Serum CYFRA 21-1 and CK19-2G2 as Predictive Biomarkers of Response to Transarterial Chemoembolization in Hepatitis C-related Hepatocellular Carcinoma Among Egyptians: A Prospective Study.

Background and aim: Cytokeratin 19 (CK19)-positive HCC is a subtype of hepatocellular carcinoma (HCC) with poor biological behavior and resistance to different treatments including transarterial chemoembolization (TACE). The current study aimed to investigate the predictive value of serum CK 19 fragment 21-1 (CYFRA 21-1) and serum CK 19 fragment 2G2 (CK 19-2G2) for TACE response in patients with hepatitis C virus (HCV)-related HCC. Methods: This prospective study assessed the pretreatment serum CYFRA 21-1 and CK 19-2G2 levels in 64 patients with HCV-related naïve HCC who underwent TACE to predict 1-year overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Additionally, 40 healthy individuals were included as controls. Pretreatment alpha-fetoprotein (AFP) was also measured for comparison. Results: After exclusions, 60 patients completed TACE sessions, and the 1-year OS was 52%, and ORR post TACE was 71.8%. HCC patients with elevated levels of CYFRA 21-1, CK 19-2G2, or baseline AFP measuring ≥400 ng/ml have decreased 1-year OS and PFS after TACE. Serum CK19-2G2 was an independent predictor of 1-year OS using multivariate hazard regression analysis. Pretreatment normal serum CYFRA 21-1 levels (P = 0.047), serum AFP measuring <400 ng/ml (P = 0.016), and lower AST (P = 0.002) were independent predictors of ORR to TACE using multivariate logistic regression analysis. The predictive ability of pretreatment elevated serum CYFRA 21-1, AFP measuring ≥400 ng/ml, AFP + CYFRA 21-1, AFP + CK 19-2G2, or AFP + CYFRA 21-1+ CK19-2G2 to predict nonresponse (progressive disease) to TACE (area under the curve = 0.795, 0.690, 0.830, 0.725, and 0.850, respectively). Conclusions: This study demonstrated that incorporating the measurement of serum CYFRA 21-1 or CK19-2G2 levels, along with AFP, during the initial diagnosis can aid in predicting poor 1-year OS, PFS, and ORR to TACE in patients with HCV-related HCC.

A predictive risk-scoring model for survival prognosis of multiple myeloma based on gain/amplification of 1q21: Experience in a tertiary hospital in South-Western China.

BACKGROUND: Chromosomal 1q gains and amplifications (+1q21) are frequently observed in patients with newly diagnosed multiple myeloma (NDMM). However, the interpretation of the high-risk (HR) prognostic implications stemming from 1q21 abnormalities remain challenging to implement effectively. METHODS: In a comprehensive analysis of 367 consecutive patients with symptomatic MM, we assessed the prognostic significance of +1q21 using FISH with a threshold of 7.4%. The patient cohort was randomly divided into a training set (66.5%, n = 244) and a validation set (33.5%, n = 133). A multivariate Cox regression analysis was conducted to identify significant prognostic factors associated with PFS. Weight scores were assigned to each risk factor based on the ß-value of the corresponding regression coefficient. A predictive risk-scoring model involving +1q21 was then developed, utilizing the total score derived from these weight scores. The model's discriminative ability was evaluated using the AUC in both the training and validation sets. Finally, we compared the performance of the +1q21-involved risk with the established R-ISS and R2-ISS models. RESULTS: Upon initial diagnosis, 159 patients (43.32%) exhibited +1q21, with 94 (59.11%) having three copies, referred to as Gain(1q21), and 65 (40.89%) possessing four or more copies, referred to as Amp (1q21). Both were significantly linked to a reduced PFS in myeloma (p < 0.05), which could be effectively mitigated by ASCT. The +1q21-involved risk model, with an AUC of 0.697 in the training set and 0.725 in the validation set, was constructed including Gain(1q21), Amp(1q21), no-ASCT, and TP53 deletion. This model, termed the ultra-high-risk (UHR) model, demonstrated superior performance in predicting shorter PFS compared to the R-ISS stage 3 and R2-ISS stage 4. CONCLUSION: The UHR model, which integrates the presence of +1q21 with no-ASCT and TP53 deletion, is designed to identify the early relapse subgroup among patients with +1q21 in NDMM.

Cardiometabolic Aspects of Congenital Adrenal Hyperplasia.

Treatment of classic congenital adrenal hyperplasia (CAH) is directed at replacing deficient hormones and reducing androgen excess. However, even in the era of early diagnosis and lifelong hormonal substitution, the presence of CAH is still associated with numerous complications and also with increased mortality. The aim of this article was to create an authoritative and balanced review concerning cardiometabolic risk in patients with CAH. The authors searched all major databases and scanned reference lists of all potentially eligible articles to find relevant articles. The risk was compared with that in other forms of adrenal insufficiency. The reviewed articles, most of which were published recently, provided conflicting results, which can be partially explained by differences in the inclusion criteria and treatment, small sample sizes and gene-environmental interactions. However, many studies showed that the presence of CAH is associated with an increased risk of weight gain, worsening of insulin sensitivity, high blood pressure, endothelial dysfunction, early atherosclerotic changes in the vascular wall and left ventricular diastolic dysfunction. These complications were more consistently reported in patients with classic than non-classic CAH and were in part related to hormonal and functional abnormalities associated with this disorder and/or to the impact of over- and undertreatment. An analysis of available studies suggests that individuals with classic CAH are at increased cardiometabolic risk. Excess cardiovascular and metabolic morbidity is likely multifactorial, related to glucocorticoid overtreatment, imperfect adrenal hormone replacement therapy, androgen excess and adrenomedullary failure. Cardiometabolic effects of new therapeutic approaches require future targeted studies.

The hepatokine FGF21 stopped lipogenesis and reduced testosterone production in mLTC-1 Leydig Cell Line.

Beyond their link to metabolic issues like type 2 diabetes, factors like lifestyle, environment, and excess weight may also influence fertility. Fibroblast growth factor 21 (FGF21), a liver-derived hormone linked to energy balance, has recently emerged as a potential player in female mammalian reproduction. In male, only two studies have described potential effects of FGF21 on fertility. A recent study has described a negative correlation observed in obese patients presenting a low testosterone level associated with elevated FGF21 plasma levels. To investigate the role of FGF21 in steroidogenesis, we have studied the involvement of FGF21 in lipid and steroid activity by Leydig cells. Leydig cell model expressed all FGF21 receptors and ß-Klotho cofactor as determined by RT-qPCR and by western-blot. Cultured mLTC-1 Leydig cell line exposed to increasing FGF21 concentration induced phosphorylation (Ser 473) of Akt and modified the CREB factor activity, suggesting the functionality of the FGF21 pathway. FGF21 consequences on mLTC-1 Leydig cells are inhibition of the lipid synthesis, leading to a reduction in the content of lipid droplets. The drop in lipid synthesis is associated with a reduction in the amount of lipids (mainly PUFA, cholesterol esterified, and triglycerides) as measured by lipidomic approach. The main consequence is to reduce the quantity of cholesterol, the steroid precursor, in mLTC-1 Leydig cells and is associated with a low production in testosterone. The decrease in androgens was also associated with a reduction in the steroid enzyme genes expression, which are under the control of CREB activity, and present a lower activity due to low cAMP intracellular levels. In vivo, steroid production was lowering after FGF21 administration in adult male mice associated to a decrease in progressive motility and velocity of sperm. In addition, these experimental data are reinforced by a data mining analysis focused on "gonad" terms in 1,319,905 article references showing the link already described between FGF21 with the fatty acids pathways, cholesterol storage, and steroid production. In conclusion, we demonstrated that Leydig cells in the testes present a functional FGF21 pathway, which regulates lipid metabolism and steroid function. In mLTC-1 Leydig cells, FGF21 reduced cholesterol, PUFA content, and testosterone production. Finally, this work highlighted that the hepatokine FGF21 could have a negative impact on androgen synthesis and testicular activity.

PPR21 is involved in the splicing of nad2 introns via interacting with PPR-SMR1 and SPR2 and is essential to maize seed development.

Pentatricopeptide repeat (PPR) proteins are a large group of eukaryote-specific RNA-binding proteins that play pivotal roles in plant organelle gene expression. Here, we report the function of PPR21 in mitochondrial intron splicing and its role in maize kernel development. PPR21 is a typical P-type PPR protein targeted to mitochondria. The ppr21 mutants are arrested in embryogenesis and endosperm development, leading to embryo lethality. Null mutations of PPR21 reduce the splicing efficiency of nad2 intron 1, 2, and 4 and impair the assembly and activity of mitochondrial complex I. Previous studies show that the P-type PPR protein EMP12 is required for the splicing of identical introns. However, our protein interaction analyses reveal that PPR21 does not interact with EMP12. Instead, both PPR21 and EMP12 interact with the small MutS-related (SMR) domain-containing PPR protein 1 (PPR-SMR1) and the short P-type PPR protein 2 (SPR2). PPR-SMR1 interacts with SPR2, and both proteins are required for the splicing of many introns in mitochondria, including nad2 intron 1, 2, and 4. These results suggest that a PPR21-(PPR-SMR1/SPR2)-EMP12 complex is involved in the splicing of nad2 introns in maize mitochondria.

Fecal let-7b and miR-21 directly modulate the intestinal microbiota, driving chronic inflammation.

Inflammatory bowel diseases (IBD) etiology is multifactorial. Luminal microRNAs (miRNAs) have been suspected to play a role in the promotion of chronic inflammation, but the extent to which fecal miRNAs are interacting with the intestinal ecosystem in a way that contribute to diseases, including IBD, remains unknown. Here, fecal let-7b and miR-21 were found elevated, associated with inflammation, and correlating with multiple bacteria in IBD patients and IL-10-/- mice, model of spontaneous colitis. Using an in vitro microbiota modeling system, we revealed that these two miRNAs can directly modify the composition and function of complex human microbiota, increasing their proinflammatory potential. In vivo investigations revealed that luminal increase of let-7b drastically alters the intestinal microbiota and enhances macrophages' associated proinflammatory cytokines (TNF, IL-6, and IL-1ß). Such proinflammatory effects are resilient and dependent on the bacterial presence. Moreover, we identified that besides impairing the intestinal barrier function, miR-21 increases myeloperoxidase and antimicrobial peptides secretion, causing intestinal dysbiosis. More importantly, in vivo inhibition of let-7b and miR-21 with anti-miRNAs significantly improved the intestinal mucosal barrier function and promoted a healthier host-microbiota interaction in the intestinal lining, which altogether conferred protection against colitis. In summary, we provide evidence of the functional significance of fecal miRNAs in host-microbiota communication, highlighting their therapeutic potential in intestinal inflammation and dysbiosis-related conditions, such as IBD.

Insights from pharmacovigilance and pharmacodynamics on cardiovascular safety signals of NSAIDs.

Background and Aim: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat fever, pain, and inflammation. Concerns regarding their cardiovascular safety have been raised. However, the underlying mechanism behind these events remains unknown. We aim to investigate the cardiovascular safety signals and receptor mechanisms of NSAIDs, employing a comprehensive approach that integrates pharmacovigilance and pharmacodynamics. Methods: This study utilized a pharmacovigilance-pharmacodynamic approach to evaluate the cardiovascular safety of NSAIDs and explore potential receptor mechanisms involved. Data were analyzed using the OpenVigil 2.1 web application, which grants access to the FDA Adverse Event Reporting System (FAERS) database, in conjunction with the BindingDB database, which provides target information on the pharmacodynamic properties of NSAIDs. Disproportionality analysis employing the Empirical Bayes Geometric Mean (EBGM) and Reporting Odds Ratio (ROR) methods was conducted to identify signals for reporting cardiovascular-related adverse drug events (ADEs) associated with 13 NSAIDs. This analysis encompassed three System Organ Classes (SOCs) associated with the cardiovascular system: blood and lymphatic system disorders, cardiac disorders, and vascular disorders. The primary targets were identified through the receptor-NSAID interaction network. Ordinary least squares (OLS) regression models explored the relationship between pharmacovigilance signals and receptor occupancy rate. Results: A total of 201,231 reports of cardiovascular-related ADEs were identified among the 13 NSAIDs. Dizziness, anemia, and hypertension were the most frequently reported Preferred Terms (PTs). Overall, nimesulide and parecoxib exhibited the strongest signal strengths of ADEs at SOC levels related to the cardiovascular system. On the other hand, our data presented naproxen and diclofenac as drugs of comparatively low signal strength. Cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were identified as central targets. OLS regression analysis revealed that the normalized occupancy rate for either COX-1 or COX-2 was significantly inversely correlated with the log-transformed signal measures for blood and lymphatic system disorders and vascular disorders, and positively correlated with cardiac disorders and vascular disorders, respectively. This suggests that higher COX-2 receptor occupancy is associated with an increased cardiovascular risk from NSAIDs. Conclusion: Cardiovascular safety of NSAIDs may depend on pharmacodynamic properties, specifically, the percentage of the occupied cyclooxygenase isoenzymes. More studies are needed to explore these relations and improve the prescription process.

Characterization of probiotic strains of Bacillus sp. from fermented palm wine (Nypa fructicans sp.) and exploration of cellulolytic potential for use as an addition in animal feed.

The main objective of this study was to assess cellulolytic probiotic strains from traditional fermented beverages such as palm wine in order to supplement the animal feed and strengthen the gut health of the animal for better digestibility and absorption. In the present study, different types of microbes were isolated from traditionally prepared palm wine and analyzed for their probiotic nature. For any microbe to be probiotic in nature, it has to sustain the harsh conditions of the human gastrointestinal tract such as acid tolerance, bile tolerance at the lower range of pH, and other properties like auto aggregation test, cell surface hydrophobicity test with non-polar hydrocarbons for evaluating its capabilities to adhere to the intestinal cells and antimicrobial nature against pathogens. Bacillus mycoides strain PR04 and Bacillus subtilis strain PR21 were found to be resistant to acid and bile in simulated artificial gastrointestinal tract model, found to be than 55% hydrophobic with xylene and n-hexadecane and also showed antimicrobial activity greater towards pathogenic strains like Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Salmonella typhimurium respectively. The cellulolytic activity of the isolates PR04 and PR21 was evaluated in (0.2-2) % CMC (carboxymethyl cellulose) plate. Bacillus mycoides PR04 and Bacillus subtilis PR21 could degrade carboxymethyl cellulose, filter paper, and sugarcane bagasse. The degradation of sugarcane bagasse was confirmed by Scanning electron microscopy and filter paper degradation after 4 days of incubation at 37 °C. Cellulase gene of the identified Bacillus sp. strains was amplified by primers CF5'-ACAGGATCCGATGAAAACGGTCAATTTCTATTTT-3' and CR5'-ACTCTCGAGATTGGGTTCTGTTCCCAAT-3'. This study proposes potential probiotic Bacillus mycoides PR04 (Accession no. OR625070) and Bacillus subtilis PR21 (Accession no. OR625072) in the application as an animal feed additive to assist in its digestibility and encourage the gut health.

Liver-secreted FGF21 induces sarcopenia by inhibiting satellite cell myogenesis via klotho beta in decompensated cirrhosis.

BACKGROUND & AIMS: Sarcopenia, a prevalent condition, significantly impacts the prognosis of patients with decompensated cirrhosis (DC). Serum fibroblast growth factor 21 (FGF21) levels are significantly higher in DC patients with sarcopenia. Satellite cells (SCs) play a role in aging- and cancer-induced sarcopenia. Here, we investigated the roles of FGF21 and SCs in DC-related sarcopenia as well as the underlying mechanisms. METHODS: We developed two DC mouse models and performed in vivo and in vitro experiments. Klotho beta (KLB) knockout mice in SCs were constructed to investigate the role of KLB downstream of FGF21. In addition, biological samples were collected from patients with DC and control patients to validate the results. RESULTS: Muscle wasting and impaired SC myogenesis were observed in the DC mouse model and patients with DC. Elevated circulating levels of liver-derived FGF21 were observed, which were significantly negatively correlated with skeletal muscle mass/skeletal muscle index. Liver-secreted FGF21 induces SC dysfunction, contributing to sarcopenia. Mechanistically, FGF21 in the DC state exhibits enhanced interactions with KLB on SC surfaces, leading to downstream phosphatase and tensin homolog upregulation. This inhibits the protein kinase B (PI3K/Akt) pathway, hampering SC proliferation and differentiation, and blocking new myotube formation to repair atrophy. Neutralizing circulating FGF21 using neutralizing antibodies, knockdown of hepatic FGF21 by adeno-associated virus, or knockout of KLB in SCs effectively improved or reversed DC-related sarcopenia. CONCLUSIONS: Hepatocyte-derived FGF21 mediates liver-muscle crosstalk, which impairs muscle regeneration via the inhibition of the PI3K/Akt pathway, thereby demonstrating a novel therapeutic strategy for DC-related sarcopenia.

Comparative evaluation of serum and gingival crevicular fluid levels of interleukin 21 in periodontally diseased and healthy patients.

Background: Periodontitis is an inflammatory reaction to subgingival pathogenic microorganisms that causes gradual deterioration of the gingiva, periodontal ligament, and alveolar bone. Interleukin (IL)-21 is the most recently found member of type I cytokine family that is upregulated during inflammation. The current study aims to investigate the biological plausibility of IL-21 as a biomarker for chronic periodontitis. Materials and methods: This cross-sectional clinico-biochemical investigation included 15 systemically healthy, 15 periodontally healthy, 15 chronic gingivitis, and 15 chronic periodontitis subjects aged 25 to 60 years. Following subject enrollment, gingival crevicular fluid (GCF) and blood samples were then taken from each subject. The concentration of IL-21 in all samples was determined using enzyme-linked immunosorbent assay (ELISA) kit. The data was examined using the Kruskal-Wallis test and the Spearman correlation test. Results: Serum IL-21 levels in chronic periodontitis patients were substantially greater than in periodontally healthy individuals. GCF IL-21 levels were substantially greater in gingivitis and chronic periodontitis patients compared to periodontally healthy individuals. In terms of clinical indicators, serum IL-21 levels correlated significantly with bleeding index (BI) in the chronic periodontitis group. In chronic periodontitis group, disease severity as evaluated by probing pocket depth (PPD) and clinical attachment loss (CAL) did not correlate with serum or GCF IL-21 levels. Conclusion: According to the current study's findings, periodontally involved patients had higher IL-21 levels than periodontally healthy patients, suggesting it can be used as biomarker. Further studies with larger sample size can shed more light on the clinical advantage of IL-21 as a possible marker for disease activity and progression.

Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer.

Microsatellite stable (MSS) colorectal cancers (CRCs) are often resistant to anti-programmed death-1 (PD-1) therapy. Here, we show that a CRC pathogen, Fusobacterium nucleatum (Fn), paradoxically sensitizes MSS CRC to anti-PD-1. Fecal microbiota transplantation (FMT) from patients with Fn-high MSS CRC to germ-free mice bearing MSS CRC confers sensitivity to anti-PD-1 compared to FMT from Fn-low counterparts. Single Fn administration also potentiates anti-PD-1 efficacy in murine allografts and CD34+-humanized mice bearing MSS CRC. Mechanistically, we demonstrate that intratumoral Fn generates abundant butyric acid, which inhibits histone deacetylase (HDAC) 3/8 in CD8+ T cells, inducing Tbx21 promoter H3K27 acetylation and expression. TBX21 transcriptionally represses PD-1, alleviating CD8+ T cell exhaustion and promoting effector function. Supporting this notion, knockout of a butyric acid-producing gene in Fn abolishes its anti-PD-1 boosting effect. In patients with MSS CRC, high intratumoral Fn predicts favorable response to anti-PD-1 therapy, indicating Fn as a potential biomarker of immunotherapy response in MSS CRC.

Genome-wide association study of image-based trait reveals the genetic architecture of dark-induced leaf senescence in rice.

Darkness is often used as an effective measure to induce leaf senescence. Although many senescence-related genes in rice have been reported, the genome-wide genetic architecture underlying leaf senescence remains poorly understood. In our study, indica and japonica rice showed contrasting responses to dark-induced leaf senescence (DILS). Genome-wide association studies (GWAS) combined with transcriptomic analyses revealed 57, 97, and 48 loci involved in the regulation of the onset, progression, and ending of DILS, respectively. Haplotype analyses showed that the senescence-related loci differentially accumulated in indica and japonica accessions and functioned additively to regulate DILS. A total of 357 candidate genes were identified that are involved in various senescence-related processes such as lipid and amino acid catabolism, photosynthesis, response to reactive oxygen species, and regulation of defense response. In addition, functional analyses of the two candidate genes, OsMYB21 and OsSUB1B, revealed that OsMYB21 positively regulates the onset of DILS, while OsSUB1B negatively regulates its progression. Thus, our results provide new insights into the genetic regulation of DILS in rice.

Improved contingent screening strategy increased trisomy 21 detection rate in the second trimester.

PURPOSE: This study aimed to establish suitable threshold values for biochemical indicators in low-risk pregnant women who underwent second trimester screening and design strategies for consecutive prenatal testing to increase trisomy 21 detection. METHODS: This study examined singleton pregnant women who underwent double, triple, or quadruple screening in the second trimester over six years. To obtain adequate detection efficiency for low-risk pregnancies, threshold values for serum biochemical indicators were established, and a cost-effectiveness assessment of the improved contingent screening strategy was conducted. RESULTS: Participants were included in serum double- (n = 88,550), triple- (n = 29,991), and quadruple-screening (n = 15,004) groups. Threshold values were defined as having a free beta subunit of human chorionic gonadotropin (free ß-hCG) multiple of the median (MoM) ≥ 2.50, alpha-fetoprotein (AFP) MoM ≤ 0.50, or unconjugated estriol (uE3) MoM ≤ 0.70 for low risk. Low-risk pregnancies, comprising 1.35% (988/73,183), 4.45% (1,171/26,286), and 11.91% (1,559/13,085) of the double-, triple-, and quadruple-screening groups, respectively, underwent further non-invasive prenatal screening. In the double-, triple-, and quadruple-screening groups, we detected 11.76% (2/17), 40.00% (2/5), and 66.67% (2/3) of trisomy 21 cases with false negative results, respectively, with the overall detection rates of 85.00% (85/100), 90.63% (29/32), and 95.24% (20/21), respectively, and decreased ratio of overall costs of 5.26%, 16.63%, and 24.36%, respectively. CONCLUSION: Utilizing threshold values of AFP, free ß-hCG, and uE3 to trigger further non-invasive prenatal screening may increase trisomy 21 detection in pregnancies deemed low risk in the second trimester while reducing the overall costs of screening strategies.

The diagnostic value of CYFRA 21-1 in oral squamous cell carcinoma: a meta-analysis.

BACKGROUND: Previous studies have revealed the importance of CYFRA 21-1 in the diagnosis of oral squamous cell cancer (OSCC). However, the results are inconsistent. This meta-analysis is to evaluate CYFRA 21-1's efficacy in distinguishing OSCC. METHODS: Systematic searches of Web of Science, PubMed, and CNKI (1996-2024) were conducted following the Preferred Reporting ltems for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Analysis of 693 patients and 548 controls yielded combined sensitivity (SEN) of 0.71 (95% CI: 0.68, 0.75), specificity (SPE) of 0.88 (95% CI: 0.85, 0.90), and area under the curve (AUC) of 0.927. Subgroup analysis showed higher SEN (0.88), SPE (0.93), and AUC (0.962) in saliva versus serum. Enzyme-linked immunosorbent assay (ELISA) demonstrated superior performance over electrochemiluminescent immunoassay (ECLIA) (AUC: 0.968 vs. 0.868). CONCLUSION: CYFRA 21-1 is effective in OSCC diagnosis, with ELISA showing better sensitivity. Saliva emerges as a promising diagnostic medium compared to serum. REGISTRATION: PROSPERO CRD42024566835.

Clinical value of peripheral blood miR-21 and miR-486 combined with CT forearly cancer diagnosis in pulmonary nodulessmoking.

PURPOSE: This study aimed to investigate the clinical significance of combining peripheral blood miR-21 and miR-486 with CT for the early cancer diagnosis in pulmonary nodules. METHODS: A total of 215 patients diagnosed with isolated pulmonary nodules with a history of smoking were selected as researchsubjects. 30 healthy volunteers with a history of smoking were recruitedas the control group.The selection of subjectswas based on the presence of isolated pulmonary nodules detected on chest CT scans. The training set consisted of 65 patients with lung nodules and 30 healthy smokers, while the verification setincluded 150 patients with lung nodules. RESULTS: Compared with the control group, the plasma expression level of miR-210 was significantly higher in the group of patients with benign pulmonary nodules (P < 0.05). The level of miR-486-5p was lower in patients with malignant pulmonary nodules compared to those with benign pulmonary nodules (P < 0.05). Moreover, the plasma level of miR-210was higher in patients with malignant pulmonary nodules compared to those with benign pulmonary nodules and healthy smokers (P < 0.05). The combination of miR-21 and miR-486 yielded an AUC of 0.865, which was significantly higher than any other gene combination (95%CI: 0.653-0.764, P < 0.05). CONCLUSIONS: This study offered preliminary evidence supporting the use of peripheral blood miR-21 and miR-486, combined with CT scans, as potential biomarkers for the early cancer diagnosis in lung nodules.

Lycopene alleviates age-related cognitive deficit via activating liver-brain fibroblast growth factor-21 signalling.

Brain function is linked with many peripheral tissues, including the liver, where hepatic fibroblast growth factor 21 (FGF21) mediates communication between the liver and brain. Lycopene (LYC), a naturally occurring carotenoid, posses multiple health-promoting properties, including neuroprotective function. Here, we investigated the effects of LYC on age-related memory impairment and the relative contribution of liver-brain FGF21 signaling in these process. The results showed that after treatment with LYC for 3 months, brain aging and age-related cognitive deficits were effectively managed. In addition, LYC ameliorated neuronal degeneration, mitochondrial dysfunction and synaptic damage, and promoted synaptic vesicle fusion in 18-month-old mice. Notably, LYC activated liver-brain FGF21 signalling in aging mice. Whereas all these central effects of LYC were negated by blocking FGF21 via i. v. injection of adeno-associated virus in aging mice. Furthermore, recombinant FGF21 elevated mitochondrial ATP levels and enhanced synaptic vesicle fusion in mouse hippocampal HT-22 cells, which promoted neurotransmitter release. Additionally, we co-cultured hepatocytes and neurons in Transwell and found that LYC enhanced hepatocytes' support for neurons. This support included improved cell senescence, enhanced mitochondrial function, and increased axon length in co-cultured neurons. In conclusion, LYC protects against age-related cognitive deficit, partly explained by activating liver-brain FGF21 signalling, hence promoting neurotransmitters release via increasing mitochondrial ATP levels and enhancing synaptic vesicle fusion. These findings revealed that FGF21 could be a potential therapeutical target in nutritional intervention strategies to improve cognitive damage caused by aging and age-related neurodegenerative diseases.

Relationship of fibroblast growth factor 21, Klotho, and diabetic retinopathy: a meta-analysis.

Background: Diabetic retinopathy (DR) is a serious microvascular complication of diabetes mellitus. Research has identified a close relationship between fibroblast growth factor 21 (FGF21) and DR. FGF21 is a member of the FGF subfamily, which is activated by the Klotho coenzyme involved in the occurrence of DR. However, the association between FGF21, Klotho, and DR remains controversial. Aim: To assess FGF21 and Klotho levels in patients with DR. Methods: A literature search of the Web of Science, Wiley Online Library, PubMed, China National Knowledge Infrastructure and Wanfang databases was performed. The title or abstract search terms "diabetic retinopathy" and "DR" were used in combination with "fibroblast growth factor 21", "FGF21", and "Klotho". Meta-analysis results are presented as standardized mean difference (SMD) with corresponding 95% confidence interval (CI). Results: Fifteen studies were included in this meta-analysis. FGF21 levels in patients with DR were significantly higher than in non-DR patients with diabetes (SMD: 2.12, 95% CI [1.40, 2.84]). Klotho levels in patients with DR were significantly lower than in non-DR patients with diabetes (SMD: -0.63, 95% CI [-1.22, - 0.04]). Conclusions: This systematic review is the first to evaluate the relationship between FGF21, Klotho levels, and DR. FGF21 levels were significantly higher in patients with DR. Fully elucidating the role of FGF21 will significantly contribute to the treatment of DR.

Variation and significance of serum microRNA-21 level in pediatric pulmonary artery hypertension associated with congenital heart disease.

Objective: This study strives to the variation and significance of microRNA-21 (miR-21) in children with congenital heart disease (CHD)-related pulmonary artery hypertension (PAH). Methods: Children with CHD (n = 179) were selected as subjects, including 101 children without PAH and 78 children with PAH. All children underwent general data collection, laboratory examination, echocardiography and cardiac catheterization. After detection of serum miR-21 expression, the predictive value and the impacts of serum miR-21 for PAH and postoperative critical illness were analyzed. Results: Serum creatine kinase isoenzyme (CK-MB), B-type natriuretic peptide (BNP) and miR-21 were elevated, but ejection fraction (EF) and cardiac index (CI) were decreased in the CHD-PAH group. Serum miR-21 assisted in predicting PAH in CHD children, with the area under curve (AUC) of 0.801 (95% CI of 0.735∼0.857), a cut-off value of 2.56, sensitivity of 73.08, and specificity of 72.28%. Serum miR-21 in children with CHD-PAH was correlated with clinicopathological indicators such as systolic pulmonary artery pressure, mean pulmonary arterial pressure, BNP and CI. Serum miR-21 helped predict the development of postoperative critical illness in children with CHD-PAH, with an AUC of 0.859 (95% CI: 0.762-0.927, cut-off value: 4.55, sensitivity: 69.57%, specificity: 92.73%). Increased serum miR-21 was an independent risk factor of postoperative critical illness in children with CHD-PAH. Conclusion: Serum miR-21 was upregulated in children with CHD-PAH, which may serve as a predictive biomarker for the onset of PAH and postoperative critical illness in CHD children.

Exploring endocrine FGFs - structures, functions and biomedical applications.

The family of fibroblast growth factors (FGFs) consists of 22 members with diverse biological functions in cells, from cellular development to metabolism. The family can be further categorized into three subgroups based on their three modes of action. FGF19, FGF21, and FGF23 are endocrine FGFs that act in a hormone-like/endocrine manner to regulate various metabolic activities. However, all three members of the endocrine family require both FGF receptors (FGFRs) and klotho co-receptors to elicit their functions. α-klotho and ß-klotho act as scaffolds to bring endocrine FGFs closer to their receptors (FGFRs) to form active complexes. Numerous novel studies about metabolic FGFs' structures, mechanisms, and physiological insights have been published to further understand the complex molecular interactions and physiological activities of endocrine FGFs. Herein, we aim to review the structures, physiological functions, binding mechanisms to cognate receptors, and novel biomedical applications of endocrine FGFs in recent years.

Interleukin-21 and Interleukin-23 levels in familial Mediterranean Fever before and after treatment: the role of cytokines in disease pathogenesis.

In a previous study, it has been shown that the population of Th17 lymphocytes was increased in patients with FMF. IL-21 and IL-23 play significant roles in the production and differentiation of Th17 cells. In this study, we aimed to evaluate serum levels of IL-21 and IL-23 in FMF patients both at diagnosis and after treatment, and to compare these levels with those of healthy controls. Twenty-seven newly diagnosed patients with FMF in attack-free periods and twenty-seven healthy volunteers enrolled in the study. The groups were comparable with respect to age and gender. IL-21 and IL-23 levels in serum samples from patients at the time of diagnosis, in remission after treatment, and from the control groups were analysed using the ELISA method. There was no significant difference between the cytokine levels of the patient group at the time of diagnosis and the cytokine levels of the control group (for IL-21, p: 0.28 and for IL-23, p: 0.56). Similarly, there was no significant difference between the patients' cytokine levels at the time of diagnosis and after treatment (for IL-21, p: 0.99 and for IL-23, p: 0.08). Interleukin levels at the time of diagnosis did not differ among patient groups based on the presence of clinical findings or the M694V genotype. Our results suggest that IL-21 and IL-23 do not play a role in the pathogenesis of the disease. However, while interpreting these findings, it should be considered that patients with active episodes were excluded and cytokine levels were not measured in tissue samples.