Dehydrogenase Levels Research Articles

Accelerated Sarcopenia Phenotype in the DJ-1/Park7-Knockout Zebrafish.

Age-dependent loss of muscle mass and function is associated with oxidative stress. DJ-1/Park7 acts as an antioxidant through multiple signalling pathways. DJ-1-knockout zebrafish show a decline in swimming performance and loss of weight gain between 6 and 9 months of age. Here, we address the degree to which this is associated with muscle degeneration and identify molecular changes preceding dysregulation of muscle performance. Loss of DJ-1 reduced the skeletal muscle fibre cross-section area. The highly mitochondrial-dependent red slow muscle was more affected than the white muscle, and degeneration of sub-sarcolemma red muscle mitochondria was observed. Using TandemMassTag-based quantitative proteomics, we identified a total of 3721 proteins in the multiplex sample of 4 and 12-month-old muscles. A total of 68 proteins, mainly associated with inflammation and mitochondrial function, were dysregulated in the young DJ-1-null adults, with Annexin A3, Sphingomyelin phosphodiesterase acid-like 3B, Complement C3a, and 2,4-dienoyl CoA reductase 1 being the most affected. The loss of DJ-1 also accelerated molecular features associated with sarcopenia, such as a decrease in the NAD+/NADH ratio and a reduction in Prostaglandin reductase 2 and Cytosolic glycerol-3-phosphate dehydrogenase levels. In view of the experimental power of zebrafish, the DJ-1-null zebrafish makes a valuable model for understanding the connection between oxidative stress and age-dependent muscle loss and function.

Progesterone increases metabolism via the pentose phosphate pathway in bovine uterine epithelial cells.

During early pregnancy, glucose is essential for the uterine epithelium and the developing embryo. In cows, progesterone increases the secretion of glucose into the uterine lumen. The uterine epithelium can convert glucose to fructose, but other fates of glucose in the uterine epithelium have been sparsely investigated. Therefore, our objective was to investigate how progesterone influences glucose metabolism in immortalized bovine uterine epithelial (BUTE) cells. BUTE cells were grown to 80% confluence and treated with vehicle (DMSO) or 10 µM progesterone for 24h. Cells were collected and analyzed. Immunohistochemistry was performed on endometrial samples collected from the bovine endometrium on days 1 and 11 of the reproductive cycle. Progesterone treatment increased glucose consumption of BUTE cells. RNAseq identified 3,072 genes regulated by progesterone. KEGG analysis indicated that progesterone altered genes associated with metabolic pathways and glutathione metabolism. Manually examining genes unique to specific glucose metabolic pathways identified an increase in the rate-limiting enzyme in the pentose phosphate pathway-glucose-6-phosphate dehydrogenase. Functionally, a major product of the pentose phosphate pathway is NADPH, and progesterone treatment increased NADPH levels in BUTE cells. In cows, immunohistochemistry confirmed that glucose-6-phosphate dehydrogenase levels were higher in the uterine epithelium in the luteal phase when progesterone concentrations are high. Progesterone increased glucose-6-phosphate dehydrogenase expression and metabolism via the pentose phosphate pathway in the bovine uterine epithelium. This metabolism could provide substrates for cell proliferation, molecules to be secreted into the uterine lumen, or maintain reduction/oxidation balance in the uterine epithelium.

Glucose-6-Phosphate Dehydrogenase Levels and Oxidative Stress Markers Among Cancer Patients in Jos, Nigeria

Glucose-6-phosphate dehydrogenase (G6PD) is a sensitive cytosolic antioxidant enzyme that could be associated with carcinogenesis. Hence, its plasma levels are a good indicator to monitor cancer-induced cellular stress. This study aimed to determine the correlation between Glucose-6-phosphate dehydrogenase and oxidative stress markers among cancer patients in Jos, Nigeria. This case-control study involved 100 subjects (60 cancer patients and 40 healthy control subjects). Their blood samples were collected to measure the levels of G6PD and oxidative stress markers (malondialdehyde, total plasma peroxide, total antioxidant potential, and oxidative stress indices). Twenty-four (40.0%) of the cancer patients were G6PD deficient. Of this, 13 (54.2%) were females G6PD. Of the G6PD deficient cancer patients, 11(45.8%) were male, conversely, 16 (44.4%) of the cancer subjects who had normal G6PD were males. Of the cancer patients, 26.7%; 13.3%, 11.7 % and 10% had prostate, breast cancer, chronic lymphocytic leukemia (CLL), and hepatocellular carcinoma (HCC), respectively were the most frequent. There was no significant association between G6PD deficiency and cancer (<I>X<sup>2</sup></I>=0.025, <i>p</i>=0.804). Among G6PD deficiency cancer patients, the oxidative stress markers were significantly (<i>p<</i>0.05) higher compared to the control group. These findings showed that relatively more of the cancer patients had normal G6PD status even in increased cellular oxidative stress which could be due to host genetic factors. This suggests the need for further experiments on molecular characterization of mechanisms responsible for the findings.

Xanthine oxidoreductase inhibition ameliorates high glucose-induced glomerular endothelial injury by activating AMPK through the purine salvage pathway

Xanthine oxidoreductase (XOR) contributes to reactive oxygen species production. We investigated the cytoprotective mechanisms of XOR inhibition against high glucose (HG)-induced glomerular endothelial injury, which involves activation of the AMP-activated protein kinase (AMPK). Human glomerular endothelial cells (GECs) exposed to HG were subjected to febuxostat treatment for 48 h and the expressions of AMPK and its associated signaling pathways were evaluated. HG-treated GECs were increased xanthine oxidase/xanthine dehydrogenase levels and decreased intracellular AMP/ATP ratio, and these effects were reversed by febuxostat treatment. Febuxostat enhanced the phosphorylation of AMPK, the activation of peroxisome proliferator-activated receptor (PPAR)-gamma coactivator (PGC)-1α and PPAR-α and suppressed the phosphorylation of forkhead box O (FoxO)3a in HG-treated GECs. Febuxostat also decreased nicotinamide adenine dinucleotide phosphate oxidase (Nox)1, Nox2, and Nox4 expressions; enhanced superoxide dismutase activity; and decreased malondialdehyde levels in HG-treated GECs. The knockdown of AMPK inhibited PGC-1α–FoxO3a signaling and negated the antioxidant effects of febuxostat in HG-treated GECs. Despite febuxostat administration, the knockdown of hypoxanthine phosphoribosyl transferase 1 (HPRT1) also inhibited AMPK–PGC-1α–FoxO3a in HG-treated GECs. XOR inhibition alleviates oxidative stress by activating AMPK–PGC-1α–FoxO3a signaling through the HPRT1-dependent purine salvage pathway in GECs exposed to HG conditions.

Optimizing carbon sources regulation in the biochemical treatment systems for coal chemical wastewater: Aromatic compounds biodegradation and microbial response strategies

The complex composition of coal chemical wastewater (CCW), marked by numerous highly toxic aromatic compounds, induces the destabilization of the biochemical treatment system, leading to suboptimal treatment efficacy. In this study, a biochemical treatment system was established to efficiently degrade aromatic compounds by quantitatively regulating the dosage of co-metabolized substrates (specifically, the chemical oxygen demand (COD) Glucose: COD Sodium acetate = 3:1, 1:3, and 1:1). The findings demonstrated that the system achieved optimal performance under the condition that the ratio of COD Glucose to COD Sodium acetate was 3:1. When the co-metabolized substrate was added to the system at an optimal ratio, examination of pollutant removal and cumulative effects revealed that the removal efficiencies for COD and total organic carbon (TOC) reached 94.61 % and 86.40 %, respectively. The removal rates of benzene series, nitrogen heterocyclic compounds, polycyclic aromatic hydrocarbons, and phenols were 100 %, 100 %, 63.58 %, and 94.12 %, respectively. Research on the physiological response of microbial cells showed that, under optimal ratio regulation, co-metabolic substrates led to a substantial rise in microbial extracellular polymeric substances (EPS) secretion, particularly extracellular proteins. When the system reached the end of its operation, the contents of loosely bound EPS (LB-EPS) and tightly bound EPS (TB-EPS) for proteins in the optimal group were 7.12 mg/g-SS and 152.28 mg/g-SS, respectively. Meanwhile, the ratio of α-Helix / (β-Sheet + Random coil) and the proportion of intermolecular interaction forces were also increased in the optimal group. At system completion, the ratio of α-Helix / (β-Sheet + Random coil) reached 0.717 (LB-EPS) and 0.618 (TB-EPS), respectively. Additionally, the proportion of intermolecular interaction forces reached 74.83 % (LB-EPS) and 55.03 % (TB-EPS). An in-depth analysis of the metabolic regulation of microorganisms indicated that the introduction of optimal ratios of co-metabolic substrates contributed to a noteworthy upregulation in the expression of Catechol 2,3-dioxygenase (C23O) and Dehydrogenase (DHA). The expression levels of C23O and DHA were measured at 0.029 U/mg Pro·g MLSS and 75.25 mg TF·(g MLSS·h)−1 (peak value), respectively. Correspondingly, enrichment of aromatic compound-degrading bacteria, including Thauera, Saccharimonadales, and Candidatus_Competibacter, occurred, along with the upregulation of associated functional genes such as Catechol 1,2-dioxygenase, Catechol 2,3-dioxygenase, Protocatechuate 3,4-dioxygenase, and Protocatechuate 4,5-dioxygenase. Considering the intricate system of multiple coexisting aromatic compounds in real CCW, this study not only obtained an optimal ratio for carbon source addition but also enhanced the efficient utilization of carbon sources and improved the capability of the system to effectively degrade aromatic compounds. Additionally, this paper established a theoretical foundation for metabolic regulation and harmless treatment within the biochemical treatment of intricate systems, exemplified by real CCW.

Predictive value of C-reactive protein, D-dimer, Hemoglobin and Lactate dehydrogenase levels in diagnosing COVID-19 patients

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused enormous issues worldwide and is the most infectious pandemic. 50 subjects (evenly distributed between sexes) were included in this study, as well as their range of ages starting from 2 to 67 years. According to the study's result, the age and gender of the subjects include susceptibility to COVID-19; males were found to be more infected than females, and the ages 36 to 67 were more common than in other age ranges. Also, BMI calculations revealed that male patients with COVID-19 had the highest percentage of obesity. The clinical parameter results have been found serum C‐reactive protein (CRP) as an essential indicator that changes significantly in infection with COVID‐19 and inflammation. The concentration of CRP is higher levels for positive COVID‐19 patients (male and female) with mild symptoms of COVID-19 than those with negative COVID‐19 infection, and CRP levels were found to be higher in male than female patients. The results of D-dimer levels determined a nonsignificant difference in D-dimer levels in COVID-19 patients and non-COVID-19 patients than the normal concentration (N: Less than 500mg/dl.). The results of hemoglobin blood levels demonstrated significant variations between COVID-19 patients and non-COVID-19 patients and a decrease in Hb concentration compared to normal concentration (N: 11-16 g/dl.); thus, a link between anemia and inflammation. The lactate dehydrogenase (LDH) levels increased in positive COVID-19 patients male were (178.79 ± 56.08) mg/dl, and positive COVID-19 patients female were (141.57 ± 46.90) mg/dl than normal (N: Less than100mg/dl.), and significant variation was observed between positive and negative COVID-19 patients. Keywords: COVID-19; C‐reactive protein; hemoglobin; lactate dehydrogenase.

Uncovering Novel Roles of miR-122 in the Pathophysiology of the Liver: Potential Interaction with NRF1 and E2F4 Signaling.

MicroRNA miR-122 plays a pivotal role in liver function. Despite numerous studies investigating this miRNA, the global network of genes regulated by miR-122 and its contribution to the underlying pathophysiological mechanisms remain largely unknown. To gain a deeper understanding of miR-122 activity, we employed two complementary approaches. Firstly, through transcriptome analysis of polyribosome-bound RNAs, we discovered that miR-122 exhibits potential antagonistic effects on specific transcription factors known to be dysregulated in liver disease, including nuclear respiratory factor-1 (NRF1) and the E2F transcription factor 4 (E2F4). Secondly, through proteome analysis of hepatoma cells transfected with either miR-122 mimic or antagomir, we discovered changes in several proteins associated with increased malignancy. Interestingly, many of these proteins were reported to be transcriptionally regulated by NRF1 and E2F4, six of which we validated as miR-122 targets. Among these, a negative correlation was observed between miR-122 and glucose-6-phosphate dehydrogenase levels in the livers of patients with hepatitis B virus-associated hepatocellular carcinoma. This study provides novel insights into potential alterations of molecular pathway occurring at the early stages of liver disease, driven by the dysregulation of miR-122 and its associated genes.

Cord Platelet Count of Full-Term Neonates in Relation to ABO Incompatibility and Glucose-6-Phosphate Dehydrogenase Levels: A Retrospective Cohort Study.

Background The immunoglobulin G of mothers with O blood type may sensitize the platelets of their neonates with A (O-A incompatibility) or B (O-B incompatibility) blood type. As the expression and antigenicity of the B antigen on platelets is less than that of the A antigens, we have hypothesized that platelet count is higher in the O-B incompatibility group compared to the O-A incompatibility group. There is controversy about whether glucose-6-phosphate dehydrogenase (G6PD) deficiency, withoutevidenceof hemolysis, is associated with a lower platelet count than G6PD-normal. Aim To assess whether platelet count is higher in the O-B than in the O-A incompatible neonates and whether it correlates with their G6PD levels. Methods This study was a retrospective cohort study on a sample of 835 healthy neonates born at ≥38 weeks gestation who were either A or B blood types with mothers that carried the blood type O Rh-positive. The platelet count (thousand per microliter) from umbilical cord venous blood (UCVB) was used. A G6PD level of 11.0 units/gram of hemoglobin (U/g Hb) was considered the lower reference limit. G6PD deficiency was defined as a G6PD level of <3.3 U/g Hb in both sexes. Intermediate G6PD deficiency in females was described as a G6PD level of 3.3-8.8 U/g Hb. Results The mean UCVB platelet count was higher in female neonates compared to male neonates (n=389, 283±65 versus n=446, 272±73, p=0.01). The mean UCVB platelet count was higher in the O-B incompatibility group in both male (n=114, 291±82 versus n=103, 266±63) and female neonates (n=83, 303±66 versus n=81, 278±58) with G6PD levels of >8.8 U/g Hb. There was a positive weak correlation between UCVB platelet counts and G6PD levels only in O-B incompatible female neonates (n=176, r=0.23, p=0.002). The partitioning and combined 95% reference intervals (RIs) of the UCVB platelet count were presented. Conclusion The platelet count was higher in the O-B incompatibility group compared to the O-A incompatibility group, but only when the G6PD level was >8.8 U/g Hb. A correlation between UCVB platelet count and G6PD levels was found only among O-B incompatible female neonates. These findings may have an important implication in estimating RIs of the UCVB platelet count, however,they need to be confirmed and explored in future research.

Spatial and Temporal Variability of the Microbiological and Chemical Properties of Soils under Wheat and Oilseed Rape Cultivation

The size of the microbial biomass and the activity of soil enzymes are among the most sensitive indicators of agricultural land quality. The aim of this study was to determine the spatial and temporal variability of microbial biomass, the activity of dehydrogenase (DHA) enzyme and the concentration of micro- (Na, Mg and Ca) and macroelements (Cu, Zn, Mn and Fe) in the soil, collected from 37 measurement sites (depth 0–30 cm) in a 40-hectare field during two growing seasons (wheat and oilseed rape). The percentage of nitrogen (%N) in the wheat grain and rapeseeds was also determined. Mapping the spatial distribution of the microbial biomass, the level of DHA activity and the concentration of the selected elements was used to assess the soil productivity. All tested soil parameters exhibited temporal and spatial variability. The creation of raster maps showing the distribution of the tested parameters allowed the observation of a higher nitrogen content in wheat grains in the south-western part of the field, with high values of DHA activity, bacterial biomass and soil pH. In the case of oilseed rape, plants grown in the northern part of the field were characterized by a higher nitrogen content in the grain, where the soil was characterized by a higher content of fungal biomass. On the basis of the obtained research results, a positive, statistically significant correlation was also shown between the biomass of bacteria and the level of DHA in the soil under the cultivation of both wheat and rape. The cultivation of both crops had a significant impact on the size of the microbial biomass pool and on the DHA activity level but did not affect the concentration of the nutrients in the soil. High concentrations of the analyzed elements at the measuring points correlated with a greater %N content in the grain/seeds of the crops harvested at those locations in the field. The results conclude that the mapping of the physicochemical parameters, microbial biomass and activity on the field permits the development of an effective strategy for maintaining sustainable soil productivity through the appropriate management of agricultural practices and the better approximation of mineral fertilization.

Sorghum Allelopathy: Alternative Weed Management Strategy and Its Impact on Mung Bean Productivity and Soil Rhizosphere Properties.

Simple SummaryPlants are subjected to a variety of biotic and abiotic stresses, which affect the rhizospheric attributes and limit agricultural crop productivity. To meet the food and energy demands of the future, several diverse approaches are used for achieving more stress-tolerant and climate-flexible crops for sustainable yields. Several organic and inorganic amendments are used to ameliorate these stresses. Crop-mediated modification (crop residues and allelopathic extracts) has great effects on weed management, improving rhizospheric attributes, and ultimately producing the best quality yield. Sorghum crop residues and their allelopathic extract can be used as a nutrient resource to enhance soil and crop productivity through their application. Sorghum-mediated crop modification will support the soil health and environmental sustainability, providing insight into the improvement of crop productivity. This study will help policymakers in modelling and enhancing sustainable crop production.The reduction of herbicide use and herbicide-resistant weeds through allelopathy can be a sustainable strategy to combat the concerns of environmental degradation. Allelopathic crop residues carry great potential both as weed suppressers and soil quality enhancers. The influence of sorghum crop residues and water extracts on the weed population, soil enzyme activities, the microbial community, and mung bean crop productivity was investigated in a two-year experiment at the Student Research Farm, University of Agriculture Faisalabad. The experimental treatments comprised two levels of sorghum water extract (10 and 20 L ha−1) and two residue application rates (4 and 6 t ha−1), and no sorghum water extract and residues were used as the control. The results indicated that the incorporation of sorghum water extract and residue resulted in significant changes in weed dynamics and the soil quality indices. Significant reduction in weed density (62%) and in the dry weight of weeds (65%) was observed in T5. After the harvest, better soil quality indices in terms of the microbial population (72–90%) and microbial activity (32–50%) were observed in the rhizosphere (0–15 cm) by the same treatment. After cropping, improved soil properties in terms of available potassium, available phosphorus soil organic matter, and total nitrogen were higher after the treatment of residue was incorporated, i.e., 52–65%, 29–45%, 62–84%, and 59–91%, respectively. In the case of soil enzymes, alkaline phosphatase and dehydrogenase levels in the soil were 35–41% and 52–77% higher, respectively. However, residue incorporation at 6 t ha−1 had the greatest effect in improving the soil quality indices, mung bean productivity, and reduction of weed density. In conclusion, the incorporation of 6 t ha−1 sorghum residues may be opted to improve soil quality indices, suppress weeds, harvest a better seed yield (37%), and achieve higher profitability (306 $ ha−1) by weed suppression, yield, and rhizospheric properties of spring-planted mung beans. This strategy can provide a probable substitute for instigating sustainable weed control and significant improvement of soil properties in the mung bean crop, which can be a part of eco-friendly and sustainable agriculture.

Assessment of Calcium Carbide and Natural Ripened Pawpaw (Carica Papaya) Fruits on Biochemical Parameters of Wistar Rats

This research was aimed at assessing calcium carbide and natural ripened pawpaw (Carica papaya) fruit on the biochemical parameters of the Wistar rats. Twenty four (24) adult Wistar rats weighing between 126.9- 213.3 g was used for this study. The experimental Wistar rats were grouped into three and were allowed to acclimatize for two weeks at libitum. Five (5) ml/kg of natural and calcium carbide ripened pawpaw fruit juice were administered orally. At the end of the four weeks feeding period, the rats were sacrificed through cervical dislocation. Blood was collected by cardiac puncture, using 5ml syringes and 23G needles into blood sample containers for biochemical analysis using the standard biochemical methods. The renal, hepatic, cardiac, heart and lipid profile parameters analyzed were albumin, total protein, urea, creatinine, Alkaline Phosphatase (ALP), Alanine aminotransferase (ALT), total bilirubin, Aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and total cholesterol and were compared with the naturally ripened pawpaw fruit group. All mean values of total protein, total cholesterol, lactate dehydrogenase and creatinine levels of calcium carbide ripened pawpaw fruit juice fed group were significantly higher when compared with the natural ripened pawpaw fruit juice. Meanwhile, albumin, total bilirubin, urea, ALT, AST and ALP levels of calcium carbide ripened fruit juice fed group were lower when compared with the natural ripened pawpaw fruit juice. Statistically, there were no significant differences of albumin and total protein parameters at 95% confidence level (P &lt; 0.05). In conclusion, the elevated levels of creatinine, total cholesterol and lactate dehydrogenase may result to kidney injury, cardiovascular and heart diseases. There is therefore need for institutional and legislative strengthening as well as enforcement to prevent the use of calcium carbide in the ripening of pawpaw and other fruits.

Pre- and intratherapeutic predictors of overall survival in patients with advanced metastasized castration-resistant prostate cancer receiving Lu-177-PSMA-617 radioligand therapy

BackgroundSystemic Lutetium-177 prostate-specific membrane antigen-617 radioligand therapy (Lu-177-PSMA-617-RLT) is a novel treatment approach in patients suffering from metastasized castration-resistant prostate cancer. Nonetheless, a therapeutic response may fail to appear in a proportion of patients. This study aims to identify routinely obtainable pre- and intratherapeutic parameters to allow a prediction of overall survival in patients receiving Lu-177-PSMA-617 radioligand therapy.MethodsBetween January 2015 and December 2020 52 patients treated with a total of 146 cycles Lu-177-PSMA-617-RLT were retrospectively analysed in a single-center trial. The median overall survival time (OS) was compared to pre-therapeutic serological parameters, the extend of metastatic spread and previously performed therapies using Kaplan–Meier estimators and multivariate Cox-regression. Bonferroni-Holm correction was performed on all statistical tests.ResultsThe median OS of all patients was 55.6 weeks. Multivariate Cox-regression revealed significant lower survival for decreased pretherapeutic hemoglobin levels (HR 0.698 per g/dl; 95%-CI 0.560–0.872; p = 0.001), increased lactate dehydrogenase (LDH) levels (HR 1.073 per 25 U/l; 95%-CI 1.024–1.125; p = 0.003) and the presence of hepatic metastasis (HR 6.981; 95%-CI 2.583–18.863; p < 0.001). Increased pretherapeutic c-reactive protein (CRP), alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) levels were also associated with a shorter survival. A prostate-specific antigen decline after one therapy cycle did not significantly correlate with an increased survival. No significant relations were observed between overall survival time and other serological parameters or previously performed therapies.ConclusionPre-therapeutic hemoglobin and LDH levels, as well as the presence of hepatic metastasis are independent predictors of overall survival in patients receiving Lu-177-PSMA-617-RLT. CRP, ALP and GGT levels cloud be utilized as additional decision aids when a Lu-177-PSMA-617-RLT is intended.Trial Registration Not applicable (retrospective observational study).

Electroacupuncture Ameliorates Acute Myocardial Ischemic Injury and Long QT Interval in Mice through the α 1A-Adrenergic Receptor: Electrophysiological, Morphological, and Molecular Evidence.

Acute myocardial ischemia (AMI) is a condition caused by a decrease in blood flow to the heart that can sometimes predispose to acquired long QT syndrome (LQTS), thereby resulting in sudden cardiac death. Recent evidence indicates that electroacupuncture (EA) can alleviate MI injury, but its specific mechanism remains unclear. This study was aimed at investigating the efficacy of EA, which utilizes α1A-adrenergic receptors (α1A-AR) in alleviating MI injury as well as the resulting LQTS. The AMI model was established by ligating the left anterior descending arteries (LAD) of both the wild-type and α1A gene-knockout mice and treating them with EA for three consecutive days. A PowerLab 16 physiological recorder was used to collect the electrocardiogram (ECG) while the serum creatine kinase isoenzymes (CK-MB), lactate dehydrogenase (LDH), and norepinephrine (NE) levels in myocardial tissue were determined by using the enzyme-linked immunosorbent assay (ELISA) kit. Moreover, TTC staining was used to observe the myocardial ischemic area, while H&E and TUNEL staining determined the pathological morphology of the myocardium. Quantitative real-time PCR (qRT-PCR) was used to detect the α1A mRNA, and Western blot was used to detect the specific proteins, such as α1A, cleaved caspase-3, Gq, PLC, p-PKCα, and p-hERG. Our results showed that EA could effectively reduce elevated ST-segment, shorten the extended QT interval, and reduce the serum myocardial enzyme content and the degree of pathological injury in wild mice with MI. EA can also decrease the expression of α1A-AR, PLC, p-PKCα, and NE content in myocardial tissues of wild mice, while those of p-hERG increased in ischemic myocardial tissue. These findings suggested that α1A-AR is involved in the development of MI as well as LQTS. Additionally, EA treatment improves the cardiac function and ischemic long QT interval and plays an important role in reducing the hERG inhibition through the α1A-AR-mediated Gq/PLC/PKCα pathway and myocardial apoptosis. Hence, it is suggested that α1A-AR might become a potential target for EA in treating AMI treatment of myocardial ischemia injury and acquired long QT intervals caused by MI.

Clinicopathologic Characteristics Associated with Prognosis in Ocular Extranodal Marginal Zone B Cell Lymphoma.

Background and Objectives: Extranodal marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT) type is the most common subtype of the ocular adnexal lymphoma. Despite its excellent prognosis, some patients experience partial remission or progressive disease. We aimed to evaluate clinicopathologic differences in the treatment responder group by comparing complete remission (CR) and non-complete remission (non-CR). Materials and Methods: This study retrospectively reviewed 48 patients who were diagnosed with ocular adnexal MALT lymphoma at Ulsan University Hospital between March 2002 and August 2018. Patients who were followed up for less than 6 months were excluded. Histologic and clinical features were analyzed. The patients were divided into two groups: CR and non-CR. Results: Among the 48 patients, 33 achieved CR and 15 achieved non-CR during the median follow-up period of 40.00 months (range, 7–109 months). In univariable analysis, more patients tend to undergo treatment in the CR group, and post-radiotherapy (post-RT) SUVmax, PET and serum lactate dehydrogenase (LDH) levels were higher in the non-CR group (p = 0.043, p = 0.016, and p = 0.042, respectively). In a multivariable analysis, only application of treatment, including radiotherapy or chemotherapy with immunotherapy, was related to CR (odd ratio 7.301, 95% confidence interval 1.273–41.862, p = 0.026). In subgroup analysis according to the site of involvement, none of the variables were significant except for the post-RT SUVmax of PET and level of serum LDH in the non-conjunctiva group (p = 0.026, and p = 0.037, respectively). Seven (14.6%) patients had a recurrence, and those with a recurring site other than the primary site had a higher Ki-67 labeling index, although it was not statistically significant (9.56% vs. 18.00%, p = 0.095). Conclusions: Although belonging to the early stages, the non-CR rate was high in patients with high serum LDH levels, and recurred patients had higher Ki-67. Thus, considering active treatment is recommended in this group of patients.

Abstract 1262: Gender bias in the association of pre-treatment cytokine signatures with response and survival in B cell lymphoma patients treated with anti-CD19 CAR T-cell therapy

Abstract Introduction: Despite the exceptional promise of anti-CD19 CAR T-cell therapy, 40-60% of relapsed or refractory large B-cell lymphoma (R/R LBCL) patients exhibit poor response and survival. Therefore, identification of pre-treatment markers of response to anti-CD19 CAR T-cell therapy is essential. Immune responses to infections and many autoimmune diseases exhibit gender bias, but it is not known if gender influences response to CAR T-cell therapy. We performed serum profiling to identify pre-treatment cytokines and chemokines associated with response and survival in male and female LBCL patients treated with axicabtagene ciloleucel (axi-cel). Methods: Serum samples were collected from peripheral blood at the time of leukapheresis from 42 R/R LBCL patients treated with axi-cel. Multiplexed bead arrays were used to quantify baseline levels of 51 serum cytokines, chemokines and cytotoxic proteins. Unpaired Wilcoxon test was used to analyze the association of baseline cytokine levels with 3-month response, and Kaplan-Meier survival analysis for association with survival outcomes. Statistical analyses were performed using R and p&amp;lt;0.05 was considered significant. Results: The median age of patients was 61 y, and 62% of the patients were male. All patients had been previously treated with R-CHOP or R-EPOCH, and had a median of 3 prior lines of therapy, including 47.6% with autologous stem cell transplantation. Male non-responders (stable/progressive disease) had significantly higher baseline levels of IL-6, IL-8, IL-1RA, MIP-1α, GM-CSF and CRP compared to responders (complete/partial response). Higher levels of IL-6, IL-8, IL-27, and CRP were significantly associated with poor overall survival (OS), and IL-6, IL-8, MIP-1β, and CRP with poor progression-free survival (PFS) in male patients. Baseline metabolic tumor volume (MTV) and lactate dehydrogenase (LDH) levels were also significantly higher in male patients with poor OS and PFS. Finally, baseline IL-8 and CRP were significantly associated with baseline MTV and LDH levels in male patients. Conclusions: Our data show that pre-treatment proinflammatory proteins IL-8, IL-6, CRP are associated with poor response and survival in axi-cel-treated male but not female LBCL patients. The correlation of high levels of these factors with high pretreatment tumor burden in male non-responder R/R LBCL patients is suggestive of an immunosuppressive tumor microenvironment that is unlikely to support optimal expansion of anti-CD19 CAR T cells, resulting in poor response and survival outcomes. Citation Format: Manishkumar S. Patel, Akansha Jalota, Agrima Mian, Peter Bazeley, Sara A. Hunter, Brian T. Hill, Neetu Gupta. Gender bias in the association of pre-treatment cytokine signatures with response and survival in B cell lymphoma patients treated with anti-CD19 CAR T-cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1262.

Abstract 3537: Pharmacologic inhibition of the glycolytic pathway improves response to immune checkpoint blockade

Abstract Preferential engagement in glycolysis is a hallmark of cancer cells and contributes to the progression and metastasis of many tumor types, including melanoma and triple-negative breast cancer (TNBC). Tumor reliance on glycolysis is emerging as a mechanism of resistance to immunotherapy, due in part to lactate-mediated immunosuppression and competition for glucose between effector T cells and tumor cells within the tumor microenvironment. Elevated serum lactate dehydrogenase (LDH) levels are associated with poor outcomes in cancer patients, and we observed that serum lactate and LDH levels correlate with primary tumor burden in mice. We recently demonstrated that genetic dampening of LDH subunit A in 4T1 TNBC results in improved and long-lasting anti-tumor responses to CTLA-4 blockade in mice. Therefore, we hypothesize that combining LDH inhibitors (LDHi) with CTLA-4 blockade will be an effective strategy to combat resistance to anti-CTLA-4 therapy. Since activated T cells rely on glycolysis, we first determined that glycolytic cancers overexpress LDH (compared with immune cells) by analyzing single-cell transcripts from patient melanoma biopsies. LDHA gene expression is significantly higher in malignant cells than infiltrating CD8+ T cells, and we replicated these findings at the protein level in whole cell lysate from B16-F10 melanoma and 4T1 TNBC tumor cells and tumor-antigen specific T cells in vitro. We show that LDHi reduces tumor lactate production and glucose consumption without inhibiting anti-tumor T-cell killing in vitro. The anti-tumor effect of LDH inhibition requires adaptive immunity, as daily treatment with LDHi results in reduced tumor burden in immunocompetent but not immune-deficient mice. Finally, we show that targeting LDH in combination with CTLA-4 blockade is more effective in slowing B16-F10 growth compared with CTLA-4 blockade alone, and that this combination promotes effector T cell activation while destabilizing regulatory T cell function. Citation Format: Svena Verma, Inna Serganova, Sadna Budhu, Lauren Dong, Myat Ko, Levi Mangarin, Taha Merghoub, Jedd Wolchok, Roberta Zappasodi. Pharmacologic inhibition of the glycolytic pathway improves response to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3537.

Attenuation of methotrexate induced hepatotoxicity by epigallocatechin 3-gallate

Methotrexate (MTX) is currently used as first-line therapy for autoimmune diseases like rheumatoid arthritis, psoriasis, and systemic lupus erythematous. However, its use is limited by its hepatotoxic potential. Epigallocatechin-3-gallate (EGCG), an abundant catechin present in tea possesses potent antioxidant activity and effectively ameliorates oxidative stress-related disorders. This study aimed to investigate the hepatoprotective influence of EGCG in a MTX-induced rat model of hepatotoxicity. Sprague Dawley rats pretreated with EGCG (40 mg kg−1 b.w., p.o.) were administered a single dose of MTX (20 mg kg−1 b.w., i.p.) and its hepatoprotective efficacy compared with folic acid (1 mg kg−1 b.w., i.p.). On day 10, blood samples were collected to determine plasma levels of aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH), while the livers were examined for histopathogical changes along with levels of oxidative stress measured in terms of myeloperoxidase (MPO) activity, protein carbonylation (PCO), lipid peroxidation (LPO), and activities of cellular enzymatic antioxidants – superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). MTX significantly increased the plasma levels of AST, ALT, ALP, and LDH, which were prevented by pretreatment with EGCG, and was corroborated by histopathology. Additionally, MTX-induced hepatic oxidative stress as measured by increased generation of MPO, enhanced PCO, LPO, and decreased activities of antioxidant enzymes was mitigated by pretreatment with EGCG. The amelioration of MTX-induced hepatotoxicity by EGCG endorsed the inclusion of an anti-oxidant during chronic administration of MTX.

Pulegone ameliorates inflammation and oxidative stress in L-arginine-induced acute pancreatitis in mice by regulating the activation of p38 MAPK pathway

Purpose: To evaluate the effects of pulegone (PLG) on inflammation and oxidative stress in L-arginineinduced acute pancreatitis (AP), and determine its molecular mechanism.Methods: Hematoxylin-Eosin (H &amp; E) staining assay were performed, and histopathological score, blood glucose concentration, and serum amylase level were evaluated in order to assess the effects of PLG on pancreatic injury in L-arginine-induced AP mice. Enzyme linked immunosorbent assay (ELISA) was conducted to assess the levels of myeloperoxidase (MPO), malonaldehyde (MDA) and inflammatory factors (IL-6, TNF-α and IL-1β) in L-arginine-induced AP mice. Serum lactate dehydrogenase (LDH) and relative levels of ROS generation in L-arginine-induced AP mice were determined using an LDH kit and immunofluorescence assay, respectively. The effect of pulegone (PLG) on the activation of p38 MAPK pathway in L-arginine-induced AP mice was evaluated by Western blot.Results: Significant pancreatic tissue injury occurred in L-arginine-induced AP mice was revealed. PLG alleviated the pathological injury of pancreatitis, and decreased the blood glucose concentration and serum amylase level in L-arginine-induced AP mice. In addition, PLG inhibited oxidative stress and inflammatory responses, and was enabled to inhibit the activation of p38 MAPK pathway in L-arginineinduced AP mice. Furthermore, PLG exhibited protective effect against the development of pancreatic injury in L-arginine-induced AP mice.Conclusion: PLG ameliorates L-arginine-induced inflammation and oxidative stress in AP mice in vivo by inhibiting p38 MAPK pathway, and therefore, is a potential therapeutic agent for the management of acute pancreatitis.

Prognostic factors for the successful conservative management of nonocclusive mesenteric ischemia

BackgroundThe criteria for deciding upon non-operative management for nonocclusive mesenteric ischemia (NOMI) are poorly defined. The aim of this study is to determine the prognostic factors for survival in conservative treatment of NOMI.MethodsPatients with bowel ischemia were identified by searching for “ICD-10 code K550” in the Diagnosis Procedure Combination database between June 2015 and May 2020. A total of 457 patients were extracted and their medical records, including the clinical factors, imaging findings and outcomes, were analyzed retrospectively. Diagnosis of NOMI was confirmed by the presence of specific findings in contrast-enhanced multidetector-row CT. Twenty-six patients with conservative therapy for NOMI, including four cases of explorative laparotomy or laparoscopy, were enrolled.ResultsAmong the 26 cases without surgical intervention, eight patients (31%) survived to discharge. The level of albumin was significantly higher, and the levels of lactate dehydrogenase, total bilirubin, C-reactive protein, and lactate were significantly lower in the survivors than the non-survivors. Sepsis-related Organ Failure Assessment (SOFA) score was significantly lower in the survivors than the non-survivors. The most reliable predictor of survival for NOMI was SOFA score (cutoff value ≤ 3 points), which had the highest AUC value (0.899) with odds ratio of 0.075 (CI: 0.0096–0.58).ConclusionsThe SOFA score and several biological markers are promising predictors to determine a treatment plan for NOMI and to avoid unnecessary laparotomy.

Real-world outcomes of Asian patients with advanced BRAF-mutant melanoma treated with first-line BRAF/MEK inhibitors, anti-PD-1 monotherapy, or combination of nivolumab plus ipilimumab: A multicenter retrospective study in Japan (B-CHECK-RWD study).

e21553 Background: The systemic treatment for advanced BRAF-mutant melanoma includes BRAF/MEK inhibitors (BRAF/MEKi), anti-PD-1 monotherapy (aPD1), and the combination of nivolumab plus ipilimumab (NIVO/IPI). Several studies have demonstrated favorable survival benefits for those treated with immunotherapy upfront. Most of these studies, however, were conducted among Caucasian-dominant cohorts; evidence for Asian patients is limited. Therefore, our objective was to assess the efficacy of first-line therapies for Asian patients in a real-world setting. Methods: We retrospectively collected the clinical data of Asian patients with advanced BRAF-mutant melanoma treated with first-line BRAF/MEKi, aPD1, or NIVO/IPI from 26 institutions in Japan. Clinical outcomes were determined by assessing the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) by first-line therapies. Kaplan‐Meier curves and log‐rank tests, as well as multivariable Cox proportional hazard models were used to estimate survival probabilities. Results: We identified 316 Asian patients treated with first-line BRAF/MEKi (n = 224), aPD1 (n = 59), or NIVO/IPI (n = 33) between 2016 and 2021. At baseline, the median age of the patients in each treatment arm was 63, 62, and 54, respectively (p = 0.053). The ORR in the first-line therapy was 69%, 29%, and 27%, respectively (p &lt; 0.001). With a median follow-up of 18.9 months, the median PFS was 16.2, 5.6, and 6.4 months (p = 0.001); and the median OS was 36.9, 37.9 months, and not reached (p = 0.386), respectively. In a multivariable analysis, the predictive factors of short PFS were first-line therapy with aPD1 (HR, 2.44; 95%CI, 1.70-3.50, p &lt; 0.001) or NIVO/IPI (1.73; 1.06–2.83, p = 0.029), BRAF V600K (p = 0.031), ECOG PS ≥2 (p = 0.011), elevated lactate dehydrogenase (LDH) levels (p = 0.001), and M1a/M1c/M1d stages (p = 0.036/ &lt; 0.001/ &lt; 0.001, respectively). Predictive factors of short OS were BRAF V600K (p = 0.042), ECOG PS ≥2 (p = 0.001), elevated LDH levels (p &lt; 0.001), and M1c/M1d stages (both p &lt; 0.001). The OS did not differ significantly by first-line therapies between BRAF/MEKi, aPD1 (1.52; 0.98–2.34, p = 0.061), and NIVO/IPI (0.63; 0.31–1.27, p = 0.194). Conclusions: Although upfront NIVO/IPI showed the longest OS numerically, its superiority over BRAF/MEKi in Asian patients seems to be modest compared with Caucasian patients. Because upfront BRAF/MEKi showed an OS that was comparable with that of aPD1, BRAF/MEKi remains an active first-line therapy option, especially for those who are not amenable to take the high risk of immune-related toxicities.