Overview, prevention and management of chemotherapy extravasation

Chemotherapy extravasation remains an accidental complication of chemotherapy administration and may result in serious damage to patients. We review in this article the clinical aspects of chemotherapy extravasation and latest advances in definitions, classification, pre-vention, management and guidelines. We review the grading of extravasation and tissue damage according to various chemotherapeutic drugs and present an update on treatment and new antidotes including dexrazoxane for anthracyclines extravasation. We highlight the importance of education and training of the oncology team for prevention and prompt pharmacological and non-pharmacological management and stress the availability of new antidotes like dexrazoxane wherever anthracyclines are being infused.

Suspension state promotes extravasation of breast tumor cells by increasing integrin β1 expression

Mechanical microenvironment can strongly affect the metastatic efficiency of circulating tumor cells.However,the effect of suspension state on their extravasation and the mechanisms involved are still unclear.To explore the influence of suspension state on extravasation(including adhesion,spreading and transendothelial migration)of breast tumor cells and its relevant molecular mechanism,MDA-MB-231 cells were cultured on poly(2-hydroxyethyl methacrylate)coated 6-well plates to minic the suspension state.Suspension state promoted adhesion,spreading and transendothelial migration of MDA-MB-231 cells to EAhy926 endothelial cells(ECs)monolayer under both the static condition and 0.5 dyne/cm^(2) flow shear stress(FSS).The number of cells adhered to ECs monolayer reached 2.15(static condition,3 d)and 1.67(FSS,3 d)times,and the number of migration reached 10.60 times,respectively,as compared to that in adhesion state.Moreover,MDA-MB-231 cells knockdown of integrin β1 provoked poor adhesion and transendothelial migration,as compared with MDA-MB-231 cells.But it made no difference in cell spreading.Our results implied the increasing expression of integrin β1 induced by suspension culture promoted the adhesion and transendothelial migration of MDA-MB-231 cells,but had no significant influence on their spreading.

Extravasation of chemotherapeutic drug from an implantable intravenous infusion port in a child:A case report

BACKGROUND Drug extravasation is a complication of totally implantable access port(TIAP)use and could cause tissue injury and sustained organ dysfunction.Therefore,the clinical management of children with TIAP is challenging.CASE SUMMARY This was a case of extravasation of a chemotherapeutic drug(paclitaxel)from an implantable infusion port in a 23-mo old child.After fully evaluating the skin at the site of extravasation,the nurse continued to use the infusion port to complete the follow-up chemotherapeutic course.The skin around the infusion port was red,and showed no ulceration,swelling,or induration at discharge.CONCLUSION Since children are more active and often noncompliant,it is necessary to appropriately train pediatric nurses caring for individuals with TIAPs,and any abnormal situation should be timely addressed.

Management of Extravasation Injuries in Preterm Infants

Extravasation injuries occur in up to 70% of neonates in intensive care, majority being preterm infants. Their fragile and premature anatomy makes prevention and management of extravasation extra difficult compared to those of full-term. With increasing advances of intensive care for preterm infants, the use of intravenous medication and nutrition will increase, thus lead to further potential risk of extravasation injuries, which has serious complications, such as full-thickness skin loss, tissue necrosis and acute limb compartment syndrome, with long-term functional and cosmetic sequelae. There is a current lack of evidence in the literature on the most appropriate therapeutic strategy for this vulnerable patient group. This review aims to highlight our trust regime on the management of extravasation injuries (non-chemotherapeutic) for preterm infants, including injury classification and assessment, and implementation of initial interventions.

Efficacy of combination of localized closure,ethacridine lactate dressing,and phototherapy in treatment of severe extravasation injuries:A case series

BACKGROUND The management of severe extravasation injuries is still controversial.Extravasation injuries can be treated in many ways.AIM To present a series of patients with severe extravasation injuries due to infusion who were managed with ethacridine lactate dressing combined with localized closure and phototherapy.METHODS In this study,we evaluated the data of eight patients,including six from the Department of Burn,one(with colorectal carcinoma)from the Veteran Cadre Department,and one(with leukemia)from the Hematology Department.Of these,three patients were male and five were female.Age of the patients ranged from 10 mo to 72 years,including two children(10 and 19 mo of age).In this study,the infusion was stopped immediately when the extravasation was identified.The extravasation event was managed routinely using a blocking solution.A ring-shaped localized closure was performed using the blocking agents.Moreover,ethacridine lactate dressing and phototherapy were applied for 3-5 d.RESULTS In this study,the drugs contained in the infusates were iodixanol,norepinephrine,alprostadil,amino acids,fat emulsion,cefoselis,cefoxitin,and potassium chloride+concentrated sodium chloride.All of the patients achieved complete healing after treatment and no obvious adverse reactions were observed.CONCLUSION The treatment of severe extravasation injuries using a combination of localized closure,ethacridine lactate dressing,and phototherapy resulted in satisfactory outcomes in patients.

A Rare Case of Severe Muscular Necrosis Due to Extravascular Leakage of Trabectedin—Severe Tissue Damage of Trabectedin Extravasation

Trabectedin is a synthetic antineoplastic drug, binding to the minor groove of DNA and affecting DNA repair pathways, resulting in G2-M cell cycle arrest and apoptosis. Trabectedin has demonstrated high efficacy against various soft tissue sarcomas. However, its extravasation causes serious complications, such as tissue necrosis and a delay in the treatment of underlying diseases. Methods: We experienced a rare case in which trabectedin extravasation caused severe pectoralis major muscle necrosis. A 45-year-old man with multiple lung metastases of follicular dendritic cell sarcoma received 2.15 mg of trabectedin totally through a central venous access device (CVAD) system in the right precordium. Computed tomography showed extensive turbidity of subcutaneous fatty tissue and swelling of the pectoralis major muscle to the upper margin of the liver, and the creatine kinase level was elevated to 759 U/L (reference value from 54 to 286). We performed surgical debridement twice, and the CVAD was concomitantly removed;thereafter, the skin defect was reconstructed with a split skin mesh graft. Results: Histopathology showed extreme degeneration of striated muscle and fatty tissue. Unfortunately, disability of the right arm abducens persisted after treatment because of debridement around the right humerus muscle. Discussion: Several reports have described cases of the extravasation of trabectedin. A few have mentioned severe muscular degeneration similar to that shown in the present case. Because trabectedin is a strong vesicant cytotoxic agent, it is principally administered through a CVAD rather than peripheral vessels and is continued during the nighttime;this can lead to a delay in patients or attending doctors noticing any extravasation. We need to spread appropriate knowledge of this drug and make an effort to prevent severe complications like in the present case.

Hydrophobic surface induced pro-metastatic cancer cells for in vitro extravasation models

In vitro vascularized cancer models utilizing microfluidics have emerged as a promising tool for mechanism study and drug screening.However,the lack of consideration and preparation methods for cancer cellular sources that are capable of adequately replicating the metastatic features of circulating tumor cells contributed to low relevancy with in vivo experimental results.Here,we show that the properties of cancer cellular sources have a considerable impact on the validity of the in vitro metastasis model.Notably,with a hydrophobic surface,we can create highly metastatic spheroids equipped with aggressive invasion,endothelium adhesion capabilities,and activated metabolic features.Combining these metastatic spheroids with the well-constructed microfluidic-based extravasation model,we validate that these metastatic spheroids exhibited a distinct extravasation response to epidermal growth factor(EGF)and normal human lung fibroblasts compared to the 2D cultured cancer cells,which is consistent with the previously reported results of in vivo experiments.Furthermore,the applicability of the developed model as a therapeutic screening platform for cancer extravasation is validated through profiling and inhibition of cytokines.We believe this model incorporating hydrophobic surface-cultured 3D cancer cells provides reliable experimental data in a clear and concise manner,bridging the gap between the conventional in vitro models and in vivo experiments.

ELK3-ID4 axis governs the metastatic features of triple negative breast cancer

Purpose:Cancer cell metastasis is a multistep process,and the mechanism underlying extravasation remains unclear.ELK3 is a transcription factor that plays a crucial role in regulating various cellular processes,including cancer metastasis.Based on the finding that ELK3 promotes the metastasis of triple-negative breast cancer(TNBC),we investigated whether ELK3 regulates the extravasation of TNBC by forming the ELK3-ID4 axis.ID4 functions as a transcriptional regulator that interacts with other transcription factors,inhibiting their activity and subsequently influencing various biological processes associated with cell differentiation,survival,growth,and metastasis.Methods:We assessed the correlation between the expression of ELK3 and that of ID4 in TNBCs using bioinformatics analyses,QRT-PCR,western blot analysis,luciferase reporter assays,and chromatin immunoprecipitation.Migration,adhesion,invasion,and lung metastasis assays were employed to determine whether the ELK3-ID4 axis regulates the metastatic features of TNBC.Results:We found that ELK3 binds directly to a binding motif close to the ID4 promoter to repress promoter activity.The expression of E-cadherin in TNBC was regulated by the ELK3-ID4 axis.In vitro and in vivo analyses showed that inhibiting ID4 expression in ELK3-knockdown MDA-MB-231(ELK3KD)cells restored the ability to extravasate and metastasize.Conclusion:The results indicate that the ELK3 regulates ID4 promoter activity,and that the ELK3-ID4 axis regulates the metastatic characteristics of TNBC cells.Additionally,the data suggest that the ELK3-ID4 axis regulates metastasis of TNBCs by modulating expression of E-cadherin.

A review of complications after ureteral reconstruction

Objective:This study aimed to provide a comprehensive overview of the complications unique to ureteral reconstruction in adults,emphasizing their presentation,diagnosis,and management in the treatment of ureteral structure disease.Methods:This review involves an in-depth analysis of existing literature and case studies pertaining to ureteral reconstruction,with a focus on examining the range of complications that can arise post-surgery.Special attention is given to the presentation of each complication,the diagnostic process involved,and the subsequent management strategies.Results:Ureteral reconstruction can treat ureteral stricture disease with low morbidity;however,complications,although uncommon,can have severe consequences.The most notable complications include urinary extravasation,stricture recurrence,urinary tract infections,compartment syndrome,symptomatic vesicoureteral reflux,and Boari flap necrosis.Each complication presents unique diagnostic challenges and requires specific management approaches.Conclusion:Ureteral reconstruction is a highly effective treatment for ureteral stricture disease.Having a strong understanding of the potential complications that patients may experience following ureteral reconstruction is not only critical to adequately counsel patients but also facilitate prompt diagnosis and management of complications when they arise.

Pelvic fractures in blunt trauma patients:A comparative study

BACKGROUND Pelvic fractures(PF)with concomitant injuries are on the rise due to an increase of high-energy trauma.Increase of the elderly population with age related comorbidities further complicates the management.Abdominal organ injuries are kindred with PF due to the proximity to pelvic bones.Presence of contrast blush(CB)on computed tomography in patients with PF is considered a sign of active bleeding,however,its clinical significance and association with outcomes is debatable.AIM To analyze polytrauma patients with PF with a focus on the geriatric population,co-injuries and the value of contrast blush.METHODS This retrospective cohort study included 558 patients with PF admitted to level 1 trauma center(01/2017-01/2023).Analyzed variables included:Age,sex,mechanism of injury(MOI),injury severity score(ISS),Glasgow coma scale(GCS),abbreviated injury scale(AIS),co-injuries,transfusion requirements,pelvic angiography,embolization,laparotomy,orthopedic pelvic surgery,intensive care unit and hospital lengths of stay,discharge disposition and mortality.The study compared geriatric and non-geriatric patients,patients with and without CB and abdominal co-injuries.Propensity score matching was implemented in comparison groups.RESULTS PF comprised 4%of all trauma admissions.89 patients had CB.286(52%)patients had concomitant injuries including 93(17%)patients with abdominal co-injuries.Geriatric patients compared to non-geriatric had more falls as MOI,lower ISS and AIS pelvis,higher GCS,less abdominal co-injuries,similar CB and angio-embolization rates,less orthopedic pelvic surgeries,shorter lengths of stay and higher mortality.After propensity matching,orthopedic pelvic surgery rates remained lower(8%vs 19%,P<0.001),hospital length of stay shorter,and mortality higher(13%vs 4%,P<0.001)in geriatric patients.Out of 89 patients with CB,45(51%)were embolized.After propensity matching,patients with CB compared to without CB had more pelvic angiography(71%vs 12%,P<0.001),higher embolization rates(64%vs 22%,P=0.02)and comparable mortality.CONCLUSION Half of the patients with PF had concomitant co-injuries,including abdominal co-injuries in 17%.Similarly injured geriatric patients had higher mortality.Half of the patients with CB required an embolization.

A review of microfluidic approaches for investigating cancer extravasation during metastasis

Metastases,or migration of cancers,are common and severe cancer complications.Although the 5-year survival rates of primary tumors have greatly improved,those of metastasis remain below 30%,highlighting the importance of investigating specific mechanisms and therapeutic approaches for metastasis.Microfluidic devices have emerged as a powerful platform for drug target identification and drug response screening and allow incorporation of complex interactions in the metastatic microenvironment as well as manipulation of individual factors.In this work,we review microfluidic devices that have been developed to study cancer cell migration and extravasation in response to mechanical(section‘Microfluidic investigation of mechanical factors in cancer cell migration’),biochemical(section‘Microfluidic investigation of biochemical signals in cancer cell invasion’),and cellular(section‘Microfluidic metastasis-on-a-chip models for investigation of cancer extravasation’)signals.We highlight the device characteristics,discuss the discoveries enabled by these devices,and offer perspectives on future directions for microfluidic investigations of cancer metastasis,with the ultimate aim of identifying the essential factors for a‘metastasis-on-a-chip’platform to pursue more efficacious treatment approaches for cancer metastasis.

Antibody-activated trans-endothelial delivery of mesoporous organosilica nanomedicine augments tumor extravasation and anti-cancer immunotherapy

Tumor vasculature constitutes a formidable hurdle for the efficient delivery of cancer nanomedicine into tumors.The leverage of passive pathway through inter-endothelial gaps in tumor blood vessels might account for limited extravasation of nanomedicine into tumor microenvironment(TME).Herein,Annexin A1 antibody-installed mesoporous organosilica nanoplatforms carrying immunotherapeutics of anti-PD-L1 antibody(aPD-L1)and Indoximod are developed to target at caveolar Annexin-A1 protein of luminal endothelial cells and to trigger the active trans-endothelial transcytosis of nanomedicine mediated by caveolae.Such strategy enables rapid nanomedicine extravasation across tumor endothelium and relatively extensive accumulation in tumor interstitium.aPD-L1 and Indoximod release from aPD/IND@MON-aANN in a reduction-responsive manner and synergistically facilitate the intratumoral infiltration of cytotoxic T lymphocytes and reverse the immunosuppressive TME,thus demonstrating substantial anti-tumor efficacy in subcutaneous 4T1 breast tumors and remarkable anti-metastatic capacity to extend the survival of 4T1 tumor metastasis model.Moreover,aPD/IND@MON-aANN nanomedicine also exhibits distinct superiority over the combination therapy of free drugs to potently attenuate the progression of urethane-induced orthotopic lung cancers.Collectively,aPD/IND@MON-aANN nanoplatforms with boosted delivery efficiency via antibody-activated trans-endothelial pathway and enhanced immunotherapeutic efficacy provides perspectives for the development of cancer nanomedicines.

Investigation on the Mode of Action of the Traditional Chinese Medical Prescription-Yiqihuoxue Formula, an Effective Extravasation Treatment for Cerebral Vascular Microemboli in ApoE-/- mice

Objective: The objective of this study was to investigate the mechanisms underlying anti-embolism and extravasational effects of traditional Chinese medical prescription YiqiHuoxue(YQHX) formula in ApoE-/-mice with cerebral vascular microemboli. Materials and Methods: An ApoE-/-mice model with microemboli was developed by infusing fluorescently labeled heterologous fibrin-rich microparticles into the internal carotid artery of ApoE -/-gene knockout male mice through the common carotid artery. Before microemboli injection, the animals were randomly divided into four groups of 10 animals, treated daily for 6 weeks by intragastric administration: The ApoE-/-control group(physiological saline, 0.2 mL/10 g/d), YQHX group(0.2 ml/10 g/d), clopidogrel group(3 mg/kg/d), and atorvastatin group(3 mg/kg/d);a further group was constituted of normal male C57 BL/6 J mice(with the same genetic background as ApoE-/-mice;normal control group;no treatment;microemboli injection). The mice in each microemboli group were divided into three subgroups, the 2-h, 24-h, and 72-h subgroups, corresponding to the time after microemboli injection. Two hours(or 24 h or 72 h) after microemboli injection, the changes in aortic intima and brain tissue were analyzed by histopathology, the amounts of fluorescent emboli being measured by fluorescence microscopy image analysis. Comparison points included the microemboli induced loss of aorta functions and pathological changes, atherosclerotic plaque, brain ultrastructure and functions, and embolus extravasation. Results: Loss of aorta functions and adverse pathological changes, atherosclerotic plaque, serious damage in brain ultrastructure and functions, and reduced thrombus elimination were obviously serious in microemboli injected ApoE-/-mice. These symptoms were significantly relieved by the YQHX pretreatment:(i) the ratio of thrombus accumulation was increased with a significant decrease in thrombus extravasation in ApoE-/-mice, while YQHX induced an increased thrombus extravasation;(ii) the degree of aortic intimal thickening and brain tissue structural disorders were significantly increased in ApoE-/-mice, but overtly inhibited in the YQHX group;(iii) YQHX restored cell viability and homeostasis in the brain;(iv) YQHX regulated the expression of pro-and anti-inflammatory cytokines in the aorta;and(v) YQHX reduced cortical nerve nuclei pyknosis, edema, liquefaction, and necrosis induced by brain hypoxia, especially in the 24 h and 72 h groups. Conclusions: These findings indicate that the protective effects of YQHX on the brain against microemboli-induced injury may be attributed to the activation of extravasation mechanisms, which are involved in the cerebrovascular injury pathway and constitutively important in the progression of ischemic stroke.

Beware of the extravasation of muscle relaxant in children

To the editor:Neuromuscular blocking drugs (NMBDs) are administered to facilitate surgical exposure and controlled ventilation. However, their use is associated with several complications, especially in the pediatric age group. Arnot-Smith and Smith analysed complications related to the use of NMBDs in anesthesia.1 Of 200000 patient safety incidents reported from 2006–2008, 17179 (8.8%) were classed as 'anesthetic', while 231 (0.1%) were attributed to the use/reversal of NMBDs1;of these 231 incidents related to the use/reversal of NMBDs, extravasation only occurred in four cases (1.7%).1 Extravasation is defined as the accidental injection/leakage of fluid into perivascular tissues, which reportedly occurs in 10%–30% of patients receiving intravenous infusions.

Iatrogenic bladder neck rupture due to traumatic urethral catheterization: A case report

BACKGROUND In this article,we present a case of iatrogenic bladder neck rupture due to catheter insertion in a 94-year-old comorbid male patient.CASE SUMMARY The patient,who had a urethral catheter inserted in the palliative service 3 d ago,was consulted because the catheter did not work.Because the fluid given to the bladder could not be recovered,computed tomography was performed,which revealed that the catheter had passed the bladder neck first into the retrovesical area then into the intraabdominal area.The appearance of the anterior urethra and verumontanum was normal at cystoscopy.However,extremely severe stenosis of the bladder neck,and perforated posterior wall of the urethral segment between the prostatic urethra and the bladder neck were observed.Internal urethrotomy was applied to the bladder neck with a urethrotome.An urethral catheter was sent over the guide wire into the bladder.The patient was followed in the palliative care service and the catheter was removed 7 d later.No extravasation was observed in the control urethrography.CONCLUSION Although catheter insertion is a simple and frequently performed procedure in hospitalized patients,it is necessary to avoid unnecessary extra-indication catheter insertion.

Homing and migration of mesenchymal stromal cells: How to improve the efficacy of cell therapy?

Mesenchymal stromal cells(MSCs) are currently being investigated for use in a wide variety of clinical applications. For most of these applications, systemic delivery of the cells is preferred. However, this requires the homing and migration of MSCs to a target tissue. Although MSC hominghas been described, this process does not appear to be highly efficacious because only a few cells reach the target tissue and remain there after systemic administration. This has been ascribed to low expression levels of homing molecules, the loss of expression of such molecules during expansion, and the heterogeneity of MSCs in cultures and MSC culture protocols. To overcome these limitations, different methods to improve the homing capacity of MSCs have been examined. Here, we review the current understanding of MSC homing, with a particular focus on homing to bone marrow. In addition, we summarize the strategies that have been developed to improve this process. A better understanding of MSC biology, MSC migration and homing mechanisms will allow us to prepare MSCs with optimal homing capacities. The efficacy of therapeutic applications is dependent on efficient delivery of the cells and can, therefore, only benefit from better insights into the homing mechanisms.

Coronary CT Angiography Using Low Iodine Delivery Rate and Tube Voltage Determined by Body Mass Index:Superiority in Clinical Practice

To explore the feasibility and superiority of iodine delivery rate(IDR)and tube voltage determined by patients'body mass index(BMI)in coronary CT angiography(CCTA),a total of 1567 patients undertaking CCTA during Feb.and Dec.2016 were enrolled and divided into two groups.In the control group,the IDR and tube voltage were fixed,while in the experimental group,the IDR and tube voltage were determined by patients,BMI.The volume of iodinated contrast media(ICM),extravasation rate,extravasation volume,extravasation recovery interval,incidence rate of adverse reactions,effective dose(ED)and image quality of the two groups were compared.The experiments demonstrated that the ICM volume,extravasation rate,extravasation volume,extravasation recovery interval,incidence of adverse reactions and ED were lower or shorter in the experimental group than in the control group,and the differences were statistically significant(all P<0.05).However,there were no significant differences in the mean CT value,image noise,signal to noise ratio and contrast to noise ratio between the two groups(all P<0.05),which were consistent with the diagnosticians*subjective evaluation outcomes.Our findings suggested that in CCTA,it is feasible to determine the IDR and tube voltage based on patients'BMI;low tube voltage and IDR are superior to the fixed tube voltage and IDR and are worthy of clinical promotion.

In vivo observation of cerebral microcirculation after experimental subarachnoid hemorrhage in mice

Acute brain injury caused by subarachnoid hemorrhage is the major cause of poor prognosis. The pathology of subarachnoid hemorrhage likely involves major morphological changes in the microcirculation. However, previous studies primarily used fixed tissue or delayed injury models. Therefore, in the present study, we used in vivo imaging to observe the dynamic changes in cerebral microcirculation after subarachnoid hemorrhage. Subarachnoid hemorrhage was induced by perforation of the bifurcation of the middle cerebral and anterior cerebral arteries in male C57/BL6 mice. The diameter of pial arterioles and venules was measured by in vivo fluorescence microscopy at different time points within 180 minutes after subarachnoid hemorrhage. Cerebral blood flow was examined and leukocyte adhesion/albumin extravasation was determined at different time points before and after subarachnoid hemorrhage. Cerebral pial microcirculation was abnormal and cerebral blood flow was reduced after subarachnoid hemorrhage. Acute vasoconstriction occurred predominantly in the arterioles instead of the venules. A progressive increase in the number of adherent leukocytes in venules and substantial albumin extravasation were observed between 10 and 180 minutes after subarachnoid hemorrhage. These results show that major changes in microcirculation occur in the early stage of subarachnoid hemorrhage. Our findings may promote the development of novel therapeutic strategies for the early treatment of subarachnoid hemorrhage.

Xiongzhi Dilong decoction interferes with calcitonin gene-related peptide(CGRP)-induced migraine in rats through the CGRP/iNOS pathway

Objective: To evaluate the effects of Xiongzhi Dilong decoction(XZDLD) and its wind medicine on calcitonin gene-related peptide(CGRP)-induced migraine and explore the mechanism through the CGRP/inducible nitric oxide synthase(iNOS) pathway.Methods: Rats were divided into control, model, XZDLD, XZDLD(external wind), XZDLD(internal wind),and olcegepant groups. CGRP was injected into the dura mater to induce a migraine. The frequency of head scratching, cage climbing, and facial grooming was observed. The pain threshold, the levels of CGRP,pituitary adenylate cyclase activating polypeptide(PACAP), substance P(SP), and the plasma protein extravasation(PPE) ratio were measured. The phosphorylation levels of p38, extracellular signalregulated kinase 1/2(ERK1/2), and expression of iNOS were detected by western blot.Results: Compared with the model group, the three modified XZDLD groups showed reduced frequency of head scratching and cage climbing in the first 30 min(all P <.05). Facial grooming frequency was reduced in XZDLD and XZDLD(external wind) groups(P =.0003 and P =.0131, respectively). External wind medicine played a more important role in increasing mechanical pain threshold than internal wind medicine. Moreover, compared with the model group, the three modified XZDLD groups demonstrated reduced plasma levels of CGRP and PACAP(all P <.05). No difference in the SP level was observed among the six groups. XZDLD reduced PPE ratio. XZDLD and XZDLD(external wind) groups suppressed the CGRP/iNOS pathway by inhibiting the p-p38/p38 ratio and the expression of iNOS. No difference in pERK1/2/ERK1/2 ratio was detected among the six groups.Conclusion: XZDLD increases pain threshold, downregulates the expression of CGRP and PACAP, and reduces PPE ratio by inhibiting the CGRP/iNOS pathway. External wind medicine is more effective than internal one on improving facial grooming and head scratching, increasing the mechanical pain threshold, and inhibiting the expression of iNOS.

Human Macrophages Utilize the Podosome Formin FMNL1 for Adhesion and Migration

Macrophages play a crucial role in detecting, regulating, and resolving immune crises, requiring migration through complex extracellular matrices. Unwarranted macrophage inflammatory activity potentiates kidney disease, rheumatoid arthritis, and transplant rejection. Proper remodeling of the actin cytoskeleton, especially at adhesion structures, is essential to the translocation of macrophages. Macrophages form actin-rich adhesions termed “podosomes”, giving them the capacity to make contacts with the substratum for traction through interstitial tissues. Macrophages express multiple formins, including FMNL1, Dia1, and Fhod1, with potential to impact actin remodeling involved in migration. Formins are a family of proteins that are best known for modifying the actin cytoskeleton via nucleation, elongation, bundling, and/or severing actin filaments. In this study we demonstrate that the formin FMNL1 is a key regulator of podosomes and is required for normal macrophage migration. Additionally, this is the first study to demonstrate defects in primary human cell migration resulting from specific formin silencing. Pharmacologic inhibition of all formin activity results in a significant decrease in podosome formation and normal macrophage migration. Furthermore, targeted suppression of FMNL1 results in decreases in macrophage migration similar to inhibition of all expressed macrophage formins. These novel findings suggest FMNL1 as a possible chemotherapeutic target to hinder macrophage migration, which could offer an innovative method for limiting unnecessary macrophage-mediated inflammation. We hypothesize that formins are required in podosome actin dynamics to support macrophage migration.