Search

Lactate dehydrogenase (LDH) is one of the crucial enzymes in aerobic glycolysis, catalyzing the last step of glycolysis, i.e. the conversion of pyruvate to lactate. Most cancer cells are characterized by an enhanced rate of tumor glycolysis to ensure the energy demand of fast-growing cancer cells leading to increased lactate production. Excess lactate creates extracellular acidosis which facilitates invasion, angiogenesis, and metastasis and affects the immune response. Lactate shuttle and lactate symbiosis is established in cancer cells, which may further increase the poor prognosis. Several genetic and phenotypic studies established the potential role of lactate dehydrogenase A (LDHA) or LDH5, the one homo-tetramer of subunit A, in cancer development and metastasis. The LDHA is considered a viable target for drug design and discovery. Several small molecules have been discovered to date exhibiting significant LDHA inhibitory activities and anticancer activities, therefore the starvation of cancer cells by targeting tumor glycolysis through LDHA inhibition with improved selectivity can generate alternative anticancer therapeutics. This review provides an overview of the role of LDHA in metabolic reprogramming and its association with proto-oncogenes and oncogenes. This review also aims to deliver an update on significant LDHA inhibitors with anticancer properties and future direction in this area.

Kidney transplant recipients appear to be particularly high risk for critical COVID-19 illness owing to chronic immunosuppression and coexisting conditions. The aim of this study is to present the clinical characteristics and outcomes of our hospital's kidney transplant recipients who were hospitalized due to COVID-19 infection.In our retrospective observational study of COVID-19 PCR-positive patients, 31 of them were hospitalized with COVID-19 pneumonia and they were evaluated using demographics, laboratory data, treatment, and outcome. The prognostic nutritional index (PNI), which is calculated using the serum albumin concentration and total lymphocytic count, was also evaluated. The baseline immunosuppressive therapy of patients at the time of admission and the treatments they received during their hospitalization were recorded. All patients were treated with favipiravir.Of the 31 renal transplant patients with COVID-19 pneumonia, 20 were male and the mean age was 52.7 ± 13.4. Nine (29%) of the patients died. All patients were treated with favipiravir for 5 days; laboratory tests were recorded before and after treatment. The mean PNI of the patients who survived was higher than the patients who died.The 9 patients who died had lower PNI and higher neutrophil-to-lymphocyte ratio (NLR), creatinine, l-lactate dehydrogenase (LDH), ferritin, and C-reactive protein (CRP) levels. Hospitalized kidney transplant recipients with COVID-19 have higher rates of mortality. The PNI exhibited good predictive performance and may be a useful clinical marker that can be used for estimating survival in COVID-19 patients.

Psychosis is a state of altered thoughts which often accompanies schizophrenia. It was suggested that changes in energetic metabolism accompany psychosis and post-psychosis states. Here, we use the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 to experimentally induce psychosis-like behavior in rats. We addressed an effect of single and repeated (5×) MK-801 application (0.3 mg/kg; i.p.) on the energy metabolism in homogenates and crude mitochondrial fraction (CMF) of the striatum (STR), prefrontal cortex (PFC), and the hippocampus (HIP) of the adult male Wistar rat (n = 39). In each brain region, we assessed activity of glycolytic (hexokinase (HK) and lactate dehydrogenase (LDH)) and Krebs cycle enzymes (citrate synthase (CS) and malate dehydrogenase (MDH)) 2 h and 3 days (3d) after the last MK-801 application together with relative respiratory rates assessment in tissue homogenate. In STR, a single MK-801 application led to a decrease in the LDH (p = 0.0035) and the increase of the MDH (p = 0.0043) activities following 3d. Therein, repeated MK-801 doses evoked increased LDH (p = 0.0204) and CS (p = 0.0019) activities in the homogenate 2 h and increased HK (p = 0.0007) 3d after the last application. Elevated HK activity within CMF was observed after 3d (p = 0.0054). In PFC, repeated MK-801 application decreased HK activity in the homogenate 3d after the final application (p = 0.0234). Correspondingly, PFC HK activity in CMF of repeated administration samples dropped (p = 0.003). In HIP, repeated MK-801 administration led to increased respiration of SDH (p = 0.0475) only 2 h after the last application and decreased CS activity (p = 0.0160) was observed 3d after the last application. Our results indicate a progressive metabolic dysregulation of glycolytic and Krebs cycle enzymes following repeated inhibition of NMDA receptors activity in a region-specific manner. Energetic alterations may form a basis for persisting cognitive problems during and following a psychosis in schizophrenia patients.

To verify the role of lactate dehydrogenase to albumin (LDH/ALB) ratio as an independent prognostic factor for mortality due to the lower respiratory tract infection (LRTI) in the emergency department (ED).We reviewed the electronic medical records of patients who were admitted to the ED for the management of LRTI between January 2018 and December 2020. Initial vital signs, laboratory data, and patient severity scores in the ED were collected. The LDH/ALB ratio was compared to other albumin-based ratios (blood urea nitrogen to albumin ratio, C-reactive protein to albumin ratio, and lactate to albumin ratio) and severity scales (pneumonia severity index, modified early warning score, CURB-65 scores), which are being used as prognostic factors for in-hospital mortality. Multivariable logistic regression was performed to identify independent risk factors.The LDH/ALB ratio was higher in the non-survivor group than in the survivor group (median [interquartile range]: 217.6 [160.3;312.0] vs. 126.4 [100.3;165.1], p 0.001). In the comparison of the area under the receiver operating characteristic curve (AUC) for predicting in-hospital mortality, the AUC of the LDH/ALB ratio (0.808, 95% confidence interval: 0.757-0.842, p 0.001) was wider than other albumin-based ratios and severity scales, except the blood urea nitrogen to albumin ratio. In the multivariable logistic regression analysis, the LDH/ALB ratio independently affected in-hospital mortality.The LDH/ALB ratio may serve as an independent prognostic factor for in-hospital mortality in patients with LRTI.

This study investigated the in vitro and short-term in vivo effects of Bisphenol A (BPA) on testicular energy metabolism and morphology in the zebrafish (Danio rerio). Testes were incubated in vitro for 1 h or fish were exposed in vivo to BPA in the tank water for 12 h. Testicular lactate, glycogen and cholesterol were measured and 14C-deoxy- d -glucose uptake and activity of lactate dehydrogenase (LDH), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. In addition, testis samples from the in vivo exposures were subject to digital analysis of testicular cells using Ilastik software and the Pixel Classification module and estimation of apoptosis by Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) immunohistochemical analysis. Our results from in vitro studies showed that BPA at 10 pM and 10 μM decreased testicular lactate content, glycogen content and LDH activity, but increased testicular AST activity. In addition, only BPA at 10 pM significantly decreased testicular ALT activity and cholesterol content. However, 14C-deoxy- d -glucose uptake was not changed. Furthermore, our results from in vivo studies showed that 10 pM BPA but not 10 μM BPA reduced testicular content of lactate and glycogen. In addition, both BPA concentrations decreased AST activity, whereas only BPA at 10 μM reduced ALT activity. However, LDH activity was not changed. Additionally, both concentrations of BPA induced spermatocyte apoptosis and a decrease in the proportion of the surface area of spermatids and spermatozoa. Collectively these data suggest that short-term BPA exposure affects energy metabolism and spermatogenesis in male zebrafish.

Mammalian Eps15 homology domain 1 (EHD1) participates in the development of non-small cell lung cancer (NSCLC). However, its role in mediating aerobic glycolysis remains unclear. Herein, microarray analysis revealed that EHD1 expression was significantly correlated with the glycolysis/gluconeogenesis pathway. Clinically, EHD1 expression was positively correlated with the maximum standard uptake value (SUVmax) in 18F-FDG PET/CT scans. Additionally, EHD1 knockdown inhibited aerobic glycolysis and proliferation in vitro and in vivo. Furthermore, Wnt/β-catenin signaling was identified as a critical EHD1-regulated pathway. Co-IP, native gel electrophoresis, and immunoblotting showed that EHD1 contributed to 14-3-3 dimerization via 14-3-3ζ and subsequent activation of β-catenin/c-Myc signaling. Analysis of the EHD1 regulatory region via ENCODE revealed the potential for c-Myc recruitment, leading to transcriptional activation of EHD1 and formation of an EHD1/14-3-3ζ/β-catenin/c-Myc positive feedback circuit. Notably, blocking this circuit with a Wnt/β-catenin inhibitor dramatically inhibited tumor growth in vivo. The positive correlations among EHD1, 14-3-3ζ, c-Myc, and LDHA were further confirmed in NSCLC tissues. Collectively, our study demonstrated that EHD1 activates a 14-3-3ζ/β-catenin/c-Myc regulatory circuit that synergistically promotes aerobic glycolysis and may constitute a promising therapeutic target for NSCLC.

Targeted-therapy failure in treating nonsmall cell lung cancer (NSCLC) frequently occurs because of the emergence of drug resistance and genetic mutations. The same mutations also result in aerobic glycolysis, which further antagonizes outcomes by localized increases in lactate, an immune suppressor. Recent evidence indicates that enzymatic lowering of lactate can promote an oncolytic immune microenvironment within the tumour. Here, we review factors relating to lactate expression in NSCLC and the utility of lactate oxidase (LOX) for governing therapeutic delivery, its role in lactate oxidation and turnover, and relationships between lactate depletion and immune cell populations. The lactate-rich characteristic of NSCLC provides an exploitable property to potentially improve NSCLC outcomes and design new therapeutic strategies to integrate with conventional therapies Refereed/Peer-reviewed

Flammulina velutipes has anti-inflammatory, immunomodulatory, antioxidant and many bioactive properties with high contents of carbohydrate, proteins and fibers. In this study, a novel proteoglycan with polysaccharide complexes and protein chain, named PGD1-1, was isolated from F. velutipes. The structural characteristics of PGD1-1 were then determined, and its anti-proliferation and pro-apoptotic activities against HepG-2 cells were demonstrated in vitro. Results proved that the average molecular weight of PGD1-1 was 32.71 kDa, and the carbohydrate and protein contents were 93.35 and 2.33%, respectively. The protein moiety was bonded to a polysaccharide chain via O-glycosidic linkage. The monosaccharides consisted of d -glucose, D-galactose and D-xylose in a molar ratio of 21.90:2.84:1.00. PGD1-1 significantly inhibited the proliferation of HepG-2 cells by affecting cell lipid peroxidation and nitric oxide production. In addition, PGD1-1 promoted the apoptosis of HepG-2 cells, especially the early apoptosis. These findings proved that PGD1-1 was a novel potent ingredient against the proliferation of HepG-2, which will provide a theoretical basis for the development and utilization of the functional ingredients of the F. velutipes.

The widespread use of nanoparticles raises many serious concerns about the safety and environmental impact of nanoparticles. Therefore, risk assessments of specific nanoparticles in occupational and environmental exposure are essential before their large-scale production and applications, especially in medicine and for usage in household items. In this study, the effects of five different metal nanoparticles on the structure, stability, and function of four metabolic enzymes were evaluated using various biophysical techniques. Our results show that Cu nanoparticles exhibited the most significant adverse effects on the structures, stability, and activities of all the metabolic enzymes. Zn nanoparticles caused moderate adverse effects on these enzymes. The rest of the metal (Al, Fe, and Ni) nanoparticles had a relatively lower impact on the metabolic enzymes. Our data indicated that Cu nanoparticles promote metal-catalyzed disulfide bond formation in these proteins. In summary, some metal nanoparticles can cause adverse effects on the structure, function, and stability of metabolic enzymes. In addition, metal nanoparticles may affect protein homeostasis in the cytosol or extracellular fluids.

Background The efficacy of small molecule inhibitors for intracellular signal mediators varies among the individuals, and their mechanism of action is broad. A phosphodiesterase 4 inhibitor apremilast shows a dramatic effect on a certain proportion of psoriatic patients by modulating the cellular metabolism and regulating the production of pro-inflammatory molecules. However, it is unclear to which disease subtype this drug benefits. While psoriasis is a Th17-mediated disease, how immune cells are affected by the modulation of cellular metabolism is not fully evaluated, either. Objective This study aims to identify the indices which predict the efficacy of apremilast in psoriasis, and to investigate the impact of metabolic activity in immune cells on the psoriatic pathogenesis. Methods The association of treatment efficacy with clinical and laboratory data of the 58 psoriatic patients was evaluated. The reflector of the associated index was also sought among the indices of cellular metabolic pathways by use of an extracellular flux analyzer. Results There was a correlation between clinical improvement and the serum lactate dehydrogenase (LDH) level in the patients treated with apremilast but not in those with biologics. Serum LDH level did not correlate with the cutaneous disease severity but correlated with the oxygen consumption rate of blood T cells. Conclusion Psoriatic patients with high serum LDH level can be benefitted by apremilast. The serum LDH level reflects the augmented respiratory activity of T cells in psoriasis. Our results would highlight the importance of regarding metabolic skew in immune cells as a treatment target in psoriasis.

A large number of studies have shown that polyphenols can regulate skeletal muscle fiber type transformation through AMPK signal. However, the effects and mechanism of naringin (a natural polyphenol) on muscle fiber type transformation still remains unclear. Thus, we hypothesized that naringin would induce the transformation of skeletal muscle fibers from type II to type I by AMPK signaling. C2C12 myotubes and BALB/c mice models were used to test this hypothesis. We found that naringin significantly increased the protein expression of slow myosin heavy chain (MyHC), myoglobin and troponin I type I slow skeletal (Troponin I-SS) and the activities of succinate dehydrogenase (SDH) and malate dehydrogenase (MDH), and significantly decreased fast MyHC protein expression and lactate dehydrogenase (LDH) activity, accompanied by the activation of AMPK and the activity of peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α) in mice and C2C12 myotubes. Further inhibition of AMPK activity by compound C showed that the above effects were significantly inhibited in C2C12 myotubes. In conclusion, naringin promotes the transformation of skeletal muscle fibers from type II to type I through AMPK/PGC-1α signaling pathway, which not only enriches the nutritional and physiological functions of naringin, but also provides a theoretical basis for the regulation of muscle fiber type transformation by nutritional approaches.

Introduction Although several reports on the risk factors for severe disease of COVID-19 already exist, reports on effective early indicators are still limited, especially from Japan. This study was conducted to clarify the patient’s characteristics whose disease progressed to severe status. Methods The medical records of all consecutive 300 Japanese patients hospitalized at our institution between February and November 2020 were retrospectively reviewed. The clinical characteristics were evaluated to compare between mild (no oxygen needed), moderate (oxygen needs of 1–4 L/min), and severe diseases (oxygen needs of 5 L/min or more). Results The median age was 68 years old, with 123 (41.0%) males and 177 (59.0%) females. Of these, 199 patients (66.3%), 55 patients (18.3%), 46 patients (15.3%) patients were in the mild disease, moderate disease, severe disease groups, respectively. Patients with severe disease were more likely to be older, have more comorbidities, and tended to have higher body mass index. In laboratory data, lymphocyte count, levels of C-reactive protein (CRP), LDH, and AST on admission were significantly associated with the severity. In multivariate analysis, age and CRP were the independent risk factors for severe disease (OR = 1.050, 1.130, respectively). The optimal cut-off value for age was 74 years old and that for CRP was 3.15 mg/dL. Conclusions Age and CRP were independently associated with disease severity of COVID-19 in multivariate analysis. Additionally, the numbers of underlying disease, lymphocyte count, and inflammatory markers such as LDH and D-dimer may also be related to disease severity.

Objectives The aim of this study was to assess the impact of COVID-19 on the morbidity and mortality on vasooclusive crisis (VOC) in sickle cell anaemia (SCA) patients. Methods One hundred patients with(fifty) or without COVID-19 PCR positivity(fifty), were enrolled in a prospective cohort study after signing a written informed consent. Results The COVID-19 positive patients had significantly higher median VOC episodes/year i.e 3 /year (IQR, 1-6 /year) v/s 2 /year (IQR, 2-12 /year) (p

Background & Aims Lactate has recently been reported to accumulate in the livers of patients progressing from simple steatosis to non-alcoholic steatohepatitis (NASH). However, the underlying mechanism(s) of lactate accumulation and the role of lactate in the progression of non-alcoholic fatty liver disease (NAFLD) are essentially unknown. Methods We compared the acetylome in liver samples taken from healthy individuals, patients with simple steatosis and patients with NASH to identify potential targets of acetylation with a role in lactate metabolism. Interactions between the acetylated target and acetyltransferases were measured in multiple cell lines. An acetyltransferase inhibitor was injected into high-fat diet (HFD)-fed mice to determine the role of lactate on NAFLD progression in vivo. Results Hyperacetylation of lactate dehydrogenase B (LDHB) was found to be associated with lactate accumulation in NAFL and NASH livers in humans and mice. P300/CBP-associated factor (PCAF)-mediated acetylation of LDHB K82 was found to significantly decrease LDHB activity and impair hepatic lactate clearance, resulting in lactate accumulation. Acetylated LDHB induced lactate accumulation which exacerbated lipid deposition and inflammatory responses by activating histone hyperacetylation in HFD-induced NASH. The administration of embelin, a PCAF inhibitor, and the generation of an acetylation-deficient mutant of LDHB ameliorated NASH. Conclusion PCAF-dependent LDHB acetylation plays a key role in hepatic lipid accumulation and inflammatory responses by impairing lactate clearance; this process might be a potential therapeutic target for the treatment of NASH. Lay summary Lactate is known to accumulate in the livers of patients during the progression of non-alcoholic fatty liver disease (NAFLD); however, the underlying mechanism(s) of this accumulation and its importance in disease progression are unknown. Herein, we show that the acetylation of an enzyme involved in lactate metabolism leads to impaired lactate clearance and exacerbates NAFLD progression.

Background Tuberculous pleural effusion (TPE) is usually characterized by lymphocytic predominance and high pleural fluid adenosine deaminase (pfADA), while parapneumonic pleural effusion (PPE) is usually characterized by neutrophilic predominance. However, in some cases, neutrophils can be predominant in TPE. In such cases, the differential diagnosis between TPE and PPE is challenging and has been rarely investigated. The aim of this study was to evaluate the accuracy of pfADA, pleural fluid lactate dehydrogenase (pfLDH) and other parameters, such as age/pfADA in the differential diagnosis of neutrophil-predominant TPE (NP-TPE) and PPE. Methods Between January 2003 and August 2018, 19 patients with NP-TPE and 54 patients with PPE at Shanghai Jiao Tong University Affiliated Sixth People's Hospital were retrospectively reviewed. Age, blood and pleural fluid findings, and eight ratios that consisted of routine biomarkers were compared between the two groups in ≤50 and >50 years old groups. ROC curve analysis was used to evaluate diagnostic performance. Results The three parameters with the largest AUC were age/pfADA, pfADA and pfLDH in ≤ 50 years old group, and pfADA, age/pfADA and the percentage of neutrophils in pleural fluid (pfN%) in >50 years old group. For patients ≤ 50 years old, pfADA combined with pfLDH or age/pfADA combined with pfLDH could increase the specificity to 100%, while the sensitivity of the former was high (84.6% vs 76.9%). For patients >50 years old, both pfADA combined with pfN% and age/pfADA combined with pfN% could increase the specificity to 90.3% with the same sensitivity. Conclusions Although pfADA played an important role in the discrimination of NP-TPE from PPE, combining pfADA with pfLDH for patients ≤50 years old or combining pfADA with pfN% for patients >50 years old might improve diagnostic performance.

Diffuse large B-cell lymphoma (DLBCL) comprises approximately 30% of all non-Hodgkin lymphomas. Multiple studies have demonstrated race-based disparities in survival among patients with DLBCL across all stages of disease, in the era both before and after rituximab. The etiology for the racial disparities in survival among patients with DLBCL is still unknown. Moreover, the Revised International Prognostic Index (R-IPI), a tool that predicts the DLBCL patients' outcome, has not yet been validated in African Americans (AA).We conducted a cohort study of patients diagnosed with DLBCL from January 1, 2007, to December 31, 2017, from our tumor registry in a single community-based inner-city cancer center. We abstracted demographic, clinical, histopathologic, treatment, and R-IPI variables. A total of 181 patients (47.5%) with biopsy-proven DLBCL were included in the retrospective analysis. The median age was 65 years, 47% were men, 41% were AA, and 44% were white.The AA group had a younger median age, higher lactate dehydrogenase levels, higher frequency of B symptoms, and higher HIV infection than the non-AA group. The AA group had significantly decreased median overall survival than the non-AA group (15.7 months; 95% confidence interval, 10.3 to 23.9, vs. 93.6 months; 95% confidence interval, 61.5 to 142.6, respectively; P .001). The survival disparities persisted after excluding patients with HIV and who did not receive chemotherapy. In addition, AA race predicts a reduced survival by univariate and multivariate analysis.AA with DLBCL may have a poorer prognosis than the non-AA population. Further studies should investigate the biology of DLBCL in the AA population.

Lactate dehydrogenase B (LDH-B) is overexpressed in lung and breast cancer, and it has been considered as a potential target to treat these types of cancer. Herein, we propose a straightforward incomplete factorial (IF) design composed of 12 combinations of two reaction buffers, three pH values, three salt (NaCl) concentrations, and three incubation times, which we called IF-BPST (Buffer/pH/Salt/Time), for the optimization of a colorimetric LDH-B assay in a final volume of 100 µL using 96-well plates. The assay is based on the absorbance change at ~570 nm and the color change of the reaction mixture due to the release of NADH that reacts with nitroblue tetrazolium (NBT) and phenazine methosulfate (PMS), resulting in the formation of a blue-purple formazan. The results obtained using the IF-BPST were comparable with those obtained by response surface methodology. Our work revealed that the NBT/PMS assay with some modifications can be used to measure the activity of LDH-B and other dehydrogenases in a high-throughput screening format at the early stages of drug discovery. LDH-B containing lysates cannot be assayed directly, however, due to the sensitivity of the method toward detergents. Thus, we suggest precipitating the proteins in the lysates to remove the interfering detergents, and then to dissolve the protein pellet in a suitable buffer and carry out the assay.

Background A pandemic caused by SARS-CoV-2 infection (COVID-19) has rapidly spread across the globe. Although many articles have established the clinical characteristics of adult COVID-19 patients so far, limited data are available for children. The aim of this study was to reveal the clinical features, laboratory findings and nucleic acid test results of ten pediatric cases. Methods In this retrospective single-center cohort study, pediatric cases with COVID-19 infection were consecutively enrolled in one hospital in Huangshi, China from January 1 to March 11, 2020. Results A total of 10 children with COVID-19 were recruited. Of them, four were the asymptomatic type, one was the mild type, and five were the moderate type (including two subclinical ones). All patients were from family clusters. Only fever, nasal discharge and nasal congestion were observed. Lymphopenia and leukopenia were uncommon in our sample but elevated levels of lactate dehydrogenase (LDH) and alpha-hydroxybutyrate dehydrogenase (α-HBDH) were observed frequently. Of these laboratory test variables, no statistical difference was identified between asymptomatic and symptomatic patients. Abnormalities in radiological data were detected in five patients, and representative findings of chest CT images were patchy shadows and ground-glass opacities. There were two cases whose oropharyngeal nucleic acid tests reversed to positive after one negative result, and two patients whose oropharyngeal swabs tested negative but rectal swabs showed positive. Conclusions Clinical symptoms were mild in children with COVID-19. Increased levels of LDH and α-HBDH were potential clinical biomarkers for pediatric cases. More attention should be paid to the SARS-CoV-2 viral assessment of rectal swabs before patients are discharged.

Highlights • Smoking was significantly associated with severe COVID-19 disease. • Patients with severe disease or ICU patients were more likely to have comorbidities. • Fever and dyspnea were significantly associated with severe COVID-19 disease. • Patients with severe disease had higher mortality rates and lower discharge rates., Objective We aimed to investigate the relationship between clinical characteristics, outcomes and the severity of severe acute respiratory syndrome coronavirus 2 pneumonia. Methods We performed a systematic review and meta-analysis using PubMed, Embase, and Cochrane Library databases to assess the clinical characteristics and outcomes of confirmed COVID-19 cases and compared severe (ICU) and nonsevere (non-ICU) groups. Results We included 12 cohort studies including 2,445 patients with COVID-19. Compared with nonsevere (non-ICU) patients, severe (ICU) disease was associated with a smoking history (P = .003) and comorbidities including chronic obstructive pulmonary disease (OR = 5.08, P < .001), diabetes (OR = 3.17, P < .001), hypertension (OR = 2.40, P < .001), coronary heart disease (OR = 2.66, P < .001), cerebrovascular diseases (OR = 2.68, P = .008), and malignancy (OR=2.21, P = .040). We found significant differences between the 2 groups for fever, dyspnea, decreased lymphocyte and platelet counts, and increased leukocyte count, C-creative protein, procalcitonin, lactose dehydrogenase, aspartate aminotransferase, alanine aminotransferase, creatinine kinase, and creatinine levels (P < .05). Significant differences were also observed for multiple treatments (P < .05). Patients in the severe (ICU) group were more likely to have complications and had a much higher mortality rate and lower discharge rate than those with nonsevere (non-ICU) disease (P < .05). Conclusions Investigation of clinical characteristics and outcomes of severe cases of COVID-19 will contribute to early prediction, accurate diagnosis, and treatment to improve the prognosis of patients with severe illness.

We investigated the effect of therapeutic plasma exchange (TPE) on life-threatening COVID-19; presenting as acute respiratory distress syndrome (ARDS) plus multi-system organ failure and cytokine release syndrome (CRS).We prospectively enrolled ten consecutive adult intensive care unit (ICU) subjects [7 males; median age: 51 interquartile range (IQR): 45.1-55.9 years old] with life-threatening COVID-19 infection. All had ARDS [PaO2/FiO2 ratio: 110 (IQR): 95.5-135.5], septic shock, CRS and deteriorated within 24 h of ICU admission despite fluid resuscitation, antibiotics, hydroxychloroquine, ARDS-net and prone position mechanical ventilation. All received 5-7 TPE sessions (dosed as 1.0 to 1.5 plasma volumes).All of the following significantly normalized (p 0.05) following the TPE completion, when compared to baseline: Sequential Organ Function Assessment score, PaO2/FiO2 ratio, levels of lymphocytes, total bilirubin, lactate dehydrogenase, ferritin, C-reactive protein and interleukin-6. No adverse effects from TPE were observed. Acute kidney injury and pulmonary embolism were observed in 10% and 20% of patients, respectively. The duration of mechanical ventilation was 9 (IQR: 7 to 12) days, the ICU length of stay was 15 (IQR: 13.2 to 19.6) days and the mortality on day-28 was 10%.TPE demonstrates a potential survival benefit and low risk in life-threatening COVID-19, albeit in a small pilot study.

The binding between the enzyme lactate dehydrogenase (LDH) and ferrihydrite nanoparticles (Fh-NPs) was investigated by means of small-angle neutron scattering (SANS), Fourier-transform infrared (FTIR) spectroscopy, fluorescence and Forster resonance energy transfer (FRET) and molecular docking. Fh-NPs - LDH compounds of dimensions under 100 nm are formed. The conformational changes and the mechanism of interaction between LDH and Fh-NPs simple and doped with Cu and Co, and the effect of these NPs on the thermal denaturation of LDH were monitored. The quenching mechanism is static, the binding occurring with moderate affinity, being mainly driven by hydrogen bonding and van der Waals forces. FRET occurs at a minimal distance of 2.55 nm. Thermal denaturation of LDH in the presence of simple and doped Fh-NPs shows that the thermodynamic parameters of protein unfolding are significantly changed with temperature. The denaturation temperature of LDH shifts to higher values in the presence of all Fh-NPs, than in the case of simple LDH. The docking approach estimates the energy corresponding to the best fit of the ferrihydrite in the LDH binding site near Trp. These results have direct implications on the uses of the complex of LDH with Fh-NPs in various biochemical, biological, or clinical applications.

Submergence tolerance is crucial when thinking in promising species for restoration of ecosystems prone to suffer extreme flooding events. In this study, two-year-old seedlings of Distylium chinense were subjected to one field study and five controlled experiments: unsubmerged and watered daily as controls (CK) and completely submerged for 30, 60, 90 and 120 days, respectively followed by a 60-day recovery period to test the submergence tolerance. The results showed that the survival decreased with the increasing flooding duration. Different submergence duration treatments affected dry mass accumulation and carbohydrate content of roots, stems and leaves. Flooding stress affected the activities of pyruvate decarboxylase (PDC), ethanol dehydrogenase (ADH) and lactic dehydrogenase (LDH) enzymes, which indicated the roots and leaves adapt to long-term flooding by reinforcing their anaerobic respiration and activities of ADH were higher than those of LDH for roots and leaves with stronger alcoholic fermentation mainly. After de-submergence, the recovery patterns of carbohydrate were coincided with those of dry mass accumulation of the roots, stems and leaves. A significant regression equation analysis showed root starch content and dry mass accumulation were the major factors affecting the seedling survival. And D. chinense accumulated substantial amounts of carbohydrate before submergence and invested more in roots and stems than in leaves, which enhances long-term survival under submergence. Carbohydrate storage is a key functional trait that can explain high survival under submergence. D. chinense may have adopted a suite of growth and respiratory metabolic adaptation strategies to survive long-term submergence.

Acute pancreatitis (AP) is an inflammatory disease with rapid progression. In severe cases, it can cause systemic inflammatory response syndrome (SIRS), multiple organ failure (POF) and even death. The study aimed to investigate the diagnostic value of C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6) and lactate dehydrogenase (LDH) in patients with severe AP.AP patients (n = 153) divided into mild AP patients (n = 81) and severe AP patients (n = 72) were selected from June 2014 to June 2016. The demographic information (age, sex) and the hematological parameters (WBC, PLT, CRP, PCT, IL-6, LDH and so on) were analyzed.Significant differences were found out of CRP, PCT, IL-6 and LDH values between AP patients and controls (P 0.05), even those results had significant difference between MAP group and SAP group (P 0.05). In SAP group, the cut-off values of CRP, PCT, IL-6 and LDH were 16.62, 2.29, 16.66, 273.04; sensitivity 55.6%, 77.8%, 80.2%, 82.7%; specificity 73%, 94%, 85%, 96% and AUC 0.637, 0.929, 0.886, 0.919, respectively. The AUC of combined detection of CRP, PCT, IL-6 and LDH was 0.989 (95%CI).The combined detection of CRP, PCT, IL-6 and LDH has a high diagnostic value for judging the severity of AP.

Oxidative stress plays a critical role in the progression of myocardial injury. Increasing evidence suggests that hiruidin can treat patients with cardio-injury. However, the mechanism of hirudin against myocardial infraction remains unknown. In the present study, we evaluated the potential role and mechanism of hirudin on both isoproterenol (ISO)-induced myocardial infraction (MI) in rats and Hypoxia-Reoxygenation model in H9C2 cells. Compared with the model group, hirudin apparently decreased the levels of myocardial Creatine Kinase Isoenzyme-MB (CK-MB), lactate dehydrogenase (LDH), and alleviated myocardial histopathological changes induced by ISO injection. The underlying mechanisms were revealed by the following observations: Hirudin exerted its cardioprotective effect via restoring super oxide dismutase (SOD), attenuating reactive oxygen species (ROS) and malondialdehyde (MDA). It induced the activation of Nuclear factor erythroid 2-related factor 2 (Nrf2) signal pathway through disrupting Keap1-Nrf2 complex, thus Nrf2 translocated from cytoplasm to nucleus to regulate Nrf2-dependent gene (HO-1, SOD) expressions. Furthermore, it should be noted that hirudin restored mitochondrial membrane potential in addition to cytochrome C-related apoptosis.

Highlights • Elevated LDH and CRP serum concentrations are associated to respiratory failure in CoVID-19 patients., Objective The dramatic worldwide CoVID-19 infection requires the identification of a reliable and inexpensive tool to quickly discriminate patients with a more unfavorable outcome. Methods We performed routine laboratory tests suitable to identify tissue damage and inflammatory status in 123 consecutive CoVID-19 patients admitted to the Emergency Department of the hospital of Piacenza (Emilia-Romagna, Northern Italy). The results were correlated with patients’ respiratory function evaluated by the partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2/FiO2). Results: The most common laboratory abnormalities were lymphocytopenia and elevated values of C-reactive protein (CRP) and lactate dehydrogenase (LDH). Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK) were also increased. The respiratory performance (PaO2/FiO2) showed a strong inverse correlation with LDH (r= 0.62, r2 0.38, p value< 0.0001) and CRP (r= 0.55, r2 0.31, p value< 0.0001). PaO2/FiO2 values also showed a significant inverse correlation with age (r= -0.37, p< 0.0001), AST (r= -0.31, p

Background Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies of the skin. Even though most patients are sufficiently treated by surgical resection, some will eventually metastasize and need systemic therapy. Phase I and II studies have shown efficacy for programmed cell death protein 1 (PD-1) inhibitors, but cohort sizes are low and real-world data especially on long-term outcome are pending. Methods Patients from six German skin cancer centers treated with PD-1 inhibitors (pembrolizumab, nivolumab or cemiplimab) for advanced cSCC were retrospectively studied. Internal patient records were analyzed for clinical outcome including response, progression-free survival (PFS), overall survival (OS) and toxicity. Results Of 46 evaluable patients (median age: 76 years), the overall response rate (RR) was 58.7%, including 15.2% with complete response. The disease control rate was 80.4%. Both median PFS and OS were not reached, Kaplan–Meier estimated 1-year PFS was 58.8%. Patients responding to therapy showed durable remission. Response was independent of the PD-1 inhibitor used and also independent of the presence of distant metastases vs. locally advanced disease. Two predictive factors were found: Patients with primaries located on the leg had a poorer therapy outcome and patients with high lactate dehydrogenase serum levels at baseline. Treatment was overall tolerated well, with less than 10% of patients discontinuing therapy due to toxicity. Conclusions PD-1 inhibitors fulfill the need for an efficient systemic therapy for advanced cSCC and should be the new standard of care. With high RRs and durable disease control, neoadjuvant and adjuvant regimens should be evaluated.

Objective To explore the clinical characteristics of Coronavirus Disease (COVID-19) patients with gastrointestinal symptoms. Methods The clinical data of 164 COVID-19 patients with gastrointestinal symptoms were extracted and analysed retrospectively. Results In total, 505 COVID-19 patients were divided into two groups: those with gastrointestinal symptoms (G group) and those without gastrointestinal symptoms (NG group). Common gastrointestinal symptoms included inappetence, diarrhoea, nausea, abdominal pain, and vomiting. Significantly higher proportions of patients with fever, dizziness, myalgia, and fatigue were noted in group G than in group NG. Compared with patients without fever, there was a significant difference between G group and NG group in moderate fever or above, while there was no significant difference between the two groups in low fever. The laboratory results showed that patients in the G group had significantly higher C-reactive protein, lactate dehydrogenase, and α-hydroxybutyrate dehydrogenase levels than those in the NG group. Moreover, the proportion of patients with severe pneumonia was significantly higher in the G group than in the NG group. Conclusion In Wuhan, the proportion of COVID-19 patients who experience gastrointestinal symptoms is relatively high. Patients who experience gastrointestinal symptoms are more likely to suffer from severe pneumonia, which may help clinicians identify patients at high risk of COVID-19 and thus reduce the incidence of this condition.

Enzyme biomarkers-such as creatine phosphokinase, aspartate aminotransferase, and alanine aminotransferase-are associated with acute decompensated heart failure (ADHF) severity and, therefore, have a prognostic value in ADHF. However, the prognostic value of lactate dehydrogenase (LDH) is unclear. This study aimed to investigate the prognostic value of LDH in ADHF.This single-centre observational retrospective study enrolled 396 patients with ADHF between June 2014 and July 2016. The patients were categorised into groups based on the tertile values of serum LDH (LDH-low [196 U/L], LDH-intermediate [196≤ LDH239 U/L] and LDH-high [LDH ≥239 U/L]). Survival analysis for all-cause mortality was performed. This study also examined the ability of adding log-transformed LDH (LogLDH) on Get With The Guideline score, which is an established risk score to predict 90-day, 180-day and 365-day mortality using time-dependent receiver operating characteristic curves.During the follow-up (median, 204 days), 100 (25%) patients died. The LDH-intermediate and LDH-high groups had worse survival (LDH-low vs LDH-intermediate, log-rank p=0.019; LDH-low vs LDH-high, log-rank p0.001). Log LDH improved the ability to predict 90-day, 180-day and 365-day all-cause mortality, which was statistically significant (90 days, area under curve [AUC] = 0.79, p=0.012; 180 days, AUC = 0.79, p=0.017; and 365 days, AUC = 0.79, p=0.025).Lactate dehydrogenase may be an important predictor of 90-day, 180-day and 365-day all-cause mortality in ADHF patients; however, further studies are needed to confirm these findings.

The World Health Organization recommends temephos as a nonsystemic organophosphorus pesticide due to its low mammalian toxicity compared with other chemical compounds. Although several studies have reported that temephos may be toxic under certain conditions, little research effort has been made to evaluate its effects on mammalian fertility. Therefore, the present study was designed to evaluate the effect of temephos on sperm functions and male fertility. Initially, cauda epididymis from mouse spermatozoa was incubated with temephos (0, 0.1, 1, 10, and 100 μM). Then, sperm motility and motion kinematics, capacitation status, intracellular adenosine triphosphate level, lactate dehydrogenase level, protein kinase A (PKA) activity, and degree of tyrosine phosphorylation were analyzed. Finally, the rates of fertilization and early embryonic development were evaluated. Sperm motility and motion kinematics were found to be significantly altered in temephos groups. In addition, the acrosome reaction and capacitation significantly increased and decreased in the 100 μM temephos group, respectively. Intracellular adenosine triphosphate levels significantly decreased in the 1, 10, and 100 μM temephos groups compared with that in the control group. Moreover, PKA activity and tyrosine phosphorylation significantly decreased in most temephos groups. Further, the rates of fertilization and early embryonic development significantly decreased in all temephos groups. Taken together, it was determined that temephos had harmful effects on male fertility. Therefore, the reproductive toxicity of temephos should be considered before its use.

Background Hairy cell leukemia is a rare B-cell lymphoproliferative disorder. It has an indolent course with relapse and remission periods. The aim of this study was to investigate the clinical characteristics and risk factors affecting the outcome of patients with hairy cell leukemia. Patients and Methods The retrospective data of 65 patients were evaluated according to initial hematologic and biochemical parameters, response rates, progression-free survival, and overall survival. Factors effecting response and survival rates were analyzed. Results The median follow-up duration was 62.8 months (range, 5.7-229.3 months). The result of the analysis showed that the patients with relapse/progressive disease had higher lactate dehydrogenase (LDH) levels at the time of diagnosis than patients without relapse/progression (median [range], 243 [137-540] vs. 179 [99-334] U/L, P = .01). Patients with LDH ≥ 200.5 IU at the time of diagnosis were demonstrated to have a shorter progression-free survival than those with LDH Conclusion Serum LDH level is significantly associated with relapse/progression in hairy cell leukemia patients. Patients with higher LDH levels at diagnosis should be monitored closely even if they experience complete remission.

The immune response after transcatheter aortic valve implantation (TAVI) in comparison to that after surgical aortic valve replacement (SAVR) remains to be fully elucidated. In a 2-part study, we assessed laboratory data obtained before, immediately after, and 24 and 48 hours after SAVR (128 patients; age ≥80 [mean 82] years) or transfemoral TAVI (102 patients; age ≥80 [mean 86] years) performed for aortic stenosis. In-hospital mortalities were similar (3% vs 0%), but leukocyte counts and aspartate aminotransferase and creatine kinas concentrations were decreased immediately and 24 hours after surgery (all, p0.001). We performed cytokine profiling in a SAVR group (11 patients; mean age, 77 years) and transfemoral TAVI group (12 patients; mean age, 84 years). By measuring normalized concentrations of 71 cytokines at 3 time points, we found a significant difference (defined as fold change1.7 and p0.05 [by Mann-Whitney U-test]) in 23 cytokines. The differentially expressed cytokines fell into 3 hierarchical clusters: cluster A (high increase after SAVR and suppressed increase after TAVI only immediately after surgery [CCL2, CCL4, and 2 others]), cluster B (high increase after SAVR and suppressed increase after TAVI at 2 time points [IL-1Ra, IL-6, IL-8, IL-10, and 5 others]), and cluster C (various patterns [TRAIL, CCL11, and 8 others]). Gene enrichment analysis identified multiple pathways associated with the inflammatory responses in SAVR and altered responses in TAVI, including cellular responses to tumor necrosis factor (p = 0.0035) and interleukin-1 (p = 0.0062). In conclusion, a robust inflammatory response follows SAVR, and a comparatively attenuated response follows TAVI.

Obesity is often accompanied by metabolic changes in adipocytes that are closely associated with metabolic disease. Although high sugar consumption contributes to obesity, it may also directly affect adipocytes by increasing the rate of glycolysis and formation of the glycolytic by-product methylglyoxal (MG). MG is a reactive dicarbonyl that irreversibly damages proteins and other cellular components. Although the accumulation of MG is clinically associated with hyperglycemia and diabetic complications, a better understanding of how proteins are regulated by MG is needed to evaluate its role in the pathogenesis of metabolic disease. Because adipocytes rely heavily on glycolysis for glucose disposal, we hypothesized that prolonged MG treatment at nontoxic concentrations would impact the landscape of proteins involved in glucose metabolism. To test this hypothesis, we treated 3T3-L1 adipocytes with MG (100 μmol/L) and used comparative proteomics to assess the effects. We identified 25 differentially expressed proteins in adipocytes treated with MG compared to the control. Our results suggested that MG induced metabolic changes typically associated with aerobic glycolysis, including a lowered expression of proteins involved in oxidative metabolism and increased expression of the glycolytic enzymes L-lactate dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. The detection of increased lactate secreted into the culture media of adipocytes treated with MG further supported these findings, as did gene expression analysis. In summary, these results indicate MG as a metabolic contributor to aerobic glycolysis in adipocytes, a potential adaptive response to increased glucose flux which over time could lead to permanent metabolic changes.

Whey permeate (WP) is a lactose-rich waste effluent, generated during cheese manufacturing and further valorization steps, such as protein extraction. The production of ethanol by WP fermentation has been proposed to increase cost-competitiveness of dairy waste processing. In previous work, the Escherichia coli W strain was selected for its efficient growth in dairy waste and it was engineered to convert lactose into ethanol as the main fermentation product from WP and concentrated WP (CWP). To improve its performance, here the lactate dehydrogenase, fumarate reductase and pyruvate formate lyase fermentative routes were disrupted, obtaining new deletion strains. In test tubes, growth and fermentation profiles obtained in standard laboratory media and CWP showed large differences, and were affected by oxygen, medium and ethanologenic gene expression level. Among the tested strains, the one with triple deletion was superior in both high-oxygen and low-oxygen test tube fermentations, in terms of ethanol titer, rate and yield. The improved performance was due to a lower inhibition by medium acidification rather than an improved ethanol flux. The parent and triple deletion strains showed similar performance indexes in pH-controlled bioreactor experiments. However, the deletion strain showed lower base consumption and residual waste, in terms of both dry matter and chemical oxygen demand after distillation. It thus represents a step towards sustainable dairy wastewater valorization for bioenergy production by decreasing process operation costs.

We report a method for suppression of lactate production by lactic acid bacteria (LAB) in culture. LAB produce lactate to regenerate NAD+ that is consumed during glycolysis. Glucose suppresses NAD+ regeneration pathways other than lactate dehydrogenase and non-glycolytic ATP production pathways. Therefore, the carbon source was changed to sucrose, and fed-batch culture was performed to limit the glycolytic flux and thus suppress lactate production. As a result, lactate productivity (i.e., the amount of lactate produced per amount of grown cell) in the sucrose/fed-batch culture was decreased compared to that in glucose/batch culture, in all five LAB strains examined. The productivity level decreased to 24% and 46% in Lactobacillus reuteri JCM 1112 and Lactococcus lactis JCM 7638, respectively. Metabolic flux analysis of Lactobacillus reuteri JCM 1112 revealed increased contributions of the mannitol production pathway to NAD+ regeneration and the arginine deiminase pathway to ATP production in the sucrose/fed-batch culture.

Objective Uterine leiomyosarcoma (uLMS) is a rare gynecologic malignancy for which the currently available treatments do not consistently provide long-term disease control. This study aimed to reveal the current clinical status of uLMS to support future clinical trials. Methods This study enrolled patients with uLMS treated at 53 Japanese institutions from 2000 to 2012. Central pathological review (CPR) was performed. All cases were confirmed by CPR, and epidemiological features, treatment, and prognosis were analyzed statistically. Results A total of 307 patients were enrolled. A diagnosis of uLMS was confirmed in 266 patients (86.6%) of patients after CPR, of whom data for 259 were analyzed. Of these, 186 (71.8%) patients underwent complete gross resection as primary therapy. Ninety-eight patients received no additional adjuvant therapy, while docetaxel and gemcitabine was the most frequent regimen among 155 patients treated with adjuvant chemotherapy. In all cases, the median overall survival (OS) was 44.2 months. Multivariate analyses of prognostic factors in all cases identified stage III and IV disease, high serum lactate dehydrogenase level, and menopausal status as poor prognostic factors. However, in stage I cases, high serum lactate dehydrogenase level and no adjuvant treatment were identified as poor prognostic factors. The 5-year OS of patients with stage I uLMS treated with adjuvant chemotherapy was significantly better than that of those without adjuvant treatment (67.8% vs 46.7%, P = 0.0461). Conclusions Despite complete removal of the primary lesion, the clinical course of patients with uLMS was poor due to recurrence of distant metastasis. The application of a suitable biomarker and effective adjuvant chemotherapy are required to improve the prognosis of patients with uLMS.

Lactate dehydrogenase C4 (LDH-C4) as a cancer/testis antigen (CTA) is abnormally expressed in some malignant tumors. However, the expression and clinical significance of LDH-C4 in breast cancer (BC) has not been characterized.We determined LDHC mRNA expression in serum and serum-derived exosomes of BC patients by quantitative RT-PCR. We also evaluated the protein expression of LDH-C4 in BC tissues using high-throughput tissue microarray analysis and immunohistochemistry.Our results showed high mRNA expression level of LDHC in serum and serum-derived exosomes of BC patients. The LDHC level in serum and exosomes could distinguish BC cases from healthy individuals based on their AUCs of 0.9587 and 0.9464, respectively. Besides, the LDHC level in exosomes of BC patients associated with tumor size, and positively correlated with HER2 and Ki-67 expressions (all with P 0.05). Serum and exosomal level of LDHC negatively correlated with medical treatment and positively with the recurrence of BC. Survival analysis showed that LDH-C4 expression negatively correlated with BC prognosis.Serum and exosomal LDHC may be an effective indicator for the diagnosis, efficacy evaluation, and monitoring the recurrence of BC. LDH-C4 may act as a biomarker that predicts BC prognosis.

This work was financed by the European Regional Development Fund (ERDF) through the Operational Competitiveness Factors Program—COMPETE and by National Funds through FCT—Foundation for Science and Technology within the scope of the project “PTDC/DTPFTO/5651/2014-POCI-01-0145-FEDER-016562” and projects NORTE-01-0145-FEDER-000024, supported by Norte Portugal Regional Operational Program (NORTE2020), under the PORTUGAL 2020 Partnership Agreement, through ERDF and UID/MULTI/04378/2019 from FCT/MEC. We also thank FCT support, through the strategic project UID/MAR/04292/2019 granted to MARE and UID/MULTI/04046/2019 to BioISI. Cristina Amaral thanks FCT for the contract under the funding program (DL 57/2016 – Norma Transitória) and through the Post-doc grant (SFRH/BPD/98304/2013). The authors thank the toxicology sector of the “Laboratório de Polícia Científica da Polícia Judiciária” for providing the smart shop product, within the protocol established with the “Faculdade de Ciências da Universidade de Lisboa” and “Faculdade de Farmácia da Universidade do Porto”. The increasing use of synthetic cannabinoids (SCBs) in recreational settings is becoming a new paradigm of drug abuse. Although SCBs effects mimic those of the Cannabis sativa plant, these drugs are frequently more potent and hazardous. It is known that endocannabinoid signalling plays a crucial role in diverse reproductive events such as placental development. Moreover, the negative impact of the phytocannabinoid Δ9-tetrahydrocannabinol (THC) in pregnancy outcome, leading to prematurity, intrauterine growth restriction and low birth weight is well recognized, which makes women of childbearing age a sensitive group to developmental adverse effects of cannabinoids. Placental trophoblast turnover relies on regulated processes of proliferation and apoptosis for normal placental development. Here, we explored the impact of the SCBs JWH-018, JWH-122 and UR-144 and of the phytocannabinoid THC in BeWo cell line, a human placental cytotrophoblast cell model. All the cannabinoids caused a significant decrease in cell viability without LDH release, though this effect was only detected for the highest concentrations of THC. Moreover, a cell cycle arrest at the G2/M phase was also observed. JWH-018 and JWH-122 increased reactive oxygen species (ROS) production and THC, UR-144 and JWH-122 caused loss of mitochondrial membrane potential. All the compounds were able to induce caspase-9 activation. The involvement of apoptotic pathways was further confirmed through the significant increase in caspase -3/-7 activities. For UR-144, this effect was reversed by the CB1 antagonist AM281, for JWH-018 and THC this effect was mediated by both cannabinoid receptors CB1 and CB2 while for JWH-122 it was cannabinoid receptor-independent. This work demonstrates that THC and SCBs are able to induce apoptotic cell death. Although they may act through different mechanisms and potencies, the studied cannabinoids have the potential to disrupt gestational fundamental events. info:eu-repo/semantics/publishedVersion

Lactate sensing has high importance for metabolic diseases diagnostics, food spoilage, sports medicine, or the construction of biofuel cell devices. Therefore, continuous lactate sensing devices which enable accurate detection should be developed. Here we present the overexpression and utilization of FMN-lactate dehydrogenase from Saccharomyces cerevisiae for oxygen-insensitive, continuous amperometric lactate biosensing. The developed sensors exhibit a high signal-to-noise ratio, low interference effect, and a wide range of linear responses using both direct and mediated electron transfer configurations. The thionine-based mediated electron transfer configuration was stable for 8 hours of continuous activity and two weeks of periodic activity with storage at 4°C. We further grafted the redox mediators on multiwall carbon-nanotubes to lower the redox mediator leaching effect. The developed grafting technique improved the biosensor stability and allowed continuous operation for at least 20 hours. Both the mediator-entrapped and the grafted bioanodes were further coupled with a bilirubin oxidase-based biocathode to construct a biofuel cell device. The various biofuel cells have generated a maximal power output of 110µW/cm2 under atmospheric conditions.

This study aimed to extract orthophosphate (ortho-P) from lipid-rich waste AF liquor (AFL) by Mg/Al layered double hydroxides (Mg/Al LDHs) adsorption, evaluate the influence of carbonate and investigate adsorption mechanisms. The carbonate influence experiment using synthetic P-rich wastewater indicated that low carbonate level was favorable for P extraction by LDHs. And then, real AFL rich in volatile fatty acids (VFAs), carbonate and ortho-P was applied as adsorbate to explore the Mg/Al LDHs adsorption performance. Experimental results indicated that 4 g/L Mg/Al LDHs could extract 88.3% of ortho-P from the AFL with low carbonate level (4829.83 mg CaCO

A comparative study was conducted between an anaerobic side-stream reactor (ASSR) process and a sludge process reduction (SPR) activated sludge (SPRAS) process for uncovering crucial metabolic mechanisms governing sludge reduction. Both of two processes were efficient in removing pollutants, while the SPRAS (62.3 %) obtained much higher sludge reduction than the ASSR (27.9 %). The highest rate coefficients of sludge decay, heterotroph lysis and particles hydrolysis were 0.106, 0.219 and 0.054 d

Herein we present a general and turn-on strategy for enzymatic bioassays on the basis of redox state dependent emission of gold nanoclusters (AuNCs). The photoluminescence of AuNCs was quenched obviously by the oxidative ferricyanide while unaffected by its corresponding reduced state, i.e., ferrocyanide. The distinctive quenching abilities for AuNCs by the redox couple (ferricyanide/ferrocyanide) enabled their utility as new fluorescent sensing platforms to detect redox-related phenomena. The proposed protocols were conducted by using the model oxidoreductases of glucose oxidase (GOx) and the enzyme cascade of lactate dehydrogenase (LDH)/diaphorase to catalytically convert ferricyanide to ferrocyanide, which switched on fluorescence of the detection systems. The detection limit for glucose and lactate was found to be as low as 0.12 and 0.09 μM, respectively. This work features the first use of the redox couple of ferricyanide/ferrocyanide in fluorescent bioanalysis, which enables versatile, signal on and highly sensitive/selective detections as compared to the state of the art fluorescently enzymatic sensing platforms. Importantly, considering the significance of ferricyanide/ferrocyanide involves in numerous other oxidoreductases mediated biocatalysis, this protocol has wide versatility that enables combination with oxidoreductases related reactions for biosensing.

Freezing is widely used during the manufacturing process of protein-based therapeutics, but it may result in undesired loss of biological activity. Many variables come into play during freezing that could adversely affect protein stability, creating a complex landscape of interrelated effects. The current approach to the selection of freezing conditions is however nonsystematic, resulting in poor process control. Here we show how mathematical models, and a design space approach, can guide the selection of the optimal freezing protocol, focusing on protein stability. Two opposite scenarios are identified, suggesting that the ice-water interface is the dominant cause of denaturation for proteins with high bulk stability, while the duration of the freezing process itself is the key parameter to be controlled for proteins that are susceptible to cold denaturation. Experimental data for lactate dehydrogenase and myoglobin as model proteins support the model results, with a slow freezing rate being optimal for lactate dehydrogenase and the opposite being true for myoglobin. A possible application of the calculated design space to the freezing and freeze-drying of biopharmaceuticals is finally described, and some considerations on process efficiency are discussed as well.

Maternal leucocytes play an important role in the pathogenesis of preeclampsia (PE). Circulating microRNAs (miRNAs) are small, noncoding RNA molecules. The purpose of this study was to investigate miR-518b, miR-155-5p, and miR-21-3p in the peripheral blood leukocytes of patients with PE, compared to controls.Using real-time quantitative PCR method, the selected miRNAs which have been associated with PE were examined from early- onset PE (EOPE) (34 weeks) (n = 48), late- onset PE (LOPE) (≥34 weeks) (n = 48), total cases of PE (n = 96), and healthy controls (n = 52).The relative expression of the target miR in patient samples was compared to the calibrator and the results were expressed as relative quantification values.Gestational age (GA) was significantly different between PE and controls. Univariate logistic regression analysis adjusted for GA at blood draw were fit to compare miR-518b, miR-155-5p, and miR-21-3p between PE and controls. The expression of miR-518b, miR-155-5p, and miR-21-3p were not significantly different in PE, compared to controls. The expression of miR-518b was upregulated in the EOPE and LOPE group, compared to controls, and the area under the receiver operating characteristic curve (AUC) of miR-518b was 0.65 and 0.62, respectively. miR-518b was positively correlated with WBC count, platelet count, serum levels of AST, ALT, LDH in EOPE. miR-21-3p expression level was negatively correlated with body mass index at blood draw and systolic blood pressure in the LOPE group.Increased miR-518b expression levels were found to be associated with EOPE and LOPE.

Background This study aimed to identify transplantation characteristics and biomarkers that predict outcomes for kidney transplant (KT) patients from donors after circulatory death (DCDs). Methods Consecutive patients receiving a KT from a DCD in our center between 2014 and 2016 were included; the reference population was recipients with a living donor KT. The urinary tubular injury biomarker-to-creatinine ratio and serum lactate dehydrogenase (LDH) were measured at post-transplant days 1 and 3. The primary outcome was the occurrence of delayed graft function (DGF). Descriptive and receiver operating characteristic analyses were performed. Results Forty-one patients were included in the analysis: 15 (36.59%) DCD KTs (9 of which suffered from DGF) and 26 (63.41%) living donor KTs. For the primary endpoint, neutrophil gelatinase-associated lipocalin, N-acetyl-beta-D-glucosaminidase, urinary tubular injury biomarker-to-creatinine ratio, and LDH areas under the curve were 1 and 0.96 (95% confidence interval: 0.84-1.0), 1 and 0.92 (95% confidence interval: 0.73-1.0), respectively. Among the transplant characteristics, only the 30-minute resistive index on the perfusion machine was significantly higher in DCD KTs with DGF vs those without DGF (0.26 mm Hg/mL/min [0.20; 0.32] vs 0.14 mm Hg/mL/min [0.12; 0.16], P = .05). Median 3-month creatinine clearance among DGF DCD KTs was 49 mL/min/1.73 m2 [IQR: 42; 65] and 65 mL/min/1.73 m2 [IQR: 62; 66] among DCD KTs without DGF (P = .22). Conclusion In the DCD KT population, clinical and biological markers were identified that provided predictive tools for DGF. Thus, systematic measurement of these biomarkers, particularly LDH, could improve the management of kidney graft recipients’ immunosuppressive therapy.

Background This meta-analysis was performed to elucidate the association between the expression of lactate dehydrogenase (LDH) and the prognosis of various malignant neoplasms. Materials and Methods Qualified studies were systematically identified from relevant databases, including PubMed, Cochrane Library, Embase, WanFang, and HowNet. A total of 17 eligible studies with 4,176 patients that complied with the inclusion criteria were enrolled in this meta-analysis. The 17 articles were published from 2011 to 2018. The hazard ratio (HR) and 95% confidence interval (95%CI) were obtained from the selected studies. Results The analysis that included all LDH-related studies showed a significant association with the overall survival (OS) outcome (HR = 1.74, P = 0.001) but exhibited an insignificant association with the disease-free survival (DFS) or recurrence-free survival (RFS) outcome (HR = 1.40, P = 0.072). High lactate dehydrogenase A (LDHA) expression was significantly relevant to inferior OS (HR = 1.88, 95%CI: 1.37-2.59) and DFS or RFS (HR = 1.56, 95%CI: 1.29-1.89). Conclusions High LDH expression and the prognostic outcome of various cancer patients are significantly correlated. High LDHA expression is a promising biomarker for forecasting the survival of patients and the recurrence of different cancers in these patients. Further associative studies are required due to the complex role of LDH genes.

The purpose of this study was to assess the prognostic value of lactate dehydrogenase (LDH) in patients with metastatic prostate cancer (PC). A systematic review and meta-analysis was performed in March 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared patients with PC with high versus low LDH to determine the predictive value of LDH for overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS). We performed a formal meta-analysis for both OS and PFS. A total of 59 articles with 14,851 patients were included in the systematic review and 45 studies with 12,224 patients for the qualitative assessment. High LDH was associated with both worse OS (pooled hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.75-2.44) and PFS (pooled HR, 1.08; 95% CI, 1.01-1.16). In subgroup analyses of both patients with castration-resistant prostate cancer (CRPC) and those with hormone-sensitive prostate cancer (HSPC), LDH was associated with OS (pooled HR, 2.02; 95% CI, 1.69-2.42 and pooled HR, 2.25; 95% CI, 1.78-2.84, respectively). In patients with CRPC, LDH was associated with OS in those treated with docetaxel systemic chemotherapy and androgen receptor-axis-targeting agents (pooled HR, 2.03; 95% CI, 1.37-3.00 and pooled HR, 1.79; 95% CI, 1.25-2.57, respectively). Elevated serum levels of LDH were associated with an increased risk of mortality and progression in patients with metastatic PC. LDH was independently associated with OS in both patients with CRPC and HSPC. LDH could be integrated into prognostic tools that help guide treatment strategy, thereby facilitating the shared decision-making process.

Metastasis Associated Protein1 (MTA1) is a chromatin modifier and its expression is significantly associated with prognosis of many cancers. However, its role in glucose metabolism remains unexplored. Here, we report that MTA1 has a significant role in glucose metabolism where MTA1 regulates the LDHA expression and activity and subsequently its function in breast cancer motility. The results showed that MTA1 expression is positively correlated with the LDHA expression levels in breast cancer patients. Further, it was found that MTA1 is necessary for the optimal expression of LDHA. The underlying molecular mechanism involves the interaction of MTA1 with c-Myc and recruitment of MTA1-c-Myc complex on to the LDHA promoter to regulate its transcription. Consequently, the LDHA knock down using LDHA specific siRNA in MCF7 cells stably expressing MTA1 reduced the migration of MCF7 cells. Altogether these findings revealed the regulatory role for MTA1 in LDHA expression and its resulting biological function.

Bisphosphonate-related osteonecrosis of the jaw is a disease appearing after tooth removal in patients undergoing bisphosphonate treatment for metastasizing cancers and osteoporosis. The complexity of the condition requires a multicellular model to address the net effects of two key risk factors: mechanical trauma (pathologic overload) and inflammation. In this work, a system comprised of a polydimethylsiloxane chip and mechanical loading device is used to expose bisphosphonate-treated osteocytes to mechanical trauma. Specifically, osteocytes are treated with the potent nitrogen-containing bisphosphonate, zoledronic acid, and exposed to short-term pathologic overload via substrate stretch. During bone remodeling, osteocyte apoptosis plays a role in attracting pre-osteoclasts to sites of damage; as such, lactate dehydrogenase activity, cell death and protein expression are evaluated as functions of load. Additionally, the effects of osteocyte soluble factors on osteoclast and osteoblast functional activity are quantified. Osteoclast activity and bone resorption are quantified in the presence and absence of inflammatory components, lipopolysaccharide and interferon gamma. Results suggest that inflammation associated with bacterial infection may hinder bone resorption by osteoclasts. In addition, osteocytes may respond to overload by altering expression of soluble signals that act on osteoblasts to attenuate bone formation. These findings give insight into the multicellular interactions implicated in bisphosphonate-related osteonecrosis of the jaw.

A Zinc-loaded montmorillonite (Zn-MMT) coating was hydrothermally prepared using Zn2+ ion intercalated sodium montmorillonite (Na-MMT) upon magnesium (Mg) alloy AZ31 as bone repairing materials. Biodegradation rate of the Mg-based materials was studied via potentiodynamic polarization curves, electrochemical impedance spectroscopy (EIS) and hydrogen evolution tests. Results revealed that both Na-MMT and Zn-MMT coatings exhibited better corrosion resistance in Dulbecco’s modified eagle medium (DMEM) + 10% calf serum (CS) than bare Mg alloy AZ31 counterparts. Hemolysis results demonstrated that hemocompatibility of the Na-MMT and Zn-MMT coatings were 5%, and lower than that of uncoated Mg alloy AZ31 pieces. In vitro MTT tests and live-dead stain of osteoblast cells (MC3T3-E1) indicated a significant improvement in cytocompatibility of both Na-MMT and Zn-MMT coatings. Antibacterial properties of two representative bacterial strains associated with device-related infection, i.e. Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), were employed to explore the antibacterial behavior of the coatings. The measured inhibitory zone and bacterial growth rate confirmed that Zn-MMT coatings exhibited higher suppression toward both E. coli and S. aureus than that of Na-MMT coatings. The investigation on antibacterial mechanism through scanning electron microscopy (SEM) and lactate dehydrogenase (LDH) release assay manifested that Zn-MMT coating led to severe breakage of bacterial membrane of E. coli and S. aureus, which resulted in a release of cytoplasmic materials from the bacterial cells. In addition, the good inhibition of Zn-MMT coatings against E. coli and S. aureus might be attributed to the slow but sustainable release of Zn2+ ions (up to 144 h) from the coatings into the culture media. This study provides a novel coating strategy for manufacturing biodegradable Mg alloys with good corrosion resistance, biocompatibility and antibacterial activity for future orthopedic applications. Statement of Significance The significance of the current work is to develop a corrosion-resistant and antibacterial Zn-MMT coating on magnesium alloy AZ31 through a hydrothermal method. The Zn-MMT coating on magnesium alloy AZ31 shows better corrosion resistance, biocompatibility and excellent antibacterial ability than magnesium alloy AZ31. This study provides a novel coating on Mg alloys for future orthopedic applications.

In the Dutch CAPRI registry, cabazitaxel treatment as the standard of care and in trials was analyzed. Patients treated with cabazitaxel in trials were fitter and showed outcomes comparable to registration trials. Conversely, those treated in daily practice showed features of more aggressive disease and worse outcome. This may be explained by a worse prognosis at cabazitaxel initiation.Background: Cabazitaxel has been shown to improve overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel in the TROPIC trial. However, trial populations may not reflect the real-world population. We compared patient characteristics and outcomes of cabazitaxel within and outside trials (standard of care, SOC). Patients and Methods: mCRPC patients treated with cabazitaxel directly after docetaxel therapy before 2017 were retrospectively identified and followed to 2018. Patients were grouped on the basis of treatment within a trial or SOC. Outcomes included OS and prostate-specific antigen (PSA) response. Results: From 3616 patients in the CAPRI registry, we identified 356 patients treated with cabazitaxel, with 173 patients treated in the second line. Trial patients had favorable prognostic factors: fewer symptoms, less visceral disease, lower lactate dehydrogenase, higher hemoglobin, more docetaxel cycles, and longer treatment-free interval since docetaxel therapy. PSA response (>= 50% decline) was 28 versus 12%, respectively (P = .209). Median OS was 13.6 versus 9.6 months for trial and SOC subgroups, respectively (hazard ratio = 0.73, P =.067). After correction for prognostic factors, there was no difference in survival (hazard ratio = 1.00, P = .999). Longer duration of androgen deprivation therapy treatment, lower lactate dehydrogenase, and lower PSA were associated with longer OS; visceral disease had a trend for shorter OS. Conclusion: Patients treated with cabazitaxel in trials were fitter and showed outcomes comparable to registration trials. Conversely, those treated in daily practice showed features of more aggressive disease and worse outcome. This underlines the importance of adequate estimation of trial eligibility and health status of mCRPC patients in daily practice to ensure optimal outcomes. (C) 2019 Elsevier Inc. All rights reserved.