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ABSTRACT Objective: This study aimed to compare the levels of HIF1-α, VEGF, TNF-α, and IL-10 in the peri-implant crevicular fluid of patients with and without peri-implantitis. Methods: Forty patients, comprising 16 with and 24 without peri-implantitis were selected. Results: Patients with peri-implantitis exhibited significantly higher HIF-1α levels than those without peri-implantitis (p=0.0005). TNF-α revealed significant positive correlations with IL-10 (p=0.0008) and VEGF (p=0.0246), whereas HIF-1α and IL-10 levels (p=0.0041) demonstrated a negative and significative correlation in the peri-implantitis group. Conclusion: This study, for the first time demonstrates the balance of HIF-1α, TNFα, IL-10, and VEGF in peri-implantitis. It shows an elevated HIF-1α levels in patients with peri-implantitis, which could have stemmed from persistent inflammation- triggered hypoxia. Furthermore, the positive correlation between TNF-α and VEGF suggests intensified proinflammatory activity in peri-implantitis. Nevertheless, further studies are essential to understand these immune dynamics in peri-implantitis.
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Polypoidal choroidal vasculopathy (PCV) occurs in the middle-aged and elderly population and is characterized by abnormal intrachoroidal vascular patterns such as branching choroidal vascular networks and polypoidal dilatation of vessel terminals, subretinal orange nodular lesions and hemorrhagic or plasma retinal pigment epithelial detachment (PED), which can cause retinal hemorrhage or vitreous hematopoiesis and is one of the major blinding fundus lesions.Intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs is currently the main method of PCV treatment, and has certain advantages in eliminating abnormal vascular networks and removing polypoidal lesions, reducing vascular exudation and promoting exudate absorption, and improving visual prognosis.However, frequent intravitreal drug injections increase the risk of infection and the treatment burden for patients.In addition, the high recurrence rate after treatment poses a significant challenge to clinical practice, so the search for new therapeutic agents that are durable and less costly is a focus of clinical research in PCV.The literature from abroad suggests that brolucizumab is a novel small-molecule anti-VEGF humanized monoclonal antibody with the advantages of high tissue penetration, high local drug concentration and bioavailability, small injectable dose, long-lasting efficacy and long injection interval, which brings new hope for the clinical treatment of PCV and improving the prognosis of affected eyes.Although the efficacy and safety of brolucizumab in the treatment of PCV have been well documented, the literature is mainly from Japan, India and Korea, and clinical practice data from China are still lacking.With the approval of the drug in several countries, it is believed that more PCV patients could benefit from this treatment in the near future.Ophthalmologists and researchers in China should closely follow the progress of brolucizumab in the treatment of PCV.
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Neovascularization is the hallmark of many fundus diseases, including diabetic retinopathy, retinal vein occlusion and neovascular age-related macular degeneration.More and more evidence suggests that vascular endothelial growth factor (VEGF) plays a critical role in neovascularization.Anti-VEGF drugs are the first-line treatment for neovascular fundus diseases and have achieved significant results.However, there are drawbacks such as short drug half-lives and the need for long-term administration to maintain effective concentrations, which increases the economic burden and medical risk for patients and reduces compliance.Therefore, finding a new method for intraocular drug delivery is of great clinical importance.Based on the principle that diabetes patients use insulin pumps to gradually release drugs, the ocular anti-VEGF drug delivery system can continuously release anti-VEGF drugs over a period of time, significantly reducing the injection frequency and improving patient compliance.At present, the research on ocular anti-VEGF drug delivery systems is still immature, and various systems are in different stages of clinical trials.According to different design principles, they can be divided into three categories with their characteristics, micropump (extraocular storage delivery systems), biodegradable implants, and non-biodegradable implants.This article summarized and analyzed the controlled ocular anti-VEGF drug release delivery systems currently in clinical trials.
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Despite the continuous improvement and development of modern cataract surgery technology, posterior capsule opacification (PCO) is still the common long-term complication causing secondary visual acuity decline after cataract surgery.Previous studies have shown that the occurrence of PCO is closely related to the proliferation, migration, epithelial-mesenchymal transition (EMT) and myofibroblast fibrosis of lens epithelial cells in the anterior capsule and lens equator.In terms of pathogenesis, recent research focuses on the role of cytokines, especially various growth factors.Vascular endothelial growth factor (VEGF) is a kind of growth factor that can promote vascular endothelial cell proliferation and migration, extracellular matrix degeneration and angiogenesis.In addition, there is increasing evidence showing that VEGF plays an important role in fibrosis, inflammation, neuroprotection and other aspects.In recent years, VEGF has been found to promote PCO formation directly or cooperatively with transforming growth factor-β2.Based on the function of VEGF and the relationship between VEGF and EMT, this paper mainly reviewed the advances in the role of VEGF in the eye and the pathogenesis of posterior capsule opacification.
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Objective:To analyze the occurrence of early hypotony after the intravitreal injection of anti-vascular endothelial growth factor (VEGF) and its risk factors.Methods:A case-control study was performed.One hundred and twenty-seven eyes of 127 patients with fundus vascular disease who received intravitreal injections of anti-VEGF drugs were enrolled in Henan Provincial People's Hospital from January 2020 to January 2022.Of the 127 patients, there were 71 males and 56 females, with an average age of (61.85±11.53) years and a mean intraocular pressure of (15.28±3.71)mmHg (1 mmHg=0.133 kPa). All subjects were intravitreally injected with 0.05 ml of anti-VEGF drugs, including 56 cases receiving ranibizumab, 38 cases receiving conbercept and 33 cases receiving aflibercept.The intraocular pressure was measured with a non-contact tonometer at 30 minutes, 1 hour and 2 hours after the injection.The cases were grouped as hypotony group or non-hypotony group according to the intraocular pressure of subjects was less than 10 mmHg or not.The differences in sex, age, distribution of left eye and right eye, disease type, intraocular pressure before injection, injection frequency, lens status, drug type, injection timing, injection site, with or without high myopia, with or without a history of glaucoma or ocular hypertension, and with or without a history of vitreoretinal surgery were analyzed to investigate the factors with a P-value <0.05, which were used as the independent variable and the occurrence of hypotony as the dependent variable in logistic regression analysis to explore the risk factors for hypotony.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Henan Eye Hospital (No.HNEEC-2022-42). Results:Hopotony occurred in 8 eyes within 2 hours after the injection.There were significant differences in intraocular pressure at different time points before and after injection between the hypotony and non-hypotony groups ( Fgroup=62.177, P<0.001; Ftime=25.128, P<0.001). The intraocular pressure of the hypotony group at 30 minutes, 1 hour and 2 hours after injection were lower than before injection, and the intraocular pressure of the non-hypotony group was higher at 30 minutes after injection than before injection (all at P<0.05). The average reduction of intraocular pressure of the hypotony group was 7.88, 7.63 and 7.23 mmHg at 30 minutes, 1 hour and 2 hours after the injection, and the intraocular pressure returned to baseline level at 1 day after injection.There was no significant difference in sex, distribution of left and right eyes, disease type, pre-injection intraocular pressure, injection frequency, lens status, drug type, injection timing, injection site, with or without a history of high myopia and with or without a history of glaucoma or ocular hypertension between the two groups.There were significant differences in age and with or without a history of vitreoretinal surgery between the two groups ( t=8.265, P<0.001; χ2=6.907, P=0.035). Multivariate logistic regression analysis showed younger patients and having a history of vitreoretinal surgery were the risk factors for early hypotony after anti-VEGF intravitreal injection (odds ratio=88.563, P<0.001; odds ratio=20.991, P=0.009). Conclusions:Patients with younger age and having a history of vitreoretinal surgery are susceptible to early hypotony after anti-VEGF intravitreal injection.
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Objective:To investigate the effects of alum ice nanoemulsion on VEGF and TGF-β1 in hypertrophic scar based on Notch signaling pathway.Methods:Totally 144 SD rats were divided into blank control group, model group, triamcinolone acetonide group and alum ice nanoemulsion low-, medium- and high-dose groups according to random number table method, with 24 rats in each group. Except for the blank control group, the rats in other groups were prepared with deep Ⅱ ° burn models. 24 hours after the successful modeling, the model group was given the same amount of normal saline, the rats in alum ice nanoemulsion low-, medium- and high-dose groups were given 8.15, 6.30 and 32.60 mg/ml alum ice nanoemulsion respectively, and the triamcinolone acetonide group was given triamcinolone acetonide twice a day, 0.2 ml each time, for 35 consecutive days. At 14, 21, 28 and 35 d, the collagen fiber surface density was calculated by VG staining. The protein expressions of vascular endothelial growth factor (VEGF), transforming growth factor-β1 (TGF-β1), Notch1 and Jagged1 were detected by Western Blot. The expressions of Notch1 mRNA and Jagged1 mRNA were detected by RT-PCR.Results:Compared with model group, triamcinolone acetonide and different doses of alum ice nanoemulsion groups could decrease collagen fiber surface density, protein expressions of VEGF, TGF-β1, Notch1, Jagged1 and mRNA expressions of Notch1, Jagged1 in different degrees ( P<0.05). Compared with the triamcinolone acetonide group, the collagen fiber surface density, protein expressions of VEGF, TGF-β1, Notch1 and Jagged1 and mRNA expressions of Notch1, Jagged1 in the alum ice nanoemulsion medium-dosage group decreased ( P<0.05). Conclusion:Alum ice nanoemulsion can inhibit hypertrophic scar formation, and its mechanism is related to down-regulating Notch signal pathway related molecules Notch1, Jagged1 protein and mRNA levels, and then down-regulating VEGF and TGF-β1 protein expressions.
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SUMMARY OBJECTIVE: In this study, we aimed to determine the impact of the antiangiogenic medications, namely, aflibercept and cabergoline in the prevention and treatment of ovarian hyperstimulation syndrome in a rat model. METHODS: A total of 36 female Wistar rats were randomly allocated to one of the five groups, including disease-free and ovarian hyperstimulation syndrome controls: Group no OHSS (control, n=6) received saline only intraperitoneally (i.p.); group just OHSS (ovarian hyperstimulation syndrome only, n=6) received 10 IU pregnant mare serum gonadotropin and 30 IU human chorionic gonadotropin subcutaneously to produce ovarian hyperstimulation syndrome; group cabergoline+OHSS (cabergoline+ovarian hyperstimulation syndrome, n=8) received 100 μg/kg oral cabergoline; group aflibercept (12.5 mg/kg)+OHSS (aflibercept+ovarian hyperstimulation syndrome, n=8) received 12.5 mg/kg i.p. aflibercept; and group aflibercept (25 mg/kg)+OHSS (aflibercept+ovarian hyperstimulation syndrome, n=8) received 25 mg/kg i.p. aflibercept. The groups were compared for ovarian weight, immunohistochemical vascular endothelial growth factor expression, spectrophotometric vascular permeability evaluated with methylene blue solution in peritoneal lavage, and body weight growth. RESULTS: Vascular endothelial growth factor immunoexpression was substantially greater in the just OHSS group (22.00±10.20%) than in the aflibercept (12.5 mg/kg)+OHSS (7.87±6.13%) and aflibercept (25 mg/kg)+OHSS (5.63±4.53%) groups (p=0.008 and p=0.005, respectively). Post-hoc tests indicated that cabergoline, 12.5 mg/kg aflibercept, and 25 mg/kg aflibercept decreased vascular permeability compared to the untreated ovarian hyperstimulation syndrome group (p=0.003, p=0.003, and p=0.001, respectively). JOH group had the heaviest ovaries, whereas aflibercept (25 mg/kg)+OHSS group had the lightest. In terms of body weight gain, cabergoline+OHSS group was substantially greater than the aflibercept (12.5 mg/kg)+OHSS and aflibercept (25 mg/kg)+OHSS groups (p=0.006 and p=0.007, respectively). CONCLUSION: Aflibercept, an antiangiogenic medication, decreased ovarian hyperstimulation syndrome by lowering the vascular permeability and vascular endothelial growth factor expression.
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SUMMARY OBJECTIVE: Coronavirus disease 2019 emerges as a disease caused by severe acute respiratory syndrome coronavirus 2. It is a systemic disease associated with vascular inflammation and endothelial damage. In this study, we aimed to investigate whether vascular endothelial growth factor gene insertion/deletion polymorphism is associated with coronavirus disease 2019 in the Turkish population. METHODS: The study included 179 participants (79 patients with coronavirus disease 2019 and 100 controls). DNA isolation was made from peripheral blood, and then the polymerase chain reaction analysis was performed. RESULTS: When we analyze vascular endothelial growth factor gene insertion/deletion polymorphism in the study group, we found that the DD genotype and D allele were found to be statistically significantly different when compared to coronavirus disease 2019 patients with high vitamin D value (p=0.005 for DD genotype and p=0.006 for D allele) in the control group. In this high-level control group, when we analyze II+ID genotype versus DD, a statistically significant difference was also detected (p=0.007). CONCLUSION: As a result of the study, we found that DD genotype and D allele were associated with vitamin D level in Turkish patients with coronavirus disease 2019.
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Objective:To investigate the predictive value of vascular endothelial growth factor (VEGF) expression and microvascular density (MVD) for the depth of infiltration in early gastric cancer.Methods:The pathological tissues of 24 patients with early gastric cancer (early gastric cancer group), 23 patients with advanced gastric cancer (advanced gastric cancer group) and 10 patients with gastritis (gastritis group) who admitted to Fenyang Hospital Affiliated of Shanxi Medical University from January 2020 to January 2022 were retrospectively collected. Immunohistochemistry was used to detect VEGF expression and MVD in the lesion tissues of each group, and the correlation of VEGF expression and MVD in gastric cancer tissues with the clinicopathological characteristics of patients was analyzed. Postoperative pathological diagnosis was treated as the gold standard. The efficacy of VEGF and MVD in predicting the depth of infiltration in gastric cancer and early gastric cancer was assessed by using the receiver operating characteristic (ROC) curve.Results:The VEGF positive expression rate was 10.00% (1/10), 29.17% (7/24) and 78.26% (18/23) in gastritis group, early gastric cancer group and advanced gastric cancer group, respectively, and the MVD was (21±5) strips/field, (23±9) strips/field and (43±15) strips/field, respectively. The positive expression rate of VEGF and MVD were related with the tumor diameter [>2 cm vs. ≤2 cm:69.70% (23/33) vs. 14.29% (2/14), (39±15) strips/field vs. (20±8) strips/field] and infiltration depth of gastric cancer [intramucosal carcinoma vs. submucosal carcinoma vs. advanced gastric cancer: 26.31% (5/19) vs. 40.00% (2/5) vs. 78.26% (18/23), (20±7) strips/field vs. (36±3) strips/field vs. (43±15) strips/field] (all P > 0.01), while not related with gender, age, tumor location, differentiation degree (all P > 0.05). The ROC curve analysis showed that the area under the curve (AUC) of VEGF and MVD in predicting the depth of infiltration in gastric cancer was 0.716 (95% CI 0.581-0.828) and 0.711 (95% CI 0.573-0.823), respectively; the optimal cut-off value of VEGF and MVD was positive and 24.8 strips/field, with the sensitivity of 53.19%, 61.70%, and the specificity of 90.00% both. The AUC of VEGF and MVD in predicting the depth of infiltration in early gastric cancer was 0.596 (95% CI 0.414-0.760) and 0.506 (95% CI 0.330-0.681) , respectively; the optimal cut-off value of VEGF and MVD was positive and 32.5 strips/field, with the sensitivity of 29.17% , 70.83%, and the specificity of 90.00%, 0, respectively. Conclusions:VEGF expression and MVD are elevated with the increase of depth of gastric cancer infiltration, while the value of the combination of both in predicting the depth of infiltration in early gastric cancer is not high.
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Diabetic macular edema (DME) is the most threatening complication of diabetic retinopathy that affects visual function, which is characterized by intractability and recurrent attacks. Currently, the clinical routine treatments for DME mainly include intravitreal injection, grid laser photocoagulation in the macular area, subthreshold micropulse laser, periocular corticosteroid injection, and vitrectomy. Although conventional treatments are effective for some patients, persistent, refractory, and recurrent DME remains a clinical challenge that needs to be urgently addressed. In recent years, clinical studies have found that certain combination therapies are superior to monotherapy, which can not only restore the anatomical structure of the macular area and effectively reduce macular edema but also improve visual function to some extent while reducing the number of treatments and the overall cost. This makes up for the shortcomings of single treatment modalities and is highly anticipated in the clinical setting. However, the application of combination therapy in clinical practice is relatively short, and its safety and long-term effectiveness need further exploration. Currently, new drugs, new formulations, and new therapeutic targets are still under research and development to address different mechanisms of DME occurrence and development, such as anti-vascular endothelial growth factor agents designed to anchor repetitive sequence proteins with stronger inhibition of vascular leakage, multiple growth factor inhibitors, anti-inflammatory agents, and stem cell therapy. With the continuous improvement of the combination application of existing drugs and treatments and the development of new drugs and treatment technologies, personalized treatment for DME will become possible.
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Objective:To investigate the expression levels of serum miR-126 and miR-9 in patients with wet age-related macular degeneration (wAMD) and their relationship with vascular endothelial growth factor (VEGF) and central macular thickness (CMT).Methods:A total of 73 wAMD patients(observation group) admitted to the ophthalmology department of Taizhou Municipal Hospital from May 2020 to May 2021 and 60 healthy subjects (control group) who underwent physical examination during the same period were selected. Real-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression levels of miR-126 and miR-9 in serum of the two groups. Serum angiogenesis regulatory factors [VEGF, tissue inhibitor of melalloproteinuses-1 (TIMP-1), endostatin (ES), platelet-derived growth factor (PDGF)] were detected by enzyme-linked immunosorbent assay (ELISA), and CMT and intraocular pressure (IOP) were measured. Pearson correlation analysis was performed to determine the correlation between miR-126 and miR-9 and serum angiogenesis regulatory factor levels, CMT and IOP. The diagnostic value of miR-126 and miR-9 in wAMD was analyzed by receiver operating characteristic (ROC) curve.Results:The relative expression level of serum miR-126 in observation group was significantly lower than that in control group ( P<0.05) , while the relative expression level of serum miR-9 was significantly higher than that in control group ( P<0.05). The levels of serum VEGF and PDGF in observation group were significantly higher than those in control group (all P<0.05), while the levels of serum TIMP-1 and ES were significantly lower than those in control group (all P<0.05). CMT and IOP in observation group were significantly higher than those in control group (all P<0.05). The expression level of serum miR-126 in observation group was negatively correlated with serum VEGF, PDGF, CMT and IOP ( r=-0.275, -0.523, -0.302, -0.542, all P<0.05), and was positively correlated with TIMP-1 and ES ( r=0.460, 0.263, all P<0.05). Serum miR-9 expression level was positively correlated with serum VEGF, PDGF, CMT and IOP ( r=0.434, 0.438, 0.396, 0.307, all P<0.05), and was negatively correlated with TIMP-1 and ES ( r=-0.256, -0.310, all P<0.05). The area under curve (AUC) values of serum miR-126 and miR-9 in diagnosing wAMD were 0.713 and 0.847 respectively. Conclusions:The expression level of serum miR-126 is significantly decreased while the expression level of miR-9 is significantly increased in patients with wAMD. miR-126 is negatively correlated with VEGF and CMT, and miR-9 is positively correlated with VEGF and CMT, which may aggravate the disease by promoting the inflammatory response. The detection of expression levels of serum miR-126 and miR-9 is helpful to provide the reference basis for early diagnosis of wAMD and early prevention and treatment.
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Objective:To investigate the therapeutic effects of conbercept combined with retinal laser photocoagulation on diabetic macular edema (DME) and the effects of the combined therapy on best corrected visual acuity, macular fovea thickness, vascular endothelial growth factor (VEGF) and human stromal cell-derived factor 1 (SDF-1) levels in aqueous humor of patients with DME.Methods:Ninety patients with DME who received treatment in Lishui People's Hospital between November 2016 and December 2019 were included in this study. They were randomly assigned to undergo retinal laser photocoagulation (control group, n = 45) or retinal laser photocoagulation combined with conbercept treatment (study group, n = 45). Therapeutic effects, best corrected visual acuity, macular fovea thickness, and VEGF and SDF-1 levels in aqueous humor were compared between the two groups. The incidence of complications was compared between the two groups. Results:Total response rate in the study group was significantly higher than that in the control group [88.89% (40/45) vs. 68.89% (31/45), χ2 = 5.40, P = 0.020]. After 3 months of treatment, VEGF and SDF-1 levels in aqueous humor were (138.71 ± 16.82) ng/L and (415.18 ± 24.87) mg/L, respectively, which were significantly lower than those in the control group [(276.13 ± 15.96) ng/L, (526.06 ± 22.91) mg/L, t = 39.76, 21.98, both P < 0.001]. After 3 months of treatment, macular fovea thickness and best corrected visual acuity in the study group were (339.52 ± 30.12) μm and 0.47 ± 0.08, respectively, which were significantly lower than those in the control group [(398.65 ± 28.23) μm, 0.36 ± 0.09, t = 6.13, 9.61, both P < 0.01]. There was no significant difference in the incidence of complications between the two groups [13.33% (6/45) vs. 11.11% (5/45), χ2 = 0.10, P > 0.05]. Conclusion:Conbercept combined with retinal laser photocoagulation for the treatment of DME has a definite therapeutic effect. The combined therapy can greatly improve the best corrected visual acuity, reduce macular fovea thickness, decrease VEGF and SDF-1 levels in aqueous humor, and does not increase the incidence of complications. Findings from this study have a certain clinical application value.
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Objective: To observe the effect of electroacupuncture (EA) of "concurrent treatment of the brain and heart" on angiogenesis and cortical vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in rats with focal cerebral ischemia, and to explore the mechanism of EA in cerebral ischemia treatment. Methods: A total of 108 Sprague-Dawley rats, 27 rats were randomly selected as the sham-operation group, and the rest rats received the right middle cerebral artery occlusion operation for model preparation firstly, and then were divided into a model group, a traditional acupoint group, and a concurrent treatment of the brain and heart group, with 27 rats in each group. In the sham-operation group, only the carotid artery was isolated. EA at Shuigou (CV26), Quchi (LI11), Hegu (LI4), and Zusanli (ST36) in the traditional acupoint group, and EA at Fengfu (GV16), Baihui (GV20), Xinshu (BL15), and Neiguan (PC6) in the concurrent treatment of the brain and heart group were performed 4 h after the operation, once a day, for 14 consecutive days. Rats in the sham-operation group and the model group were identically fixed without any treatment. Before and after treatment, the modified neurological severity score (mNSS), regional cerebral blood flow (rCBF), and CD34 positive expression by immunohistochemistry were measured. The positive protein expression levels of VEGF and BDNF were detected by immunofluorescence, and the mRNA expression levels of VEGF and BDNF were detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results: Compared with the sham-operation group, the mNSS, rCBF, and ischemic side cortical micro-vessel density (MVD) decreased, and the protein and mRNA expression levels of VEGF and BDNF increased in the model group (P<0.01). Compared with the model group, the mNSS of the two EA groups decreased, and the mNSS of the concurrent treatment of the brain and heart group was lower than that of the traditional acupoint group on the 14th day (P<0.05). Compared with the model group, the rCBF in the two EA groups increased, and the rCBF reached the highest on the 14th day (P<0.05 or P<0.01), and the rCBF in the concurrent treatment of the brain and heart group was higher than that in the traditional acupoint group (P<0.05); the MVD of the two EA groups was higher than that of the model group, and the MVD of the concurrent treatment of the brain and heart group was higher than that of the traditional acupoint group on the 7th and 14th days (P<0.05 or P<0.01). Compared with the model group, the protein and mRNA expression levels of VEGF and BDNF in the two EA groups increased (P<0.01). The VEGF expression level was the highest on the 7th day in the concurrent treatment of the brain and heart group (P<0.05), and the BDNF expression level was higher on the 7th and 14th days than on the 3rd day (P<0.05). The mRNA expression levels of VEGF and BDNF in both EA groups reached the highest on the 7th day (P<0.05 or P<0.01). Conclusion: EA therapy can up-regulate the VEGF and BDNF expression levels and increase the rCBF in the cortex of rats with focal cerebral ischemia, which may be one mechanism of EA in the cerebral ischemia treatment. The therapeutic effect is accumulated with the effective time, and the concurrent treatment of the brain and heart group is superior to the traditional acupoint group in promoting angiogenesis.
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Objective:To investigate the role of umbilical cord mesenchymal stem cell-derived exosomes (ucMSC-exos) in acute skin wound healing in mice.Methods:ucMSC-exos were extracted by ultracentrifugation, and identified by transmission electron microscopy, Western blot analysis of exosome surface markers CD63 and TSG101, and particle size analysis. Firstly, in vitro cultured third- to fifth-passage human skin fibroblasts (HSF) were incubated with high-glucose Dulbecco′s modified Eagle′s medium (DMEM) containing 0, 1 and 2 μg/ml exosome suspension for 24 hours (negative control group, 1- and 2-μg/ml groups, respectively) , and cell counting kit-8 (CCK8) assay was performed to evaluate the effect of ucMSC-exos on the proliferative activity of HSF. Secondly, 24 male BALB/c mice aged 8 weeks were selected to construct a mouse model of full-thickness skin wound, and then divided into ucMSC-exos group and phosphate-buffered saline (PBS) group by using a random number table to be subcutaneously injected with exosome suspension and PBS respectively at multiple equidistant sites located about 1 mm apart from the wound edge. On days 0, 4, 7, 10 and 14 after operation, the wounds in mice were observed, and the percentage of residual wound area was calculated in the above two groups. On days 7 and 14 after operation, wound tissues were resected and subjected to hematoxylin and eosin (HE) and Masson staining to observe structural changes of skin tissues. On day 14 after operation, wound tissues were collected in the two groups, and real-time quantitative PCR (qRT-PCR) and Western blot analysis were performed to determine the mRNA and protein expression of type Ⅰ collagen, fibronectin and vascular endothelial growth factor, respectively. Statistical analysis was carried out by using one-way analysis of variance, least significant difference- t test, two-way repeated measures analysis of variance and unpaired t-test. Results:Under the transmission electron microscope, the ucMSC-exos were oval in shape with a diameter of about 100 nm; Western blot analysis showed positive expression of ucMSC-exos surface proteins CD63 and TSG101; particle size analysis showed that 96.2 % of the ucMSC-exos had diameters of 30 - 150 nm. CCK8 assay showed that the relative proliferative activity of HSF was significantly higher in the 1- and 2-μg/ml groups (0.97 ± 0.05, 1.08 ± 0.07, respectively) than in the negative control group (0.71 ± 0.04; t = 2.00, 7.05, respectively, both P < 0.05) , and significantly higher in the 2-μg/ml group than in the 1-μg/ml group ( t = 5.09, P < 0.05) . On days 4, 7, 10 and 14 after operation, the percentage of residual wound area was significantly lower in the ucMSC-exos group than in the PBS group (all P < 0.05) . HE and Masson staining showed increased numbers of hair follicles, glands and granulation tissues, more neovascularization, and neater arrangement of collagens in neonatal skin tissues of the mice in the ucMSC-exos group compared with the PBS group. qRT-PCR and Western blot analysis showed significantly increased mRNA and protein expression of type Ⅰ collagen, fibronectin and vascular endothelial growth factor in the ucMSC-exos group compared with the PBS group (all P < 0.01) . Conclusion:Subcutaneous injections of ucMSC-exos can promote acute skin wound healing in mice, likely by promoting the synthesis of extracellular matrix and vascular endothelial growth factor in wound tissues of mice and proliferation of HSF.
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Objective:To study the roles of hepatoma-derived growth factor (HDGF), vascular endothelial growth factor (VEGF) and mucin 5B (MUC5B) in hepatolithiasis associated with intrahepatic cholangiocarcinoma (HICC).Methods:The clinical data and tissue specimens of 116 patients who underwent hepatectomy at the Third Affiliated Hospital of Wenzhou Medical University from October 1999 to October 2019 were retrospectively analyzed. There were 41 patients with HICC (the HICC group), 38 patients with intrahepatic cholangiolithiasis (the intrahepatic cholangiolithiasis group), and 37 patients with benign liver tumor who underwent hepatectomy (the control group). There were 47 males and 69 females, with age of (66.1±3.2) years old. The positive expressions of HDGF, VEGF and MUC5B in the three groups were compared. In 41 patients with HICC, the correlation between positive expressions of HDGF, VEGF and MUC5B with patients’ clinical characteristics were studied.Results:Compared with the control group, the positive expression rates of HDGF, VEGF and MUC5B in the HICC group and the intrahepatic cholangiolithiasis group were significantly increased, ( P<0.05). Compared with the intrahepatic cholangiolithiasis group, the positive expression rates of HDGF, VEGF and MUC5B in the HICC group were significantly increased ( P<0.05). Positive expression of VEGF in HICC patients was correlated with tumor differentiation, tumor local invasion, tumor length, tumor stage, tumor carbohydrate antigen CA19-9 level and lymph node metastasis ( P<0.05). Spearman correlation analysis showed that HDGF was positively correlated with VEGF expression in HICC tissues specimens ( r=0.935, P<0.01). Survival analysis showed that the cumulative survival rates (36.7%, 17.1%, 7.3%) of patients with positive expression of VEGF were significantly lower than that of patients with negative expression (51.2%, 26.8%, 19.5%) at 1, 3, 5 years after surgery ( P<0.01). The cumulative survival rate (34.1%, 17.1%, 4.9%) of patients with MUC5B positive expression were significantly lower than that of patients with negative expression (53.7%, 31.7%, 17.1%) at 1, 3, 5 years after surgery ( P<0.01). Conclusion:HDGF can be used as a reference indicator for early assessment of HICC. Overexpressions of VEGF and MUC5B can be used as important indicators for HICC in evaluating disease progression and prognosis.
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In 2022, the Taiwan, China fundus disease expert group issued the Consensus on the Optimal Treat-and-Extend Regimens for Neovascular Age-Related Macular Degeneration. The following explanations are given to help Chinese ophthalmologists better to refer to and use the Consensus. The main contents are as follows: The treat-and-extend(T& E)regimen of anti-vascular endothelial growth factor(VEGF)treatment in patients with neovascular age-related macular degeneration(nARMD)should aim at maintaining long-term vision and reducing the number of injections. We can start the treatment by injecting once a month for consecutive 3mo. After the initial treatment, the treatment interval of patients with stable conditions can be gradually extended(2 or 4wk each time)until 16wk. If the disease is still steady after injecting 2 or 3 times at the most prolonged interval, we can suspend the treatment, and then the patient needs to be rechecked every 3-4mo; If the disease is active again, the treatment interval needs to be shortened and can be extended again after controlling the disease. We can adopt a relatively conservative approach for patients with apparent negative recovery factors. Complications such as subconjunctival hemorrhage, macular fibrosis and macular atrophy deserve our attention during treatment. In the future, we can explore the best injection scheme for nARMD patients with different subtypes and baseline conditions to realize personalized therapy.
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@#AIM: To explore the effect of SiWuWuZi decoction combined with intravitreal injection of conbercept on patients with wet age-related macular degeneration(ARMD)and its effects on serum vascular endothelial growth factors(VEGF), transforming growth factor-β1(TGF-β1)and inflammatory factors.<p>METHODS: A retrospective study. A total of 60 cases(60 eyes)wet ARMD patients admitted to the ophthalmology department of our hospital from May 2019 to November 2020 were divided into 30 cases(30 eyes)of the control group were treated with intravitreal injection of conbercept, while observation group 30 cases(30 eyes)was added with SiWuWuZi decoction on the basis of treatment for control group. The best corrected visual acuity(BCVA), the neovascular area were not be vanished fundus hemorrhage, exudation, choriocapillario-Bruch's membrane-retinal pigment epithelium complex(CBRC), and retinal neuroepithelial layer(RNL), serum VEGF, TGF-β1, interleukin-6(IL-6)and interleukin-13(IL-13)levels and overall efficacy after 3mo were compared.<p>RESULTS: After 3mo treatment, BCVA, fundus hemorrhage, exudation, CBRC and RNL thickness in 2 groups were improved compared with before treatment(<i>P</i><0.05), and the observation group was better than the control group(<i>P</i><0.05). Compared with before treatment, serum VEGF, TGF-β1, IL-6 and IL-13 in 2 groups after 3mo treatment were decreased(<i>P</i><0.001), and serum VEGF, TGF-β1, IL-6 and IL-13 levels in observation group were significantly lower than those in control group(<i>P</i><0.05). The overall effect of observation group was significantly better than control group(<i>P</i>=0.037). <p>CONCLUSION: SiWuWuZi decoction combined with intravitreal injection of conbercept can gradually vanish fundus neovascularization in patients with wet ARMD, serum levels of VEGF, TGF-β1 and inflammatory factors, improve ocular microcirculation and promote vision recovery in patients with wet ARMD.
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ABSTRACT Objective: To evaluate the effects of photobiomodulation therapy in redox status, angiogenesis marker - vascular endothelial growth factor - and in the functional recovery in denervated muscle. Methods: A total of 32 female Wistar rats underwent a crush injury and were randomly divided into four groups: Light Emitting Diode Group 2 and Control Group 2 (muscle collected 2 days after injury), and Light Emitting Diode Group 21 and Control Group 21 (muscle collected 21 days afterinjury). Light Emitting Diode Group 2 and Light Emitting Diode Group 21 received two and ten light emitting diode applications (630±20nm, 9J/cm2, 300mW), respectively, and the Control Group 2 and Control Group 21 did not receive any treatment. The function was evaluated by grasping test at four moments (pre-injury, 2, 10 and 21 post-injury days). The flexor digitorum muscle was collected for analysis of immunolocalization of vascular endothelial growth factor and redox parameters. Results: Functional improvement was observed at the second and tenth post-injury day in treated groups compared to control (p<0.005). The muscle tissue of treated groups presented higher immunohistochemical expression of vascular endothelial growth factor. Photobiomodulation therapy decreased the oxidative damage to lipid in Light Emitting Diode Group 2 compared to Control Group 2 (p=0.023) in the denervated muscle. Conclusion: Photobiomodulation therapy accelerated the functional recovery, increased angiogenesis and reduced lipid peroxidation in the denervated muscle at 2 days after injury.
RESUMO Objetivo: Avaliar os efeitos da terapia de fotobiomodulação no estado redox, no marcador de angiogênese - fator de crescimento endotelial vascular - e na recuperação funcional do músculo desnervado. Métodos: Um total de 32 ratas Wistar foi submetido a uma lesão por esmagamento e dividido aleatoriamente em quatro grupos: Grupo Diodo Emissor de Luz 2 e Grupo Controle 2 (músculo coletado 2 dias após a lesão), além do Grupo Diodo Emissor de Luz 21 e do Grupo Controle 21 (músculo coletado 21 dias após a lesão). Grupo Diodo Emissor de Luz 2 e Grupo Diodo Emissor de Luz 21 receberam duas e dez aplicações de diodo emissor de luz (630±20nm, 9J/cm2e 300mW), respectivamente, e Grupo Controle 2 e Grupo Controle 21 não receberam tratamento. A função foi avaliada pelo teste de preensão em quatro momentos (pré-lesão, 2, 10 e 21 dias após a lesão). O músculo flexor dos dedos foi coletado para análise dos parâmetros redox e da imunolocalização do fator de crescimento endotelial vascular. Resultados: Houve melhora funcional no segundo e décimo dia pós-lesão nos grupos tratados em comparação aos controles (p<0,005). O tecido muscular dos grupos tratados apresentou maior expressão imuno-histoquímica do fator de crescimento endotelial vascular. A terapia de fotobiomodulação diminuiu o dano oxidativo aos lipídeos no Grupo Diodo Emissor de Luz 2 comparado ao Grupo Controle 2 (p=0,023) no músculo desnervado. Conclusão: A terapia de fotobiomodulação acelerou a recuperação funcional, aumentou a angiogênese e reduziu a peroxidação lipídica no músculo desnervado 2 dias após a lesão.
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Animals , Female , Rats , Low-Level Light Therapy , Oxidation-Reduction , Rats, Wistar , Muscle, Skeletal , Vascular Endothelial Growth Factor AABSTRACT
The intervention therapy targeting vascular endothelial growth factor (VEGF) has become a specific and effective method for the treatment of diabetic retinopathy (DR). However, some patients did not respond or responded poorly to anti-VEGF therapy, and its effects of eliminating edema and improving vision appear to be unstable in the same patient. Hypoxia-inducible factor-1α (HIF-1α), an important upstream transcriptional regulator of VEGF, is an oxygen concentration-sensitive protein expressed in tissues under hypoxia. It can simultaneously target many downstream target genes except VEGF, such as placental growth factor and angiopoietin-like protein 4, to cause blood-retinal barrier damage and neovascularization, and thus participate in various pathological changes of DR to promote the occurrence and development of DR. Therefore, direct intervention of HIF-1α or targeting one or more downstream target genes regulated by HIF-1α to treat DR may have better efficacy. In the future, the development of effective and safe HIF inhibitors or anti-VEGF with HIF-1α other target gene inhibitors may have broader clinical application prospects.
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Objective:To observe the expression of vascular endothelial growth factor (VEGF) and aquaporin 4 (AQP4) in the inner limiting membrane (ILM) of diabetic retinopathy (DR) with macular edema, and analyze the correlation between VEGF and AQP4 expression.Methods:A cross-sectional study. From September 2019 to September 2020, 38 eyes of 38 patients with DR and idiopathic macular hole (iMH) who underwent vitrectomy (PPV) combined with ILM stripping at the Hangzhou campus of The Affiliated Eye Hospital of Wenzhou Medical University at Hangzhou were included in the study. Among them, there were 25 males and 13 females who aged 37-76 years old, average age was 59±10 years old; All eye included 15 right eyes and 23 left eyes. iMH and DR included 9 eyes in 9 cases and 29 eyes in 29 cases, respectively, and they were divided into iMH group and DR group. The DR group was divided into DME group and no DME group according to whether it was accompanied by diabetic macular edema (DME), with 14 eyes and 15 eyes respectively. After the stripped ILM tissue was fixed, immunofluorescence analysis was performed to obtain a picture of the fluorescence mode of AQP4 and VEGF, and the fluorescence intensity value of VEGF and AQP4 was measured by Image J software. The differences of VEGF and AQP4 immunofluorescence values in the specimens between groups were compared by one-way analysis of variance. The correlation between the fluorescence intensity of AQP4 and the fluorescence intensity of VEGF was analyzed by Pearson correlation analysis.Results:The average fluorescence intensity valuesof VEGF and AQP4 in ILM specimens of DME group, no DME group and iMH group were 38.96±7.53, 28.25±3.12, 30.07±4.84 and 49.07±8.73, 37.96±6.45, 38.08±5.04, respectively. The average fluorescence intensity of VEGF and AQP4 in the ILM specimens of the DME group was significantly higher than that of the no DME group and iMH group, and the difference was statistically significant ( F=13.977, 9.454; P<0.05). The average fluorescence intensity values of VEGF and AQP4 on IML specimens in the DR group were 33.80±7.91, 43.76±9.44, respectively. The results of Pearson correlation analysis showed that the fluorescence intensity of VEGF and AQP4 in the ILM specimens of the DR group was significantly positively correlated ( r=0.597, P=0.003). Conclusions:The expressions of VEGF and AQP4 in ILM of eyes with DR and DME are significantly increased compared with those without DME. The expression of VEGF and AQP4 in ILM of eyes with DR is positively correlated.