Metabolic Characteristics Research Articles

A meta-analytical approach for estimating methane suppression from dietary additives in ruminants

IntroductionMethane production inhibitors included in feed additives are increasingly used to suppress methane production in the rumen. Most products interact with the rumen microbiome and/or component biochemical pathways that scavenge free hydrogen ions (H+) to make methane (CH4 ). The capacity of these agents to inhibit rumen methane production is determined by the ability of the chemical to block methane production pathways, the amount of agent delivered to the rumen (i.e. the dose) and the absorption, distribution, metabolism and excretion (i.e. the pharmacokinetic) characteristics of the chemical that contribute to removal from the site of action (the rumen). The intrinsic inhibitory capacity of an agent determines the maximum rate of methane suppression. This maximal rate may reduce according to pharmacokinetic effects arising from dose rate and frequency. Most studies of additive methane reduction efficacy use total mixed ration (TMR; with the additive included into the ration) feeding systems and estimate methane reduction (absolute or relative) across a 24-hour period. Few studies report critical pharmacokinetic parameters, making it difficult to extrapolate findings into non-TMR systems (such as grazing) where differing doses and dose frequencies apply.MethodsWe consider the likely behaviour of a rumen-acting oral additive to reduce methane production applying basic pharmacokinetic principles to propose an analytical approach to data from multiple field studies employing different dose rates and dose frequencies to estimate methane suppression responses. This is based upon a logistic transformation of relative efficacy (percentage reduction in methane comparing treatment with control groups) as the dependent variable and includes total dose, dose frequency, quadratic and interaction terms between total dose and dose frequency as independent variables that potentially capture any pharmacokinetic effects on performance. The model was tested using simulation and verified against real data (cattle 3-nitrooxypropanol (3-NOP) methane-reduction studies).ResultsGood fit between predicted and observed methane suppression was obtained.DiscussionWe propose use of the general form of this logistic model with dose and dose frequency components included that address basic pharmacological impacts on methane suppression as the standard approach to meta-analysis.

Determination and analysis of gene expression involved in glucose metabolism under the conditions of the development of experimental diabetes of dexamethasone type (type 2 diabetes)

Type 2 diabetes is one of the most common and serious chronic diseases today, which has become a global health care problem. Type 2 diabetes accounts for about 90–95 % of all cases of diabetes and significantly affects patients’ quality life due to the development of numerous complications, such as cardiovascular diseases, chronic renal failure, retinopathy, neuropathy. Modern research in the field of diabetology pays considerable attention to the understanding of the genetic mechanisms of the pathogenesis of type 2 diabetes, which makes it possible to develop new approaches to its diagnosis and treatment. Individualization of laboratory diagnostics and treatment, which considers the genetic, metabolic and clinical characteristics of each patient, is a key direction in improving the effectiveness of the treatment of type 2 diabetes. Type 2 diabetes is a complex polygenic disease, that develops under the influence of both genetic and external factors, which requires an integrated approach to its diagnosis, treatment and prevention. Taking into account the constant increase in the prevalence of this disease, the relevance of scientific research in this area is beyond doubt. The development of new pharmacological agents, improvement of laboratory diagnostic strategies and individualization of treatment are key directions for overcoming the problem of type 2 diabetes and improving the quality of life of patients. The aim of the work: identification and analysis of genes panel, involved in glucose metabolism under the conditions of the development of experimental type 2 diabetes. Materials and methods. Analysis of the gene expression, involved in glucose metabolism was performed using the real-time reverse transcription polymerase chain reaction method CFX-96 Touch™ (Bio-Rad, USA) using the RT2Profiler™ PCR Array Rat Diabetes kit (QIAGEN, Germany). Results. Based on the results of the PCR study, the activity of the studied genes involved in glucose metabolism can be divided as follows: G6pc, Gpd1 – genes with high expression compared to the control group of animals; Ace, Acly, Foxg1, Foxp3, Gcgr, Gck, Gsk3b, Hmox1, Pygl, Snap23, Snap25 – genes with low expression compared to the control group of animals; Cebpa, Dpp4, Sell – genes in which no changes were detected in the samples in relation to the control group of animals; Ccr2, Fbp1, Gcg – genes, whose expression was not detected. Conclusions. The development of dexamethasone type 2 diabetes significantly (where ∆∆Ct <30) increases the expression of Gpd1 genes by 8 times and G6pc by 2 times compared to the control group of animals. During the development of type 2 dexamethasone diabetes, significantly (where ∆∆Ct <30) the Gsk3b and Hmox1 genes had a 17-fold low expression; Pygl at 11; Foxg1 in 7; Gck in 6; Ace and Foxp3 in 4; Acly in 3; Gcgr, Snap23, Snap25 in 2 times compared to the control group of animals. The expression of Ccr2, Fbp1, Gcg genes during the development of type 2 dexamethasone diabetes was not detected.

Nutritional Glutamine-Modified Iron-Delivery System with Enhanced Endocytosis for Ferroptosis Therapy of Pancreatic Tumors.

Heterogeneous reprogrammed nutrient metabolic networks formed by oncogenes exhibit the potential for exploring novel druggable targets and developing innovative anticancer therapeutics. Herein, based on the heterogeneous metabolic characteristics of glutamine (Gln) addiction in pancreatic cancer cells, an iron-delivery system (IDS) with enhanced endocytosis is designed for efficient ferroptosis therapy. The IDS is characterized by Gln modification and can be recognized as a source of Gln nutrients for efficient endocytic uptake by pancreatic tumor cells. Because the IDS is flexible to combine with amino acid-like components, the IDS with enhanced endocytosis is further produced by loading the Gln transporter inhibitor of V9302. V9302 is capable of suppressing molecular Gln uptake via transporter ASCT2, which generates Gln deprivation to direct metabolic reprogramming of cancer cells and enhances cellular uptake of Gln-modified IDS via RAS-stimulated macropinocytosis. The enhanced endocytosis and high iron content of IDS facilitate ferroptosis in mice pancreatic tumor models; thus, an amino acid-like ferroptosis inducer of l-buthionine sulfoximine (BSO) is further combined. The enhanced endocytosis resulting from the synergism of Gln and V9302 enables the efficient delivery of iron and BSO for ferroptosis tumor therapy. This work provides an alternative approach for enhancing intracellular drug delivery of the tumors with heterogeneous nutrient metabolism by virtue of combining nutrient-modified nanodrugs with the corresponding nutrient transporter inhibitors.

Metabolic Characteristics of the Amphipod Gammarus oceanicus (Crustacea: Amphipoda) Exposed to Octylphenol (4t-Op)

Metabolic Characteristics of the Amphipod Gammarus oceanicus (Crustacea: Amphipoda) Exposed to Octylphenol (4t-Op)

Characteristics of Hyaluronan Metabolism During Myofibroblast Differentiation in Orbital Fibroblasts.

To study the impact of myofibroblast differentiation (MD) on hyaluronan (HA) turnover in orbital fibroblasts (OFs) focusing on the expression of its key enzymes and their potential implications in the pathogenesis of thyroid eye disease (TED). Primary cultures of OFs were established from tissue samples (TED OFs, n = 4; non-TED OFs, n = 5). MD was induced by TGF-β1 (5 ng/mL). Measurements were performed after 24- and 72-hour treatments. The proliferation rate was determined by 5-bromo-2'-deoxyuridine (BrdU) incorporation. HA level and size were measured using an aggrecan-based ELISA-like method and agarose gel electrophoresis, respectively. mRNA expressions of myofibroblast markers and enzymes with a role in HA metabolism were determined using real-time PCR. Upregulation of type I collagen alpha1 chain, alpha-smooth muscle actin, and fibronectin indicated that OFs underwent MD after stimulation by TGF-β. After 72hours, proliferation of untreated cultures declined, but it remained higher in myofibroblasts. Pericellular HA content, but not HA in the supernatant of myofibroblasts, increased compared to untreated cells. TGF-β was a potent stimulator of hyaluronan synthase 1 (HAS1) expression. The expression of hyaluronidase-1 and cell migration-inducing protein (CEMIP) diminished following MD, whereas the expression of transmembrane protein 2, the regulator of HA catabolism through CEMIP, was elevated. The size distribution of HA shifted toward a high-molecular-weight form following treatment with TGF-β. OFs undergoing MD are characterized by decreased HA turnover as a consequence of the inhibition of hyaluronidases and HAS1 induction. Our results suggest that hyaluronidases could be potential targets in the treatment of TED.

Clinical analysis and follow-up results of 25 children with glycogen storage disease

Objective: To investigate the clinical characteristics, genetic characteristics and follow-up of hepatic glycogen accumulation in order to further improve the prognosis of children with hepatic glycogen accumulation. Methods: Clinical data of hospitalized children diagnosed with hepatic glycogen accumulation disease in the Department of gastroenterology, Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2010 to April 2023 were collected and retrospectively analyzed. The results of laboratory examination and gene sequencing were analyzed, and the patients with more than 3 cases (n) were grouped according to the genetic results: Group 1 was type Ⅰ (n=8), group 2 was type Ⅲ (n=5), and group 3 was type Ⅸ a (n=8). The growth, development and prognosis of the children were followed up, and the related clinical characteristics of pediatric hepatic glycogen accumulation were summarized. Results: A total of 25 children with hepatic accumulation of glycogen were included in the study, including 15 males and 10 females. The mean age of diagnosis was (29.1±13.5) months. There were 12 cases (48%) with varying degrees of hypoglycemia, and 2 cases (8%) with severe hypoglycemia. There were 19 cases with height retardation (76%), 4 cases with anemia (16%), 3 cases with proteinuria (12%), and 1 case with cholestasis (4%). The genetic results showed that there were 4 cases of type Ⅰ a (16%), 4 cases of type Ⅰ b (16%), 1 case of type Ⅱ (4%), 5 cases of type Ⅲ (20%), 2 cases of type Ⅳ (8%), 1 case of type Ⅵ (4%), and 8 cases of type Ⅸ (32%). By analyzing the three subgroups, there were statistically significant differences in uric acid and triglyceride (P<0.05), while there were no statistically significant differences in aminotransferase levels, fasting blood glucose, lactic acid, cholesterol and low density lipoprotein levels (P>0.05). The height-specific age Z scores of the three groups were compared, which were -2.86±1.62, -1.46±1.06 and -1.83±0.98, respectively. After at least 1 year of follow-up, the growth and development of groups 2 and 3 were significantly improved compared with group 1 (P<0.05), and the Z scores were -2.28±1.07, 0.20±1.54 and 0.10±1.44. After more than 1 year of follow-up, all the children with type IX had stopped using raw corn starch and had normal transaminase. 4 patients with type Ia were taking raw corn starch orally regularly. Aminotransferase, uric acid and lactic acid were normal, and hypoglycemia was detected among them.Among the 4 cases of type Ⅰb, 1 case had recurrent respiratory and intestinal infections, and 2 cases had Crohn's disease.4 cases of type Ⅲ had stopped using raw corn starch and adopted high protein and low carbohydrate diet. The aminotransferase was normal except for high creatine kinase. One case of type Ⅵ died of liver failure.2 cases were type Ⅳ, 1 died and 1 had a slightly elevated transaminase level. Conclusion: When it is found that the children have liver enlargement, elevated aminotransferase, fasting hypoglycemia, and backward growth and development, it is necessary to be vigilant about liver glycogen accumulation.Clinical manifestations, biochemical indicators combined with genetic examination are helpful for the diagnosis of hepatic glycogen accumulation. Meanwhile, nutritional management is targeted according to the metabolic characteristics of different subtypes, and attention is paid to growth and development.

Hematopoietic stem cell metabolism within the bone marrow niche - insights and opportunities.

Hematopoiesis unfolds within the bone marrow niche where hematopoietic stem cells (HSCs) play a central role in continually replenishing blood cells. The hypoxic bone marrow environment imparts peculiar metabolic characteristics to hematopoietic processes. Here, we discuss the internal metabolism of HSCs and describe external influences exerted on HSC metabolism by the bone marrow niche environment. Importantly, we suggest that the metabolic environment and metabolic cues are intertwined with HSC cell fate, and are crucial for hematopoietic processes. Metabolic dysregulation within the bone marrow niche during acute stress, inflammation, and chronic inflammatory conditions can lead to reduced HSC vitality. Additionally, we raise questions regarding metabolic stresses imposed on HSCs during implementation of stem cell protocols such as allo-SCT and gene therapy, and the potential ramifications. Enhancing our comprehension of metabolic influences on HSCs will expand our understanding of pathophysiology in the bone marrow and improve the application of stem cell therapies.

Integrated untargeted/targeted metabolomics identifies a putative oxylipin signature in patients with atrial fibrillation and coronary heart disease.

Atrial fibrillation (AF) and coronary heart disease (CHD) are closely related to metabolic dysregulation. However, the metabolic characteristics of AF patients with concomitant CHD remain unclear. The aims of this study were to elucidate the metabolic profiles of patients with AF and CHD to seek new therapeutic targets and related factors of AF combined with CHD. Untargeted metabolomics and targeted oxylipins profiling were performed to characterize the serum metabolome landscape of patients with AF, CHD, and AF comorbid CHD. The serum metabolic fingerprints of patients with AF comorbid CHD were significantly differentiated from normal controls (NC) and individuals with AF or CHD alone, and the differentiated metabolites dominated by a variety of lipid alterations in the phospholipid and fatty acid metabolism. Furthermore, the targeted profiles of oxylipins demonstrated that the levels of arachidonic acid derivatives including prostaglandins, leukotrienes, hydroxy-docosahexaenoic acids, hydroxy-eicostetraenoic acids and hydroxy-eicosatrienoic acids in patients with AF and CHD were significantly different from those in the NC, AF, and CHD groups. Several prostaglandins were positively associated with echocardiographic indicators of myocardial remodeling. This study updates metabolic insights of AF and CHD and provides potential therapeutic targets for preventing or treating AF comorbid CHD.

Bridging the Gap: linking Torulaspora delbrueckii Genotypes to Fermentation Phenotypes and Wine Aroma.

Climate change and consumer preferences are driving innovation in winemaking, with a growing interest in non-Saccharomyces species. Among these, Torulaspora delbrueckii (Td) has gained recognition for its ability to reduce volatile acidity and enhance aromatic complexity in wine. However, knowledge regarding its phenotypic and genomic diversity impacting alcoholic fermentation remains limited. Aiming to elucidate the metabolic differences between Td and Saccharomyces cerevisiae (Sc) and the Td intraspecies diversity, we conducted a comprehensive metabolic characterization of fifteen Td strains. This analysis delved beyond standard fermentation parameters (kinetics and major metabolites production) to explore non-conventional aromas and establish genotype-phenotype links. Our findings confirmed that most Td strains produce less acetic acid and more succinate and glycerol than Sc. The overall aromatic profiles of Td strains differed from Sc, exhibiting higher levels of monoterpenes and higher alcohols, while producing less acetate esters, fatty acids, their corresponding ethyl esters, and lactones. Moreover, we identified the absence of genes responsible for specific aroma profiles, such as decreased ethyl esters production, as well as the absence of cell wall genes, which might negatively affect Td performance when compared to Sc. This work highlights the significant diversity within Td and underscores potential links between its genotype and phenotype.

Multi Targeted Therapy for Alzheimer's Disease by Guanidinium-Modified Calixarene and Cyclodextrin Co-Assembly Loaded with Insulin.

Amyloid-β (Aβ) is considered a primary therapeutic target for Alzheimer's disease (AD). However, just eliminating Aβ in patients with AD has exhibited restricted clinical efficacy, possibly failing to address the metabolic abnormalities caused by AD, such as insulin resistance. To address this concern, our research has employed two types of macrocyclic amphiphiles, guanidinium-modified calixarene and cyclodextrin coassembly (GCD), as delivery systems for insulin. This approach aimed to tackle the metabolic dysregulation characteristic of AD in an innovative manner by exploring beyond the conventional strategy of Aβ removal. As a result, GCD and insulin coassembly could effectively improve plaque deposition and insulin resistance. The coassembly could also reduce abnormal neuronal apoptosis and synaptic damage and improve cognitive impairment in 5xFAD mice. Therefore, the GCD and insulin coassembly shows promise as a viable therapeutic option for AD.

Effect of GLP-1 receptor agonists on prostate cancer risk reduction: a systematic review and meta-analysis.

Prostate cancer is one of the most prevalent malignancies among men globally. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), primarily used for type 2 diabetes mellitus (T2DM) management, have been investigated for their potential effects on cancer risks. This systematic review and meta-analysis aimed to assess the association between GLP-1 RA use and risk reduction of prostate cancer. A comprehensive literature search was conducted across PubMed, Embase, and Web of Science up to July 30, 2024. Studies that met the inclusion criteria randomized controlled trials, cohort studies, case-control studies, and observational studies assessing the incidence of prostate cancer in GLP-1 RA-treated patients were included. The quality of studies was evaluated using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias tool. Meta-analysis was performed using a random effects model. A total of five studies were included, analyzing data from diverse international contexts. The included studies showed a reduced risk of prostate cancer with both adjusted and unadjusted effect estimates with GLP-1 RAs. The meta-analysis revealed an RR of 0.72 (95% CI: 0.610 to 0.832), indicating a statistically significant 28% reduction in prostate cancer risk associated with GLP-1 RA use compared to placebo or other antidiabetic drugs. Moderate heterogeneity was observed (I2 = 51%). Sensitivity analysis confirmed the results. The findings suggest a significant protective association between GLP-1 RA use and reduced prostate cancer risk in men, particularly those with T2DM. This supports the potential of GLP-1 RAs not only in diabetes management but also as a strategy to mitigate cancer risk. Further research is required to confirm these findings and explore the underlying mechanisms, considering different dosages, durations of therapy, and patient subgroups based on demographic and metabolic characteristics.

Improved Rapid Equilibrium Dialysis-Mass Spectrometry (RED-MS) Method for Measuring Small Molecule-Protein Complex Binding Affinities in Solution.

Rapid equilibrium dialysis (RED) is predominantly used for the characterization of drug absorption, distribution, metabolism, and excretion (ADME) properties in plasma and biological fluids. We describe herein improvements in the use of RED in conjunction with mass spectrometry (RED-MS) to enable robust binding affinity measurements of small molecules for recombinant proteins and complexes from a single dialysis data set. The affinities calculated from RED-MS correlated well with measurements by both surface plasmon resonance (SPR) and affinity selection mass spectrometry (AS-MS). The method was particularly useful for quantifying the binding of small molecules to large protein complexes that were not amendable by common biophysical characterization techniques. Compound pooling and integration with automated liquid handling increased assay throughput and enabled the analysis of hundreds of measurements per week. RED-MS offers a viable option for measuring compound binding in solution and may facilitate small molecule affinity optimization toward difficult-to-drug protein complexes.

Integrated stress response-upregulated mitochondrial SLC1A5var enhances glucose dependency in human breast cancer cells in vitro

Breast cancer is the most commonly diagnosed cancer among women. The growth of triple-negative breast cancer (TNBC) cells is glucose-dependent. The integrated stress response (ISR) is a cellular stress response to glucose depletion. The ISR-solute carrier family 7 member 11 pathway is activated during glucose depletion and contributes to glucose dependence by decreasing intracellular glutamate levels. Solute carrier family 1 member 5 (SLC1A5) and the mitochondrial solute carrier family 1 member 5 variant (SLC1A5var) are glutamine transporters that play essential roles in the reprogramming of cancer metabolism. However, whether ISR can regulate mitochondrial SLC1A5var expression and further affect glucose dependence remains unclear. Glucose depletion-, oligomycin-, and salubrinal-activated activating transcription factor-4 (ATF4) induced SLC1A5var expression. ATF4 is critical for SLC1A5var regulation, as it binds to specific regulatory elements in its promoter. SLC1A5var knockdown decreases glucose depletion-induced cell death, whereas SLC1A5var overexpression increases glucose depletion-induced cell death in TNBC cells. SLC1A5var knockdown reduced cancer cell proliferation, colony formation, and migration, whereas SLC1A5var overexpression increased cell proliferation and migration. Moreover, the knockdown of SLC1A5var reduces the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) while increasing the maximal OCR and ECAR under glucose depletion. These results suggest that activated ISR-induced increased expression of SLC1A5var may regulate mitochondrial oxidative phosphorylation and glycolytic metabolic characteristics to enhance glucose depletion-induced cell death. In conclusion, SLC1A5var plays a vital role in metabolic reprogramming and may be a potential target for breast cancer treatment.

Central role of hypoxia-inducible factor-1α in metabolic reprogramming of cancer cells: A review.

Metabolic reprogramming is one of the characteristics of tumor cell metabolism. In tumor cells, there are multiple metabolic enzymes and membrane proteins to regulate metabolic reprogramming, and hypoxia inducible factor-1α (HIF-1α) can be regulated in transcription, translation, posttranslational modification and other aspects through multiple pathways, and HIF-1α affects multiple metabolic enzymes and membrane proteins during metabolic reprogramming, thus playing a central role in the metabolic reprogramming process, and thus has some implications for tumor therapy and understanding chemotherapy drug resistance. HIF-1α affects a number of metabolic enzymes and membrane proteins in the metabolic reprogramming process, thus playing a central role in the metabolic reprogramming process, which has certain significance for the treatment of tumors and the understanding of chemotherapeutic drug resistance. In this paper, we review the central role of HIF-1α in metabolic reprogramming, chemotherapeutic agents targeting HIF-1α, and chemotherapeutic drug resistance.

Regional and ethnic factors of obesity and diabetes mellitus in women of re-productive age in the Pribaikal region

Introduction. Overweight is currently one of the leading global medical problems. Overweight and obesity contribute significantly to the development of diseases such as diabetes, cardiovascular disorder and can also cause premature death. Obesity has a negative impact on reproductive function; almost a quarter of women of childbearing age are overweight and about a third of them are obese.Aim. To study the characteristics of carbohydrate metabolism, hormonal indicators, and clinical-metabolic profiles, as well as to assess the potential risk of developing diabetes mellitus in women of fertile age with overweight and obesity residing in the Baikal region.Materials and methods. The study involved 60 overweight and obese women of reproductive age in the Pribaikalye region, including 33 women of Russian nationality (group 1) and 27 women of Buryat nationality (group 2). Anthropo-metric, sociodemographic and behavioural criteria were analysed, as well as questionnaires using the FINDRISC Scale. General clinical analyses of blood and urine were performed, lipid profile parameters, glucose, insulin, creatinine, transaminases, estradiol, thyroid hormone, leptin levels in blood plasma were studied. In addition, an oral glucose tolerance test was performed and the insulin resistance index (HOMA-IR) was calculated.Results. In the group of Buryat women with lower body weight as compared to Russians, higher levels of leptin, HOMA- IR index, and larger waist circumference are observed. In Buryat women, low physical activity makes a significant contribution to the development of overweight and obesity, while for Russian women, excessive caloric intake is more important. In accordance with the results of the FINDRISC scale survey, the greatest contribution to the potential development of diabetes mellitus in the Russian group is body mass index (weight), and in the Buryat group, in addition to these indicators, waist circumference and reduced physical activity.Conclusions. The results of the study will be of great help in the development of pro-grammes for the prevention of diabetes and obesity, taking into account regional and ethnic differences among the population.

Pharmacogenetic features of tramadol metabolism affecting the quality of postoperative analgesia in vascular surgery

BACKGROUND: The issue of the efficacy and safety of medications employed for postoperative analgesia has not been resolved to date. Insufficient analgesia constitutes one of the primary risk factors for developing cardiovascular complications postoperatively. Tramadol is a medication that is frequently used for postoperative pain relief following minor and moderately traumatic operations. The biotransformation of this drug is considerably slowed by the presence of CYP2D6 gene polymorphisms G1846A and C100T, which play a significant role in its metabolism. In such patients, a decrease in the quality of postoperative analgesia can be anticipated, which will consequently lead to an increase in cardiac complications. AIM: To assess the efficacy of a postoperative analgesia regimen based on tramadol and the incidence of cardiac complications during vascular operations depending on the presence/absence of polymorphisms of the CYP2D6 gene polymorphisms, an isoenzyme of cytochrome P-450. MATERIALS AND METHODS: An examination of 109 patients undergoing planned vascular surgery was conducted. The frequency of occurrence of polymorphisms G1846A and C100T of the CYP2D6 gene was determined. All patients were assessed for the severity of postoperative pain syndrome during activity and at rest using a visual analog scale on the first day following surgery. Cardiovascular complications that arose while the patients were in the hospital were documented. To assess the autonomic nervous system, patients underwent cardiointervalography. RESULTS: Polymorphism G1846A was detected in 28 (25.7%), while C100T was detected in four (3.7%) patients. Patients without polymorphisms were included in group 1 (n=77). Patients with polymorphisms were assigned to group 2 (n=32). Pain syndrome at rest and during activity was higher in group 2 patients (p 0.05). The tension index before surgery did not differ between the groups; however, it was greater in group 2 patients after surgery (p 0.001). Cardiac complications were identified in 9.1% of group 1 and 18.8% of group 2 patients (p=0.20). CONCLUSION: The frequency of polymorphisms G1846A and C100T of the CYP2D6 gene in patients who underwent vascular surgery was 29.4%. Such patients experienced pain syndrome of greater severity. The patient groups did not exhibit any significant differences in the frequency of cardiac complications.

Evaluation of drug-drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects.

SKLB1028 is a novel multi-target protein kinase inhibitor under investigation for the treatment of FLT3-ITD mutated acute myeloid leukemia. Based on the preclinical characterization of SKLB1028 metabolism, three drug-drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Fourteen healthy Chinese male subjects were enrolled in each study. In Study 1, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 11) and multiple doses of itraconazole (200 mg twice daily on day 8 and 200 mg once daily from days 9 to 18). Itraconazole was given with a loading dose on Day 8 and the total administration of itraconazole was 11 days. In Study 2, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 12) and multiple doses of gemfibrozil (600 mg twice daily from days 8 to 19). In Study 3, subjects were administered a single dose of SKLB1028 (150 mg on days 1 and 15) and multiple doses of rifampin (600 mg once daily from day 8 to 22). Itraconazole increased the AUC and Cmax of SKLB1028 by approximately 28% and 41%, respectively. Compared to the single drug, co-administration with gemfibrozil increased the AUC of SKLB1028 by ~26% and the Cmax by ~21%. Co-administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies.

Investigating the causal links between obstructive sleep apnea and gastrointestinal diseases mediated by metabolic syndrome through mendelian randomization

Previous studies have pointed to a potential link between Obstructive Sleep Apnea (OSA) and gastrointestinal diseases, suggesting that this relationship might be influenced by the presence of Metabolic Syndrome. However, the exact role of these factors in determining gastrointestinal diseases has not been thoroughly explored. In our study, we utilized data from the Genome-wide Association Studies (GWAS) database, focusing on OSA, metabolic syndrome characteristics such as Body Mass Index (BMI), waist circumference, triglycerides, cholesterol, hypertension, type 2 diabetes, and common gastrointestinal diseases including chronic gastritis, gastric ulcers, irritable bowel syndrome, colorectal cancer, inflammatory bowel disease, cholecystitis, nonalcoholic fatty liver, and dyspepsia. By applying Single-variable and Multi-variable Mendelian randomization methods, we aimed to assess the correlation between OSA and gastrointestinal diseases and investigate whether this correlation is influenced by metabolic syndrome. Our findings revealed a strong association between OSA and an increased risk of chronic gastritis, gastric ulcers, inflammatory bowel disease, and nonalcoholic fatty liver disease. No significant connections were found with irritable bowel syndrome, colorectal cancer, cholecystitis, or dyspepsia. Additionally, OSA was linked to metabolic syndrome traits like BMI, waist circumference, triglycerides, hypertension, and type 2 diabetes. Further analysis showed that BMI, triglycerides, and hypertension were causally related to inflammatory bowel disease; BMI, waist circumference, hypertension, and type 2 diabetes to nonalcoholic fatty liver disease; and triglycerides, hypertension, and type 2 diabetes to chronic gastritis. The multivariable analysis indicated that hypertension mediates the relationship between OSA and chronic gastritis; BMI, triglycerides, and hypertension mediate the link between OSA and inflammatory bowel disease; and waist circumference mediates the connection between OSA and nonalcoholic fatty liver disease. To wrap up, this finding helps us understand how these issues might be related and stresses the role of metabolic syndrome in preventing them, which could lessen their effect on health.

Development of a non-targeted metabolomics-based screening method for elucidating the metabolic characteristics and potential applications of Lacticaseibacillus paracasei

Development of a non-targeted metabolomics-based screening method for elucidating the metabolic characteristics and potential applications of Lacticaseibacillus paracasei

Prognostic Role of Pleural Fluid SUVpeak Value obtained from 18F-FDG PET/CT in patients with Malignant Pleural Effusion

PurposeAssessing the prognosis of patients with malignant pleural effusion (MPE) is cruical to manage the treatment. We aimed to investigate the role of pleural fluid SUVpeak value in predicting mortality. MethodsIn our single center, prospective cohort study, we enrolled 158 patients with MPE. PET/CT was independently evaluated by two nuclear medicine physicians. To identify independent predictors of 90-day mortality, we conducted both univariate and multivariate Cox regression analyses. Furthermore, we assessed the discriminatory ability of these predictors compared to the LENT score using the DeLong statistic. ResultsIn our study, we enrolled 158 patients with a mean age of 66.29±12.6 years, of whom 100 (63.3%) were male. The majority of patients (84.9%) had primary lung cancer, while 24 (15.1%) had metastases from extrapulmonary malignancies. Among the followed-up patients, 51 (32%) died within 90 days, with a median survival of 30 (17-61) days. LENT score (HR: 1.52, 95% CI: 1.14-2.03), pleural fluid albumin value (HR: 0.92, 95% CI: 0.87-0.97), pleural fluid SUVpeak value (HR: 1.39, 95% CI: 1.15-1.69), and pleural effusion size (HR: 1.01, 95% CI: 1.001-1.02) were found to be significant predictors. Furthermore, in assessing the predictive performance for 90-day mortality, ROC curve of a combination of the independent predictors was significantly higher than that of LENT score alone. ConclusionOur study revealed that the metabolic characteristics of pleural fluid might predict 90-day mortality in patients with MPE. We established that the incorporation of pleural fluid SUVpeak value into the LENT score has the potential to enhance its discriminative ability.