Orchestration of macrophage polarization dynamics by fibroblast-secreted exosomes during skin wound healing.

Macrophages undertake pivotal yet dichotomous functions during skin wound healing, mediating both early pro-inflammatory immune activation and late anti-inflammatory tissue remodeling processes. The timely phenotypic transition of macrophages from inflammatory M1 to pro-resolving M2 activation states is essential for efficient healing. However, the endogenous mechanisms calibrating macrophage polarization in accordance with the evolving tissue milieu remain undefined. Here, we reveal an indispensable immunomodulatory role for fibroblast-secreted exosomes in directing macrophage activation dynamics. Fibroblast exosomes permitted spatiotemporal coordination of macrophage phenotypes independent of direct intercellular contact. Exosomes enhanced macrophage sensitivity to both M1 and M2 polarizing stimuli, yet also accelerated timely switching from M1 to M2 phenotypes. Exosomes inhibition dysregulated macrophage responses resulting in aberrant inflammation and impaired healing, while provision of exogenous fibroblast exosomes corrected defects. Topical application of fibroblast exosomes onto chronic diabetic wounds normalized dysregulated macrophage activation to resolve inflammation and restore productive healing. Our findings elucidate fibroblast-secreted exosomes as remote programmers of macrophage polarization that calibrate immunological transitions essential for tissue repair. Harnessing exosomes represents a previously unreported approach to steer productive macrophage activation states with immense therapeutic potential for promoting healing in chronic inflammatory disorders.

Spatiotemporal orchestration of macrophage activation trajectories by Vγ4 T cells during skin wound healing.

Dysregulated macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes underlies impaired cutaneous wound healing. This study reveals Vγ4+ γδ T cells spatiotemporally calibrate macrophage trajectories during skin repair via sophisticated interferon-γ (IFN-γ) conditioning across multiple interconnected tissues. Locally within wound beds, infiltrating Vγ4+ γδ T cells directly potentiate M1 activation and suppress M2 polarization thereby prolonging local inflammation. In draining lymph nodes, infiltrated Vγ4+ γδ T cells expand populations of IFN-γ-competent lymphocytes which disseminate systemically and infiltrate into wound tissues, further enforcing M1 macrophages programming. Moreover, Vγ4+γδ T cells flushed into bone marrow stimulate increased IFN-γ production, which elevates the output of pro-inflammatory Ly6C+monocytes. Mobilization of these monocytes continually replenishes the M1 macrophage pool in wounds, preventing phenotypic conversion to M2 activation. Thus, multi-axis coordination of macrophage activation trajectories by trafficking Vγ4+ γδ T cells provides a sophisticated immunological mechanism regulating inflammation timing and resolution during skin repair.

Luminol-conjugated cyclodextrin biological nanoparticles for the treatment of severe burn-induced intestinal barrier disruption.

Background: The breakdown of intestinal barrier integrity occurs after severe burn injury and is responsible for the subsequent reactions of inflammation and oxidative stress. A new protective strategy for the intestinal barrier is urgently needed due to the limitations of the traditional methods. Recently, the application of nanoparticles has become one of the promising therapies for many inflammation-related diseases or oxidative damage. Herein, we developed a new anti-inflammatory and antioxidant nanoparticle named luminol-conjugated cyclodextrin (LCD) and aimed to evaluate its protective effects in severe burn-induced intestinal injury. Methods: First, LCD nanoparticles, engineered with covalent conjugation between luminol and ß-cyclodextrin (ß-CD), were synthesized and examined. Then a mouse burn model was successfully established before the mouse body weight, intestinal histopathological manifestation, permeability, tight junction (TJ) expression and pro-inflammatory cytokines were determined in different groups. The proliferation, apoptosis, migration and reactive oxygen species (ROS) of intestinal epithelial cells (IECs) were assessed. Intraepithelial lymphocytes (IELs) were isolated and cultured for analysis by flow cytometry. Results: LCD nanoparticle treatment significantly relieved the symptoms of burn-induced intestinal injury in the mouse model, including body weight loss and intestinal permeability abnormalities. Moreover, LCD nanoparticles remarkably recovered the mechanical barrier of the intestine after severe burn, renewed TJ structures, promoted IEC proliferation and migration, and inhibited IEC apoptosis. Mechanistically, LCD nanoparticles dramatically alleviated pro-inflammation factors (tumor necrosis factor-α, IL-17A) and ROS accumulation, which could be highly involved in intestinal barrier disruption. Furthermore, an increase in IL-17A and the proportion of IL-17A+Vγ4+ γδ T subtype cells was also observed in vitro in LPS-treated Vγ4+ γδ T cells, but the use of LCD nanoparticles suppressed this increase. Conclusions: Taken together, these findings demonstrate that LCD nanoparticles have the protective ability to ameliorate intestinal barrier disruption and provide a therapeutic intervention for burn-induced intestinal injury.

The mutual regulation between γδ T cells and macrophages during wound healing.

Macrophages are the main cells shaping the local microenvironment during wound healing. As the prime T cells in the skin, γδ T cells participate in regulating microenvironment construction, determining their mutual regulation helps to understand the mechanisms of wound healing, and explore innovative therapeutic options for wound repair. This review introduced their respective role in wound healing firstly, and then summarized the regulatory effect of γδ T cells on macrophages, including chemotaxis, polarization, apoptosis and pyroptosis. Lastly, the retrograde regulation on γδ T cells by macrophages was also discussed. The main purpose is to excavate novel interventions for treating wound, and provide new thought for further research.

Skin γδ T Cells and Their Function in Wound Healing.

For the skin immune system, γδ T cells are important components, which help in defensing against damage and infection of skin. Compared to the conventional αß T cells, γδ T cells have their own differentiation, development and activation characteristics. In adult mice, dendritic epidermal T cells (DETCs), Vγ4 and Vγ6 γδ T cells are the main subsets of skin, the coordination and interaction among them play a crucial role in wound repair. To get a clear overview of γδ T cells, this review synopsizes their derivation, development, colonization and activation, and focuses their function in acute and chronic wound healing, as well as the underlining mechanism. The aim of this paper is to provide cues for the study of human epidermal γδ T cells and the potential treatment for skin rehabilitation.

Novel method to decrease the exposure time of the extraction string of the ureteral stent and its efficiency and safety verification in the clinic.

Ureteral stent removal by an extraction string is advantageous. However, the increased risk of complications attributed to the continuous exposure of the string outside the urethra must be managed. This paper introduces a method to decrease the exposure time, and conducts a retrospective study to verify its efficiency and safety. A total of 231 male patients undergoing routine ureteroscopy (URS) were included, and all of them accepted indwelling ureteral stents with strings. Among them, 123 patients (Normal-S group) underwent the normal method to determine the length of string (Lstring), which was shortened to 4 cm (cm) past the urethral meatus; 108 patients (Novel-S group) underwent the novel method (Lstring = Lurethra + 2 cm), the length of urethra (Lurethra) was measured during ureteroscopy by ureteroscope body. The demographic characteristics, stent indwelling and removal-related variables, complications, and medical costs in each group were recorded. There was no significant difference in demographic characteristics, the rate of UTI, the operative duration of URS, or the VAS pain scores for stent removal between the 2 groups. For the Novel-S group, the stent dwelling time was longer, the self-rated discomfort and symptom, the stent dislodgement rate, the numbers of clinic or emergency visits and the overall medical cost post operation was lower in comparison with the Normal-S group, while the rate of removal of stents by hand was lower, the time for removing ureteral stents was longer. This novel method improved stenting comfort, avoided ureteral stent dislodgement, decreased complications, and lowered medical costs, it was safe and reliable and merits widespread application.

Methylene blue usage for determining accessory artery ligation in donor kidneys.

Objectives. We present a technique for determining whether to ligate or preserve accessory arteries in donor kidneys before implantation. Methods. Forty-three living-related donor kidneys in patients from January 2014 to February 2018 at our institution were included, all of which had dual arteries without the same stem. Among them, 19 cases of accessory arterial blood supply were evaluated using methylene blue (MB) perfusion, and accessory arteries supplying less than 10% of the total MB perfusion volume were ligated. The other 24 cases were assessed using a conventional method in which arteries with diameters less than 2 mm were ligated. The back-table surgical time, Doppler ultrasonography index, renal function and complications were compared between the 2 groups. Results. All patients underwent successful kidney transplantation. The back-table surgical time in the MB group was longer than that in the conventional group (42.70 ± 4.70 min vs 34.64 ± 5.30 min, P < .05). The serum creatinine level in the MB group was significantly lower than that in the conventional group 1 month after the operation (103.15 ± 19.26 µmol/L vs 119.17 ± 28.32 µmol/L, P < .05). No differences in the Doppler ultrasonography index or postoperative complications were noted. Conclusions. MB perfusion provides an easy and effective method to make decisions regarding arterial ligation and helps preserve renal function without increasing the number of complications after transplantation.

Keratinocyte growth factor ameliorates mycophenolate mofetil-induced intestinal barrier disruption in mice.

OBJECTIVES: Although mycophenolate mofetil-induced (MMF) effectively improves long-term graft survival, the gastrointestinal (GI) side effects due to MMF-induced GI barrier damage limit its use in clinic. Keratinocyte growth factor (KGF) plays a crucial role in the intestinal protection and repair process. This study is designed to investigate the protective effect of KGF on MMF-induced intestinal mucosal barrier disruption and the potential mechanism. METHODS: Thirty adult male C57BL/6 mice were assigned to one of the following groups: the MMF group, the MMF + KGF group, and the control group (n = 10 in each group). Animals in the MMF group received MMF (500 mg/kg) by gavage once daily for 15 consecutive days; animals in the MMF + KGF group received MMF (500 mg/kg) by gavage and KGF (5 mg/kg) by intraperitoneal injection once daily for 15 consecutive days; and control mice were given an equal volume of vehicle during the 15-day experimental period. In each group, intestinal paracellular permeability, histopathological changes and shifts in tight junction (TJ) protein were evaluated; further, proliferation and apoptosis of intestinal epithelial cells (IECs) were assessed, and intraepithelial lymphocytes (IELs) were isolated and analyzed by flow cytometry. RESULTS: MMF caused intestinal mucosal injury, increased intestinal mucosal permeability, and altered expression of TJ protein. Moreover, MMF treatment inhibited IEC proliferation and increased apoptosis. MMF treatment resulted in a lower proportion of γδ+ T cells in IELs (γδ+ IELs). Conversely, concurrent administration of KGF with MMF effectively alleviated MMF-induced intestinal mucosal disruption, inhibited the increase in intestinal permeability, and maintained TJ protein expression. KGF also reversed the MMF-mediated inhibition of proliferation and promotion of apoptosis in IECs. In addition, KGF significantly enhanced the proportion of γδ+ IELs. CONCLUSION: Our findings suggest that MMF induces intestinal epithelial barrier disruption in mice. KGF may play a protective role to ameliorate the disruption and provide a therapeutic intervention for gastrointestinal disorders induced by MMF.

Endo-Satinsky Clamp Hybrid In Situ Perfusion in Retroperitoneoscopic Donor Nephrectomy For Right-sided Kidney.

OBJECTIVE: To introduce our hybrid technique using an endo-Satinsky clamp and in situ cold perfusion for right-sided retroperitoneoscopic donor nephrectomy (RDN) and to investigate efficacy and safety compared with those standard right-sided RDN. METHODS: This retrospective study included 16 transplant donors who underwent right-sided RDN from January 2016 to January 2018. Donors received either hybrid RDN (n = 6) or standard RDN (n = 10). Perioperative outcomes, including operative time, estimated blood loss, warm ischemic time, hospital stay, length of renal vein obtained as well as postoperative renal function of their recipients were collected and compared between the hybrid RDN and standard RDN groups. RESULTS: Procedures were performed successfully in all 16 donors. The hybrid RDN group required longer operation times (135 vs 115 minutes), demonstrated increased blood loss (175 vs 140 mL), but shorter warm ischemic times (1.5 vs 5.5 minutes) and resulted in longer length of the procured renal vein (2.8 vs 1.7 cm) as compared with the standard RDN group. No difference in perioperative complication rates was witnessed between the 2 groups. Also, there were no significant differences in serum creatinine levels and glomerular filtration rates of recipients between the 2 groups at both postoperative day 3 and 1 month. CONCLUSION: The hybrid RDN potentially extends the length of the right donor renal vein. The perioperative outcomes of hybrid RDN were comparable with those of the standard RDN. This hybrid technique can be a technically safe and feasible option for right kidney donation.

Neutralization of interleukin-17A alleviates burn-induced intestinal barrier disruption via reducing pro-inflammatory cytokines in a mouse model.

BACKGROUND: The intestinal barrier integrity can be disrupted due to burn injury, which is responsible for local and systemic inflammatory responses. Anti-inflammation strategy is one of the proposed therapeutic approaches to control inflammatory cascade at an early stage. Interleukin-17A (IL-17A) plays a critical role in inflammatory diseases. However, the role of IL-17A in the progression of burn-induced intestinal inflammation is poorly understood. In this study, we aimed to investigate the effect of IL-17A and associated pro-inflammatory cytokines that were deeply involved in the pathogenesis of burn-induced intestinal inflammatory injury, and furthermore, we sought to determine the early source of IL-17A in the intestine. METHODS: Mouse burn model was successfully established with infliction of 30% total body surface area scald burn. The histopathological manifestation, intestinal permeability, zonula occludens-1 expression, pro-inflammatory cytokines were determined with or without IL-17A-neutralization. Flow cytometry was used to detect the major source of IL-17A+ cells in the intestine. RESULTS: Burn caused intestinal barrier damage, increase of intestinal permeability, alteration of zonula occludens-1 expressions, elevation of IL-17A, IL-6, IL-1ß and tumor necrosis factor-α (TNF-α), whereas IL-17A neutralization dramatically alleviated burn-induced intestinal barrier disruption, maintained zonula occludens-1 expression, and noticeably, inhibited pro-inflammatory cytokines elevation. In addition, we observed that the proportion of intestinal IL-17A+Vγ4+ T subtype cells (but not IL-17A+Vγ1+ T subtype cells) were increased in burn group, and neutralization of IL-17A suppressed this increase. CONCLUSIONS: The main original findings of this study are intestinal mucosa barrier is disrupted after burn through affecting the expression of pro-inflammatory cytokines, and a protective role of IL-17A neutralization for intestinal mucosa barrier is determined. Furthermore, Vγ4+ T cells are identified as the major early producers of IL-17A that orchestrate an inflammatory response in the burn model. These data suggest that IL-17A blockage may provide a unique target for therapeutic intervention to treat intestinal insult after burn.

Inhibition of microRNA-132 attenuates inflammatory response and detrusor fibrosis in rats with interstitial cystitis via the JAK-STAT signaling pathway.

Interstitial cystitis (IC) is a heterogeneous syndrome with unknown etiology, and microRNAs (miRs) were found to be involved in IC. In our study, we aim to explore the role of miR-132 in the inflammatory response and detrusor fibrosis in IC through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway in rat models. A rat model of IC was established and treated with the miR-132 mimic, miR-132 inhibitor, and/or JAK-STAT signaling pathway inhibitor AG490. Enzyme-linked immunosorbent assay was applied to measure the expression of interleukin (IL)-6, IL-10, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1). The urodynamic test was performed to assess urodynamic parameters, and reverse transcription quantitative polymerase chain reaction and Western blot analysis for the expression of miR-132, STAT4, suppressors of cytokine signaling 3 (SOCS3), JAK2, vascular endothelial growth factor (VEGF), IFN-γ, and TNF-α. IC rats treated with miR-132 inhibitor and AG490 had decreased collagen fiber, inflammatory cell infiltration, and mast cells, lower expression of IL-6, IL-10, IFN-γ, TNF-α, ICAM-1, collagens I and III, and alleviated urodynamic parameters and decreased expression of STAT4, VEGF, JAK2, IFN-γ, TNF-α, and increased expression of SOCS3. Taken together, our data indicate that downregulation of miR-132 alleviates inflammatory response and detrusor fibrosis in IC via the inhibition of the JAK-STAT signaling pathway.

Uridine diphosphate-glucuronosyltransferase 2B15 D85Y gene polymorphism is associated with lower prostate cancer risk: a systematic review and meta-analysis.

UGT2B15 (uridine diphosphate-glucuronosyltransferase 2B15) catalyzes the conversion of lipophilic C19 steroid androgens such as dihydrotestosterone (DHT) into water-soluble metabolites that can be excreted. Studies of the association between the UGT2B15 gene D85Y polymorphism and prostate cancer have yielded contradictory results. We therefore systematically searched in the PubMed, EMBASE, Science Direct/Elsevier, CNKI, and Cochrane Library databases, and identified six relevant studies with which to perform a meta-analysis of the relation between UGT2B15 D85Y polymorphism and prostate cancer risk. Our meta-analysis revealed a significant association between UGT2B15 D85Y gene polymorphism and prostate cancer in all genetic models (P<0.05). The combined odds ratios and 95% confidence intervals were as follows: additive model, 0.53 and 0.32-0.88; dominant model, 0.51 and 0.33-0.79; recessive model, 0.76 and 0.60-0.96; co-dominant model, 0.55 and 0.35-0.86; and allele model, 0.70 and 0.55-0.89. These results are consistent with the idea that the UGT2B15 D85Y enzyme variant reduces the risk of prostate cancer by efficiently metabolizing dihydrotestosterone (DHT), which is associated with prostate cancer progression.

Improving doctor-patient communication: content validity examination of a novel urinary system-simulating physical model.

Effective doctor-patient communication is essential for establishing a successful doctor-patient relationship and implementing high-quality health care. In this study, a novel urinary system-simulating physical model was designed and fabricated, and its content validity for improving doctor-patient communication was examined by conducting a randomized controlled trial in which this system was compared with photographs. A total of 240 inpatients were randomly selected and assigned to six doctors for treatment. After primary diagnosis and treatment had been determined, these patients were randomly divided into the experimental group and the control group. Patients in the experimental group participated in model-based doctor-patient communication, whereas control group patients received picture-based communication. Within 30 min after this communication, a Demographic Information Survey Scale and a Medical Interview Satisfaction Scale (MISS) were distributed to investigate patients' demographic characteristics and their assessments of total satisfaction, distress relief, communication comfort, rapport, and compliance intent. The study results demonstrated that the individual groups were comparable with respect to demographic variables but that relative to patients in the picture-based communication group, patients in the model-based communication group had significantly higher total satisfaction scores and higher ratings for distress relief, communication comfort, rapport, and compliance intent. These results indicate that the physical model is more effective than the pictures at improving doctor-patient communication and patient outcomes. The application of the physical model in doctor-patient communication is helpful and valuable and therefore merits widespread clinical popularization.

Ureteroscopy and cystoscopy training: comparison between transparent and non-transparent simulators.

BACKGROUND: Simulators have been widely used to train operational skills in urology, how to improve its effectiveness deserves further investigation. In this paper, we evaluated training using a novel transparent anatomic simulator, an opaque model or no simulator training, with regard to post-training ureteroscopy and cystoscopy proficiency. METHODS: Anatomically correct transparent and non-transparent endourological simulators were fabricated. Ten experienced urologists provided a preliminary evaluation of the models as teaching tools. 36 first-year medical students underwent identical theoretical training and a 50-point examination of theoretical knowledge. The students were randomly assigned to receive training with the transparent simulator (Group 1), the non-transparent simulator (Group 2) or detailed verbal instruction only (Group 3). 12 days after the training session, the trainees' skills at ureteral stent insertion and removal were evaluated using the Uro-Scopic Trainer and rated on an Objective Structured Assessment of Technical Skills (OSATS) scale. RESULTS: The new simulators were successfully fabricated in accordance with the design parameters. Of the ten urologists invited to evaluate the devices, 100% rated the devices as anatomically accurate, 90% thought both models were easy to use and 80% thought they were good ureteroscopy and cystoscopy training tools. The scores on the theoretical knowledge test were comparable among the training groups, and all students were able to perform ureteral stent insertion and removal. The mean OSATS scores of groups 1, 2 and 3 were 21.83 ± 3.64, 18.50 ± 4.03 and 15.58 ± 2.23 points, respectively, (p = 0.001). CONCLUSIONS: Simulator training allowed students to achieve higher ureteroscopic and cystoscopic proficiency, and transparent simulators were more effective than non-transparent simulators.

Novel Transparent Urinary Tract Simulator Improves Teaching of Urological Operation Skills at a Single Institution.

OBJECTIVE: This randomized controlled study compared a novel transparent urinary tract simulator with the traditional opaque urinary tract simulator as an aid for efficiently teaching urological surgical procedures. METHODS: Senior medical students were tested on their understanding of urological theory before and after lectures concerning urinary system disease. The students received operative training using the transparent urinary tract simulator (experimental group, n = 80) or the J3311 opaque plastic urinary tract simulator (control, n = 80), specifically in catheterization and retrograde double-J stent implantation. The operative training was followed by a skills test and student satisfaction survey. RESULTS: The test scores for theory were similar between the two groups, before and after training. Students in the experimental group performed significantly better than those in the control group on the procedural skills test, and also had significantly better self-directed learning skills, analytical skills, and greater motivation to learn. CONCLUSION: During the initial step of training, the novel transparent urinary tract simulator significantly improved the efficiency of teaching urological procedural skills compared with the traditional opaque device.

Preclinical evaluation of a newly designed ureteral stent and magnetic retrieval catheter for minimally invasive stent removal.

OBJECTIVE: To develop a simple minimally invasive method for ureteral stent removal that does not require cystoscopy or fluoroscopic guidance. MATERIALS AND METHODS: We developed a novel ureteral stent comprising the main body of a stent and an iron oxide-coated net that was woven of processed polyester sutures. The ureteral stent was retrieved by a magnetic retrieval catheter with small hooks on the neck surface. Detailed analysis of the necessary mechanical and magnetic properties was performed, and we conducted retrieval tests of the ureteral stent from a specially designed urinary system model. RESULTS: The breaking strength and Young modulus of the processed polyester sutures were 10.12 ± 0.30 N and 9143 ± 7 N/tex, respectively. Thermogravimetric tests showed that the iron (III) oxide powders on the processed sutures accounted for 23% of the total weight. The magnetization value of the magnetic retrieval catheter was 578 emu/g. The dissolution times of polyvinyl alcohol wrapped the net in saline or urine were 24.2 ± 2.0 and 23.6 ± 3.1 hours, respectively. All stents in both the experimental and the control groups were successfully removed from the specially designed urinary model. However, the retrieval time in the experimental group was significantly shorter than that in the control group (38.6 ± 12.6 vs 59 ± 15.7 seconds; P <.05). CONCLUSION: Ureteral stent removal using a magnetic retrieval catheter with small capture devices is considered feasible. This technique is easy to learn and should be considered as suitable for use on an outpatient basis.

[Design of a multifunctional and transparent urinary system model].

This article describes a novel Multifunctional and Transparent Urinary System Model (MTUSM), which can be applied to anatomy teaching, operational training of clinical skills as well as simulated experiments in vitro. This model covers kidneys, ureters, bladder, prostate, male and female urethra, bracket and pedestal, etc. Based on human anatomy structure and parameters, MTUSM consists of two transparent layers i. e. transparent organic glass external layer, which constraints the internal layer and maintains shape of the model, and transparent silica gel internal layer, which possesses perfect elasticity and deformability. It is obvious that this model is preferable in simulating the structure of human urinary system by applying hierarchical fabrication. Meanwhile, the transparent design, which makes the inner structure, internal operations and experiments visual, facilitates teaching instruction and understanding. With the advantages of simple making, high-findelity, unique structure and multiple functions, this model will have a broad application prospect and great practical value.

Correction method for fisheye image based on the virtual small-field camera.

A distortion correction method for a fisheye image is proposed based on the virtual small-field (SF) camera. The correction experiment is carried out, and a comparison is made between the proposed method and the conventional global correction method. From the experimental results, the corrected image by this method satisfies the law of perspective projection, and the image looks as if it was captured by an SF camera with the optical axis pointing at the corrected center. This method eliminates the phenomena of center compression, edge stretch, and field loss, and the image character is more obvious, which benefits the afterward target detection and information extraction.