Growth Factor Levels Research Articles

Correlation between serum cytokine levels and the effect of allogeneic serum-based eye drops

IntroductionThe Institute of Hematology and Transfusion Medicine (IHTM) in Warsaw has produced autologous serum eye drops (ASEDs) for the treatment of Dry Eye Syndrome (DES) since 1991. In 2019, IHTM introduced allogeneic tears (alloSEDs) for patients on long-term treatment. Materials and methods114 patients who applied alloSEDs were included in the study.They were asked to complete the OSDI questionnaire before and after using ASEDs and 100 units of alloSEDs drops from each donation. The OSDI index rates DES severity (0 no symptoms; 100 severe). We also compared the content of IL-1β, IL-2, IL- 6, IL-10 and VEGF in ASEDs (38 samples) and alloSEDs (15 serum samples). The study data covered the 2019–2022 period. Results114 patients participated in the study. We compared the the effectiveness of ASEDs and alloSEDs. The average, OSDI dropped from 68.42 ± 5,86 (before application) to 51.05 ± 19,06 (after application). Data from the questionnaires (prepared at IHTM) completed and returned (41/114) present the most common indications for the use of serum drops, including DES with no underlying disease, DES secondary to GvHD (Graft versus Host Disease), Sjögren's Syndrome (SS). The study reported higher cytokine levels associated with disease entities such as SS. After application of drops with high cytokine levels, patients reported adverse reactions such as sand under the eyelids, impaired visual acuity, and worse eye lubrication. ConclusionsAlloSEDs with acceptably low values of pro-inflammatory cytokines and sufficiently high levels of VEGF growth factor may contribute to alleviation of inflammatory eye symptoms.

B-flow/spatiotemporal image correlation M-mode ultrasound provides novel method to quantify spiral artery remodeling during normal human pregnancy.

During human pregnancy placental extravillous trophoblasts replace the vascular smooth muscle and elastic tissue within the walls of the uterine spiral arteries, thereby remodeling these arteries into distensible low resistance vessels to promote placental perfusion. The present study, determined whether B-flow/ spatio-temporal image correlation (STIC) M-mode ultrasonography provides an in vivo imaging method to digitally quantify spiral artery luminal distensibility, as a physiological index of spiral artery remodeling, during advancing stages of normal human pregnancy. A prospective longitudinal observational study was conducted to quantify spiral artery distensibility, i.e. vessel luminal diameter at systole minus diameter at diastole, by B-flow/STIC M-mode ultrasonography during the first, second and third trimesters in 290 women exhibiting normal pregnancy. Maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1), growth factors that modulate events important in spiral artery remodeling, were quantified in a subset of the subjects at the first, second and third semesters. Median [first quartile, third quartile] spiral artery distensibility progressively increased (P < 0.0001) between the first trimester (0.17 [0.14, 0.21]), second (0.23 [0.18, 0.28]) and third (0.26 [0.21, 0.35]) trimesters of pregnancy. Spiral artery volume flow (ml/cardiac cycle) progressively increased (P < 0.001) between the first 2.49 [1.38, 4.99], second 3.86 [2.06, 6.91] and third 7.79 [3.83, 14.98] trimesters. Coinciding with the elevation in spiral artery distensibility, the median ratio of serum PlGF/sFlt-1 levels increased (P < 0.001) between the first (7.2 [4.5, 10], second (22.7 [18.6, 42.2]) and third (56.2 [41.9, 92.5] trimesters. The present study shows that B-flow/STIC M-mode ultrasonography provides an in vivo imaging technology to digitally quantify structural/physiological expansion of the walls of the spiral arteries during the cardiac cycle as a consequence of their transformation into compliant vessels during advancing stages of normal human pregnancy. This article is protected by copyright. All rights reserved.

Anti-lung cancer targets of ellagic acid and biological interaction with a blood carrier protein

Ellagic acid (C14H6O8, 4,4′,5,5′6,6′-hexahydroxydiphenic acid 2,6,2′6′-dilactone) as a metabolite polyphenol compound has shown potential anticancer activities. However, its potential interaction affinity with plasma carrier proteins and antimetastatic activities are still unknown. Therefore, in this study, the anticancer and antimetastatic activities of ellagic acid in H358 metastatic lung cancer cells were assessed by MTT, qRT-PCR and western blotting. Then, the interaction of ellagic acid with human transferrin (HTf) as a drug carrier protein was measured. The results showed that ellagic acid-triggered cytotoxicity in H358 metastatic cells with an IC50 concentration of 7.18 µM. was mediated by overexpression of Bax/Bcl-2 ratio and caspase-3 mRNA as well as caspase-3 activity. Additionally, after being incubated with ellagic acid, the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), a hallmark of angiogenesis, and the metastasis markers matrix metalloproteinase-2 (MMP-2) and MMP-9 were noticeably reduced. In protein–ligand interaction section, we found that one molecule of ellagic acid potentially binds to one molecule of HTf mediated by the involvement of hydrogen bonds and van der Waals forces, supported by molecular docking simulations. In conclusion, our novel data suggested that ellagic acid can show promising antimetastatic activity against H358 lung cancer cells as well as ideal binding affinity to a drug carrier protein model.

Human Fibroblast-Derived Matrix Hydrogel Accelerates Regenerative Wound Remodeling Through the Interactions with Macrophages.

Herein, a novel extracellular matrix (ECM) hydrogel is proposed fabricated solely from decellularized, human fibroblast-derived matrix (FDM) toward advanced wound healing. This FDM-gel is physically very stable and viscoelastic, while preserving the natural ECM diversity and various bioactive factors. Subcutaneously transplanted FDM-gel provided a permissive environment for innate immune cells infiltration. Compared to collagen hydrogel, excellent wound healing indications of FDM-gel treated in the full-thickness wounds are noticed, particularly hair follicle formation via highly upregulated β-catenin. Sequential analysis of the regenerated wound tissues disclosed that FDM-gel significantly alleviated pro-inflammatory cytokine and promoted M2-like macrophages, along with significantly elevated vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) level. A mechanistic study demonstrated that macrophages-FDM interactions through cell surface integrins α5β1 and α1β1 resulted in significant production of VEGF and bFGF, increased Akt phosphorylation, and upregulated matrix metalloproteinase-9 activity. Interestingly, blocking such interactions using specific inhibitors (ATN161 for α5β1 and obtustatin for α1β1) negatively affected those pro-healing growth factors secretion. Macrophages depletion animal model significantly attenuated the healing effect of FDM-gel. This study demonstrates that the FDM-gel is an excellent immunomodulatory material that is permissive for host cells infiltration, resorbable with time, and interactive with macrophages, where it thus enables regenerative matrix remodeling toward a complete wound healing.

Longitudinal changes in brain-derived neurotrophic factor (BDNF) but not cytokines contribute to hippocampal recovery in anorexia nervosa above increases in body mass index.

Physical sequelae of anorexia nervosa (AN) include a marked reduction in whole brain volume and subcortical structures such as the hippocampus. Previous research has indicated aberrant levels of inflammatory markers and growth factors in AN, which in other populations have been shown to influence hippocampal integrity. Here we investigated the influence of concentrations of two pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-α] and interleukin-6 [IL-6]) and brain-derived neurotrophic factor (BDNF) on the whole hippocampal volume, as well as the volumes of three regions (the hippocampal body, head, and tail) and 18 subfields bilaterally. Investigations occurred both cross-sectionally between acutely underweight adolescent/young adult females with AN (acAN; n = 82) and people recovered from AN (recAN; n = 20), each independently pairwise age-matched with healthy controls (HC), and longitudinally in acAN after partial renourishment (n = 58). Hippocampal subfield volumes were quantified using FreeSurfer. Concentrations of molecular factors were analyzed in linear models with hippocampal (subfield) volumes as the dependent variable. Cross-sectionally, there was no evidence for an association between IL-6, TNF-α, or BDNF and between-group differences in hippocampal subfield volumes. Longitudinally, increasing concentrations of BDNF were positively associated with longitudinal increases in bilateral global hippocampal volumes after controlling for age, age2, estimated total intracranial volume, and increases in body mass index (BMI). These findings suggest that increases in BDNF may contribute to global hippocampal recovery over and above increases in BMI during renourishment. Investigations into treatments targeted toward increasing BDNF in AN may be warranted.

The causal association between circulating cytokines with the risk of frailty and sarcopenia under the perspective of geroscience.

Circulating cytokines were considered to play a critical role in the initiation and propagation of sarcopenia and frailty from observational studies. This study aimed to find the casual association between circulating cytokines and sarcopenia and frailty from a genetic perspective by two-sample Mendelian randomization (MR) analysis. Data for 41 circulating cytokines were extracted from the genome-wide association study dataset of 8,293 European participants. Inverse-variance weighted (IVW) method, MR-Egger, and weighted median method were applied to assess the relationship of circulating cytokines with the risk of aging-related syndromes and frailty. Furthermore, MR-Egger regression was used to indicate the directional pleiotropy, and Cochran's Q test was used to verify the potential heterogeneity. The "leave-one-out" method was applied to visualize whether there was a causal relationship affected by only one anomalous single-nucleotide polymorphisms. Genetic predisposition to increasing levels of interleukin-10 (IL-10), IL-12, and vascular endothelial growth factor (VEGF) was associated with the higher risk of low hand grip strength according to the IVW method [R = 1.05, 95% CI = 1.01-1.10, P = 0.028, false discovery rate (FDR)-adjusted P = 1.000; OR = 1.03, 95% CI = 1.00-1.07, P = 0.042, FDR-adjusted P = 0.784; OR = 1.02, 95% CI = 1.00-1.05, P = 0.038, FDR-adjusted P = 0.567]. Furthermore, genetically determined higher macrophage colony-stimulating factors (M-CSFs) were associated with a lower presence of appendicular lean mass (OR = 1.01, 95% CI = 1.00-1.02, P = 0.003, FDR-adjusted P = 0.103). Monokine induced by interferon-γ (MIG) and tumor necrosis factor-beta (TNF-β) were associated with a higher risk of frailty (OR = 1.03, 95% CI = 1.01-1.05, P < 0.0001, FDR-adjusted P= 0.012; OR = 1.01, 95% CI = 1.00-1.03, P = 0.013, FDR-adjusted P = 0.259). In this study, we did not find heterogeneity and horizontal pleiotropy between the circulating cytokines and the risk of frailty and sarcopenia. Genetic predisposition to assess IL-10, IL-12, and VEGF levels was associated with a higher risk of low hand grip strength and M-CSF with the presence of appendicular lean mass. The high levels of TNF-β and MIG were associated with a higher risk of frailty. More studies will be required to explore the molecular biological mechanisms underlying the action of inflammatory factors.

Paroxetine Effect on Nerve Growth Factor, Human Neurotrophin-4, Brain-Derived Neurotrophic Factor Levels in Post-stroke Depression.

The aim of this study is to explore paroxetine's effect on nerve growth factor (NGF), human neurotrophin-4 (NT-4), and brain-derived neurotrophic factor (BDNF) levels in post-stroke depression. Ninety-two post-stroke depression patients from April 2021 to April 2023 in our hospital were selected and numbered 1 to 92 after enrollment. Forty-six patients with odd number and 46 patients with even number were, respectively, included in the control and observation group. In addition to basic treatment, control group was treated with flupentixol melitracen tablets orally, and observation group received paroxetine hydrochloride orally. The levels of NGF, NT-4, BDNF, 5-hydroxytryptamine (5-HT), homocysteine (Hcy), noradrenaline (NE), Hamilton Depression Scale (HAMD) changes of National Institute of Health Stroke Scale (NIHSS). NGF, NT-4, and BDNF levels were compared between groups at T0, T1, and T2 levels were higher, and the levels at T2 were higher than those at T1, and observation group levels were higher (P < 0.05); NGF, NT-4, and BDNF levels were compared among groups, time, and interaction. 5-HT, Hcy, and NE levels at T0 were compared between groups; 5-HT and NE levels at T1 and T2 were higher than those at T0, the levels at T2 were higher than those at T1, and observation group levels were higher (P < 0.05); Hcy level at T1 and T2 was lower, its level at T2 was lower than those at T1, and observation group levels were lower (P < 0.05); 5-HT, Hcy, and NE levels were compared among groups, time, and interaction (P < 0.05). HAMD and NIHSS at T0 were compared; T1 and T2 were lower than T0, T2 was lower than T1, and observation group was lower (P < 0.05); HAMD and NIHSS were compared among groups, time, and interaction (P < 0.05). For post-stroke depression, paroxetine treatment can effectively improve NGF, NT-4, BDNF, 5-HT, Hcy, and NE levels and effectively reduce the degree of neurological damage and depression, which has high clinical application value.

Prognostic influence of fibroblast growth factor 23 on the course of coronary heart disease in patients with chronic kidney disease

Objective: to study the prognostic impact of the level of fibroblast growth factors 23 on coronary heart disease depending on the stage of chronic kidney disease. Materials and methods: the study included 108 patients with coronary heart disease (CHD), stable angina (stress), functional class 1–3, chronic kidney disease (CKD) C1–C4, average age was 67,62±12,51 years (55 men and 53 women). The level of fibroblast growth factor 23 was assessed using the Biomedica FGF 23 multimatrix enzyme-linked immunosorbent assay. After 12 months of follow-up, the presence of a cumulative endpoint including the occurrence of acute coronary syndrome, stroke, transient ischemic attack, heart failure and death. Differences in data and correlations between them were considered statistically significant at p&lt;0.05. Results: the developed prognostic model to determine the likelihood of cardiovascular complications in patients with coronary artery disease and CKD found that the FGF 23 level is equal to 27.9 with a sensitivity of 62.7% and specificity of 62.5% to distinguish patients with ischemic heart disease and CKD in whom a cumulative endpoint will occur over 12 months of follow-up. Conclusions: to identify patients at high risk of cardiovascular complications in coronary artery disease and CKD, it is advisable to use determination of FGF 23 level.

Investigation of Vascular Endothelial Growth Factor and Endostatin Levels in Some Rat Tissues in Response to Cold Stress and Diet

Objective: Obesity, the disease of our age, is a condition that occurs when there is an excess of fat tissue in the body. It is not merely a concern about weight gain, but rather a medical issue that elevates the risk of various diseases including heart disease, diabetes, high blood pressure, and certain cancers. This study aimed to explore the impact of a high-fat diet under normal conditions and cold stress, as well as the influence of propolis as a dietary supplement, on vascular endothelial growth factor (VEGF) and endostatin levels in rats fed with propolis. Material and Methods: Thirty-six 3-month-old female Wistar rats (6 rats in each group) sourced from Inonu University Experimental Animal Production and Research Center were utilized for the study. Propolis was administered by gavage, dissolved in water, at a dosage of 2 mL per day for two weeks. Results: The group exhibiting at least a 20% increase in weight due to high-fat diet consumption was categorized as the obese group. Tissues including heart, liver, lung, brown adipose, and white adipose tissues were procured from the obese, propolis-treated, and control groups. Endostatin and vascular endothelial growth factor levels were assessed in the tissues using the ELISA method. The study revealed an elevation in VEGF levels in brown adipose tissue in both cold stress and propolis treatment groups, accompanied by a reduction in white adipose tissue compared to the control group. Additionally, VEGF levels displayed a general increase in lung, liver, and heart tissues. Conversely, endostatin levels, an antiangiogenic factor, decreased in brown adipose tissue while increasing in white adipose tissue. In liver, lung, and heart tissues, endostatin levels exhibited a general decrease. Conclusion: The findings suggest that both cold stress and propolis treatment influence VEGF and endostatin levels in various rat tissues, indicating potential implications for obesity-related conditions and angiogenesis regulation.

BAP31 Promotes Angiogenesis via Galectin-3 Upregulation in Neuroblastoma.

Neuroblastoma (NB) is one of the highly vascularized childhood solid tumors, and understanding the molecular mechanisms underlying angiogenesis in NB is crucial for developing effective therapeutic strategies. B-cell receptor-associated protein 31 (BAP31) has been implicated in tumor progression, but its role in angiogenesis remains unexplored. This study investigated BAP31 modulation of pro-angiogenic factors in SH-SY5Y NB cells. Through protein overexpression, knockdown, antibody blocking, and quantification experiments, we demonstrated that overexpression of BAP31 led to increased levels of vascular endothelial growth factor A (VEGFA) and Galectin-3 (GAL-3), which are known to promote angiogenesis. Conditioned medium derived from BAP31-overexpressing neuroblastoma cells stimulated migration and tube formation in endothelial cells, indicating its pro-angiogenic properties. Also, we demonstrated that BAP31 enhances capillary tube formation by regulating hypoxia-inducible factor 1 alpha (HIF-1α) and its downstream target, GAL-3. Furthermore, GAL-3 downstream proteins, Jagged 1 and VEGF receptor 2 (VEGFR2), were up-regulated, and blocking GAL-3 partially inhibited the BAP31-induced tube formation. These findings suggest that BAP31 promotes angiogenesis in NB by modulating GAL-3 and VEGF signaling, thereby shaping the tumor microenvironment. This study provides novel insights into the pro-angiogenic role of BAP31 in NB.

Causal relationship between circulating inflammatory factors and osteoporosis: a bidirectional Mendelian randomization study.

Osteoporosis (OP), a persistent metabolic bone disorder linked with inflammation, has an undetermined cause. In our research, we employed bidirectional Mendelian randomization (MR) to investigate the interplay between OP and inflammation agents. We performed two-way pooled-level MR analyses to characterize the causal relationship between 41 circulating inflammatory modulators and OP. Genetic variation data for the 41 regulatory factors associated with inflammation were obtained from genome-wide association studies (GWASs) of human cytokines. Bone mineral density (BMD) was utilized as a phenotype for OP in our approach. The BMD dataset, sourced from the GEFOS consortium, a large GWAS meta-analysis study and UK Biobank, was classified based on varied sections [whole body (TB), lumbar spine (LS), femoral neck (FN), forearm (FA), and heel] and age brackets (0-15 years, 15-30 years, 30-45 years, 45-60 years, and above 60 years). Primary MR analyses were executed using the inverse variance weighting (IVW) method, and sensitivity analyses were performed using the MR-Egger, weighted median, simple model, and weighted model. Cochran's Q test was utilized to evaluate the existence of heterogeneity. We used MR-Egger regression and MR multiplicity of residuals and outliers (MR-PRESSO) to assess pleiotropy. After false discovery rate (FDR) correction, elevated levels of circulating interleukin-8 (IL-8) [β = 0.072 (0.031-0.114), p < 0.01], macrophage inflammatory protein-1b (MIP-1β) [β = 0.008 (0.003-0.013), p < 0.01; β = 0.026 (0.009-0.042), p < 0.01], and cutaneous T-cell attracting chemokine (CTACK) [β = 0.037 (0.017-0.056), p < 0.01] was associated with a reduced risk of OP. Reduced levels of hepatocyte growth factor (HGF), IL-1ra, IL-10, macrophage colony-stimulating factor (MCSF), and MIP-1α were associated with a reduced risk of OP [β = -0.030 (-0.047 - -0.013), p < 0.01; β = -0.025 (-0.041 - -0.010), p < 0.01; β = -0.018 (-0.029 - -0.007), p < 0.01; β = -0.060 (-0.097 - -0.024), p < 0.01; β = -0.118 (-0.190 - -0.047), p < 0.01]. We observed a significant causal correlation between FN-BMD and MCP-3 (FDR < 0.05). The occurrence of OP may also lead to elevated levels of MCP3 [β = -0.466 (-0.714 - -0.217), p < 0.01]. The reliability of the results was confirmed by sensitivity analyses. This study demonstrated the pathogenic role of circulating inflammatory modulators in OP using bidirectional MR analysis. This further deepens the understanding of OP pathogenesis and provides new ideas for therapeutic intervention in OP.

Comparison of intravesical chemotherapy regimens after radical nephroureterectomy for upper tract urothelial carcinoma and analysis of risk factors for postoperative recurrence.

Upper tract urothelial carcinoma (UTUC) is a relatively rare but aggressive type of urologic cancer that includes renal pelvic tumors and ureteral tumors with a poor prognosis. Full-length nephroureterectomy plus sleeve bladder resection is the standard treatment for the disease, but patients are prone to recurrence of bladder tumors after surgery. Intravesical infusion therapy is the main means to prevent the recurrence and progression of bladder cancer. Epirubicin and gemcitabine are widely used in clinical practice as first-line or salvage therapy for intravesical chemotherapy; however, the efficacy of these agents is rarely discussed. The purpose of this study was to investigate the effects of epirubicin and gemcitabine on the occurrence of bladder cancer after radical nephroureterectomy for UTUC and to analyze the risk factors affecting the recurrence of postoperative bladder cancer. A total of 215 patients with diagnosed UTUC and treated in our hospital from June 2019 to August 2021 were retrospectively selected as the research subjects, and they were divided into an observation group (120 cases) and a control group (95 cases) according to different treatment methods. The patients in the control group were treated with epirubicin, while those in the observation group received gemcitabine. All patients were followed up by telephone or outpatient examination for 12 months to record the occurrence of adverse reactions. The occurrence of bladder cancer was recorded at 3 months, 6 months, and 12 months after the surgery. According to the occurrence of bladder cancer after surgery, the patients were divided into a bladder cancer group (63 cases) and a non-bladder cancer group (152 cases). Multivariate Logistic regression analysis was used to analyze the risk factors of bladder cancer after surgery. The total incidence of adverse reactions in the control group was 49.47%, which was higher than that in the observation group with 15.00% (p<0.01). The incidence of bladder tumors in the observation group and the control group was 0.00% and 2.11% at 3 months, 5.00% and 8.42% at 6 months, 13.33% and 15.79% at 12 months, without significant difference (p>0.05). After 12 months of perfusion, the levels of acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in the two groups were significantly lower than those before perfusion (p<0.05). In the observation group, the levels of these three factors were slightly decreased compared with those in the control group, without a significant difference (p>0.05). Between the bladder cancer and non-bladder cancer groups, there were significant differences in tumor location, number of lesions, tumor stage, preoperative ureteral examination, and preoperative history of bladder cancer (p<0.05). The above indexes were all risk factors for postoperative bladder cancer (p<0.05). Epirubicin and gemcitabine reduced the occurrence of bladder cancer and effectively inhibited tumor angiogenesis after radical nephroureterectomy for UTUC. The tumor location, number of lesions, tumor stage, preoperative ureteral examination, and preoperative history of bladder cancer were risk factors for postoperative bladder cancer.

Dietary Supplementation of Astragalus membranaceus Extract Affects Growth Performance, Antioxidant Capacity, Immune Response, and Energy Metabolism of Largemouth Bass (Micropterus salmoides).

The present study investigated the effects of Astragalus membranaceus extract (AME) on growth performance, immune response, and energy metabolism of juvenile largemouth bass (Micropterus salmoides). Seven diets containing 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, and 0.6% AME (Con, AME0.1, AME0.2, AME0.3, AME0.4, AME0.5, and AME0.6 groups) were formulated and fed to M. salmoides for 8 weeks. Final body weight (FBW), feed intake (FI), weight gain (WG), and specific growth rate (SGR) were all significantly higher in AME0.4 group than in Con group (P < 0.05). Feed conversion rate (FCR) was significantly improved in AME0.5 group compared with Con group (P < 0.05). Whole-body crude protein contents were significantly increased in AME0.2 group (P < 0.05). Whole-body crude lipid contents were significantly lower in AME0.2 and AME0.3 groups, while muscle lipid was upregulated by dietary AME (P < 0.05). Hepatic malondialdehyde (MDA) contents were significantly lowered in AME0.3 and AME0.4 groups, and catalase (CAT) activities were significantly increased in AME0.1 and AME0.2 groups (P < 0.05). Plasma aspartate aminotransferase (AST) level was significantly lowered in AME0.5, and AME0.6 groups, and alanine aminotransferase (ALT) level was lowered in AME0.5 groups (P < 0.05). Plasma triglyceride was declined in AME0.6 group, and glucose was decreased by 0.3%-0.5% AME (P < 0.05). Significantly higher hepatocyte diameter, lamina propria width, and submucosal layer thickness were recorded in AME0.6 groups, while the longest villi height was obtained in AME0.2 and AME0.3 groups (P < 0.05). The mRNA expression levels of insulin-like growth factor 1 (igf1) revealed the growth-promoting effect of AME. The anti-inflammatory and antiapoptotic effects of AME were demonstrated by transcription levels of interleukin 8 (il-8), tumor necrosis factor-alpha (tnf-a), caspase, B-cell lymphoma-xl (Bcl-xl), bcl-2 associated x (Bax), and bcl-2-associated death protein (Bad). The transcription levels of lipid metabolism and gluconeogenesis related genes, including acetyl-CoA carboxylase alpha (acc1), fatty acid synthase (fasn), fatty acid binding protein 1 (fabp1), phosphoenolpyruvate carboxykinase 2 (pepck2), and glucose-6-phosphatase catalytic subunit 1a (g6pc), were reduced by AME treatment, while the levels of glycolysis-related genes, including glucokinase (gck) and pyruvate kinase (pk), were the highest in AME0.2 and AME0.3 groups (P < 0.05). According to polynomial regression analysis of SGR, WG, FCR, whole-body crude lipid, MDA, and ALT, the optimal AME supplementation level was estimated to be 0.320%-0.429% of the diet. These results provided insights into the roles of AME in regulating immunity and metabolism, which highly indicated its potential as immunostimulants and metabolic regulators in diverse aquatic animals.

Effects of Empagliflozin-Induced Glycosuria on Weight Gain, Food Intake and Metabolic Indicators in Mice Fed a High-Fat Diet.

Sodium glucose-linked transporter 2 (SGLT2) inhibitors promote glucose, and therefore calorie, excretion in the urine. Patients taking SGLT2 inhibitors typically experience mild weight loss, but the amount of weight loss falls short of what is expected based on caloric loss. Understanding the mechanisms responsible for this weight loss discrepancy is imperative, as strategies to improve weight loss could markedly improve type 2 diabetes management and overall metabolic health. Two mouse models of diet-induced obesity were administered the SGLT2 inhibitor empagliflozin in the food for 3 months. Urine glucose excretion, body weight, food intake and activity levels were monitored. In addition, serum hormone measurements were taken, and gene expression analyses were conducted. In both mouse models, mice receiving empagliflozin gained the same amount of body weight as their diet-matched controls despite marked glucose loss in the urine. No changes in food intake, serum ghrelin concentrations or activity levels were observed, but serum levels of fibroblast growth factor 21 (FGF21) decreased after treatment. A decrease in the levels of deiodinase 2 (Dio2) was also observed in the white adipose tissue, a primary target tissue of FGF21. These findings suggest that compensatory metabolic adaptations, other than increased food intake or decreased physical activity, occur in response to SGLT2 inhibitor-induced glycosuria that combats weight loss, and that reductions in FGF21, along with subsequent reductions in peripheral Dio2, may play a role.

Lactate/Hydroxycarboxylic Acid Receptor 1 in Alzheimer's Disease: Mechanisms and Therapeutic Implications-Exercise Perspective.

Lactate has a novel function different from previously known functions despite its traditional association with hypoxia in skeletal muscle. It plays various direct and indirect physiological functions. It is a vital energy source within the central nervous system (CNS) and a signal transmitter regulating crucial processes, such as angiogenesis and inflammation. Activating lactate and its associated receptors elicits effects like synaptic plasticity and angiogenesis alterations. These effects can significantly influence the astrocyte-neuron lactate shuttle, potentially impacting cognitive performance. Decreased cognitive function relates to different neurodegenerative conditions, including Alzheimer's disease (AD), ischemic brain injury, and frontotemporal dementia. Therefore, lactic acid has significant potential for treating neurodegenerative disorders. Exercise is a method that induces the production of lactic acid, which is similar to the effect of lactate injections. It is a harmless and natural way to achieve comparable results. Animal experiments demonstrate that high-intensity intermittent exercise can increase vascular endothelial growth factor (VEGF) levels, thus promoting angiogenesis. In vivo, lactate receptor-hydroxycarboxylic acid receptor 1 (HCAR1) activation can occur by various stimuli, including variations in ion concentrations, cyclic adenosine monophosphate (cAMP) level elevations, and fluctuations in the availability of energy substrates. While several articles have been published on the benefits of physical activity on developing Alzheimer's disease in the CNS, could lactic acid act as a bridge? Understanding how HCAR1 responds to these signals and initiates associated pathways remains incomplete. This review comprehensively analyzes lactate-induced signaling pathways, investigating their influence on neuroinflammation, neurodegeneration, and cognitive decline. Consequently, this study describes the unique role of lactate in the progression of Alzheimer's disease.

The impact of chronic fentanyl administration on the cerebral cortex in mice: Molecular and histological effects

PurposeFentanyl, a fully synthetic opioid, is widely used for severe pain management and has a huge abuse potential for its psychostimulant effects. Unlike other opioids, the neurotoxic effects of chronic fentanyl administration are still unclear. In particular, little is known about its effect on the cerebral cortex. The current study aims to test the chronic toxicity of fentanyl in the mice model. MethodsAdult male Balb/c mice were chronically treated with low (0.05 mg/kg, i.p) and high (0.1 mg/kg, i.p) doses of fentanyl for 5 consecutive weeks, and various neurotoxic parameters, including apoptosis, oxidative stress, and neuroinflammatory response were assessed in the cortex. Potential histological as well as neurochemical changes were also evaluated. ResultsThe results of this study show that chronic fentanyl administration induced intense levels of apoptosis, oxidative stress, and neuroinflammation in the cerebral cortex. These findings were found to be correlated with histopathological characteristics of neural degeneration and white matter injury. Moreover, fentanyl administration was found to reduce the expression of both NMDA receptor subunits and dopamine receptors and elevate the level of epidermal growth factor (EGF). ConclusionFentanyl administration induced neurotoxic effects in the mouse cerebral cortex that could be primarily mediated by the evoked oxidative-inflammatory response. The altered expression of NMDA receptors, dopamine receptors, and EGF suggests the pernicious effects of fentanyl addiction that may end in the development of toxic psychosis.

SENP1 attenuates hypoxia‑reoxygenation injury in liver sinusoid endothelial cells by relying on the HIF‑1α signaling pathway.

Liver sinusoidal endothelial cells (LSECs) have an important role in hepatic ischemia‑reperfusion injury (I/R), but the specific molecular mechanism of action is unknown. LSEC proliferation is regulated and fenestration is maintained via the Sentrin/SUMO‑specific protease 1 (SENP1)/hypoxia‑inducible factor‑1α (HIF‑1α) signaling axis under hypoxic conditions. In the present study, a hypoxia‑reoxygenation (H‑R) injury model was established using mouse LSECs to explore the relationship between SENP1 and H‑R injury invitro, and the specific underlying mechanism was identified, revealing new targets for the clinical attenuation of hepatic I/R injury. Following the culture of LSECs under H‑R conditions, it was demonstrated that the expression of SENP1 was upregulated by reverse transcription‑quantitative polymerase chain reaction and western blotting (WB). In addition, scanning electron microscopy indicated that fenestrae damage was increased, a Cell Counting Kit‑8 assay demonstrated that the proliferation of cells was impaired and flow cytometry showed that apoptosis was increased. After silencing SENP1 expression with short interfering RNA, the proliferation activity of LSECs decreased, the fenestrae damage increased, the apoptosis rate increased and the expression levels of SENP1, HIF‑1α, heme oxygenase and Bcl‑2 were downregulated (as demonstrated by WB), while the expression levels of apoptosis‑related proteins, cleaved‑caspase‑3 and Bax, were upregulated. Enzyme‑linked immunosorbent assay detection showed that the level of vascular endothelial growth factor in the supernatant decreased and the level of IL‑6 and TNF‑α increased. Following the administration of an HIF‑1α signaling pathway agonist, the situation was reversed. These results therefore suggested that SENP1 attenuated the reduction in proliferation, apoptosis and fenestration of LSECs observed following H‑R injury through the HIF‑1α signaling pathway. In conclusion, SENP1 may attenuate H‑R injury in LSECs in a HIF‑1α signaling pathway‑dependent manner.

Development of novel hybrid 3D-printed degradable artificial joints incorporating electrospun pharmaceutical- and growth factor-loaded nanofibers for small joint reconstruction

Small joint reconstruction remains challenging and can lead to prosthesis-related complications, mainly due to the suboptimal performance of the silicone materials used and adverse host reactions. In this study, we developed hybrid artificial joints using three-dimensional printing (3D printing) for polycaprolactone (PCL) and incorporated electrospun nanofibers loaded with drugs and biomolecules for small joint reconstruction. We evaluated the mechanical properties of the degradable joints and the drug discharge patterns of the nanofibers. Empirical data revealed that the 3D-printed PCL joints exhibited good mechanical and fatigue properties. The drug-eluting nanofibers sustainedly released teicoplanin, ceftazidime, and ketorolac in vitro for over 30, 19, and 30 days, respectively. Furthermore, the nanofibers released high levels of bone morphogenetic protein-2 and connective tissue growth factors for over 30 days. An in vivo animal test demonstrated that nanofiber-loaded joints released high concentrations of antibiotics and analgesics in a rabbit model for 28 days. The animals in the drug-loaded degradable joint group showed greater activity counts than those in the surgery-only group. The experimental data suggest that degradable joints with sustained release of drugs and biomolecules may be utilized in small joint arthroplasty.

The effects of TRX suspension training on sarcopenic biomarkers and functional abilities in elderlies with sarcopenia: a controlled clinical trial

BackgroundSarcopenia is an age-related progressive loss of muscle mass and strength that can be modulated by resistance training. This study aimed to investigate the effects of TRX Suspension Training (TST) on serum levels of neuromuscular and growth factors and functional indices in elderly men with sarcopenia, an age-related condition characterized by progressive muscle mass and strength loss.MethodsNineteen sarcopenic elderly men (age = 74.87 ± 4.58 years) were randomly assigned into two groups, the TST group (n = 10) and the control group (n = 9). Serum concentrations of regulatory muscle markers, anthropometric and body composition indices, and functional tests were evaluated at baseline and after 8 weeks. The training protocol consisted of eight weeks of TRX exercises, with three weekly sessions.ResultsAfter 8 weeks of training, growth factors such as Follistatin (FST) (P = 0.001), 22 kDa C-terminal agrin fragment (CAF) (P = 0.031), and growth differentiation factor 15 (GDF15) (P = 0.049) increased significantly in the training group in comparison to the control group and Myostatin (MSTN) (P = 0.002) had a significant decrease. However, there was no significant difference in ASMM/m2 (P = 0.527), SMM/m2 (P = 0.621), or Body fat mass (P = 0.433) within or between groups. In addition, the TRX Suspension Training had a significant effect on the functional tests and improved gait speed (P = 0.037), chair stand (P = 0.016), and TUG (P = 0.016) as well as Handgrip strength (P = 0.035).ConclusionOur findings highlight the efficacy of TRX Suspension Training in enhancing the serum levels of muscle growth factors and functional capacities among elderly individuals with sarcopenia. Therefore, considering the ongoing COVID-19 pandemic, this protocol can prove beneficial for this demographic group.Trial registryIranian Registry of Clinical Trials identifier: IRCT20230727058944N1, prospectively registered 20-09-2023, https://en.irct.ir/trial/71635

Effect of ferric citrate hydrate on fibroblast growth factor 23 and platelets in non-dialysis-dependent chronic kidney disease and non-chronic kidney disease patients with iron deficiency anemia.

Iron deficiency anemia (IDA) increases levels of C-terminal fibroblast growth factor 23 (cFGF23) and platelet count (PLT), each of which is associated with cardiovascular events. Therefore, we hypothesized that iron replacement with ferric citrate hydrate (FC) would decrease cFGF23 levels and PLT in patients with IDA. In a randomized, open-label, multicenter, 24-week clinical trial, patients with non-dialysis-dependent chronic kidney disease (CKD) and non-CKD complicated by IDA (8.0 ≤ hemoglobin < 11.0g/dL; and serum ferritin < 50ng/mL [CKD]; < 12ng/mL [non-CKD]) were randomized 1:1 to FC-low (500mg:approximately 120 mg elemental iron/day) or FC-high (1000mg: approximately 240mg elemental iron/day). If sufficient iron replacement had been achieved after week 8, further treatment was discontinued. Seventy-three patients were allocated to FC-low (CKD n = 21, non-CKD n = 15) and FC-high (CKD n = 21, non-CKD n = 16). Regardless of CKD status, FC increased serum ferritin and transferrin saturation, did not change intact FGF23 or serum phosphorus, but decreased cFGF23. In FC-low group, median changes in cFGF23 from baseline to week 8 were -58.00 RU/mL in CKD and -725.00 RU/mL in non-CKD; in FC-high group, the median changes were -66.00RU/mL in CKD and -649.50 RU/mL in non-CKD. By week 8, FC treatment normalized PLT in all patients with high PLT at baseline (>35.2 × 104/µL; FC-low: 1 CKD, 8 non-CKD; FC-high: 3 CKD, 8 non-CKD). Regardless of CKD status, iron replacement with FC decreased elevated cFGF23 levels and normalized elevated PLT in patients with IDA. jRCT2080223943.