Lactate Dehydrogenase Research Articles

Triple combination of vemurafenib, cobimetinib, and atezolizumab in real clinical practice in the Russian Federation: results of the A1 cohort of the ISABELLA study.

Among several treatment options for BRAF-mutant metastatic melanoma, a combination of BRAF inhibitor, MEK inhibitor, and anti-PDL1 antibody seems to be a new emergent approach recently registered in the Russian Federation. It is still not clear which patient population benefits more from this simultaneous use of three drugs instead of its sequencing. This study aimed to evaluate patients' characteristics treated in real practice in 14 Russian regions by triple combination and to analyze their outcomes depending on biomarkers (PD-L1 expression). This was a part (cohort A1) of a prospective non-interventional study of clinical outcomes and biomarkers in patients with skin melanoma. Patients were included in cohort A1 if combination treatment with vemurafenib (vem) + cobimetinib (cobi) + atezolizumab (atezo) was initiated no earlier than 12 weeks (84 days) prior to written informed consent to participate in this study. The index event was the initiation of therapy with all three drugs vem + cobi + atezo (i.e., triple combination). The primary efficacy endpoint of the study was the 24-month overall survival (OS), defined as the time from the index date to the date of death from any cause. If the patient did not experience an event, the OS will be censored at the date of the last contact. Objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) in the Intention to treat (ITT) population, in biomarker positive population, and in population with brain metastases were also evaluated. Quality of life questionnaires were pre-planned by protocol if it was a part of routine practice. Adverse events were also collected. Between March 2021 and May 2023, 59 patients were enrolled in 19 centers from 14 regions of Russia. Thirty-one of 59 (52.4%) patients had central nervous system metastases, and 18 of 31 (58.4%) were symptomatic. Forty of 59 patients (68%) received the triple combination as the first-line treatment. The median follow-up period was 16.83 [95% confidence interval (CI) 13.8-19.8] months. The mean duration of therapy with this regimen was 9.95 months (95% CI 7.48-13.8). ORR was 55.1%; progression as the best outcome was seen in 16.3%. The median DoR was 12.95 months (95% CI 11.0-14.8 months), with a median of 20.3 months (95% CI 9.1-31.5 months) when triple therapy was administered in the first-line treatment. In patients with brain metastases (N = 31), ORR was 45.1%; the median DoR was 12.95 (95% CI 11.0-14.8 months). The median PFS in the entire population was 13.6 months (95% CI 8.6-18.6); the 24-month PFS was 22%. The estimated median OS in the entire population was 15.8 months (95% CI NA); 24-month OS was 45% (95% CI 0.32-0.64). In multivariate Cox regression model, biomarkers of interest [lactate dehydrogenase, Programmed cell death ligand-1 (PD-L1)] did not have statistically significant impact on PFS, OS, or DoR probably due to high data missing rate. No unexpected adverse events were reported. Grades 3-4 AEs were seen in 23 of 59 patients (38%) with most common were skin and liver toxicity. Triple combination of atezolizumab, vemurafenib, and cobimetinib had proven its efficacy and tolerability in real settings. No impact of potential predictive biomarkers was seen (NCT05402059).

Proteomic analysis of CD29+ Müller cells reveals metabolic reprogramming in rabbit myopia model

The prevalence of myopia is rapidly increasing, significantly impacting the quality of life of affected individuals. Prior research by our group revealed reactive gliosis in Müller cells within myopic retina, prompting further investigation of their role in myopia, which remains unclear. In this study, we analyzed protein expression changes in CD29+ Müller cells isolated from a form deprivation-induced rabbit model of myopia using magnetic activated cell sorting to investigate the role of these cells in myopia. As the principal glial cells in the retina, Müller cells exhibited significant alterations in the components of metabolic pathways, particularly glycolysis and angiogenesis, including the upregulation of glycolytic enzymes, such as lactate dehydrogenase A and pyruvate kinase, implicated in the adaptation to increased metabolic demands under myopic stress. Additionally, a decrease in the expression of proteins associated with oxygen transport suggested enhanced vulnerability to oxidative stress. These findings highlight the proactive role of CD29+ Müller cells in modifying the retinal environment in response to myopic stress and provide valuable insights into mechanisms that could help mitigate myopia progression.

The Anticancer Poperties of Diosgenin on Colorectal Cancer Cells Induced by Wnt/Β Catenin Signaling Pathway

Background: Colorectal cancer (CC) is one of the most prevalent cancers globally. Due to the severe side effects and the development of drug resistance in CC treatments, current therapeutic strategies often prove ineffective. As a result, there is a growing interest in exploring traditional medicinal plants as alternative treatment options for various human diseases. Diosgenin, a bioactive compound derived from plants, has shown potential in inhibiting the growth of human CC cells. The Wnt/β-catenin signaling pathway plays a critical role in colorectal tumorigenesis. Objectives: This study investigates the effects of Diosgenin on the Wnt/β-catenin pathway in CC cells. Methods: Colorectal cancer cells were treated with Diosgenin, and cell viability and plasma membrane integrity were assessed using the MTT assay and lactate dehydrogenase (LDH) activity assay, respectively. Apoptosis was evaluated through Annexin V/PI staining. The expression of Wnt/β-catenin-related genes was analyzed by quantitative PCR (qPCR). Results: Diosgenin significantly inhibited CC cell viability in a time- and concentration-dependent manner after 24, 48, 72, and 96 hours of exposure (P < 0.05). The IC50 values were determined to be 203.55, 122.95, 70.11, and 7.34 µM at 24, 48, 72, and 96 hours, respectively. Diosgenin at its IC50 concentration induced a significant increase in cell apoptosis after 24 hours of treatment (P < 0.05). Additionally, it caused a significant reduction in the expression of β-catenin, cyclin D1, and Pin1 (βCP). Conclusions: Diosgenin exhibits anti-CC effects by inhibiting the expression of βCP genes involved in the Wnt/β-catenin pathway, suggesting its potential as a therapeutic agent for CC.

ATRAZINE AS AN ENDOCRINE DISRUPTOR AND ITS EFFECTS ON MALE REPRODUCTIVE HEALTH

Atrazine has been widely used in Brazilian agriculture, especially in corn and soybean crops. Due to its widespread use, this literature review is relevant to systematize the main studies that evaluate the impact of atrazine as an endocrine disruptor leading to changes in fertility quality, especially in males. In several tests and studies carried out with the exposure of animals to atrazine, negative effects related to changes in factors that are essential for male fertility were observed. Therefore, inhibition of the hypothalamic-pituitary-testicular axis, decreased reproductive cells’s metabolic activity, reduced testosterone levels, reduced lactate dehydrogenase (LDH) enzyme, negative effects on spermatogenesis and morphological changes in the gonads and sperm are results of atrazine toxicity on the male reproductive system that contribute to infertility. In general, it is concluded that atrazine has a potential endocrine disruptor effect, leading to changes in the form of hormone production, especially in hormones related to male sexual reproduction. For this reason, assessing the risks of exposure to this toxin at different stages of life and over several generations, combined with knowledge of its pathophysiological mechanism on the male reproductive system, is essential to preserve the reproductive health of future generations.

Dietary niacin supplementation improves meat quality, muscle fiber type, and mitochondrial function in heat-stressed Taihe black-bone silky fowls.

A recent study has shown that niacin supplementation induces the conversion of type II to type I muscle fibres, thereby promoting a phenotypic shift in oxidative metabolism in porcine skeletal muscle. These effects may be mediated by modulation of the AMPK1/SIRT1 pathway, which activates peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a key regulator of fibre conversion, thereby promoting skeletal muscle mitochondrial biogenesis and myofibre conversion. In this study, we explored how niacin (NA) supplementation impacts the quality of meat and the characteristics of muscle fibers in Taihe Black-bone Silky Fowls (TBsf) exposed to heat conditions. Chickens were rationally assigned to five different treatment groups with five replicates of six chickens each: thermophilic (TN), heat stress (HS) and HS + NA (HN) groups, with the HN group being supplemented with 200, 400 and 800 mg/kg (HS + NA0.02, HS + NA0.04 and HS + NA0.08) NA in the premix, respectively. The results of the experiment showed that addition of 800 mg/kg NA to the diet significantly improved TBsf muscle tenderness compared to HS. Dietary enrichment with 200-800 mg/kg NA significantly increased total antioxidant capacity, superoxide dismutase, and glutathione peroxidase activities, while significantly decreasing malondialdehyde compared to HS. Incorporation of 200-800 mg/kg NA into the diet significantly reduced lactate dehydrogenase activity and myosin heavy chain (MyHC-IIB) gene expression. Furthermore, adding 800 mg/kg NA can significantly enhance the mRNA expression of mitochondrial transcription factors (TFAM and TFB1M) in TBsf skeletal muscle. Adding 400 and 800 mg/kg of NA significantly increased the mRNA expression of AMP-activated protein kinase 1 (AMPK1), PGC-1α, cytochrome c oxidase (Cytc), and nuclear respiratory factor (NRF-1) in the skeletal muscle of TBsf. Supplementing NA at 200-400 mg/kg significantly increased the expression of Sirtuin 1 (SIRT1) mRNA in TBsf skeletal muscle. The experimental results showed that the addition of NA to the diet reduced the shear force of TBsf muscle under heat exposure conditions. It increased the proportion of type I muscle fibres by increasing the antioxidant capacity of the muscle and by promoting mitochondr fibreial biogenesis. Considering the results of this study, it is recommended that TBsf be supplemented with 400-800 mg/kg of NA in the diet to reduce the adverse effects of heat stress on meat quality.

The effect of eccentric arm cycling on muscle damage and injury-related biomarkers.

There is a scarcity of information regarding the effect of upper-body eccentric exercise on biomarkers of muscle damage. This study sought to investigate the effect of eccentric arm cycling on muscle damage [exercise-induced muscle damage (EIMD)]. Ten subjects performed a 15 min eccentric arm cycling protocol (cadence 49 ± 7 rpm, power absorbed 248 ± 34 W). Maximal voluntary contraction (MVC) of the elbow flexors was evaluated at rest and at 5 min, 24 h, and 48 h post-exercise. In addition, blood samples were drawn at rest and thereafter at 30 min, 24 h, and 48 h intervals after exercise for quantification of creatine kinase (CK), myoglobin, lactate dehydrogenase (LDH) and endothelin (ET-1) concentrations. Delayed onset muscle soreness (DOMS) was assessed using a category ratio scale (0-10). Myoglobin was increased from baseline at 30 min post-exercise (+114%, 46.08 ± 22.17 µg/L, p = 0.018). Individual peak values were higher than baseline values for CK (+72.8%, 204 ± 138 U/L, p = 0.046) and LDH (+17%, 3.3 ± 0.88 nmole/min/mL, p = 0.017), but not for ET-1 (+9%, 1.4 ± 0.48 pg/mL, p = 0.45). DOMS was reported at 24 h (median 4) and 48 h (median 4) post-exercise and MVC of the elbow flexors were reduced from baseline (216 ± 44 N) at 5 min (-34%, 147 ± 61 N, p < 0.001), 24 h (-17%, 181 ± 56 N, p = 0.005) and 48 h (-9%, 191 ± 54 N, p = 0.003). Eccentric arm cycling incites EIMD with reduced MVC and elevation of myoglobin, CK and LDH.

Prediction of major intravascular hemolysis during pulsed electric field ablation of atrial fibrillation using a pentaspline catheter.

Pulsed electric field (PEF) has emerged as a promising energy source for catheter ablation of atrial fibrillation (AF). However, data regarding the in-vivo effect of PEF energy on erythrocytes during AF ablation procedures are scarce. This study aimed to quantify the impact of PEF energy on erythrocyte damage during AF ablation by assessing specific hemolytic biomarkers. A total of 60 patients (age: 68 years, males: 72%, serum creatinine: 91 µmol/L) with AF underwent catheter ablation of AF using PEF energy delivered by a multipolar pentaspline Farawave catheter (Farapulse, Boston Scientific, Inc.). Ablation beyond pulmonary vein isolation was performed at the operator's discretion. Peripheral venous blood was sampled for assessing the plasma levels of free hemoglobin (fHb), direct (conjugated) bilirubin, lactate dehydrogenase (LDH), and creatinine before, immediately after the ablation, and on the next day. Following the PEF ablation with duration of [median (interquartile range)] 75 (58, 95) min, with 74 (52, 92) applications and PVI only in 27% of patients, fHb, LDH, and direct bilirubin significantly increased, from 40 (18, 65) to 493 (327, 848) mg/L, from 3.1 (2.6, 3.6) to 6.8 (5.0, 7.9) µkat/L, and from 12 (9, 17) to 28 (16, 44) µmol/L, respectively (all p < .0001). A strong linear correlation was found between the peak fHb and the number of PEF applications (R = 0.81, p < .001). The major hemolysis (defined as fHb >500 mg/L) was predicted by the number of PEF applications with the corresponding area under the receiver operating characteristic curve of 0.934. The optimum cut-off value of >74 PEF applications predicted the major hemolysis with 89% sensitivity and 87% specificity. Catheter ablation of AF using PEF energy delivered from a pentaspline catheter is associated with significant intravascular hemolysis. More than 74 PEF applications frequently resulted in major hemolysis. However, the critical amount of PEF energy that may cause kidney injury in susceptible patients remains to be investigated.

The Impact of Labor Oxytocin Use on Newborn Liver Enzymes.

Oxytocin is commonly used during labor and delivery for induction of labor and prevention of postpartum hemorrhage. While previous studies have explored the effects of labor oxytocin use on maternal and neonatal outcomes, there is a paucity of research on its impact on newborn liver enzyme function. This study aimed to assess the effects of labor oxytocin use on liver enzyme function in newborns. A case-control study was conducted. The case group consisted of 70 newborns whose mothers received oxytocin during labor, while the control group consisted of 70 newborns whose mothers did not receive oxytocin. Complete blood count (CBC), lactate dehydrogenase (LDH), creatine phosphokinase (CPK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total and indirect bilirubin levels were measured in all newborns on the second day of life. The levels of AST and total and indirect bilirubin were found to be higher in the case group than in the control group (51 vs. 42, 7.8 vs. 4.6, and 7.4 vs. 4, respectively; p < 0.005). The levels of CPK and LDH were also higher in the case group (p < 0.005). However, the difference in ALT levels was not significant between the study groups. The observed increase in liver enzymes in this study can indicate the effect of maternal oxytocin on the newborn's liver function. While the changes in liver enzyme levels due to oxytocin use were not found to be high enough to cause liver damage, the increase in CPK and LDH levels could potentially elevate bilirubin levels due to hemolysis. Further research is needed to confirm these findings and explore the underlying mechanisms.

RBM15 drives the progression of lung adenocarcinoma by regulating N6-methyladenosine-mediated LDHA mRNA stability

Abnormal N6-methyladenosine (m6A) methylation in RNA plays a pivotal role in the pathogenesis of many types of tumors by influencing mRNA metabolism, alternative splicing, translocation, stability and translation. However, the specific regulators and underlying mechanisms of m6A modification in the progression of lung adenocarcinoma are not well understood. In this study, we analyzed the RNA-seq transcriptome data downloaded from The Cancer Genome Atlas (TCGA) database, and identified “m6A writer” RNA binding motif protein 15 (RBM15) expression was significantly elevated in lung adenocarcinoma (LUAD) biopsies, and the higher RBM15 levels were correlated with the poorer overall survival (OS) of LUAD patients. Further study confirmed RBM15 was prominently expressed in LUAD tissues and cell lines. Moreover, silencing RBM15 in PC9 and H1299 cells reduced cell proliferation both in vitro and in vivo, while overexpression of RBM15 in A549 cells promoted cell growth. Mechanistically, lactate dehydrogenase A (LDHA) acted as a downstream target of RBM15. RBM15-mediated m6A modification of LDHA mRNA enhanced its stability to exert an oncogenic role in LUAD. Taken together, our findings suggest that the RBM15/LDHA axis might be a novel and promising therapeutic target for LUAD.

Efficacy and safety of immunotherapy combined with chemotherapy in patients with ES-SCLC: A systematic review and network meta-analysis of RCTs and RWSs.

To evaluate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors in the treatment of extensive-stage small-cell lung cancer (ES-SCLC), we conducted a systematic review and meta-analysis that included randomized controlled trials (RCTs) and real-world studies (RWS). By scanning PubMed, Web of science, Embase, and other relevant clinical information public databases, nine RCTs and eight RWSs involving 5205 patients were included in the study. We directly compared the differences between chemotherapy and PD-1/PD-L1 inhibitors plus chemotherapy, and determined the optimal treatment strategy through network meta-analysis (NMA). Compared to chemotherapy, the addition of PD-1/PD-L1 inhibitors significantly improves the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in SCLC patients. Regarding safety, both RCTs and RWSs indicated no significant difference in grade 3-4 adverse events between chemotherapy and chemoimmunotherapy. NMA showed serplulimab plus chemotherapy (Serp_Chemo) appears to provide the best OS, PFS, and ORR benefit, while nivolumab plus chemotherapy shows higher toxicity than other regimens. In subgroup analysis, for elderly patients (age ≥65) and non-elderly (age <65) patients, the most promising quality regimens for achieving better OS extension are atezolizumab plus chemotherapy (Atez_Chemo) and Serp_Chemo, respectively. For patients with PD-L1 ≥ 1% and lactate dehydrogenase (LDH) > upper limit of normal (ULN), there is no apparent OS benefit from immune therapy. In ES-SCLC treatment, adding PD-1/PD-L1 inhibitors to standard chemotherapy improves OS, PFS, and ORR, with Serp_Chemo shows the most promise. Atez_Chemo and Serp_Chemo provided better survival for elderly and non-elderly patients, respectively.

N-butanol extract of Broussonetia papyrifera (L.) L′Hér. ex Vent root bark alleviates atopic dermatitis by targeting E3 ubiquitin ligase WWP1 to promote NLRP3 degradation

BackgroundBroussonetia papyrifera (L.) L′Hér. ex Vent (B. papyrifera) is a deciduous tree widely distributed in Asia. Previous studies have revealed that leaves of B. papyrifera ameliorated atopic dermatitis (AD)-like symptoms and inflammatory response. However, the impact and underlying mechanism of other parts of B. papyrifera on AD remain elusive. MethodsThe AD mice induced by 1-Chloro-2,4-dinitrochlorobenzene were used to observe the histopathological alterations in the skin tissues using hematoxylin-eosin staining and toluidine blue staining techniques. Serum levels of inflammatory factors were quantified utilizing ELISA. Pyroptosis was analyzed by lactate dehydrogenase release and flow cytometry in human keratinocytes. The activation of Nod-like receptor protein 3 (NLRP3) inflammasome was analyzed by western blots. Furthermore, the mechanism underlying the inhibition of NLRP3 inflammasome by N-butanol extracts of B. papyrifera root bark (NE-BPRB) was investigated using cellular thermal shift assay and surface plasmon resonance techniques. ResultsTreatment with NE-BPRB significantly ameliorated symptoms of AD mice and reduced serum levels of pro-inflammatory factors. NE-BPRB intervention exhibited inhibitory effects on NLRP3 inflammasome activation and pyroptosis in vitro and in vivo. NE-BPRB and its primary bioactive constituent chlorogenic acid (CA) promote the K48-linked ubiquitination of NLRP3, leading to its proteasomal degradation by binding WW domain containing E3 ubiquitin protein ligase 1 (WWP1). ConclusionsThe NE-BPRB and its primary bioactive constituent, CA, effectively inhibit the formation of the NLRP3 inflammasome and impede cell pyroptosis by promoting K48-linked ubiquitin-dependent proteasomal degradation of NLRP3 through binding to the E3 ubiquitin ligase WWP1, thereby resulting in improved AD.

Hydroalcoholic Extract of Fumaria Parviflora L. Can Potentially Detoxificate HepG2 Cell Line Following Carbon Tetrachloride Exposure

Background: Fumaria Parviflora L. (FP) is a well-known herb in Iranian traditional medicine, widely used for gastrointestinal diseases. Additionally, the detrimental effects of carbon tetrachloride (CT) on the liver and kidneys have been scientifically established. Objectives: This study was designed to assess the therapeutic effects of FP on HepG2 cells exposed to CT toxicity. Methods: After treatment with hydroalcoholic extract of the FP plant and/or CT, cell viability (using the MTT technique and lactate dehydrogenase assay) and apoptosis (using the diphenylamine assay and Annexin V/PI staining) were investigated. The ratio of BCL2/BAX mRNA expression levels was measured using real-time PCR. Data were analyzed using SPSS software. Results: A significant (P &lt; 0.05) reduction in cell viability was observed at doses of 100 and 200 µg/mL of FP in HepG2 cells. The decreased survival rate following CT exposure was concentration-dependent and significant (P &lt; 0.05). The IC50 of CT was determined to be 1.05 μg/mL for 24 hours. Effective detoxification associated with CT was found at 6.25 µg/mL in both the pre-treatment and simultaneous treatment groups. Cell apoptosis was significantly (P &lt; 0.05) decreased following FP administration in CT-treated cells, with an increase in the ratio of BCL2/BAX mRNA expression levels. Conclusions: The hydroalcoholic extract of FP demonstrated hepatoprotective effects on CT-treated HepG2 cells.

EGCG enhances antitumor effect of apatinib in nonsmall cell lung cancer by targeting VEGF signaling to inhibit glycolysis.

Nonsmall cell lung cancer (NSCLC), one of the most aggressive malignancies globally, is characterized by poor prognosis and limited life expectancy. Epigallocatechin-3-gallate (EGCG), a natural polyphenol found in green tea, has emerged as a promising anticancer agent due to its potent antitumor properties. However, the role and the underlying mechanisms of EGCG in NSCLC remain poorly understood. Hence, this research aimed to explore the effect of EGCG on the antitumor effect of apatinib in NSCLC throughvascular endothelial growth factor(VEGF)-regulated glycolysis. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine staining, wound healing, transwell, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and flow cytometry assays were carried out to evaluate the proliferation, migration, invasion, and apoptosis of H1299 cells, respectively. Furthermore, western blot analysis was used to detect the expressions of VEGF, p-vascular endothelial growth factor receptor-2, hypoxia-inducible factor 1α, neuropilin-1, phosphorylated-phosphatidylinositol 3-kinase, and phosphorylated-AKT. The transfection efficiency of H1299 cells with VEGF overexpression plasmid was also assessed by western blot analysis. Glycolysis was analyzed by estimating extracellular acidification rate, lactate concentration, glucose uptake, and the expressions of lactate dehydrogenase A, pyruvate kinase M2, and hexokinase 2. The results demonstrated that VEGF activated glycolysis in NSCLC cells. EGCG alone and apatinib alone or in combination inhibited cell viability, proliferation, invasion, migration, and glycolysis whereas promoted apoptosis in NSCLC cells. EGCG regulated glycolysis levels in NSCLC through VEGF overexpression, and enhanced the antitumor effect of apatinib in NSCLC through VEGF-regulated glycolysis. Taken together, EGCG strengthened the protective effects of apatinib in NSCLC through glycolysis mediated by VEGF.

Gastrointestinal toxicity following sub-acute exposure of erythrosine in rats: biochemical, oxidative stress, DNA damage and histopathological studies.

Erythrosine, a synthetic food dye, has been controversial due to its potential health risks. This study examines the effect of erythrosine on activity of antioxidative enzymes, oxidative stress indices, DNA damage through comet assay, and histopathological changes on stomach, intestine, and colon over a period of 28 days in rats. Twenty-four rats were randomly divided into four groups (n = 6). The first is the control group and then one each for three doses of erythrosine based on acceptable daily intake (¼ ADI, ½ ADI, and ADI, 0.1 mg/kg body weight). The results revealed that with increasing dosages the activity of catalase decreased in stomach and intestine but in colon, the catalase activity increased. Superoxide dismutase and glutathione-S-transferase activity decreased in dose-dependent manner in all three tissues. While, in stomach and intestine, the acetylcholinesterase activity showed increment in ¼ ADI dose group and then declined in ½ ADI and ADI dose-administered rats. The oxidative stress indicators showed elevated levels of lipid peroxidation, hydrogen peroxide concentration, and lactate dehydrogenase activity suggesting heightened free radical activity and potential oxidative damage. The comet test was used to evaluate DNA damage, revealing substantial damage in the erythrosine administered groups. Histopathological examination showed inflammatory infiltration and other degenerative changes in gastrointestinal tract, highlighting the dye's adverse effects. The research underscores the need for a comprehensive reevaluation of the safety and toxicity of food dyes like erythrosine, especially considering the inconsistencies in existing studies regarding the dye's safety.

Selenomethionine Mitigates Effects of Nocardia cyriacigeorgica-Induced Inflammation, Oxidative Stress, and Apoptosis in Bovine Mammary Epithelial Cells

Nocardia cyriacigeorgica causes bovine mastitis, reduces milk quantity and quality, and is often resistant to antimicrobials. Selenomethionine (SeMet) is a form of selenium, which reduces reactive oxygen species (ROS)-mediated apoptosis and intramammary infections. However, the protective effects of SeMet on N. cyriacigeorgica-infected bovine mammary epithelial cells (bMECs) are unclear. The objective of this study was to evaluate whether SeMet mitigated N. cyriacigeorgica-induced inflammatory injury, oxidative damage and apoptosis in bMECs. Cells were cultured with or without being pretreated with 40 µM of SeMet for 12 h, then challenged with N. cyriacigeorgica (multiplicity of infection = 5:1) for 6 h. Although N. cyriacigeorgica was resistant to lincomycin, erythromycin, enrofloxacin, penicillin, amoxicillin, cephalonium, cephalexin, and ceftriaxone, 40 μM SeMet increased cell viability and inhibited lactate dehydrogenase release in infected bMECs. Furthermore, N. cyriacigeorgica significantly induced mRNA production and protein expression of TNF-α, IL-1β, IL-6, and IL-8 at 6 h. Cell membrane rupture, cristae degeneration and mitochondria swelling were evident with transmission electron microscopy. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-px) activities were down-regulated after 3, 6, or 12 h, whereas malondialdehyde (MDA) and ROS contents were significantly upregulated, with cell damage and apoptosis rapidly evident (the latter increased significantly in a time-dependent manner). In contrast, bMECs pretreated with 40 μM SeMet before infection, SOD, and GSH-px activities were upregulated (p &lt; 0.05); MDA and ROS concentrations were downregulated (p &lt; 0.05), and apoptosis was reduced (p &lt; 0.05). In conclusion, 40 μM SeMet alleviated inflammation, oxidative stress and apoptosis induced by N. cyriacigeorgica in bMECs cultured in vitro.

Prospective cohort study on the clinical significance of interferon-γ, D-dimer, LDH, and CRP tests in children with severe mycoplasma pneumonia.

Mycoplasma pneumoniae is a significant cause of respiratory infections in children, often leading to severe pneumonia. This study aimed to assess the clinical relevance of interferon-gamma (interferon-γ), D-dimer, lactate dehydrogenase (LDH), and C-reactive protein (CRP) as biomarkers in the severity of mycoplasma pneumonia in pediatric patients. In this prospective study, 203 pediatric patients with mycoplasma pneumonia were classified into mild (123 patients) and severe (80 patients) groups. Biomarkers including interferon-γ, D-dimer, LDH, and CRP were measured and analyzed. Statistical methods employed included Pearson and Spearman correlation analyses, logistic regression, and receiver operating characteristic curve analysis. The severe group exhibited significantly higher median and interquartile ranges for interferon-γ, D-dimer, LDH, and CRP compared to the mild group. Logistic regression identified IL-10, IL-6, interferon-γ, tumor necrosis factor-alpha, D-dimer, and LDH as independent predictors of severity, with the model achieving 92% accuracy. Receiver operating characteristic curve analysis showed optimal diagnostic efficacy for interferon-γ, D-dimer, and LDH, with the best threshold values being 8.11, 0.64, and 379, respectively. A significant positive correlation was observed between IL-6 and LDH, as well as between interferon-γ and D-dimer. This study showed that interferon-γ >8.11, D-dimer >0.64, and LDH >379 have an important role in the assessment of severe mycoplasma pneumonia.

Change in Activities of Enzymes of Energy and Carbohydrate Metabolism in Pink Salmon Oncorhynchus gorbuscha (Walb.) Smolts with Change in Environmental Salinity.

Activities of key enzymes of energy and carbohydrate metabolism (cytochrome c oxidase (COX), lactate dehydrogenase (LDH), aldolase, glucose 6-phosphate dehydrogenase (G6PDH), and 1-glycerophosphate dehydrogenase (1-GPDH)) were studied in pink salmon Oncorhynchus gorbuscha (Walb.) smolts from the White Sea in a cage experiment simulating the transition from a freshwater to a marine environment. A decrease in COX, G6PDH, and 1-GPDH activities and an increase in LDH and aldolase activities were observed in juveniles with an increase in water salinity. Based on the findings, a redistribution of energy substrates between the reactions of aerobic and anaerobic metabolism towards higher anaerobic ATP synthesis was assumed for pink salmon. This may indicate that adaptive mechanisms rearrange metabolism to provide energy for osmoregulation in pink salmon juveniles when the salinity changes in their habitat.

Post Artesunate Delayed Hemolysis in Pediatric Patients in the United States

Abstract Background Malaria continues to pose a major threat to global public health, causing millions of infections and hundreds of thousands of deaths each year. Intravenous artesunate is the current first line therapy for severe malaria and has substantially reduced its mortality. Some patients develop severe delayed hemolysis after artesunate therapy, a phenomenon termed post artesunate delayed hemolysis (PADH). A recent study of U.S. adults treated with artesunate found that 2.7% of patients experienced PADH and 56% of those patients required blood transfusion. Thus, the U.S. Food and Drug Administration recommends that patients treated with artesunate receive weekly post-treatment monitoring of hemoglobin and hemolytic markers for four weeks after therapy. While PADH in adults frequently requires blood transfusion, the frequency and severity of PADH in pediatric patients in non-endemic countries is not known. Understanding the risk of PADH in pediatric patients is essential to determine appropriate monitoring for this condition. Methods Multicenter Retrospective Chart Review To estimate rates of PADH in pediatric patients (0-18 years of age), we used ICD-10 diagnosis codes to identify patients treated for malaria at seven hospitals (The Children’s Hospital of Philadelphia, Riley Hospital for Children, Texas Children’s Hospital, Seattle Children’s Hospital, UCSF Benioff Children’s Hospital, NYU Langone Medical Center, and Bellevue Hospital), between April 2017 and July 2022. We reviewed post-discharge laboratory values and clinic visits to identify patients with laboratory findings of PADH and determine clinical outcomes. Pediatric Health Information System (PHIS) Database Review To estimate rates of severe PADH requiring repeat emergency room visit or hospitalization, we used ICD-10 diagnosis codes to identify patients who were treated for malaria with artesunate between January 2019 and July 2023 in a database of 49 children’s hospitals (PHIS). We reviewed patient visits within eight weeks of treatment to identify patients with repeat presentations related to anemia or hemolysis. Results In our retrospective chart review, four of seventeen patients (25%) treated with artesunate had laboratory evidence of PADH. None of these patients were symptomatic and none required readmission or medical intervention. Haptoglobin levels remained low in most patients up to four weeks after treatment, regardless of the presence of PADH, and lactate dehydrogenase (LDH) levels slowly declined over this period. We identified 92 patients in the PHIS database who were treated with artesunate. Of these, three patients (3.3%) had a repeat presentation within four weeks with one or more diagnosis suggestive of new onset anemia. Repeat presentations occurred 5-13 days after initial admission for malaria. Conclusion PADH is common in US pediatric patients treated with artesunate for severe malaria. However, severe hemolysis requiring repeat emergency room visit or readmission is rare. We find that haptoglobin and LDH levels were not useful as initial screening labs for PADH in pediatric patients. Together, our findings call into question the utility of weekly laboratory monitoring, as opposed to symptom-based monitoring, to identify pediatric patients at risk of readmission for PADH. Additional studies are necessary to determine which patients would benefit from weekly laboratory monitoring and which can be monitored clinically.

USP4 promotes PTC progression by stabilizing LDHA and activating the MAPK and AKT signaling pathway.

Ubiquitin-specific protease 4 (USP4) has been identified as a promising oncogenic factor implicated in various human malignancies. However, the exact biological functions and underlying mechanisms of USP4 in the progression of papillary thyroid carcinoma (PTC) remain elusive. In this study, we observed a marked upregulation of USP4 expression in PTC tumor tissues. Elevated levels of USP4 were significantly correlated with aggressive clinicopathological features and poor prognosis. Functional assays for loss-of-function demonstrated that silencing USP4 hindered the proliferation of PTC cells. Furthermore, our investigation revealed a specific interaction between USP4 and lactate dehydrogenase A (LDHA), wherein USP4 played a crucial role in stabilizing LDHA protein levels via deubiquitination in PTC cells. Notably, this study demonstrated that USP4 promotes PTC proliferation by modulating the MAPK and AKT signaling pathways. In summary, our findings elucidate the critical involvement of the USP4/LDHA axis in driving PTC progression through the modulation of MAPK and AKT pathways, thereby identifying USP4 as a potential therapeutic target for the treatment of PTC.

Clinicopathological analysis of primary central nervous system lymphoma in patients with or without HIV infection

The clinicopathological features of HIV-related primary central nervous system lymphoma (PCNSL) and immunocompetent primary central nervous system lymphoma (IC-PCNSL) were found to be distinct. Thirty-seven patients with HIV-related PCNSL and thirty patients with IC-PCNSL were included in our study. Hematoxylin & eosin (HE) staining, immunohistochemical detection using CD10, MUM1, CD20, Bcl-2, Bcl-6, p53, C-MYC, Ki67, methyltransferase like factor 3 (METTL3) antibodies and Epstein–Barr encoding region (EBER) in situ hybridization were performed. All of the patients were classified as the diffuse large B-cell lymphoma (DLBCL) histological type. Patients with HIV-related PCNSL were younger and more likely to be male, with elevated lactate dehydrogenase (LDH) and low sugar content in cerebrospinal fluid (CSF) compared to patients with IC-PCNSL.The positive rates of METTL3, Bcl-2, p53 and EBER were significantly higher in HIV-related PCNSL patients than in IC-PCNSL patients. Furthermore, we also found that the expression of METTL3 was lower in germinal centre B-cell (GCB)-like DLBCL (n = 7) than in non-GCB like DLBCL (n = 30) in HIV-related PCNSL (P = 0.030); however, in IC-PCNSL patients, the expression of METTL3 was not significantly different between GCB-like DLBCL and non-GCB-like DLBCL (P = 0.670). Although the manifestations are similar in PCNSL patients with and without HIV, HIV-related PCNSL differs from IC-PCNSL in terms of pathological characteristics including METTL3, Bcl-2, p53 and EBER. We therefore suggest that the pathogenesis of HIV-related PCNSL and IC-PCNSL may differ according to host immune status.