Association between organic nitrogen substrates and the optical purity of D-lactic acid during the fermentation by Sporolactobacillus terrae SBT-1.

The development of biotechnological lactic acid production has attracted attention to the potential production of an optically pure isomer of lactic acid, although the relationship between fermentation and the biosynthesis of highly optically pure D-lactic acid remains poorly understood. Sporolactobacillus terrae SBT-1 is an excellent D-lactic acid producer that depends on cultivation conditions. Herein, three enzymes responsible for synthesizing optically pure D-lactic acid, including D-lactate dehydrogenase (D-LDH; encoded by ldhDs), L-lactate dehydrogenase (L-LDH; encoded by ldhLs), and lactate racemase (Lar; encoded by larA), were quantified under different organic nitrogen sources and concentration to study the relationship between fermentation conditions and synthesis pathway of optically pure lactic acid. Different organic nitrogen sources and concentrations significantly affected the quantity and quality of D-lactic acid produced by strain SBT-1 as well as the synthetic optically pure lactic acid pathway. Yeast extract is a preferred organic nitrogen source for achieving high catalytic efficiency of D-lactate dehydrogenase and increasing the transcription level of ldhA2, indicating that this enzyme plays a major role in D-lactic acid formation in S. terrae SBT-1. Furthermore, lactate racemization activity could be regulated by the presence of D-lactic acid. The results of this study suggest that specific nutrient requirements are necessary to achieve a stable and highly productive fermentation process for the D-lactic acid of an individual strain.

Letter to editor: C­reactive protein levels, the prognostic nutritional index, and the lactate dehydrogenase­to­lymphocyte ratio are important prognostic factors in primary central nervous system lymphoma: a single­center study of 223 patients.

This critique evaluates a letter to the editor discussing prognostic factors in primary central nervous system lymphoma (PCNSL), focusing on C-reactive protein (CRP) levels, prognostic nutritional index (PNI), and lactate dehydrogenase (LDH)-to-lymphocyte ratio. While the letter provides valuable insights, limitations including reliance on a single-center dataset, lack of consideration for potential confounders, insufficient contextualization within existing literature, and limited discussion of clinical implications are identified. Addressing these limitations is crucial for enhancing the relevance and applicability of the findings in PCNSL management.

Krebs von den Lungen-6 levels at admission predicts exercise-induced hypoxemia before and after discharge in patients with COVID-19.

BACKGROUND: There are no reports of exercise-induced hypoxemia in patients with coronavirus disease 2019 (COVID-19). Additionally, the predictive factors and prevalence of exercise-induced hypoxemia are unknown. This study investigated the incidence and predictive factors of exercise-induced hypoxemia before and after discharge in patients with COVID-19. METHODS: We enrolled 77 patients diagnosed with COVID-19 who were hospitalized between November 2020 and October 2021 and who underwent a 6-min walk test before and after discharge. Based on the test results, we classified patients into exercise-induced and non-exercise-induced hypoxemia groups and investigated the predictive factors of exercise-induced hypoxemia using logistic regression analysis. RESULTS: The incidences of exercise-induced hypoxemia in patients with COVID-19 were 37.7% and 19.5% before and after discharge, respectively. At admission, the Krebs von den Lungen-6 levels was the associated factor for exercise-induced hypoxemia in patients with COVID-19 before and after discharge, with cut-off values of 314 U/mL and 367 U/mL, respectively. Age and lactate dehydrogenase levels were the associated factors for exercise-induced hypoxemia in patients with COVID-19 before discharge, with cut-off values of 61 years and 492 U/L, respectively. CONCLUSIONS: Some patients with COVID-19 may continue to experience exercise-induced hypoxemia after discharge. Age, lactate dehydrogenase, and Krebs von den Lungen-6 levels at admission could serve as predictive markers of exercise-induced hypoxemia before and after discharge in these patients.

Hepatoprotective effects of leaf extract of Annona senegalensis against aflatoxin B1 toxicity in rats.

Global aflatoxin contamination of agricultural commodities is of the most concern in food safety and quality. This study investigated the hepatoprotective effect of 80% methanolic leaf extract of Annona senegalensis against aflatoxin B1 (AFB1)-induced toxicity in rats. A. senegalensis has shown to inhibit genotoxicity of aflatoxin B1 in vitro. The rats were divided into six groups including untreated control, aflatoxin B1 only (negative control); curcumin (positive control; 10 mg/kg); and three groups receiving different doses (100 mg/kg, 200 mg/kg, and 300 mg/kg) of A. senegalensis extract. The rats received treatment (with the exception of untreated group) for 7 days prior to intoxication with aflatoxin B1. Serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, and creatinine were measured. Hepatic tissues were analysed for histological alterations. Administration of A. senegalensis extract demonstrated hepatoprotective effects against aflatoxin B1-induced toxicity in vivo by significantly reducing the level of serum aspartate aminotransferase and alanine aminotransferase and regenerating the hepatocytes. No significant changes were observed in the levels of alkaline phosphatase, lactate dehydrogenase, and creatinine for the AFB1 intoxicated group, curcumin+AFB1 and Annona senegalensis leaf extract (ASLE)+AFB1 (100 mg/kg, 200 mg/kg, and 300 mg/kg body weight [b.w.]) treated groups. Annona senegalensis is a good candidate for hepatoprotective agents and thus its use in traditional medicine may at least in part be justified.Contribution: The plant extract investigated in this study can be used in animal health to protect the organism from toxicity caused by mycotoxins.

Neuroprotective Effect of Sterculia setigera Leaves Hydroethanolic Extract.

Plants are a valuable source of information for pharmacological research and new drug discovery. The present study aimed to evaluate the neuroprotective potential of the leaves of the medicinal plant Sterculia setigera. In vitro, the effect of Sterculia setigera leaves dry hydroethanolic extract (SSE) was tested on cultured cerebellar granule neurons (CGN) survival when exposed to hydrogen peroxide (H2O2) or 6-hydroxydopamine (6-OHDA), using the viability probe fluorescein diacetate (FDA), a lactate dehydrogenase (LDH) activity assay, an immunocytochemical staining against Gap 43, and the quantification of the expression of genes involved in apoptosis, necrosis, or oxidative stress. In vivo, the effect of intraperitoneal (ip) injection of SSE was assessed on the developing brain of 8-day-old Wistar rats exposed to ethanol neurotoxicity by measuring caspase-3 activity on cerebellum homogenates, the expression of some genes in tissue extracts, the thickness of cerebellar cortical layers and motor coordination. In vitro, SSE protected CGN against H2O2 and 6-OHDA-induced cell death at a dose of 10 µg/mL, inhibited the expression of genes Casp3 and Bad, and upregulated the expression of Cat and Gpx7. In vivo, SSE significantly blocked the deleterious effect of ethanol by reducing the activity of caspase-3, inhibiting the expression of Bax and Tp53, preventing the reduction of the thickness of the internal granule cell layer of the cerebellar cortex, and restoring motor functions. Sterculia setigera exerts neuroactive functions as claimed by traditional medicine and should be a good candidate for the development of a neuroprotective treatment against neurodegenerative diseases.

The impact of preoperative serum lactate dehydrogenase on mortality and morbidity after noncardiac surgery.

Preoperative serum lactate dehydrogenase (LDH) has been reported to be associated with adverse outcomes following thoracic surgery. However, its association with outcomes in noncardiac surgery as a whole has not been investigated. We conducted a retrospective cohort study at West China Hospital, Sichuan University, from 2018 to 2020, including patients undergoing noncardiac surgery. Multivariable logistic regression and propensity score weighting were employed to assess the link between LDH levels and postoperative outcomes. Preoperative LDH was incorporated into four commonly used clinical models, and its discriminative ability, reclassification, and calibration were evaluated in comparison to models without LDH. Among 130,879 patients, higher preoperative LDH levels (cut-off: 220 U/L) were linked to increased in-hospital mortality (4.382% vs. 0.702%; OR 1.856, 95% CI 1.620-2.127, P < 0.001), myocardial injury after noncardiac surgery (MINS) (3.012% vs. 0.537%; OR 1.911, 95% CI 1.643-2.223, P < 0.001), and ICU admission (15.010% vs. 6.414%; OR 1.765, 95% CI 1.642-1.896, P < 0.001). The inverse probability of treatment-weighted estimation supported these results. Additionally, LDH contributed significantly to four surgical prognostic models, enhancing their predictive capability. Our study revealed a significant association between preoperative LDH and in-hospital mortality, MINS, and ICU admission following noncardiac surgery. Moreover, LDH provided supplementary predictive information, extending the utility of commonly used surgical prognostic scores.

Cellular senescence in testicular cancer. Is there a correlation with the preoperative markers and the extent of the tumor? An experimental study.

PURPOSE: The aim of this experimental study is to investigate the correlation between the presence of senescent cells and the tumor size, the lymphovascular invasion (LVI), the invasion of rete testis (RTI), the preoperative tumor markers or pathological stage in patients who underwent orchiectomy for malignant purposes. METHODS: This experimental study included patients with a history of radical orchiectomy performed from January 2011 to January 2019. The testicular tissue specimens underwent an immunohistopathological process for the detection of the presence of cellular senescence. Besides, the tumor size, the histopathological type, the pathological stage of the tumor and the presence of Lymphovascular (LVI) or rete testis (RTI) invasions were also recorded. Additionally, the preoperative serum levels of alpha-fetoprotein, beta-human chorionic gonadotropin and lactate dehydrogenase were recorded. After the completion of immunohistochemical analysis, the rate of senescent cells in each specimen was also recorded. RESULTS: The mean senescent cell rate was estimated to be 14.11±11.32% and 15.46±10.58% in patients with presence of LVI or absence of LVI, respectively (p=0.46). The mean senescent cell rate was calculated at 18.13±12.26% and 12.56±9.38% (p=0.096) in patients with presence of RTI or absence of RTI, respectively. The mean senescent cell rate in the pT1 group was calculated at 14.58 ± 9.82%, while in T2 and T3 groups the mean senescent cell rate was estimated to be 15.22 ± 12.03% and 15.35 ± 14.21%, respectively (p=0.98). A statistically significant correlation was detected between the senescence rate and the tumor size (Pearson score 0.40, p=0.027) and between the rate of senescent cells and the preoperative level of lactate dehydrogenase (LDH) (Pearson score -0.53, p=0.002). CONCLUSIONS: The presence of cellular senescence was correlated with the extent of the testicular tumor in terms of tumor size as well as the preoperative level of the LDH serum marker.

Secondary hemophagocytic lymphohistiocytosis in pediatric patients with visceral leishmaniasis and Epstein-Barr virus infection.

Visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (VL-HLH) is indistinguishable from those of HLH of other etiologies due to the overlap symptoms, posing a serious threat to life. In this study, we aimed to provide insights for early diagnosis and improve outcomes in pediatric patients with VL-HLH. We retrospectively analyzed the clinical and laboratory data of 10 pediatric patients with VL-HLH and 58 pediatric patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The median time from symptom onset to cytopenia in patients with VL-HLH and EBV-HLH was 11 days (interquartile range, 7-15 days) and five days (interquartile range, 3.75-9.25 days) (P = 0.005). Both groups showed liver injury and increased lactate dehydrogenase levels; however the levels of aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and lactate dehydrogenase in patients with VL-HLH were significantly lower than those in patients with EBV-HLH (P < 0.05). The fibrinogen and triglyceride levels were almost normal in VL-HLH patients but were significantly altered in EBV-HLH cases ( P < 0.05). The positive rate of first bone marrow microscopy examination, anti-rK39 IgG detection, and blood metagenomic next-generation sequencing was 50%, 100%, and 100%, respectively. After VL diagnosis, eight patients were treated with sodium stibogluconate and two were treated with liposomal amphotericin B. All the patients with VL-HLH recovered. Our study demonstrates that regular triglyceride and fibrinogen levels in pediatric patients with VL-HLH may help in differential diagnosis from EBV-HLH. VL-HLH is milder than EBV-HLH, with less severe liver injury and inflammatory responses, and timely treatment with antileishmanial agents is essential to improve the outcomes of pediatric patients with VL-HLH.

Effects of Extracellular Calcium Concentration on Hepatic Ischemia-Reperfusion Injury in a Rat Model.

OBJECTIVES: Hypocalcemia is frequently identified during liver transplant. However, supplementation of extracellular calcium could induce increased intracellular calcium concentration, as a potential factor for injury to the liver graft. We evaluated the effects of regulating extracellular calcium concentrations on hepatic ischemia-reperfusion injury. MATERIALS AND METHODS: We randomly divided 24 Sprague-Dawley rats into 3 groups: group C received normal saline (n = 8), group L received citrate to induce hypocalcemia (n = 8), and group L-Co received citrate followed by calcium gluconate to ameliorate hypocalcemia (n = 8). Liver enzyme levels and extracellular calcium were measured before surgery, 1 hour after ischemia, and 2 hours after reperfusion. The primary outcome was liver enzyme levels measured 2 hours after reperfusion. In addition, we evaluated intracellular calcium levels, lactate dehydrogenase activity, and histopathological results in liver tissue. RESULTS: Three groups demonstrated significant differences in extracellular calcium concentrations, but intracellular calcium concentrations in liver tissue were not significantly different. Group L showed significantly lower mean arterial pressure than other groups at 1 hour after ischemia (93.6 ± 20.8 vs 69.4 ± 14.2 vs 86.6 ± 10.4 mmHg; P = .02, for group C vs L vs L-Co, respectively). At 2 hours after reperfusion, group L showed significantly higher liver enzymes than other groups (aspartate aminotransferase 443.0 ± 353.2 vs 952.3 ± 94.8 vs 502.4 ± 327.3 U/L, P = .01; and alanine aminotransferase 407.9 ± 406.5 vs 860.6 ± 210.9 vs 333.9 ± 304.2 U/L, P = .02; for group C vs L vs L-Co, respectively). However, no significant difference was shown in lactate dehydrogenase and histological liver injury grade. CONCLUSIONS: Administering calcium to rats with hypocalcemia did not increase intracellular calcium accumulation but instead resulted in less hepatic injury compared with rats with low extracellular calcium concentrations in this rat model study.

Roles of heat shock protein A12A in the development of diabetic cardiomyopathy.

Long-term hyperglycemia can lead to diabetic cardiomyopathy (DCM), a main lethal complication of diabetes. However, the mechanisms underlying DCM development have not been fully elucidated. Heat shock protein A12A (HSPA12A) is the atypic member of the Heat shock 70kDa protein family. In the present study, we found that the expression of HSPA12A was upregulated in the hearts of mice with streptozotocin-induced diabetes, while ablation of HSPA12A improved cardiac systolic and diastolic dysfunction and increased cumulative survival of diabetic mice. An increased expression of HSPA12A was also found in H9c2 cardiac cells following treatment with high glucose (HG), while overexpression of HSPA12A-enhanced the HG-induced cardiac cell death, as reflected by higher levels of propidium iodide cells, lactate dehydrogenase leakage, and caspase 3 cleavage. Moreover, the HG-induced increase of oxidative stress, as indicated by dihydroethidium staining, was exaggerated by HSPA12A overexpression. Further studies demonstrated that the HG-induced increases of protein kinase B and forkhead box transcription factors 1 phosphorylation were diminished by HSPA12A overexpression, while pharmacologically inhibition of protein kinase B further enhanced the HG-induced lactate dehydrogenase leakage in HSPA12A overexpressed cardiac cells. Together, the results suggest that hyperglycemia upregulated HSPA12A expression in cardiac cells, by which induced cell death to promote DCM development. Targeting HSPA12A may serve as a potential approach for DCM management.

The catalytic action of human d-lactate dehydrogenase is severely inhibited by oxalate and is impaired by mutations triggering d-lactate acidosis.

d-lactate dehydrogenases are known to be expressed by prokaryotes and by eukaryotic invertebrates, and over the years the functional and structural features of some bacterial representatives of this enzyme ensemble have been investigated quite in detail. Remarkably, a human gene coding for a putative d-lactate dehydrogenase (DLDH) was identified and characterized, disclosing the occurrence of alternative splicing of its primary transcript. This translates into the expression of two human DLDH (hDLDH) isoforms, the molecular mass of which is expected to differ by 2.7 kDa. However, no information on these two hDLDH isoforms is available at the protein level. Here we report on the catalytic action of these enzymes, along with a first analysis of their structural features. In particular, we show that hDLDH is strictly stereospecific, with the larger isoform (hDLDH-1) featuring higher activity at the expense of d-lactate when compared to its smaller counterpart (hDLDH-2). Furthermore, we found that hDLDH is strongly inhibited by oxalate, as indicated by a Ki equal to 1.2 µM for this dicarboxylic acid. Structurally speaking, hDLDH-1 and hDLDH-2 were determined, by means of gel filtration and dynamic light scattering experiments, to be a hexamer and a tetramer, respectively. Moreover, in agreement with previous studies performed with human mitochondria, we identified FAD as the cofactor of hDLDH, and we report here a model of FAD binding by the human d-lactate dehydrogenase. Interestingly, the mutations W323C and T412 M negatively affect the activity of hDLDH, most likely by impairing the enzyme electron-acceptor site.

An engineered poly(A) tail attenuates gut ischemia/reperfusion-induced acute lung injury.

BACKGROUND: Gut ischemia/reperfusion causes the release of damage-associated molecular patterns, leading to acute lung injury and high mortality. Cold-inducible ribonucleic acid-binding protein is a ribonucleic acid chaperon that binds the polyadenylation tail of messenger ribonucleic acid intracellularly. Upon cell stress, cold-inducible ribonucleic acid-binding protein is released, and extracellular cold-inducible ribonucleic acid-binding protein acts as a damage-associated molecular pattern, worsening inflammation. To inhibit extracellular cold-inducible ribonucleic acid-binding protein, we have recently developed an engineered polyadenylation tail named A12. Here, we sought to investigate the therapeutic potential of A12 in gut ischemia/reperfusion-induced acute lung injury. METHODS: Male C57BL6/J mice underwent superior mesenteric artery occlusion and were treated with intraperitoneal A12 (0.5 nmol/g body weight) or vehicle at the time of reperfusion. Blood and lungs were collected 4 hours after gut ischemia/reperfusion. Systemic levels of extracellular cold-inducible ribonucleic acid-binding protein, interleukin-6, aspartate transaminase, alanine transaminase, and lactate dehydrogenase were determined. The pulmonary gene expression of cytokines (interleukin-6, interleukin-1ß) and chemokines (macrophage-inflammatory protein-2, keratinocyte-derived chemokine) was also assessed. In addition, lung myeloperoxidase, injury score, and cell death were determined. Mice were monitored for 48 hours after gut ischemia/reperfusion for survival assessment. RESULTS: Gut ischemia/reperfusion significantly increased the serum extracellular cold-inducible ribonucleic acid-binding protein levels. A12 treatment markedly reduced the elevated serum interleukin-6, alanine transaminase, aspartate transaminase, and lactate dehydrogenase by 53%, 23%, 23%, and 24%, respectively, in gut ischemia/reperfusion mice. A12 also significantly decreased cytokine and chemokine messenger ribonucleic acids and myeloperoxidase activity in the lungs of gut ischemia/reperfusion mice. Histological analysis revealed that A12 attenuated tissue injury and cell death in the lungs of gut ischemia/reperfusion mice. Finally, administration of A12 markedly improved the survival of gut ischemia/reperfusion mice. CONCLUSION: A12, a novel extracellular cold-inducible ribonucleic acid-binding protein inhibitor, diminishes inflammation and mitigates acute lung injury when employed as a treatment during gut ischemia/reperfusion. Hence, the targeted approach toward extracellular cold-inducible ribonucleic acid-binding protein emerges as a promising therapeutic strategy for alleviating gut ischemia/reperfusion-induced acute lung injury.

Evaluation of Scorpion Stings in Children.

INTRODUCTION: Scorpion stings are a significant public health problem in many parts of the world. Children are at a higher risk of developing severe complications from scorpion envenoming, including cardiac, respiratory, and neurologic complications. In Turkey, members of the Buthidae family are the most common culprits in severe envenoming events. METHODS: This retrospective-descriptive study was conducted in Turkey. Children aged 0 to 18 y admitted to the emergency department of Kahta State Hospital between December 2017 and December 2020 were included in the study. Patient information was reviewed, and 78 patients with complete demographic, laboratory, and clinical data were included in the study. RESULTS: Out of the 78 patients, 24.4% were six years old or younger while the 75.6% were older than six years. Alpha blocker was given to 12.8% of the patients, and antivenom was given to 43.6% of the patients. Of the 78 patients, 71.8% were followed up in the emergency department, 21.8% were followed up in the inpatient unit, and 6.4% were followed up in the intensive care unit. Two patients (2.6%) died within 1 month. There was a significant difference regarding lactate dehydrogenase value according to the sting site (P=0.014). Lactate dehydrogenase values of patients stung on the head and neck and upper extremity were higher than those of patients bitten on lower extremities. CONCLUSIONS: Elevated levels of specific laboratory parameters, such as leukocytes, aspartate transaminase, and lactate dehydrogenase, are linked to worse outcomes. Additionally, stings on the head, neck, and upper extremities are more strongly associated with severity. These findings guide tailored treatment strategies for scorpion stings, with the potential for further refinement through broader studies across diverse regions and populations.

Lactate dehydrogenase-to-albumin ratio: A superior inflammatory marker for predicting contrast-associated acute kidney injury after percutaneous coronary intervention.

PURPOSE: Inflammation is commonly considered a mechanism underlying contrast-associated acute kidney injury (CA-AKI). This study aimed to explore the predictive capability of the novel inflammatory marker lactate dehydrogenase-to-albumin ratio (LAR) for CA-AKI following percutaneous coronary intervention (PCI), and further compare it with other common inflammatory biomarkers. METHODS: This study enrolled 5,435 patients undergoing elective PCI. The primary outcome was CA-AKI, and the secondary outcome was all-cause mortality. All patients were grouped into three groups based on the LAR tertiles. RESULTS: Three hundred fifteen patients (5.8%) experienced CA-AKI during hospitalization. The fully adjusted logistic regression suggested a significant increase in the risk of CA-AKI in LAR Tertile 3 (odds ratio [OR]: 2.51, 95% confidence interval [CI]: 1.68-3.83, p < .001) and Tertile 2 (OR: 2.11, 95% CI: 1.42-3.20, p < .001) compared to Tertile 1. Additionally, receiver operating characteristic (ROC) analysis demonstrated that LAR exhibited significantly superior predictive capability for CA-AKI compared to other inflammatory biomarkers. Regarding the secondary outcome, multivariate COX regression analysis showed a positive correlation between elevated LAR levels and all-cause mortality. CONCLUSION: In patients undergoing elective PCI, LAR was significantly independently associated with CA-AKI, and it stood out as the optimal inflammatory biomarker for predicting CA-AKI.

Probiotic Lactobacillus spp. improves Drosophila memory by increasing lactate dehydrogenase levels in the brain mushroom body neurons.

Probiotics are live microorganisms that offer potential benefits to their hosts and can occasionally influence behavioral responses. However, the detailed mechanisms by which probiotics affect the behavior of their hosts and the underlying biogenic effects remain unclear. Lactic acid bacteria, specifically Lactobacillus spp. are known probiotics. Drosophila melanogaster, commonly known as the fruit fly, is a well-established model organism for investigating the interaction between the host and gut microbiota in translational research. Herein, we showed that 5-day administration of Lactobacillus acidophilus (termed GMNL-185) or Lacticaseibacillus rhamnosus (termed GMNL-680) enhances olfactory-associative memory in Drosophila. Moreover, a combined diet of GMNL-185 and GMNL-680 demonstrated synergistic effects on memory functions. Live brain imaging revealed a significant increase in calcium responses to the training odor in the mushroom body ß and γ lobes of flies that underwent mixed feeding with GMNL-185 and GMNL-680. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and whole-mount brain immunohistochemistry revealed significant upregulation of lactate dehydrogenase (LDH) expression in the fly brain following the mixed feeding. Notably, the genetic knockdown of Ldh in neurons, specifically in mushroom body, ameliorated the beneficial effects of mixed feeding with GMNL-185 and GMNL-680 on memory improvement. Altogether, our results demonstrate that supplementation with L. acidophilus and L. rhamnosus enhances memory functions in flies by increasing brain LDH levels.

Pneumocystis jirovecii pneumonia mortality risk associated with preceding long-term steroid use for the underlying disease: A multicenter, retrospective cohort study.

OBJECTIVE: Long-term steroid use increases the risk of developing Pneumocystis pneumonia (PcP), but there are limited reports on the relation of long-term steroid and PcP mortality. METHODS: Retrospective multicenter study to identify risk factors for PcP mortality, including average steroid dose before the first visit for PcP in non-human immunodeficiency virus (HIV)-PcP patients. We generated receiver operating characteristic (ROC) curves for 90-day all-cause mortality and the mean daily steroid dose per unit body weight in the preceding 10 to 90 days in 10-day increments. Patients were dichotomized by 90-day mortality and propensity score-based stabilized inverse probability of treatment weighting (IPTW) adjusted covariates of age, sex, and underlying disease. Multivariate analysis with logistic regression assessed whether long-term corticosteroid use affected outcome. RESULTS: Of 133 patients with non-HIV-PcP, 37 died within 90 days of initial diagnosis. The area under the ROC curve for 1-40 days was highest, and the optimal cutoff point of median adjunctive corticosteroid dosage was 0.34 mg/kg/day. Past steroid dose, underlying interstitial lung disease and emphysema, lower serum albumin and lower lymphocyte count, higher lactate dehydrogenase, use of therapeutic pentamidine and therapeutic high-dose steroids were all significantly associated with mortality. Underlying autoimmune disease, past immunosuppressant use, and a longer time from onset to start of treatment, were associated lower mortality. Logistic regression analysis after adjusting for age, sex, and underlying disease with IPTW revealed that steroid dose 1-40 days before the first visit for PcP (per 0.1 mg/kg/day increment, odds ratio 1.36 [95% confidence interval = 1.16-1.66], P<0.001), low lymphocyte counts, and high lactate dehydrogenase revel were independent mortality risk factor, while respiratory failure, early steroid, and sulfamethoxazole/trimethoprim for PcP treatment did not. CONCLUSION: A steroid dose before PcP onset was strongly associated with 90-day mortality in non-HIV-PcP patients, emphasizing the importance of appropriate prophylaxis especially in this population.

PARP-1 inhibitor alleviates cerebral ischemia/reperfusion injury by reducing PARylation of HK-1 and LDH in mice.

Poly (ADP-ribose) polymerase-1 (PARP-1) activity significantly increases during cerebral ischemia/reperfusion. PARP-1 is an NAD+-consumption enzyme. PARP-1 hyperactivity causes intracellular NAD+ deficiency and bioenergetic collapse, contributing to neuronal death. Besides, the powerful trigger of PARP-1 causes the catalyzation of poly (ADP-ribosyl)ation (PARylation), a posttranslational modification of proteins. Here, we found that PARP-1 was activated in the ischemic brain tissue during middle-cerebral-artery occlusion and reperfusion (MCAO/R) for 24 h, and PAR accumulated in the neurons in mice. Using immunoprecipitation, Western blotting, liquid chromatography-mass spectrometry, and 3D-modeling analysis, we revealed that the activation of PARP-1 caused PARylation of hexokinase-1 and lactate dehydrogenase-B, which, therefore, caused the inhibition of these enzyme activities and the resulting cell energy metabolism collapse. PARP-1 inhibition significantly reversed the activity of hexokinase and lactate dehydrogenase, decreased infarct volume, and improved neuronal deficiency. PARP-1 inhibitor combined with pyruvate further alleviated MCAO/R-induced ischemic brain injury in mice. As such, we conclude that PARP-1 inhibitor alleviates neuronal death partly by inhibiting the PARylation of metabolic-related enzymes and reversing metabolism reprogramming during cerebral ischemia/reperfusion injury in mice. PARP-1 inhibitor combined with pyruvate might be a promising therapeutic approach against brain ischemia/reperfusion injury.

Pyramiding D-lactate dehydrogenase with the glyoxalase pathway enhances abiotic stress tolerance in plants.

Methylglyoxal is a common cytotoxic metabolite produced in plants during multiple biotic and abiotic stress. To mitigate the toxicity of MG, plants utilize the glyoxalase pathway comprising glyoxalase I (GLYI), glyoxalase II (GLYII), or glyoxalase III (GLYIII). GLYI and GLYII are the key enzymes of glyoxalase pathways that play an important role in abiotic stress tolerance. Earlier research showed that MG level is lower when both GLYI and GLYII are overexpressed together, compared to GLYI or GLYII single gene overexpressed transgenic plants. D-lactate dehydrogenase (D-LDH) is an integral part of MG detoxification which metabolizes the end product (D-lactate) of the glyoxalase pathway. In this study, two Arabidopsis transgenic lines were constructed using gene pyramiding technique: GLYI and GLYII overexpressed (G-I + II), and GLYI, GLYII, and D-LDH overexpressed (G-I + II + D) plants. G-I + II + D exhibits lower MG and D-lactate levels and enhanced abiotic stress tolerance than the G-I + II and wild-type plants. Further study explores the stress tolerance mechanism of G-I + II + D plants through the interplay of different regulators and plant hormones. This, in turn, modulates the expression of ABA-dependent stress-responsive genes like RAB18, RD22, and RD29B to generate adaptive responses during stress. Therefore, there might be a potential correlation between ABA and MG detoxification pathways. Furthermore, higher STY46, GPX3, and CAMTA1 transcripts were observed in G-I + II + D plants during abiotic stress. Thus, our findings suggest that G-I + II + D has significantly improved MG detoxification, reduced oxidative stress-induced damage, and provided a better protective mechanism against abiotic stresses than G-I + II or wild-type plants.

The impact of MYD88 and PIM1 in mature large B-cell non-Hodgkin lymphomas: Defining element of their evolution and prognosis.

Sequence studies of the entire exome and transcriptome of lymphoma tissues have identified MYD88 and PIM1 as involved in the development and oncogenic signaling. We aimed to determine the frequency of MYD88 and PIM1 mutations, as well as their expressions in conjunction with the clinicopathological parameters identified in mature large B-cell non-Hodgkin lymphomas. The ten-year retrospective study included 50 cases of mature large B-cell lymphoma, diagnosed at the Pathology Department of the Emergency County Hospital of Constanta and Sacele County Hospital of Brasov. They were statistically analyzed by demographic, clinicopathological, and morphogenetic characteristics. We used a real-time polymerase chain reaction technique to identify PIM1 and MYD88 mutations as well as an immunohistochemical technique to evaluate the expressions of the 2 genes. Patients with lymphoma in the small bowel, spleen, brain, and testis had a low-performance status Eastern Cooperative Oncology Group (P = .001). The Eastern Cooperative Oncology Group performance status represented an independent risk factor predicting mortality (HR = 9.372, P < .001). An increased lactate dehydrogenase value was associated with a low survival (P = .002). The international prognostic index score represents a negative risk factor in terms of patient survival (HR = 4.654, P < .001). In cases of diffuse large B-cell lymphoma (DLBCL), immunopositivity of MYD88 is associated with non-germinal center B-cell origin (P < .001). The multivariate analysis observed the association between high lactate dehydrogenase value and the immunohistochemical expression of PIM1 or with the mutant status of the PIM1 gene representing negative prognostic factors (HR = 2.066, P = .042, respectively HR = 3.100, P = .004). In conclusion, our preliminary data suggest that the oncogenic mutations of PIM1 and MYD88 in our DLBCL cohort may improve the diagnosis and prognosis of DLBCL patients in an advanced stage.

Evaluation of intestinal necrosis with laser Doppler in experimental mesenteric ischemia model.

BACKGROUND: Acute mesenteric ischemia (AMI) is responsible for one in a thousand emergency hospital admissions in America and Europe and is associated with high morbidity and mortality rates. Current diagnostic and treatment methods fall short of desired outcomes, often resulting in delayed diagnoses and difficulties in detecting ischemic bowel tissue during treatment. This study evaluates the diagnostic value of commonly used biochemical markers in clinical practice-creatine kinase, C-reactive protein (CRP), and lactate dehydrogenase (LDH)-alongside blood flow measurements using laser Doppler in a rat model of experimental mesenteric ischemia. We also compare these markers with pathological ischemia scoring. METHODS: Rats were divided into five groups: control, 1 hour, 2 hours, 3 hours, and 4 hours. Mesenteric ischemia was induced for the respective durations in each group. After these periods, we measured blood flow using laser Doppler. We also collected blood samples and intestinal biopsies for biochemical parameter analysis. These values were assessed in relation to intestinal viability using the Chiu ischemia scoring system. RESULTS: Blood flow measurement with laser Doppler correlated with both the duration and severity of bowel ischemia. No significant relationship was found between CRP levels and the duration of ischemia. However, creatine kinase and lactate dehydrogenase (LDH) levels were significantly higher in ischemia lasting into the third and fourth hours. CONCLUSION: Creatine kinase and lactate dehydrogenase (LDH) levels may be useful biomarkers in patients with suspected acute mesenteric ischemia (AMI). Blood flow measurements using laser Doppler can accurately identify intestinal loops for resection during surgery.