bFGF, TGF-ß and PDGF. The protein levels of TGF-ß sensors, including TGF-ß, Smad7 and phosphor-Smad3, and total Smad3, were assayed via western blotting after TGF-ß knockout or AAN-II treatment. The results show that, for this model, AAN-II facilitates ulcer healing by suppressing the development of inflammation and promoting fibroblast proliferation and secretion of proangiogenic factors. AAN-II enhances the activation of the TGF-ß1-Smad3 signaling pathway during skin ulcer healing. In addition, the results demonstrate that AAN-II and TGF-ß have synergistic effects on ulcer healing. Our findings indicate that AAN-II can promote healing of pressure-induced venous skin ulcers via activation of TGF-ß-Smad3 signaling in fibroblast cells and provide evidence that could be used in the development of more effective treatments.

Xueshuantong Injection in Treating Deep Venous Thrombosis: A Systematic Review and Trial Sequential Analysis.

AIMS: In recent years, the incidence of deep venous thrombosis (DVT) presents an increasing trend year by year. The current evidence regarding the efficacy and safety of Xueshuantong injection for DVT is controversial. This systematic review (SR) aimed to assess the efficacy and safety of Xueshuantong injection in the treatment of DVT systematically and provide an evidence-based reference for clinical treatment. METHODS: Nine electronic databases were used to identify the literature consisting of randomized controlled trials (RCTs) with a date of search of 1 November 2020. Clinical effective rate and incidence rate of adverse events were investigated as primary outcomes. Patency rate of femoral vein, patency rate of popliteal vein, patency rate of posterior tibial vein, circumference difference, activated partial thromboplastin time (APTT), and D-dimer (D-D) were investigated as secondary outcomes. Revman 5.4.1 was used to analyze the results. Analysis of the power of evidence was performed with Trial Sequential Analysis (TSA). RESULTS: A total of 12 articles including 1018 patients were included. The results of the meta-analysis showed that the clinical effective rate in the experimental group was higher than that in the control group, the incidence rate of adverse events in the experimental group was higher than that in the control group; after the operation, the patency rate of femoral vein, patency rate of popliteal vein, patency rate of posterior tibial vein, circumference difference, APTT, and D-D in the experimental group were significantly improved compared with those in the control group, and the difference between the groups was statistically significant. TSA suggested that the meta-analysis concerning the clinical effectiveness of Xueshuantong injection in the treatment of DVT was of adequate power to reach firm conclusions. CONCLUSION: Based on the current analysis, Xueshuantong injection as an add-on treatment provided better treatment effect for DVT with adequate power but this benefit should be considered with caution because of the small number of studies included in the meta-analysis and the high or unclear risk of bias of the included trials, suggesting that further studies are needed.

Safety and efficacy of larval therapy on treating leg ulcers: a protocol for systematic review and meta-analysis.

INTRODUCTION: Leg ulcers (LUs) not only seriously affect life and work of patients, but also bring huge economic burden to the society. As a potential underused biological debridement, larval therapy provides help for the treatment of LUs. The purpose of our research is to assess whether patients with LUs can benefit from larval therapy. METHODS AND ANALYSIS: The following electronic databases will be searched: PubMed, EMBASE, Web of Science, the Cochrane Library, China National Knowledge Infrastructure Database, Wanfang Database and Chinese Biological Medicine. Randomised controlled trials are eligible for inclusion. There will be no restrictions with respect to language and search date is up to June 2020. Primary outcomes investigated are complete healing rate after treatment, time to ulcer healing, reduction of wound surface area and adverse events. Risk ratios will be used for categorical data; weighted mean difference will be used for measurement data. Subgroup analysis and sensitivity analysis will be considered if heterogeneity exists. The results of data synthesis will be performed by narrative summary and quantitative analysis. ETHICS AND DISSEMINATION: This systematic review does not require the approval of the ethics committee because individual data on patients are not collected. The results of the study will be disseminated in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42020176953.