Potential mosquito-associated melioidosis and analysis of sample processing results in Hainan, China, 2023

Burkholderia(B.)pseudomallei is a Gram-negative bacterium causing melioidosis,a tropical infection that is being recognized as a growing public health problem[1].Melioidosis,with mortality rates ranging from under 10%to 40%,is a significant concern in Southeast Asia,Australia,and beyond[2].The underdiagnosis,particularly in rural areas,emphasizes the need for improved awareness,surveillance,and management,potentially classifying melioidosis as a neglected tropical disease[3].

Non-Hodgkin's lymphoma involving chronic difficult-to-heal wounds:A case report

BACKGROUND Non-Hodgkin's lymphoma(NHL)is a malignant tumor that originates from the lymphoid tissues and can potentially affect numerous organs within the body.Among these,the skin stands out as one of the primary sites affected by NHL,often presenting with multiple extra-nodal manifestations.In this report,we present an unusual case of NHL involving chronic wounds in the lower extremities that were difficult to heal.The scars were successfully treated using radiotherapy in combination with extended excision debridement and peroneal artery perforator flap grafting,resulting in satisfactory outcomes.CASE SUMMARY A 19-year-old male patient presented with ulceration of the skin on the left calf near the ankle accompanied by purulent discharge.Subsequent pathologic biopsy confirmed a diagnosis of NHL(extranodal NK/T-cell lymphoma,nasal type).Initial treatment comprised local radiotherapy and wound care;however,the wound exhibited prolonged non-healing.Consequently,the patient underwent a series of interventions including radiotherapy,wound enlargement excision debridement,and peroneal artery perforator flap grafting.Ultimately,successful healing was achieved with favorable postoperative outcomes characterized by good texture of the flap without any signs of rupture or infection.CONCLUSION The combination of radiotherapy,wound enlargement excision debridement,and peroneal artery perforator flap grafting may present a favorable treatment modality for chronic non-healing lower leg wounds resulting from NHL.

Current understanding of osteoarthritis pathogenesis and relevant new approaches

Osteoarthritis(OA)is the most common degenerative joint disease that causes painful swelling and permanent damage to the joints in the body.The molecular mechanisms of OA are currently unknown.OA is a heterogeneous disease that affects the entire joint,and multiple tissues are altered during OA development.To better understand the pathological mechanisms of OA,new approaches,methods,and techniques need to be used to understand OA pathogenesis.In this review,we first focus on the epigenetic regulation of OA,with a particular focus on DNA methylation,histone modification,and microRNA regulation,followed by a summary of several key mediators in OA-associated pain.We then introduce several innovative techniques that have been and will continue to be used in the fields of OA and OA-associated pain,such as CRISPR,scRNA sequencing,and lineage tracing.Next,we discuss the timely updates concerning cell death regulation in OA pathology,including pyroptosis,ferroptosis,and autophagy,as well as their individual roles in OA and potential molecular targets in treating OA.Finally,our review highlights new directions on the role of the synovial lymphatic system in OA.An improved understanding of OA pathogenesis will aid in the development of more specific and effective therapeutic interventions for OA.

Inhibition of aberrant Hif1αactivation delays intervertebral disc degeneration in adult mice

The intervertebral disc(IVD) is the largest avascular tissue. Hypoxia-inducible factors(HIFs) play essential roles in regulating cellular adaptation in the IVD under physiological conditions. Disc degeneration disease(DDD) is one of the leading causes of disability, and current therapies are ineffective. This study sought to explore the role of HIFs in DDD pathogenesis in mice. The findings of this study showed that among HIF family members, Hif1α was significantly upregulated in cartilaginous endplate(EP) and annulus fibrosus(AF) tissues from human DDD patients and two mouse models of DDD compared with controls. Conditional deletion of the E3 ubiquitin ligase Vhl in EP and AF tissues of adult mice resulted in upregulated Hif1α expression and age-dependent IVD degeneration. Aberrant Hif1α activation enhanced glycolytic metabolism and suppressed mitochondrial function. On the other hand, genetic ablation of the Hif1α gene delayed DDD pathogenesis in Vhl-deficient mice. Administration of 2-methoxyestradiol(2ME2), a selective Hif1α inhibitor, attenuated experimental IVD degeneration in mice. The findings of this study show that aberrant Hif1α activation in EP and AF tissues induces pathological changes in DDD, implying that inhibition of aberrant Hif1α activity is a potential therapeutic strategy for DDD.

P-MSC-derived extracellular vesicles facilitate diabetic wound healing via miR-145-5p/CDKN1A-mediated functional improvements of high glucose-induced senescent fibroblasts

Background:Persistent hyperglycaemia in diabetes causes functional abnormalities of human dermal fibroblasts(HDFs),partially leading to delayed skin wound healing.Extracellular vesicles(EVs)containing multiple pro-healing microRNAs(miRNAs)have been shown to exert therapeutic effects on diabetic wound healing.The present study aimed to observe the effects of EVs derived from placental mesenchymal stem cells(P-MSC-EVs)on diabetic wound healing and high glucose(HG)-induced senescent fibroblasts and to explore the underlying mechanisms.Methods:P-MSC-EVs were isolated by differential ultracentrifugation and locally injected into the full-thickness skin wounds of diabetic mice,to observe the beneficial effects on wound healing in vivo by measuring wound closure rates and histological analysis.Next,a series of assays were conducted to evaluate the effects of low(2.28 x 1010 particles/ml)and high(4.56 x 1010 particles/ml)concentrations of P-MSC-EVs on the senescence,proliferation,migration,and apoptosis of HG-induced senescent HDFs in vitro.Then,miRNA microarrays and real-time quantitative PCR(RT-qPCR)were carried out to detect the differentially expressed miRNAs in HDFs after EVs treatment.Specific RNA inhibitors,miRNA mimics,and small interfering RNA(siRNA)were used to evaluate the role of a candidate miRNA and its target genes in P-MSC-EV-induced improvements in the function of HG-induced senescent HDFs.Results:Local injection of P-MSC-EVs into diabetic wounds accelerated wound closure and reduced scar widths,with better-organized collagen deposition and decreased p16INK4a expression.In vitro,P-MSC-EVs enhanced the antisenescence,proliferation,migration,and antiapoptotic abilities of HG-induced senescent fibroblasts in a dose-dependent manner.MiR-145-5p was found to be highly enriched in P-MSC-EVs.MiR-145-5p inhibitors effectively attenuated the P-MSC-EV-induced functional improvements of senescent fibroblasts.MiR-145-5p mimics simulated the effects of P-MSC-EVs on functional improvements of fibroblasts by suppressing the expression of cyclin-dependent kinase inhibitor 1A and activating the extracellular signal regulated kinase(Erk)/protein kinase B(Akt)signaling pathway.Furthermore,local application of miR-145-5p agomir mimicked the effects of P-MSC-EVs on wound healing.Conclusions:These results suggest that P-MSC-EVs accelerate diabetic wound healing by improv-ing the function of senescent fibroblasts through the transfer of miR-145-5p,which targets cyclin-dependent kinase inhibitor 1A to activate the Erk/Akt signaling pathway.P-MSC-EVs are promising therapeutic candidates for diabetic wound treatment.

Exosomes: roles and therapeutic potential in osteoarthritis

Exosomes participate in many physiological and pathological processes by regulating cell–cell communication, which are involved in numerous diseases, including osteoarthritis(OA). Exosomes are detectable in the human articular cavity and were observed to change with OA progression. Several joint cells, including chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and secrete exosomes that influence the biological effects of targeted cells. In addition, exosomes from stem cells can protect the OA joint from damage by promoting cartilage repair, inhibiting synovitis, and mediating subchondral bone remodeling.This review summarizes the roles and therapeutic potential of exosomes in OA and discusses the perspectives and challenges related to exosome-based treatment for OA patients in the future.

Novel neutrophil extracellular trap-related mechanisms in diabetic wounds inspire a promising treatment strategy with hypoxia-challenged small extracellular vesicles

Neutrophil extracellular traps(NETs)have been considered a significant unfavorable factor for wound healing in diabetes,but the mechanisms remain unclear.The therapeutic application of small extracellular vesicles(sEVs)derived from mesenchymal stem cells(MSCs)has received considerable attention for their properties.Hypoxic preconditioning is reported to enhance the therapeutic potential of MSC-derived sEVs in regenerative medicine.Therefore,the aim of this study is to illustrate the detailed mechanism of NETs in impairment of diabetic wound healing and develop a promising NET-targeting treatment based on hypoxic pretreated MSC-derived sEVs(Hypo-sEVs).Excessive NETs were found in diabetic wounds and in high glucose(HG)-induced neutrophils.Further research showed that high concentration of NETs impaired the function of fibroblasts through activating endoplasmic reticulum(ER)stress.Hypo-sEVs efficiently promoted diabetic wound healing and reduced the excessive NET formation by transferring miR-17-5p.Bioinformatic analysis and RNA interference experiment revealed that miR-17-5p in Hypo-sEVs obstructed the NET formation by targeting TLR4/ROS/MAPK pathway.Additionally,miR-17-5p overexpression decreased NET formation and overcame NET-induced impairment in fibroblasts,similar to the effects of Hypo-sEVs.Overall,we identify a previously unrecognized NET-related mechanism in diabetic wounds and provide a promising NET-targeting strategy for wound treatment.

MiR146a-loaded engineered exosomes released from silk fibroin patch promote diabetic wound healing by targeting IRAK1

Unhealable diabetic wounds need to be addressed with the help of newer,more efficacious strategies.Exosomes combined with biomaterials for sustained delivery of therapeutic agents are expected to bring new hope for chronic wound treatment.Here,the engineered exosomes modified for efficiently loading miR146a and attaching to silk fibroin patch(SFP)were demonstrated to promote diabetic wound healing.Silk fibroin binding peptide(SFBP)was screened through phage display,and SFBP-Gluc-MS2(SGM)and pac-miR146a-pac fusion protein were constructed.The designed exosomes(SGM-Exos,miR146a-Exos,and SGM-miR146a-Exos)were isolated from the engineered placental mesenchymal stem cells(PMSCs)transduced with SGM or/and pac-miR146a-pac protein.Gluc signals indicated SGM-Exo@SFP markedly increased the binding rate and the stability of SGM-Exo.Moreover,the loading efficiency of miR146a in SGM-miR146a-Exos was ten-fold higher than that in miR146a-Exos.Superior to untreated,SGM-miR146a-Exo-only treated,and SFP-only treated groups,SGM-miR146a-Exo@SFP drived wound healing associated with less inflammation,collagen deposition,and neovascularization.The transcriptomics analysis suggested anti-inflammatory and regenerative effects with SGM-miR146a-Exo@SFP treatment.Here,we show efficient exosome@biomaterial-based miRNA delivery systems for regenerative medicine and tissue engineering.

Single-cell RNA-seq and bulk-seq identify RAB17 as a potential regulator of angiogenesis by human dermal microvascular endothelial cells in diabetic foot ulcers

Background:Angiogenesis is crucial in diabetic wound healing and is often impaired in diabetic foot ulcers(DFUs).Human dermal microvascular endothelial cells(HDMECs)are vital components in dermal angiogenesis;however,their functional and transcriptomic characteristics in DFU patients are not well understood.This study aimed to comprehensively analyse HDMECs from DFU patients and healthy controls and find the potential regulator of angiogenesis in DFUs.Methods:HDMECs were isolated from skin specimens of DFU patients and healthy controls via magnetic-activated cell sorting.The proliferation,migration and tube-formation abilities of the cells were then compared between the experimental groups.Both bulk RNA sequencing(bulk-seq)and single-cell RNA-seq(scRNA-seq)were used to identify RAB17 as a potential marker of angiogenesis,which was further confirmed via weighted gene co-expression network analysis(WGCNA)and least absolute shrink and selection operator(LASSO)regression.The role of RAB17 in angiogenesis was examined through in vitro and in vivo experiments.Results:The isolated HDMECs displayed typical markers of endothelial cells.HDMECs isolated from DFU patients showed considerably impaired tube formation,rather than proliferation or migration,compared to those from healthy controls.Gene set enrichment analysis(GSEA),fGSEA,and gene set variation analysis(GSVA)of bulk-seq and scRNA-seq indicated that angiogenesis was downregulated in DFU-HDMECs.LASSO regression identified two genes,RAB17 and CD200,as characteristic of DFU-HDMECs;additionally,the expression of RAB17 was found to be significantly reduced in DFU-HDMECs compared to that in the HDMECs of healthy controls.Overexpression of RAB17 was found to enhance angiogenesis,the expression of hypoxia inducible factor-1α and vascular endothelial growth factor A,and diabetic wound healing,partially through the mitogen-activated protein kinase/extracellular signal-regulated kinase signalling pathway.Conclusions:Our findings suggest that the impaired angiogenic capacity in DFUs may be related to the dysregulated expression of RAB17 in HDMECs.The identification of RAB17 as a potential molecular target provides a potential avenue for the treatment of impaired angiogenesis in DFUs.

Clinical and genetic profiles of 985 Chinese families with skeletal dysplasia

To the Editor:Skeletal dysplasia is a group of clinical and genetic heterogeneous disorders with primary involvement of the musculoskeletal system,including bone,cartilage,tendons,ligaments,and muscles,and is usually characterized by short stature,motion limitation,or fragility fractures,sometimes complicated with extra-skeletal phenotypes.

Autophagy in the pathogenesis and therapeutic potential of post-traumatic osteoarthritis

Autophagy,as a fundamental mechanism for cellular homeostasis,is generally involved in the occurrence and progression of various diseases.Osteoarthritis(OA)is the most common muscu-loskeletal disease that often leads to pain,disability and economic loss in patients.Post-traumatic OA(PTOA)is a subtype of OA,accounting for>12%of the overall burden of OA.PTOA is often caused by joint injuries including anterior cruciate ligament rupture,meniscus tear and intra-articular fracture.Although a variety of methods have been developed to treat acute joint injury,the current measures have limited success in effectively reducing the incidence and delaying the progression of PTOA.Therefore,the pathogenesis and intervention strategy of PTOA need further study.In the past decade,the roles and mechanisms of autophagy in PTOA have aroused great interest in the field.It was revealed that autophagy could maintain the homeostasis of chondrocytes,reduce joint inflammatory level,prevent chondrocyte death and matrix degradation,which accordingly improved joint symptoms and delayed the progression of PTOA.Moreover,many strategies that target PTOA have been revealed to promote autophagy.In this review,we summarize the roles and mechanisms of autophagy in PTOA and the current strategies for PTOA treatment that depend on autophagy regulation,which may be beneficial for PTOA patients in the future.

A photoactivatable and phenylboronic acid-functionalized nanoassembly for combating multidrug-resistant gram-negative bacteria and their biofilms

Background:Multidrug-resistant(MDR)gram-negative bacteria-related infectious diseases have caused an increase in the public health burden and mortality.Moreover,the formation of biofilms makes these bacteria difficult to control.Therefore,developing novel interventions to combat MDR gram-negative bacteria and their biofilms-related infections are urgently needed.The purpose of this study was to develop a multifunctional nanoassembly(IRNB)based on IR-780 and N,N-di-sec-butyl-N,N-dinitroso-1,4-phenylenediamine(BNN6)for synergistic effect on the infected wounds and subcutaneous abscesses caused by gram-negative bacteria.Methods:The characterization and bacteria-targeting ability of IRNB were investigated.The bac-tericidal efficacy of IRNB against gram-negative bacteria and their biofilms was demonstrated by crystal violet staining assay,plate counting method and live/dead staining in vitro.The antibacterial efficiency of IRNB was examined on a subcutaneous abscess and cutaneous infected wound model in vivo.A cell counting kit-8 assay,Calcein/PI cytotoxicity assay,hemolysis assay and intravenous injection assay were performed to detect the biocompatibility of IRNB in vitro and in vivo.Results:Herein,we successfully developed a multifunctional nanoassembly IRNB based on IR-780 and BNN6 for synergistic photothermal therapy(PTT),photodynamic therapy(PDT)and nitric oxide(NO)effect triggered by an 808 nm laser.This nanoassembly could accumulate specifically at the infected sites of MDR gram-negative bacteria and their biofilms via the covalent coupling effect.Upon irradiation with an 808 nm laser,IRNB was activated and produced both reactive oxygen species(ROS)and hyperthermia.The local hyperthermia could induce NO generation,which further reacted with ROS to generate ONOO−,leading to the enhancement of bactericidal efficacy.Furthermore,NO and ONOO−could disrupt the cell membrane,which converts bacteria to an extremely susceptible state and further enhances the photothermal effect.In this study,IRNB showed a superior photothermal-photodynamic-chemo(NO)synergistic therapeutic effect on the infected wounds and subcutaneous abscesses caused by gram-negative bacteria.This resulted in effective control of associated infections,relief of inflammation,promotion of re-epithelization and collagen deposition,and regulation of angiogenesis during wound healing.Moreover,IRNB exhibited excellent biocompatibility,both in vitro and in vivo.Conclusions:The present research suggests that IRNB can be considered a promising alternative for treating infections caused by MDR gram-negative bacteria and their biofilms.

Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes

Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.

IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization

Cartilage development is controlled by the highly synergistic proliferation and differentiation of growth plate chondrocytes,in which the Indian hedgehog(IHH)and parathyroid hormone-related protein-parathyroid hormone-1 receptor(PTHrP-PTH1R)feedback loop is crucial.The inositol-requiring enzyme 1a/X-box-binding protein-1 spliced(IRE1α/XBP1s)branch of the unfolded protein response(UPR)is essential for normal cartilage development.However,the precise role of ER stress effector IRE1α,encoded by endoplasmic reticulum to nucleus signaling 1(ERN1),in skeletal development remains unknown.Herein,we reported that loss of IRE1α accelerates chondrocyte hypertrophy and promotes endochondral bone growth.ERN1 acts as a negative regulator of chondrocyte proliferation and differentiation in postnatal growth plates.Its deficiency interrupted PTHrP/PTH1R and IHH homeostasis leading to impaired chondrocyte hypertrophy and differentiation.XBP1s,produced by p-IRE1α-mediated splicing,binds and up-regulates PTH1R and IHH,which coordinate cartilage development.Meanwhile,ER stress cannot be activated normally in ERN1-deficient chondrocytes.In conclusion,ERN1 deficiency accelerates chondrocyte hypertrophy and cartilage mineralization by impairing the homeostasis of the IHH and PTHrP/PTH1R feedback loop and ER stress.ERN1 may have a potential role as a new target for cartilage growth and maturation.

Total body water percentage and 3rd space water are novel risk factors for training-related lower extremity muscle injuries in young males

Purpose:To identify the risk factors for training-related lower extremity muscle injuries in young males by a non-invasive method of body composition analysis.Methods:A total of 282 healthy young male volunteers aged 18-20 years participated in this cohort study.Injury location,degree,and injury rate were adjusted by a questionnaire based on the overuse injury assessment methods used in epidemiological studies of sports injuries.The occurrence of training injuries is monitored and diagnosed by physicians and treated accordingly.The body composition was measured using the BodyStat QuadScan 4000 multifrequency Bio-impedance system at 5,50,100 and 200 kHz to obtain 4 impedance values.The Shapiro-Wilk test was used to check whether the data conformed to a normal distribution.Data of normal distribution were shown as mean±SD and analyzed by t-test,while those of non-normal distribution were shown as median(Q1,Q3)and analyzed by Wilcoxon rank sum test.The receiver operator characteristic curve and logistic regression analysis were performed to investigate risk factors for developing training-related lower extremity injuries and accuracy.Results:Among the 282 subjects,78(27.7%)developed training injuries.Lower extremity training injuries revealed the highest incidence,accounting for 23.4%(66 cases).These patients showed higher percentages of lean body mass(p=0.001),total body water(TBW,p=0.006),extracellular water(p=0.020)and intracellular water(p=0.010)as well as a larger ratio of basal metabolic rate/total weight(p=0.006),compared with those without lower extremity muscle injuries.On the contrary,the percentage of body fat(p=0.001)and body fat mass index(p=0.002)were lower.Logistic regression analysis showed that TBW percentage>65.35%(p=0.050,odds ratio=3.114)and 3rd space water>0.95%(p=0.045,odds ratio=2.342)were independent risk factors for lower extremity muscle injuries.Conclusion:TBW percentage and 3rd space water measured with bio-impedance method are potential risk factors for predicting the incidence of lower extremity muscle injuries in young males following training.

Changes in the gut microbiota of osteoporosis patients based on 16S rRNA gene sequencing:a systematic review and meta-analysis

Background:Osteoporosis(OP)has become a major public health issue,threatening the bone health of middle-aged and elderly people from all around the world.Changes in the gut microbiota(GM)are correlated with the maintenance of bone mass and bone quality.However,research results in this field remain highly controversial,and no systematic review or meta-analysis of the relationship between GM and OP has been conducted.This paper addresses this shortcoming,focusing on the difference in the GM abundance between OP patients and healthy controls based on previous 16S ribosomal RNA(rRNA)gene sequencing results,in order to provide new clinical reference information for future customized prevention and treatment options of OP.Methods:According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA),we comprehensively searched the databases of Pub Med,Web of Science,Embase,Cochrane Library,and China National Knowledge Infrastructure(CNKI).In addition,we applied the R programming language version 4.0.3 and Stata 15.1 software for data analysis.We also implemented the Newcastle-Ottawa Scale(NOS),funnel plot analysis,sensitivity analysis,Egger’s test,and Begg’s test to assess the risk of bias.Results:This research ultimately considered 12 studies,which included the fecal GM data of 2033 people(604 with OP and 1429 healthy controls).In the included research papers,it was observed that the relative abundance of Lactobacillus and Ruminococcus increased in the OP group,while the relative abundance for Bacteroides of Bacteroidetes increased(except for Ireland).Meanwhile,Firmicutes,Blautia,Alistipes,Megamonas,and Anaerostipes showed reduced relative abundance in Chinese studies.In the linear discriminant analysis Effect Size(LEfSe)analysis,certain bacteria showed statistically significant results consistently across different studies.Conclusions:This observational meta-analysis revealed that changes in the GM were correlated with OP,and variations in some advantageous GM might involve regional differences.

Autophagy,not apoptosis,plays a role in lumen formation of eccrine gland organoids

Background:Sweat secreted by eccrine sweat glands is transported to the skin surface through the lumen.The eccrine sweat gland develops from the initial solid bud to the final gland structure with a lumen,but how the lumen is formed and the mechanism of lumen formation have not yet been fully elucidated.This study aimed to investigate the mechanism of lumen formation of eccrine gland organoids(EGOs).Methods:Human eccrine sweat glands were isolated from the skin for tissue culture,and the primary cultured cells were collected and cultured in Matrigel for 14 daysin vitro.EGOs at different development days were collected for hematoxylin and eosin(H&E)staining to observe morphological changes and for immunofluorescence staining of proliferation marker Ki67,cellular motility marker filamentous actin(F-actin),and autophagy marker LC3B.Western blotting was used to detect the expression of Ki67,F-actin,and LC3B.Moreover,apoptosis was detected using a terminal deoxynucleotidyl transferase dUTP nick end labeling(TUNEL)apoptosis assay kit,and the expression of poly(ADP-ribose)polymerase and Caspase-3 was detected by Western blot.In addition,3-methyladenine(3MA)was used as an autophagy inhibitor to detect whether the formation of sweat glands can be effectively inhibited.Results:The results showed that a single gland cell proliferated rapidly and formed EGOs on day 4.The earliest lumen formation was observed on day 6.From day 8 to day 14,the rate of lumen formation in EGOs increased significantly.The immunofluorescence and Western blot analyses showed that the expression of Ki67 gradually decreased with the increase in days,while the F-actin expression level did not change.Notably,the expression of autophagy marker LC3B was detected in the interior cells of EGOs as the apoptosis signal of EGOs was negative.Compared with the control group,the autophagy inhibitor 3MA can effectively limit the formation rate of the lumen and reduce the inner diameter of EGOs.Conclusion:Using our model of eccrine gland 3D-reconstruction in Matrigel,we determined that autophagy rather than apoptosis plays a role in the lumen formation of EGOs.

FGF/FGFR signaling in health and disease

Growing evidences suggest that the fibroblast growth factor/FGF receptor(FGF/FGFR)signaling has crucial roles in a multitude of processes during embryonic development and adult homeostasis by regulating cellular lineage commitment,differentiation,proliferation,and apoptosis of various types of cells.In this review,we provide a comprehensive overview of the current understanding of FGF signaling and its roles in organ development,injury repair,and the pathophysiology of spectrum of diseases,which is a consequence of FGF signaling dysregulation,including cancers and chronic kidney disease(CKD).In this context,the agonists and antagonists for FGF-FGFRs might have therapeutic benefits in multiple systems.

Nebulized heparin for inhalation injury in burn patients:a systematic review and meta-analysis

Background:Smoke inhalation injury increases overall burn mortality.Locally applied heparin attenuates lung injury in burn animal models of smoke inhalation.It is uncertain whether local treatment of heparin is benefit for burn patients with inhalation trauma.We systematically reviewed published clinical trial data to evaluate the effectiveness of nebulized heparin in treating burn patients with inhalation injury.Methods:A systematic search was undertaken in PubMed,the Cochrane Library,Embase,Web of Science,the Chinese Journals Full-text Database,the China Biomedical Literature Database and the Wanfang Database to obtain clinical controlled trails evaluating nebulized heparin in the treatment of burn patients with inhalation injury.Patient and clinical characteristics,interventions and physiological and clinical outcomes were recorded.Cochrane Risk of Bias Evaluation Tool and the Newcastle–Ottawa Scale were used to evaluate data quality.Potential publication bias was assessed by Egger’s test.A sensitivity analysis was conducted to assess the stability of the results.The meta-analysis was conducted in R 3.5.1 software.Results:Nine trials were eligible for the systematic review and meta-analysis.Nebulized heparin can reduce lung injury and improve lung function in burn patients with inhalation injury without abnormal coagulation or bleeding,but the findings are still controversial.Mortality in the heparintreated group was lower than that of the traditional treatment group(relative risk(RR)0.75).The duration of mechanical ventilation(DOMV)was shorter in the heparin-treated group compared to the traditional treatment group(standardized mean difference(SMD)−0.78).Length of hospital stay was significantly shorter than that in the traditional treatment group(SMD−0.42),but incidence rates of pneumonia and unplanned reintubation were not significantly different in the study groups(RRs 0.97 and 0.88,respectively).No statistically significant publication biases were detected for the above clinical endpoints(p>0.05).Conclusions:Based on conventional aerosol therapy,heparin nebulization can further reduce lung injury,improve lung function,shorten DOMV and length of hospital stay,and reduce mortality,although it does not reduce the incidence of pneumonia and/or the unplanned reintubation rate.