Roles of fibroblast growth factors in the treatment of diabetes

Diabetes affects about 422 million people worldwide,causing 1.5 million deaths each year.However,the incidence of diabetes is increasing,including several types of diabetes.Type 1 diabetes(5%-10%of diabetic cases)and type 2 diabetes(90%-95%of diabetic cases)are the main types of diabetes in the clinic.Accumulating evidence shows that the fibroblast growth factor(FGF)family plays important roles in many metabolic disorders,including type 1 and type 2 diabetes.FGF consists of 23 family members(FGF-1-23)in humans.Here,we review current findings of FGFs in the treatment of diabetes and management of diabetic complications.Some FGFs(e.g.,FGF-15,FGF-19,and FGF-21)have been broadly investigated in preclinical studies for the diagnosis and treatment of diabetes,and their therapeutic roles in diabetes are currently under investigation in clinical trials.Overall,the roles of FGFs in diabetes and diabetic complications are involved in numerous processes.First,FGF intervention can prevent high-fat diet-induced obesity and insulin resistance and reduce the levels of fasting blood glucose and triglycerides by regulating lipolysis in adipose tissues and hepatic glucose production.Second,modulation of FGF expression can inhibit renal and cardiac fibrosis by regulating the expression of extracellular matrix components,promote diabetic wound healing process and bone repair,and inhibit cancer cell proliferation and migration.Finally,FGFs can regulate the activation of glucoseexcited neurons and the expression of thermogenic genes.

Clinical Evaluation of Platelet Rich Growth Factors (PRGFS) in Treatment of Temporomandibular Joint Disc Displacement—Study Report

Objective: The aim of the study was to evaluate the effect of platelet rich growth factors (PRGFs) in treatment of temporomandibular joint disc displacement. Materials and Methods: The study subjects included 8 females having bilateral anterior disc displacement with reduction and 1 female having bilateral anterior disc displacement without reduction with the age range between 20 - 35 years. The process of obtaining PRGFs was carried out following the Anitua Technique. Results: Clinical parameters of Interincisal distance, Lateral excursion of mandible using digital caliper in millimeters and Visual Analogue Scale (VAS 0/10) for pain intensity score were used. All of these parameters were running through the intervals of two, four, and eight weeks till the end of the follow-up period at twenty-six weeks (six months). The participated patients showed the clinical improvement in the different clinical statuses such as interincisal distance;lateral excursion of mandible and Pain Score. Conclusion: the study reported early efficacy of PRGFs after the arthrocentesis of the joint in treatment of TMJ disc displacement, and according to our results, the injection of PRGFs could be a possible alternative treatment for patients who did not respond to standard treatment.

An anti-aging skin strategy:promoting repair and regeneration in UV-induced photoaging micro-environment using growth factors-rich platelet lysates composite Self-protection Collagen Hydrogel

Skin photoaging is induced and sustained by UV-induced oxidative damage,and stimulating regeneration of the UV-induced aging has remained a great challenge due to high-level oxidative stress factor(ROS)-induced chronic oxidative damage and inactivation of bio-macromolecule-based regeneration in oxidative photoaging micro-environment.In this study,we designed a“seed and soil”strategy to pursue a safer and more efficient way to prevent and treat photoaging by simultaneously changing UV-induced ROS-rich micro-environment into a proregenerative one(the“soil”)and providing growth factor-rich platelet lysates(PL,the“seed”)using PL-impregnated,collagen-reinforce hydrogel(PL/Col).SD rats were used to establish photoaging model by 8 weeks of UV irradiation.The effectiveness of different treatments was evaluated by making pathological sections and detecting photoaging-related indicators.Rats treated with PL/Col demonstrated a significant acceleration in skin healing and enhancement in the quality of trauma repairing.After treated with PL/Col,the rats showed smooth yellowish appearance,integral structure of skin collagen fiber and epidermis,a decrease in inflammation and a reshaped active micro-environment with reduced levels of SOD enzyme activity,GSH enzyme activity and MDA toxic products.Treatment of PL/Col in skin photoaging has shown potential anti-oxidation and anti-aging effects and is worthy of further study in related field.

Therapeutic role of growth factors in treating diabetic wound

Wounds in diabetic patients,especially diabetic foot ulcers,are more difficult to heal compared with normal wounds and can easily deteriorate,leading to amputation.Common treatments cannot heal diabetic wounds or control their many complications.Growth factors are found to play important roles in regulating complex diabetic wound healing.Different growth factors such as transforming growth factor beta 1,insulin-like growth factor,and vascular endothelial growth factor play different roles in diabetic wound healing.This implies that a therapeutic modality modulating different growth factors to suit wound healing can significantly improve the treatment of diabetic wounds.Further,some current treatments have been shown to promote the healing of diabetic wounds by modulating specific growth factors.The purpose of this study was to discuss the role played by each growth factor in therapeutic approaches so as to stimulate further therapeutic thinking.

Biological characteristics of dynamic expression of nerve regeneration related growth factors in dorsal root ganglia after peripheral nerve injury

The regenerative capacity of peripheral nerves is limited after nerve injury.A number of growth factors modulate many cellular behaviors,such as proliferation and migration,and may contribute to nerve repair and regeneration.Our previous study observed the dynamic changes of genes in L4–6 dorsal root ganglion after rat sciatic nerve crush using transcriptome sequencing.Our current study focused on upstream growth factors and found that a total of 19 upstream growth factors were dysregulated in dorsal root ganglions at 3,9 hours,1,4,or 7 days after nerve crush,compared with the 0 hour control.Thirty-six rat models of sciatic nerve crush injury were prepared as described previously.Then,they were divided into six groups to measure the expression changes of representative genes at 0,3,9 hours,1,4 or 7 days post crush.Our current study measured the expression levels of representative upstream growth factors,including nerve growth factor,brain-derived neurotrophic factor,fibroblast growth factor 2 and amphiregulin genes,and explored critical signaling pathways and biological process through bioinformatic analysis.Our data revealed that many of these dysregulated upstream growth factors,including nerve growth factor,brain-derived neurotrophic factor,fibroblast growth factor 2 and amphiregulin,participated in tissue remodeling and axon growth-related biological processes Therefore,the experiment described the expression pattern of upstream growth factors in the dorsal root ganglia after peripheral nerve injury.Bioinformatic analysis revealed growth factors that may promote repair and regeneration of damaged peripheral nerves.All animal surgery procedures were performed in accordance with Institutional Animal Care Guidelines of Nantong University and ethically approved by the Administration Committee of Experimental Animals,China(approval No.20170302-017)on March 2,2017.

Comprehensive assessment of growth factors,inflammatory mediators, and cytokines in vitreous from patients with proliferative diabetic retinopathy

AIM: To assess alterations in growth factors, inflammatory mediators, and cytokines associated with vitreous-retinal diseases in vitreous humor from patients with proliferative diabetic retinopathy(PDR), and to identify potential new treatment targets and strategies.METHODS: Control vitreous samples were collected from patients with macular hole, epiretinal membranes, or rhegmatogenous retinal detachments, and PDR samples from patients with complications of PDR, who required pars plana vitrectomy. Specimens were stored at-80℃ and then investigated by Luminex multi-factor assay. Parametric and nonparametric analyses of demographic characteristics and cytokine expression levels were conducted using SPSS.RESULTS: There were no significant differences in demographic characteristics between patients with and without PDR. Expression levels of growth factors [plateletderived growth factor(PDGF)-AA, glial cell line-derived neurotrophic factor(GDNF), and vascular endothelial growth factor A(VEGFA)], inflammatory mediators [interleukin(IL)-8, IL-11, and tumor necrosis factor-α(TNF-α)] and cytokines [chemokine C-X-C ligand(CXCL)10, interferon-γ(IFN-γ), and granulocyte macrophage-colony stimulating factor(GM-CSF)] were significantly elevated in vitreous humor from patients with PDR compared with those in the control group(all P<0.05). Further, VEGFA levels were lower in patients with PDR treated with anti-VEGF injection than those who were not(P<0.05), and there was no difference between the PDR group treated with anti-VEGF and controls(P>0.05).CONCLUSION: This proof-of-concept study demonstrates the potential for combinational therapeutic strategies to ameliorate diabetic retinopathy progression by targeting growth factors, inflammatory factors, and cytokines, in addition to VEGFA.

Analysis and Optimisation of Halomonas Growth Factors Based on PCA and RSM

The biomass of petroleum-degrading bacteria, such as Halomonas spp., is crucial to the alleviation of severe oil spills through bioremediation. In this paper, the bacterium(HDMP1) was isolated and identified. Growth factors were analysed and optimised through the single-factor experiments, the factor analysis(FA), the principal component analysis(PCA), and the response surface methodology(RSM). Results indicated that HDMP1 was identified as genus Halomonas. In the single-factor experiments, the range of suitable growth conditions for HDMP1 covered: a salt concentration of 2%-4%, a medium pH value of approximately 9, an inoculum concentration of 1.0%, a substrate concentration of 1.0%-1.4%, and a rotation rate of 140 r/min. The evaluation by FA and PCA indicated that three significant growth factors were the salt concentration, the pH value, and the rotation rate. A maximum biomass of HDMP1 was obtained under the conditions covering a salt concentration of 3.5%, a medium pH of 8, and a rotation rate of 151 r/min by optimization.

Content of blood cell components,inflammatory cytokines and growth factors in autologous platelet-rich plasma obtained by various methods

BACKGROUND The evaluation of the efficacy of platelet-rich plasma(PRP) in clinical practice yields conflicting results and raises numerous controversies. This may be due to different concentrations of biologically active components in PRP obtained with the use of different methods of gravity separation.AIM To compare the content, repeatability and correlations between biologically active components in PRP obtained with four different commercial systems.METHODS From a whole blood sample of each of 12 healthy male volunteers, 4 PRP samples were prepared using 4 different commercial kits [Arthrex Autologous Conditioned Plasma(ACP), Mini GPS Ⅲ, Xerthra, Dr. PRP] in accordance with the instructions provided by the manufacturers. A comparative analysis of blood cell components-13 selected inflammatory cytokines and 7 growth factors-in the obtained PRP samples was performed using the Kruskal-Wallis test by ranks. The repeatability of results in each method was evaluated by the estimation of the coefficient of variation. The Spearman correlation was used to estimate the relationship between blood cell content and cytokines.RESULTS Significantly higher concentrations of platelets(PLT), white blood cells(WBC) and red blood cells(RBC) were found in PRP obtained with the use of Mini GPS Ⅲ than in PRP obtained using other systems. Significant differences in the content of growth factors and cytokines in PRP were found. A positive correlation of the amount of PLT, RBC and WBC with the concentration of most of the growth factors was found but in only three inflammatory cytokines. The obtained correlations between blood cell components and cytokines differed between the systems in terms of statistical significance, which may be due to insufficient sample size. The repeatability of the obtained PLT concentration also varied between protocols with the lowest in Xerthra and the highest in Arthrex ACP.CONCLUSION Significant differences in the content of biologically active components and their repeatability were found in PRP obtained by various methods, providing new data for further research.

Clinical Use of Growth Factors in the Improvement of Skin Wound Healing

To discuss the normal mechanism of wound healing (WH), the role of growth factors (GF) in prec-linical and clinical studies and its importance in the healing of abnormal wound therapy. For search, we used the PUBMED and LILACS database, and the following descriptors: skin, wound healing, growth factor and clinical trials. We also prioritized the analysis of the Clinical Trials in the previous 10 years. Although there are many studies being conducted in the pre-clinical phase, we see that there are few studies in the clinical phase. 274 studies were identified, and 58 were selected. After tissue injury, repair occurs through coordinated biological actions that are healing. The importance of the study of healing in the skin is not only because of its anatomical location, easy access and exposure, but also because of its vital function. There is accumulating evidence that the process of healing after injury may be mediated by several GF. However, may this class of molecules even act effectively on the clinical response of this pathological condition? Many preclinical studies (in vitro and in vivo) reinforce the importance and efficacy of GF in the regeneration of damaged skin. Furthermore, recent studies have reported the use in adjuvant or not, of GF in clinical treatment to improve WH in humans. Therefore, we conclude that it seems to be effective by the use of GF in adjuvant or not in WH. However, it still seems to be necessary to carry out more clinical trials in phase I and II.

Inflammatory priming of mesenchymal stem cells:Focus on growth factors enhancement

Multipotent mesenchymal stromal cells(MSCs)are actively involved in reparation and inflammation processes,providing damaged tissue reparation and suppressing immune cell responses in vivo.The effects are mostly due to the production of a wide range of paracrine factors,including growth factors and immunomodulatory mediators.To induce immunosuppressive activity,MSCs are primed by inflammatory cytokines,which results in an increased production of immunomodulatory molecules.However,stimulation of reparative properties is also necessary.This viewpoint manuscript highlights the possibilities of inflammatory priming to increase the production of growth factors by MSCs.

The Growth Factors Involved in Microalgae Cultivation for Biofuel Production: A Review

The growing demand for energy and the negative environmental impacts of fossil fuel use are triggering global searches for a renewable and eco-friendly alternative biofuel. Microalgae are considered as one of the most promising feedstocks for biofuel production, due to many advantages including cultivation in non-arable land and being able to grow in wastewater or seawater. That is why;microalgae-based biofuels are regarded as one of the best candidates to replace fossil fuels. There are two main types of microalgae cultivation systems: Open Raceway Ponds and Closed Photobioreactos (PBRs). Due to some limitations in Open Raceways, PBRs have become the most favorable choice for biofuel producers, even though it is costly. To make the process viable, the growth of microalgae for biofuel production should be cost-effective. One way to achieve this goal is to optimize the environmental factors that influence their growth during the cultivation stage to increase the accumulation of bio-compounds of fuel. Algal growth relies mostly on nutrients, CO2 concentration, pH and salinity, light intensity and quality, temperature and finally mixing, which directly affects all other factors. Thus, before designing PBR, a thorough study on these growth parameters is needed. In the present study, we reviewed and evaluated these growth influencing factors in an extensive way to optimize biofuel production.

Growth Factors and Supporting Cells of Nerve Conduits for Peripheral Nerve Regeneration

Peripheral nerve injury is a common disease that endangers human health.There is a variety of methods to repair peripheral nerve injury,the current"gold standard"approach is autograft,however it still faces many disadvantages.A new choice is the use of artificial nerve conduits,which are tubular structures and are designed to bridge nerve gaps.In order to bridge longer nerve gaps and gain ideal nerve regeneration effects,multiple technologies have been developed to the design of nerve conduits,such as selecting sutible materials,supplementing growth factors,transplanting supporting cells and so on.This review mainly introduce current progess in growth factors supplementation and supporting cells transplantation technology of nerve conduits.

Effects of the Nocth signaling pathway on expression of inflammatory factors and transforming growth factors in diabetic foot ulcers

Objective:persistent hyperinflammation is an important reason for the development of diabetic foot ulcer.Notch signaling is an important signaling pathway involved in the inflammatory response and cell proliferation in diabetic foot ulcer rats.This paper aims to explore the effect of Notch signaling on inflammatory factors,chemokines and growth factors through the intervention of Notch signaling in diabetic foot ulcer rats.Methods:the experimental model was made by using high-fat feed combined with streptozotocin(STZ)to cause diabetes,and the experimental model of diabetic foot ulcer was established by constant temperature and constant pressure scald apparatus.The normal ulcer model was used as a control.The intervention controls of the experimental model included normal saline,western medicine growth factor,Notch agonist Jagged1,Notch signaling inhibitor ly-411575,and the intervention of traditional Chinese medicine Zizhu ointment for 7 days.Serum il-1,il-6,TNF-radiation,and il-17 were detected by ELISA.Real-time PCR was used to detect the inflammatory factors,chemokines,and growth factors associated with Notch signaling in wound tissues:tnf-uum,il-1,il-6,il-17,interleukin-8,ip-10,McP-1,TGF-uum,TGF-livelihood.Results:serum levels of il-1,il-6,TNF-radiation and il-17 in diabetic foot ulcer rats were significantly higher than that in normal ulcer rats.The contents of il-1,il-6,TNF-radiation and il-17a in ly-411575 group and Zizhu ointment group were significantly reduced.Real-time PCR results of wound tissue showed that the levels of inflammatory cytokines il-1,il-6,TNF-radiation,il-17 and chemokines ip-10,il-8 and McP-1 in the wound tissue of diabetic foot ulcer rat model were significantly higher than that of normal ulcer model,and the levels of growth factor TGF-exposure were lower than that of normal ulcer model.LY-411575 significantly reduced il-1,il-6,TNF-maxima,il-17,and the chemokines ip-10,il-8,and McP-1 in diabetic foot ulcer rats,and reduced the expression of TGF-,TGF-earth.Jagged1 can increase the expression of TGF--,TGF---,suggesting that inhibition of the Notch signaling pathway can reduce the expression of the inflammatory factors il-1,il-6,TNF--,il-17a,il-8,and the growth factors TGF--,TGF---.Zizhu ointment can reduce the levels of il-1,il-6,TNF-benand,il-17,and the chemokines ip-10,il-8,and McP-1 on the wound surface of diabetic foot rats,and improve the expression of TGF-benand TGF-SUNS.Ly-411575 inhibited the expression of TGF-bento and TGF-promoting of Zizhu ointment.Conclusion:the expression of inflammatory cytokines and chemokines was higher and the expression of growth factors was lower in diabetic foot ulcer rats than in normal ulcer rats.Inhibition of Notch signaling pathway can reduce the expression of inflammatory factors,chemokines and growth factors in experimental model rats,and Notch signaling pathway can promote inflammation and cell proliferation.Zizhu ointment can reduce the levels of inflammatory cytokines and chemokines in diabetic foot ulcer rats,improve the expression of growth factors,and reduce wound inflammation,which may be related to the inhibition of Nocth signal expression.

Effect of hepatocyte growth factor on inflammatory factors associated with CCL_(4)-induced hepatocyte injury

Objective:The aim of this study is to investigate the effects of Hepatocyte Growth Factor(HGF)on the expression levels of IL-8,TNF-α,IL-4,and IL-21 in mice with liver injury induced by CCL_(4).Methods:An acute liver injury mouse model was established using CCL_(4),and hepatocytes and white blood cells were separated by gradient density centrifugation.Different concentrations of HGF were added in vitro,and the expression levels of cytokines were detected using ELISA.Results:In the in vivo injury model,the hepatocyte experiment results showed that the expression level of IL-8 was reduced in the 10 ng/mL HGF group compared to the injured hepatocyte group(P<0.05),and increased in the 50 ng/mL HGF group compared to the 10 ng/mL HGF group(P<0.05).For IL-4,the expression levels were reduced in both the 25 ng/mL HGF group(P<0.05)and the 50 ng/mL HGF group(P<0.05)compared to the injured hepatocyte group.The white blood cell experiment results showed that the expression levels of TNF-αwere reduced in both the 10ng/ml HGF group(P<0.05)and the 25 ng/mL HGF group(P<0.05)compared to the injured white blood cell group.In the in vitro injury model,hepatocyte experiment results showed that the expression levels of TNF-αwere reduced in both the 25 ng/mL HGF group(P<0.05)and the 50 ng/mL HGF group(P<0.05)compared to the normal control group.For IL-4,the expression level was reduced in the 25 ng/mL HGF group compared to the normal control group(P<0.05).The white blood cell experiment results showed that the expression level of TNF-αwas increased in the 50 ng/mL HGF group compared to the 10 ng/mL HGF group(P<0.001);for IL-21,the expression levels were reduced in the CCL_(4) model group(P<0.05),10 ng/mL HGF group(P<0.05),25 ng/mL HGF group(P<0.05),and 50 ng/mL HGF group(P<0.05)compared to the normal control group.Conclusion:when the liver of mice is acutely damaged by CCL_(4),HGF can reduce the expression levels of inflammatory cytokines IL-8,TNF-α,IL-4 in hepatocytes,and TNF-αin liver white blood cells.

Growth hormone promotes the reconstruction of injured axons in the hypothalamo-neurohypophyseal system

Previous studies have shown that growth hormone can regulate hypothalamic energy metabolism, stress, and hormone release. Therefore, growth hormone has great potential for treating hypothalamic injury. In this study, we established a specific hypothalamic axon injury model by inducing hypothalamic pituitary stalk electric lesions in male mice. We then treated mice by intraperitoneal administration of growth hormone. Our results showed that growth hormone increased the expression of insulin-like growth factor 1 and its receptors, and promoted the survival of hypothalamic neurons, axonal regeneration, and vascular reconstruction from the median eminence through the posterior pituitary. Altogether, this alleviated hypothalamic injury-caused central diabetes insipidus and anxiety. These results suggest that growth hormone can promote axonal reconstruction after hypothalamic injury by regulating the growth hormone-insulin-like growth factor 1 axis.

Fibroblast growth factor 21 inhibits ferroptosis following spinal cord injury by regulating heme oxygenase-1

Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury.Fibroblast growth factor 21 can inhibit ferro ptosis and promote neurofunctional recovery,while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis.The relationship between heme oxygenase-1and ferroptosis remains controve rsial.In this study,we used a spinal co rd injury rat model to show that the levels of fibroblast growth factor 21 in spinal co rd tissue decreased after spinal cord injury.In addition,there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury.Furthe r,heme oxygenase-1 aggravated fe rroptosis after spinal cord injury,while fibroblast growth factor 21 inhibited fe rroptosis by downregulating heme oxygenase-1.Thus,the activation of fibroblast growth factor 21 may provide a potential treatment for spinal co rd injury.These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.

Chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor for neurotrophic keratopathy

Neurotrophic keratopathy is a persistent defect of the corneal epithelium,with or without stromal ulceration,due to corneal nerve deficiency caused by a variety of etiologies.The treatment options for neurotrophic keratopathy are limited.In this study,an ophthalmic solution was constructed from a chitosan-based thermosensitive hydrogel with long-term release of murine nerve growth factor(CTH-mNGF).Its effectiveness was evaluated in corneal denervation(CD)mice and patients with neurotrophic keratopathy.In the preclinical setting,CTH-mNGF was assessed in a murine corneal denervation model.CTH-mNGF was transparent,thermosensitive,and ensured sustained release of mNGF for over 20 hours on the ocular surface,maintaining the local mNGF concentration around 1300 pg/mL in vivo.Corneal denervation mice treated with CTH-mNGF for 10 days showed a significant increase in corneal nerve area and total corneal nerve length compared with non-treated and CTH treated mice.A subsequent clinical trial of CTH-mNGF was conducted in patients with stage 2 or 3 neurotrophic keratopathy.Patients received topical CTH-mNGF twice daily for 8 weeks.Fluorescein sodium images,Schirmer’s test,intraocular pressure,Cochet-Bonnet corneal perception test,and best corrected visual acuity were evaluated.In total,six patients(total of seven eyes)diagnosed with neurotrophic keratopathy were enrolled.After 8 weeks of CTH-mNGF treatment,all participants showed a decreased area of corneal epithelial defect,as stained by fluorescence.Overall,six out of seven eyes had fluorescence staining scores<5.Moreover,best corrected visual acuity,intraocular pressure,Schirmer’s test and Cochet-Bonnet corneal perception test results showed no significant improvement.An increase in corneal nerve density was observed by in vivo confocal microscopy after 8 weeks of CTH-mNGF treatment in three out of seven eyes.This study demonstrates that CTH-mNGF is transparent,thermosensitive,and has sustained-release properties.Its effectiveness in healing corneal epithelial defects in all eyes with neurotrophic keratopathy suggests CTH-mNGF has promising application prospects in the treatment of neurotrophic keratopathy,being convenient and cost effective.

Anti-vascular endothelial growth factor drugs combined with laser photocoagulation maintain retinal ganglion cell integrity in patients with diabetic macular edema: study protocol for a prospective, non-randomized, controlled clinical trial

The integrity of retinal ganglion cells is tightly associated with diabetic macular degeneration that leads to damage and death of retinal ganglion cells,affecting vision.The major clinical treatments for diabetic macular edema are anti-vascular endothelial growth factor drugs and laser photocoagulation.However,although the macular thickness can be normalized with each of these two therapies used alone,the vision does not improve in many patients.This might result from the incomplete recovery of retinal ganglion cell injury.Therefore,a prospective,non-randomized,controlled clinical trial was designed to investigate the effect of anti-vascular endothelial growth factor drugs combined with laser photocoagulation on the integrity of retinal ganglion cells in patients with diabetic macular edema and its relationship with vision recovery.In this trial,150 patients with diabetic macular edema will be equally divided into three groups according to therapeutic methods,followed by treatment with anti-vascular endothelial growth factor drugs,laser photocoagulation therapy,and their combination.All patients will be followed up for 12 months.The primary outcome measure is retinal ganglion cell-inner plexiform layer thickness at 12 months after treatment.The secondary outcome measures include retinal ganglion cell-inner plexiform layer thickness before and 1,3,6,and 9 months after treatment,retinal nerve fiber layer thickness,best-corrected visual acuity,macular area thickness,and choroidal thickness before and 1,3,6,9,and 12 months after treatment.Safety measure is the incidence of adverse events at 1,3,6,9,and 12 months after treatment.The study protocol hopes to validate the better efficacy and safety of the combined treatment in patients with diabetic macula compared with the other two monotherapies alone during the 12-month follow-up period.The trial is designed to focus on clarifying the time-effect relationship between imaging measures related to the integrity of retinal ganglion cells and best-corrected visual acuity.The trial protocol was approved by the Medical Ethics Committee of the Affiliated Hospital of Beihua University with approval No.(2023)(26)on April 25,2023,and was registered with the Chinese Clinical Trial Registry(registration number:ChiCTR2300072478,June 14,2023,protocol version:2.0).

Milk fat globule epidermal growth factor 8 alleviates liver injury in severe acute pancreatitis by restoring autophagy flux and inhibiting ferroptosis in hepatocytes

BACKGROUND Liver injury is common in severe acute pancreatitis(SAP).Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes,which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis.Our previous study found that milk fat globule epidermal growth factor 8(MFG-E8)alleviates acinar cell damage during SAP via binding toαvβ3/5 integrins.MFG-E8 also seems to mitigate pancreatic fibrosis via inhibiting chaperone-mediated autophagy.AIM To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux.METHODS SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50μg/kg cerulein plus lipopolysaccharide.mfge8-knockout mice were used to study the effect of MFG-E8 deficiency on SAPinduced liver injury.Cilengitide,a specificαvβ3/5 integrin inhibitor,was used to investigate the possible mechanism of MFG-E8.RESULTS The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice,enhanced autophagy flux in hepatocyte,and worsened the degree of ferroptosis.Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner.Mechanistically,MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells.Cilengitide abolished MFG-E8’s beneficial effects in SAP-induced liver injury.CONCLUSION MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury.MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrinαVβ3/5.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.