Cytokine Vascular Endothelial Growth Factor Research Articles

Enhanced Brain Clearance of Tau and Amyloid-β in Alzheimer's Disease Patients by Transcranial Radiofrequency Wave Treatment: A Central Role of Vascular Endothelial Growth Factor (VEGF).

While drainage/removal of fluid and toxins from the brain by cerebrospinal fluid (CSF) directly into venous blood is well-known, a second drainage route has recently been (re)discovered-meningeal lymphatic vessels (mLVs)-which are responsible for up to half of total brain fluid/toxin drainage. The cytokine vascular endothelial growth factor (VEGF) increases mLV diameter and numbers to increase mLV drainage, resulting in increased mLV drainage. Alzheimer's disease (AD) is characterized by low plasma and CSF levels of VEGF. To determine if non-invasive transcranial radiofrequency wave treatment (TRFT), through modulation of VEGF levels in blood and CSF, can affect removal of toxins tau and amyloid-β (Aβ) from the brain. Eight mild/moderate AD subjects were given twice-daily 1-hour TRFT sessions at home by their caregivers. Blood and CSF samples were taken at baseline and following completion of 2 months of TRFT. In plasma and/or CSF, strong baseline correlations between VEGF levels and AD markers (t-tau, p-tau, Aβ1-40, Aβ1-42) were eliminated by TRFT. This effect was primarily due to TRFT-induced increases in VEGF levels in AD subjects with low or unmeasurable "baseline" VEGF levels. These increased VEGF levels were associated with increased clearance/drainage of tau and Aβ from the brain, likely through VEGF's actions on mLVs. A new mechanism of TRFT is identified (facilitation of brain tau and Aβ clearance via VEGF) that is likely contributory to TRFT's reversal of cognitive impairment in AD subjects. TRFT may be particularly effective for cognitive benefit in AD subjects who have low VEGF levels.

Exploring causal correlations between circulating levels of cytokines and colorectal cancer risk: A Mendelian randomization analysis.

Colorectal cancer has the highest mortality rate of all digestive system diseases. Considering the debate about cytokines and biases that exist in traditional observational study designs, we performed a two-sample Mendelian randomization (MR) analysis to explore the association of circulating cytokines with CRC risk. In this study, we used cytokine genetic variants from a recently published genome-wide association study (GWAS) including 14,824 European-ancestry participants. Summary-level data for colorectal cancer were obtained from genome-wide association analyses of the FinnGen consortium. In addition, we conducted independent supplementary analyses using genetic variation data of colorectal cancer and cytokines from a large public GWAS in 2021. Among 91 circulating factors, we only found IL-12B to be significantly associated with CRC risk (odds ratio [OR]: 1.19; 95% confidence interval [CI]: 1.00-1.42; p = .046). We used 2021 data for analysis and found that higher Interleukin-12p70 levels (IL-12p70) were revealed to have a significant positive association with CRC risk (OR: 1.27; 95% CI: 1.13-1.43; p < 1.22 × 10-3). Moreover, CRC was suggestively correlated with an elevated level of vascular endothelial growth factor (VEGF) (OR: 1.17; 95% CI: 1.02-1.35; p = .026), macrophage colony-stimulating factor (M-CSF) (OR: 0.85; 95% CI: 0.76-0.96; p = .005), IL-13 (OR: 1.15; 95% CI: 1.02-1.30; p = .028), IL-10 (OR: 1.23; 95% CI: 1.01-1.49; p = .037), and IL-7 (OR: 1.19; 95% CI: 1.02-1.39; p = .024). Our MR studies support that one cytokine IL-12 is significantly associated with CRC risk and that five cytokines VEGF, M-CSF, IL-13, IL-10, and IL-7 are associated with CRC risk.

Effect of aflibercept combined with triamcinolone acetonide on aqueous humor growth factor and inflammatory mediators in diabetic macular edema.

To investigate the efficacy of aflibercept combined with sub-tenon injection of triamcinolone acetonide (TA) in treating diabetic macular edema (DME) and to examine changes in growth factors and inflammatory mediator levels in aqueous humor after injection. Totally 67 DME patients (67 eyes) and 30 cataract patients (32 eyes) were enrolled as the DME group and the control group, respectively. The DME group was divided into the aflibercept group (34 cases) and the aflibercept combined with TA group (combined group, 33 cases). The aqueous humor of both groups was collected during the study period. The aqueous levels of vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1β (IL-1β) were detected using a microsphere suspension array technology (Luminex 200TM). Aqueous cytokines, best-corrected visual acuity (BCVA), central macular thickness (CMT), and complications before and after treatment were compared between the aflibercept group and combined group. The concentrations of VEGF, MCP-1, IL-6, and IL-8 in the aqueous humor were significantly higher in the DME group than those of the control group (all P<0.01). After 1mo of surgery, the concentrations of VEGF, MCP-1, IL-6, and IL-8 in the aqueous humor were significantly lower in the combined group than those of the aflibercept group (all P<0.01). The BCVA and CMT values of the two groups were statistically different after 1 and 2mo of treatment (P<0.01). However, the difference was not statistically significant after 3mo of treatment (P>0.05). The cytokines VEGF, MCP-1, IL-6, and IL-8 in the aqueous humor of DME patients are significantly increased. Aflibercept and aflibercept combined with TA have good efficacy in DME patients, can effectively reduce CMT, improve the patient's vision, and have high safety. Aflibercept combined with TA can quickly down-regulate the aqueous humor cytokines and help to relieve macular edema rapidly. However, the long-term efficacy is comparable to that of aflibercept alone.

CRISPR/Cas genome editing revealed non-angiogenic role of VEGFA gene in porcine luteal cells: a preliminary report.

The angiogenic cytokine vascular endothelial growth factor A (VEGFA) also exerts non-angiogenic effects on endocrine functionality of porcine luteal cells critical for progesterone (P4) production. The expression dynamics of VEGFA-FLT/KDR system were investigated using RT-qPCR during luteal stages and VEGFA gene knock out (KO) porcine luteal cells were generated using CRISPR/Cas9 technology. The downstream effects of VEGFA ablation were studied using RT-qPCR, Annexin V, MTT, ELISA for P4 estimation and scratch wound assay. Bioinformatics analysis of RNA-Seq data of porcine mid-luteal stage was conducted for exploring protein-protein interaction network, KEGG pathways, transcription factors and kinase mapping for VEGFA-FLT/KDR interactomes. The VEGFA-FLT/KDR system expressed throughout the luteal stages with highest expression during mid- luteal stage. Cellular morphology, structure and oil-red-o staining for lipid droplets did not differ significantly between VEGFA KO and wild type cells, however, VEGFA KO significantly decreased (p < 0.05) viability and proliferation efficiency of edited cells on subsequent passages. Expression of apoptotic gene, CASP3 and hypoxia related gene, HIF1A were significantly (p < 0.05) upregulated in KO cells. The relative mRNA expression of VEGFA and steroidogenic genes STAR, CYP11A1 and HSD3B1 decreased significantly (p < 0.05) upon KO, which was further validated by the significant (p < 0.05) decrease in P4 output from KO cells. Bioinformatics analysis mapped VEGFA-FLT/KDR system to signalling pathways associated with steroidogenic cell functionality and survival, which complemented the findings of the study. The ablation of VEGFA gene resulted in decreased steroidogenic capability of luteal cells, which suggests that VEGFA exerts additional non-angiogenic regulatory effects in luteal cell functionality.

Polylactic acid-based dressing with oxygen generation and enzyme-like activity for accelerating both light-driven biofilm elimination and wound healing.

Photodynamic therapy (PDT) is a widely used therapeutic approach for eradicating bacterial biofilms in infected wound, but its effectiveness is limited by the hypoxic environment within the biofilm. This study aimed to investigate whether the efficiency of photodynamic removing biofilm is improving by providing oxygen (O2), as well as the expression of cytokines involved in infected wound healing. Manganese dioxide (MnO2) nanoparticles with catalase-like activity were grown in situ on graphitic phase carbon nitride (g-C3N4, CN) nanosheets to construct an all-in-one CN-MnO2 nanozyme, which was then incorporated into poly-L-lactic acid (PLLA) to prepare CN-MnO2/PLLA wound dressing by electrospinning. Subsequently, the in vitro antibacterial biofilm ratio and antibacterial ratio of CN-MnO2/PLLA wound dressing were examined by spread plate and crystal violet staining under irradiation with 808nm near-infrared light and 660nm visible light. Meanwhile, the rat skin injury model was established, and hematoxylin and eosin (H&E), Masson's, tumor necrosis factor-α (TNF-α), Arginase 1 (Arg-1), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (BFGF) were evaluated in vivo to assess the effect of CN-MnO2/PLLA wound dressing on wound healing. Biofilm density caused by Staphylococcus aureus and Pseudomonas aeruginosa had elimination rates of 83 and 62%, respectively, when treated with CN-MnO2/PLLA dressing. Additionally, the dressing exhibited high antibacterial efficacy against both bacteria, achieving 99 and 98.7% elimination of Staphylococcus aureus and Pseudomonas aeruginosa, respectively. Furthermore, in vivo experiments showed that the CN-MnO2/PLLA wound dressing achieved complete healing of infected wounds on Day 14, with a wound healing rate of >99% by increasing collagen deposition, expression of anti-inflammatory cytokine Arg-1, vascularization cytokine VEGF, and epithelial cell BFGF, and inhibiting the expression of inflammatory cytokine TNF-α. The CN-MnO2/PLLA wound dressing exhibited excellent antibacterial properties in vitro and in vivo. In addition, CN-MnO2/PLLA wound dressing accelerated rapid wound healing through an anti-inflammatory, pro-vascular regeneration and skin tissue remodeling mechanism.

Evaluating the levels of Tumor Necrosis Factorα-, Interleukin-6 and Vascular endothelial growth factor in patients with Colorectal Cancer

Cytokines are polypeptides with several functions that are produced by a variety of bodily cells. They are clinically significant for illness diagnosis, treatment, and prevention. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) are the most important cytokines for cell division and proliferation. Vascular endothelial growth factor (VEGF) is produced in excess in mesenchymal, epithelial, and especially in tumor cells. In this study the serum levels of IL-6, TNF-α and VEGF were detected for 41 colorectal cancer patients and 41 healthy control group at Nanakaly Hospital by comparing their serum concentrations for patients paining from colorectal carcinoma (CRC) with those of the control subjects. The result shows a significant increase in the cytokines TNF-α, IL-6 and VEGF in patients with CRC when compared with the healthy group. A significant positive correlation (p&lt;0.0001) was found between TNF-α with IL-6 (r= 0.8200) and VEGF (r= 0.7305). According to this study, there is a direct correlation between CRC and blood levels of (TNF-a, IL-6, and VEGF). This suggests that these cytokines are crucial for the development and spread of colorectal cancer.

Perfluorooctane sulfonate promotes the migration of colorectal cancer cells by inducing epithelial-mesenchymal transition

The potential association between colorectal cancer (CRC) and environmental pollutants is worrisome. Previous studies have found that some perfluoroalkyl acids, including perfluorooctane sulfonate (PFOS), induced colorectal tumors in experimental animals and promoted the migration of and invasion by CRC cells in vitro, but the underlying mechanism is unclear. Here, we investigated the effects of PFOS on the proliferation and migration of CRC cells and the potential mechanisms involving activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition (EMT). It was found that PFOS promoted the growth and migration of HCT116 cells at non-cytotoxic concentrations and increased the mRNA expression of the migration-related angiogenic cytokines vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). In a mechanistic investigation, the up-stream signal pathway PI3K/Akt-NF-κB was activated by PFOS, and the process was suppressed by LY294002 (PI3K/Akt inhibitor) and BAY11-7082 (NF-κB inhibitor) respectively, leading to less proliferation of HCT116 cells. Furthermore, matrix metalloproteinases (MMP) and EMT-related markers were up-regulated after PFOS exposure, and were also suppressed respectively by LY294002 and BAY11-7082. Moreover, the up-regulation of EMT markers was suppressed by a MMP inhibitor GM6001. Taken together, our results indicated that PFOS promotes colorectal cancer cell migration and proliferation by activating the PI3K/Akt-NF-κB signal pathway and epithelial-mesenchymal transition. This could be a potential toxicological mechanism of PFOS-induced malignant development of colorectal cancer.

Hydrolyzed Collagen Powder Dressing Improves Wound Inflammation, Perfusion, and Breaking Strength of Repaired Tissue.

Objective: Hydrolyzed collagen-based matrices are widely used as wound care dressings. Information on the mechanism of action of such dressings is scanty. The objective of this study was to test the effect of a specific hydrolyzed collagen powder (HCP), which is extensively used for wound care management in the United States. Approach: The effects of HCP on resolution of wound inflammation, perfusion, closure, and breaking strength of the repaired skin were studied in an experimental murine model. Results: In early (day 7) inflammatory phase of wound macrophages, HCP treatment boosted phagocytosis and efferocytosis of wound-site macrophages. In these cells, inducible reactive oxygen species were also higher on day (d) 7. HCP treatment potentiated the expression of anti-inflammatory interleukin (IL)-10 cytokine and proangiogenic vascular endothelial growth factor (VEGF) production. Excisional wounds dressed with HCP showed complete closure on day 21, while the control wounds remained open. HCP treatment also demonstrated improved quality of wound healing as marked by the improved breaking strength of the closed wound tissue/repaired skin. Innovation: These data represent first evidence on the mechanism of action of clinically used HCP. Conclusion: HCP dressing favorably influenced both wound inflammation and vascularization. Improved breaking strength of HCP-treated repaired skin lays the rationale for future studies testing the hypothesis that HCP-treated closed wounds would show fewer recurrences.

The exploration of neuroinflammatory mechanism by which CRHR2 deficiency induced anxiety disorder

Inflammation stimulates the hypothalamic-pituitary adrenal (HPA) axis and triggers glial neuroinflammatory phenotypes, which reduces monoamine neurotransmitters by activating indoleamine 2,3-dioxygenase enzyme. These changes can induce psychiatric diseases, including anxiety. Corticotropin releasing hormone receptor 2 (CRHR2) in the HPA axis is involved in the etiology of anxiety. Omega(n)-3 polyunsaturated fatty acids (PUFAs) can attenuate anxiety through anti-inflammation and HPA axis modulation. However, the underlying molecular mechanism by CRHR2 modulates anxiety and its correlation with neuroinflammation remain unclear. Here, we first constructed a crhr2 zebrafish mutant line, and evaluated anxiety-like behaviors, gene expression associated with the HPA axis, neuroinflammatory response, neurotransmitters, and PUFAs profile in crhr2+/+ and crhr2−/− zebrafish. The crhr2 deficiency decreased cortisol levels and up-regulated crhr1 and down-regulated crhb, crhbp, ucn3l and proopiomelanocortin a (pomc a) in zebrafish. Interestingly, a significant increase in the neuroinflammatory markers, translocator protein (TSPO) and the activation of microglia M1 phenotype (CD11b) were found in crhr2−/− zebrafish. As a consequence, the expression of granulocyte-macrophage colony-stimulating factor, pro-inflammatory cytokines vascular endothelial growth factor, and astrocyte A1 phenotype c3 were up-regulated. While microglia anti-inflammatory phenotype (CD206), central anti-inflammatory cytokine interleukin-4, arginase-1, and transforming growth factor-β were downregulated. In parallel, crhr2-deficient zebrafish showed an upregulation of vdac1 protein, a TSPO ligand, and its downstream caspase-3. Furthermore, 5-HT/5-HIAA ratio was decreased and n-3 PUFAs deficiency was identified in crhr2−/− zebrafish. In conclusion, anxiety-like behavior displayed by crhr2-deficient zebrafish may be caused by the HPA axis dysfunction and enhanced neuroinflammation, which resulted in n-3 PUFAs and monoamine neurotransmitter reductions.

Correlation and efficacy of TACE combined with lenvatinib plus PD-1 inhibitor in the treatment of hepatocellular carcinoma with portal vein tumor thrombus based on immunological features.

Although the appearance of portal vein tumor thrombus (PVTT) is significantly associated with unfavorable prognosis, there is insufficient evidence to confirm the efficacy and safety of the triple combination of transarterial chemoembolization (TACE), lenvatinib, and programmed cell death-1 (PD-1) inhibitor for patients with hepatocellular carcinoma (HCC) and PVTT. Furthermore, it remains unclear which patient type can obtain the best survival benefit from this combination therapy. The data of 160 patients with HCC and PVTT treated with TACE combined with lenvatinib plus PD-1 inhibitor (TACE+LEN + PD-1 group) or TACE combined with lenvatinib (TACE+LEN group) were retrospectively collected and analyzed. To estimate the efficacy and safety of combination therapy for patients with advanced HCC, tumor response, progression-free survival (PFS), overall survival (OS), biochemical indices, and adverse events (AEs) were assessed in this study. More importantly, tumor immune-related cytokines were used to identify biomarkers predicting the therapeutic response of combination therapy. TACE+LEN + PD-1 was superior to TACE+LEN in OS (23.5 vs. 18.3 months, p=0.0002) and PFS (7.5 vs. 4.3 months, p < 0.0001). Moreover, TACE+LEN + PD-1 achieved more preferable benefits with respect to disease control rate (80.00% vs. 56.67%) and objective response rate (38.57% vs. 24.45%) compared with TACE+LEN in patients with HCC and PVTT (p=0.025). Multivariate analysis showed that Child-Pugh grade, PVTT classification, treatment option, and interleukin (IL)-6, IL-17, interferon (IFN)-α, and vascular endothelial growth factor (VEGF) levels were independent factors related to OS, whereas PVTT classification, treatment option, and IL-6 and IFN-α levels were independent factors related to PFS. Furthermore, the subgroup analysis illustrated that the inflammatory cytokines VEGF, IL-6, IL-17, and IFN-α might be novel biomarkers for predicting the survival prognosis of patients with advanced HCC and PVTT treated with TACE+LEN + PD-1. The safety in the combination group was acceptable. Compared with TACE+LEN, the triple combination treatment of TACE+LEN + PD-1 has more promising clinical outcomes and acceptable safety in patients with HCC and PVTT. Child-Pugh grade, PVTT classification, and IL-6, IL-17, IFN-α, and VEGF levels are independent prognostic factors for survival time.

Triptonide Ameliorates Middle Cerebral Artery Occlusion-induced Cerebral Ischemic Damage in Rats via Regulation of In flammatory Response

Background Cerebral ischemic stroke is the second major cause of mortality worldwide that results in persisting disability and mental agony. Ischemic stroke is induced by the diminished blood circulation to the brain, which can be due to obstruction by arteriosclerosis, fibromuscular dysplasia, or thrombosis. Triptonide is a diterpene triepoxide, purified out of extracts of Tripterygium wilfordii Hook F, and is an emerging target against, for example, cancers and inflammatory insults. Materials and Methods Taking this into consideration, this study was designed to analyze the effect of triptonide on ischemic/reperfusion (I/R) cerebral infarction stroke rats. Results Our study showed that triptonide decreased the infarct volume and brain edema produced by I/R. Moreover, triptonide protected the rats from any neurological deficits, which were analyzed using a five-point scoring system, augmented antioxidant enzymes like superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione content, and lowered the activity of acetylcholinesterase. Triptonide also decreased the levels of pro-inflammatory cytokines such as interleukin-1 β (IL-1 β), TNF- α, and IL-6, while it augmented anti-inflammatory cytokines IL-10 and vascular endothelial growth factor. In this study, cerebral infarction stroke rats showed an increase in malondialdehyde levels. Triptonide preserved the normal brain architecture from various neurotoxic effects. Conclusion Thus, triptonide can be targeted for drug discovery in the future to protect against cerebral infarction stroke.

Expression analysis of cytokines IL-5, IL-6, IL-8, IL-17 and VEGF in breast cancer patients.

To investigate the relationship between changes in peripheral blood vascular endothelial growth factor (VEGF), interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-17 (IL-17) concentrations in breast cancer patients and their significance and clinical value in breast cancer staging and invasive metastasis. From September 2021 to April 2022, 60 breast cancer patients from Chongqing Medical University Hospital No. 2022 were enrolled in the breast breast cancer surgery group, while 30 patients with benign breast disease were enrolled in the control group during the same period. Venous blood samples were collected at admission and 1 week after surgery to determine the expression of these factors in serum. Statistical methods such as Wilcoxon test and Spearman correlation analysis were used to analyze the relationship between the above factors and the clinicopathological characteristics of the patients. By analyzing data from patients with benign and malignant breast tumors, an association was found with serum levels of IL-6, IL-17 and VEGF. Their respective areas under the operating characteristic curve were 0.649, 0.734 and 0.656 (P < 0.05). There were significant differences in the cytokine expression levels of IL-17 and VEGF in different molecular typing (P values were 0.008 and 0.040, respectively). The expression levels of IL-17 and VEGF were higher in HER-2 receptor-positive and triple-negative patients than in hormone receptor-positive patients (P < 0.05). Also, no significant correlation was found between the various cytokines mentioned in the article and breast cancer lymph node metastasis and Tumor Node Metastasis stage (TNM stage). In addition, in the breast cancer surgery group, postoperative VEGF levels were lower (P < 0.05) and IL-6 levels were higher (P < 0.05) compared to preoperative levels. Serum IL-6, IL-17, and VEGF are strongly associated with breast cancer development and can be used as a reference indicators for breast cancer diagnosis. In addition, post-operative VEGF levels decreases and IL-6 levels increases compared to pre-operative levels, which can also be used as an a postoperative follow-up indicator. In contrast, IL-5 and IL-8 have not found to be significantly associated with breast cancer patients in this study, which requires further study.

Effects of Cyclooxygenase-2 in Canine Melanoma-derived Extracellular Vesicles on Tumor Microenvironment In Vitro.

Tumor cell-derived extracellular vesicles (TEVs) promote tumor growth and metastasis; thus, they have drawn the attention of researchers. TEVs regulate the tumor microenvironment by facilitating crosstalk between immune and stromal cells. Macrophages are one of the key components involved in malignant behavior in melanomas. Generally, when activated, macrophages polarize into M1 (pro-inflammatory) or M2 (anti-inflammatory, pro-tumor) phenotypes. However, the role of canine melanoma-derived EVs in macrophage polarization is elusive. In this study, we aimed to analyze the pro- and anti-inflammatory cytokines that are common markers for M1 or M2 macrophages in vitro. The analysis was performed under coculture conditions of canine melanoma-derived (LMeC) EVs with canine macrophages (DH82). Quantitative reverse transcription polymerase chain reaction, western blotting, and immunofluorescence were used. Canine melanoma-derived EVs polarized M1 macrophages (inducible nitric oxide synthase, tumor necrosis factor α) into M2 macrophages [cluster of differentiation (CD)206, interleukin-10] and cyclooxygenase-2 is a major factor in macrophage polarization in canine melanoma-derived EVs. Furthermore, we also found that melanoma-derived EVs induced the expression of angiogenic cytokines (vascular endothelial growth factor, transforming growth factor β) in endothelial cells. Melanoma-derived EVs perform an immunomodulatory function and can be used as targets in anti-inflammatory treatment.

Analysis of cytokine gene polymorphisms in patients with chronic diffusional liver diseases in Perm krai

Aim. To estimate the concentration of tumor necrosis factor-alpha (TNF-α), interleukin-6 (interleukin, IL-6), vascular endothelial growth factor (VEGF) in blood serum and to analyze the polymorphism of TNF-α cytokine genes in region 308G / A (rs1800629), IL-6 in region 174G / C (rs1800795) and VEGFA in region 634G / C (rs2010963) in patients with chronic diffuse liver diseases (CDLD) living in the Perm region. Materials and methods. In 193 patients with CDLD and 90 healthy donors, the concentration of cytokines in the blood serum was studied by ELISA and the analysis of cytokine gene polymorphism by PCR was performed. Results. In patients with CDLD, the concentration of pro-inflammatory cytokines TNF-α, IL-6 and the level of VEGF in the blood serum were significantly higher than in the control (p <0.001, respectively), while the maximum level of inflammation markers was noted in liver cirrhosis, and VEGF production - in chronic hepatitis C. Comparative analysis of single nucleotide polymorphisms of cytokine genes showed significant differences in the occurrence of the GA and AA genotypes of the TNF-α gene (G-308A), the carriage of the CG variant of the IL-6 gene (C-174G), as well as the C allele and CC homozygote for marker VEGF (G-634C), which in the population of patients with CDLD in the Perm region were recorded significantly more often than in the cohort of donors, which allows us to consider them as genetic markers of the risk of developing CDLD. Conclusion. An increase in the concentration of pathogenetically significant cytokines TNF-α, IL-6 and VEGF in liver diseases can develop against the background of gene polymorphisms of these molecules. Genetic markers can be used to assess the risk of developing and progression of CDLD.

Mesenchymal Stem Cell Sheet Centrifuge-Assisted Layering Augments Pro-Regenerative Cytokine Production.

A focal advantage of cell sheet technology has been as a scaffold-free three-dimensional (3D) cell delivery platform capable of sustained cell engraftment, survival, and reparative function. Recent evidence demonstrates that the intrinsic cell sheet 3D tissue-like microenvironment stimulates mesenchymal stem cell (MSC) paracrine factor production. In this capacity, cell sheets not only function as 3D cell delivery platforms, but also prime MSC therapeutic paracrine capacity. This study introduces a “cell sheet multilayering by centrifugation” strategy to non-invasively augment MSC paracrine factor production. Cell sheets fabricated by temperature-mediated harvest were first centrifuged as single layers using optimized conditions of rotational speed and time. Centrifugation enhanced cell physical and biochemical interactions related to intercellular communication and matrix interactions within the single cell sheet, upregulating MSC gene expression of connexin 43, integrin β1, and laminin α5. Single cell sheet centrifugation triggered MSC functional enhancement, secreting higher concentrations of pro-regenerative cytokines vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and interleukin-10 (IL-10). Subsequent cell sheet stacking, and centrifugation generated cohesive, bilayer MSC sheets within 2 h, which could not be accomplished within 24 h by conventional layering methods. Conventional layering led to H1F-1α upregulation and increased cell death, indicating a hypoxic thickness limitation to this approach. Comparing centrifuged single and bilayer cell sheets revealed that layering increased VEGF production 10-fold, attributed to intercellular interactions at the layered sheet interface. The “MSC sheet multilayering by centrifugation” strategy described herein generates a 3D MSC-delivery platform with boosted therapeutic factor production capacity.

Nafamostat mesylate prevents metastasis and dissemination of neuroblastoma through vascular endothelial growth factor inhibition.

Neuroblastoma is a highly malignant disease with a poor prognosis and few treatment options. Despite conventional chemotherapy for neuroblastoma, resistance, invasiveness, and metastatic mobility limit the treatment efficacy. Therefore, it is necessary to develop new strategies for treating neuroblastoma. The present study aimed to evaluate the anticancer effects of nafamostat mesylate, a previously known serine protease inhibitor, on neuroblastoma cells. Effects of nafamostat mesylate on neuroblastoma cell migration and proliferation were analyzed by wound healing assay and WST-8 assay, respectively. To elucidate the mechanisms underlying the effects of nafamostat mesylate on neuroblastoma, the expression levels of NF-κB were measured via western blotting, and the production of the cytokine vascular endothelial growth factor (VEGF) in the cell culture supernatants was determined via ELISA. In addition, a mouse model of hematogenous metastasis was used to investigate the effects of nafamostat mesylate on neuroblastoma. It was determined that nafamostat mesylate significantly inhibited migration and invasion of Neuro-2a cells, but it had no effect on cell proliferation at 24 h after treatment. Exposure of Neuro-2a cells to nafamostat mesylate resulted in decreased vascular endothelial growth factor production, which could be a pivotal mechanism underlying the inhibitory effects of neuroblastoma metastasis. The results of the present study suggest that nafamostat mesylate may be an effective treatment against neuroblastoma invasion and metastasis.

On assessing risks of developing and progressing non-alcoholic fatty liver disease using TNF-α, IL6, and VEGF factors and polymorphisms of their genes

Our research aim was to develop a system for calculating risks of development and progression of non-alcoholic fatty liver disease (NAFLD). The system would be based on interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF) and TNF-α gene polymorphism in the region -308G/A (rs1800629), IL-6 in the region –174G/C (rs1800795), and VEGFA in the region –634G/C (rs2010963). We examined 52 patients with NAFLD and 65 healthy donors. The examination involved estimating levels of cytokines TNF-α, IL-6 and VEGF in blood serum. We also studied the polymorphism of the TNF-α genes in the -308G/A region, IL-6 in the -174G/C region, and VEGFA in the -634G/C region. Women aged from 32 to 54 years prevailed among patients with NAFLD (67 %). We established in this research that concentrations of the pro-inflammatory cytokines TNF-α, IL-6 and the level of VEGF in the blood serum were significantly higher in patients with NAFLD than in the reference group (p = 0.03; p = 0.00003 and р = 0.001 accordingly). This confirms an occurring inflammatory syndrome and endothelial dysfunction that are typical for this pathology. Patients with NAFLD tended to have the AA genotype of the TNF-α -308G/A gene (rs1800629) significantly more frequently than healthy donors (р = 0.04). Homozygote CC and allele C of the VEGFA gene (G-634C) in the position rs2010963 were significantly more often detected in the test group (patients with NAFLD) than in the reference one (p = 0.02 and p = 0.01 respectively). We didn’t detect any statistically significant differences in the IL-6 gene polymorphism in the -174G/C (rs1800795) region in the analyzed groups. TNF-α -308G/A gene polymorphism correlated with activating production of TNF-α and IL-6 cytokines (Ki = 0.588; p = 0.043 and Ki = 0.597; p = 0.04, respectively), which can lead to developing immune-inflammatory syndrome in its carriers. When determining genetic profiles, we established that 51 % donors had low risks of NAFLD development whereas the risk was high for 75 % of patients with the disease. The risk of developing NASP is associated with carrying the AA genotype of the TNF-α -308G/A gene and the CC genotype of the VEGFA -634G/C gene. Assessment of a genetic profile using these markers provides an opportunity to assess risks of developing NAFLD in healthy people and to predict its progression in patients with the disease.

К оценке риска развития и прогрессирования неалкогольного стеатоза печени с использованием факторов TNF-α, IL-6, VEGF и полиморфизмов их генов

Our research aim was to develop a system for calculating risks of development and progression of non-alcoholic fatty liver disease (NAFLD). The system would be based on interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), vascular endothelial growth factor (VEGF) and TNF-α gene polymorphism in the region -308G/A (rs1800629), IL-6 in the region –174G/C (rs1800795), and VEGFA in the region –634G/C (rs2010963). We examined 52 patients with NAFLD and 65 healthy donors. The examination involved estimating levels of cytokines TNF-α, IL-6 and VEGF in blood serum. We also studied the polymorphism of the TNF-α genes in the -308G/A region, IL-6 in the -174G/C region, and VEGFA in the -634G/C region. Women aged from 32 to 54 years prevailed among patients with NAFLD (67 %). We established in this research that concentrations of the pro-inflammatory cytokines TNF-α, IL-6 and the level of VEGF in the blood serum were significantly higher in patients with NAFLD than in the reference group (p = 0.03; p = 0.00003 and р = 0.001 accordingly). This confirms an occurring inflammatory syndrome and endothelial dysfunction that are typical for this pathology. Patients with NAFLD tended to have the AA genotype of the TNF-α -308G/A gene (rs1800629) significantly more frequently than healthy donors (р = 0.04). Homozygote CC and allele C of the VEGFA gene (G-634C) in the position rs2010963 were significantly more often detected in the test group (patients with NAFLD) than in the reference one (p = 0.02 and p = 0.01 respectively). We didn’t detect any statistically significant differences in the IL-6 gene polymorphism in the -174G/C (rs1800795) region in the analyzed groups. TNF-α -308G/A gene polymorphism correlated with activating production of TNF-α and IL-6 cytokines (Ki = 0.588; p = 0.043 and Ki = 0.597; p = 0.04, respectively), which can lead to developing immune-inflammatory syndrome in its carriers. When determining genetic profiles, we established that 51 % donors had low risks of NAFLD development whereas the risk was high for 75 % of patients with the disease. The risk of developing NASP is associated with carrying the AA genotype of the TNF-α -308G/A gene and the CC genotype of the VEGFA -634G/C gene. Assessment of a genetic profile using these markers provides an opportunity to assess risks of developing NAFLD in healthy people and to predict its progression in patients with the disease.

Predictors of anti-VEGF efficacy in chronic central serous chorioretinopathy based on intraocular cytokine levels and pigment epithelium detachment subtypes.

The aim of this study was to compare intraocular cytokines among different types of pigment epithelial detachments (PEDs) in patients with chronic central serous chorioretinopathy (CSC) and to investigate the association of cytokine levels and PED types with response to anti-vascular endothelial growth factor (VEGF) therapy. We included 88 patients with chronic CSC and 30 controls. The anti-VEGF agent conbercept was given intravitreally to chronic CSC patients. Cytokines VEGF, interleukin-6 (IL-6), IL-8, IL-10, interferon-inducible protein-10 and monocyte chemoattractant protein-1 in aqueous humour were measured. Treatment efficacy, cytokine levels, changes in best-corrected visual acuity (BCVA) and optical coherence tomography parameters were assessed at baseline and 1 month after treatment. Patients were divided into three groups: flat irregular PED (FIPED) with choroidal neovascularization (CNV), FIPED without CNV and focal PED. Vascular endothelial growth factor (VEGF) was the only cytokine significantly higher in chronic CSC FIPED patients. There were no significant differences in VEGF between FIPED patients with or without CNV (p = 0.234). At 1 month after conbercept injection, treatment effective rates in FIPED patients with or without CNV were significantly higher than in patients with focal PED (p < 0.05). Best-corrected visual acuity (BCVA) was improved in both FIPED groups (p < 0.05), but not in the focal PED group (p = 0.180). All three groups had significant decreases in central macular thickness (p < 0.05), and PED heights in FIPED patients were reduced (p < 0.05). Patients with FIPED in chronic CSC had elevated intraocular VEGF levels and responded favourably to conbercept. Anti-VEGF treatment may be an option for FIPED CSC patients with or without secondary CNV.

Clinical Effect, Analysis of Amoxicillin Clavulanate Potassium Combined with Shenling Baizhu Powder in the Treatment of Gastric Ulcer with Helicobacter pylori Infection

We attempt to investigate the improvement of clinical efficacy of amoxicillin-clavulanate potassium combined with Shenling Baizhu powder in treating gastric ulcer patients with Helicobacter pylori infection and the effect on related serum indexes. We selected 90 patients with gastric ulcer complicated with Helicobacter pylori infection in our hospital from January 2019 to May 2021 and randomly divided them into observation group (45 cases treated with amoxicillin clavulanate potassium combined with Shenling Baizhu powder) and control group (45 cases treated with amoxicillin-clavulanate potassium), compared both groups on the clinical effective rate and Helicobacter pylori eradication rate (per-protocol analysis) before and after treatment, the serum mucosal cytokines (vascular endothelial growth factor, epidermal growth factor, cyclooxygenase-2), matrix metalloproteinase and infection indicators (procalcitonin, C-reactive protein, interleukin-6) concentration level changes. After treatment, observation group possessed remarkably higher serum levels of vascular endothelial growth factor, epidermal growth factor and cyclooxygenase-2 than control group (p<0.05); it possessed remarkably lower procalcitonin, C-reactive protein and interleukin-6 serum levels than control group (p<0.05); and it possessed remarkably lower matrix metalloproteinase-7, matrix metalloproteinase-9 and matrix metalloproteinase plasma levels than control group (p<0.05); after per-protocol analysis, Helicobacter pylori radical cure rate of observation group (86.67 %) was remarkably higher than control group (66.67 %) (p<0.05). Amoxicillin-clavulanate potassium combined with Shenling Baizhu powder can significantly improve the clinical efficacy of gastric ulcer complicated with Helicobacter pylori infection, increase the clearance rate of Helicobacter pylori, increase the level of cellular and mucosal cytokines in serum and reduce the level of serum cytokines. The concentration levels of procalcitonin, C-reactive protein and interleukin-6 can provide clinical guidance value for effectively treating gastric ulcer with Helicobacter pylori infection.