Search Results (309)

Liver fibrosis, a critical pathological feature of chronic liver injury, is closely associated with macrophage-mediated inflammatory responses and metabolic reprogramming. Blocking the fibrosis process will be beneficial to the treatment and recovery of the disease. Liver macrophages are a remarkably heterogeneous population of immune cells that play multiple functions in homeostasis and are central to liver fibrosis. Glycolysis-mediated macrophage metabolic reprogramming leads to an increase in the proportion of M1 macrophages and the release of pro-inflammatory cytokines. The present study aimed to investigate the therapeutic effect and mechanism of acid B (SAL B) against carbon tetrachloride (CCl₄)-induced liver fibrosis. Here, we demonstrate that SAL B reduced the production of inflammatory factors in CCl₄-induced liver fibrosis. Mechanistically, SAL B increased the expression of migration inhibitor 1 (MIG1) by inhibiting DNMT1-mediated methylation of the MIG1 promoter. Subsequently, MIG1 reduced the transcription of lactate dehydrogenase A (LDHA) and hexokinase 2 (HK2) which blocked glycolysis-mediated macrophage M1 polarization. In summary, our results suggested that SAL B is a promising intervention for ameliorating liver fibrosis. Full article

Background and Objectives: Metabolic tumor volume (MTV) and inflammation-based indices have recently gained attention as potential prognostic markers of diffuse large B-cell lymphoma (DLBCL). We aimed to evaluate the prognostic significance of metabolic and systemic inflammatory parameters in predicting treatment response, relapse, and overall survival (OS) in patients with DLBCL. Materials and Methods: This retrospective cohort study included 70 patients with DLBCL. Clinical characteristics, laboratory values, and metabolic parameters, including maximum standardized uptake value (SUVmax^liver and SUVmax), heterogeneity indices HI1 and HI2, and MTV were analyzed. Survival outcomes were assessed using Kaplan–Meier and log-rank tests. Receiver operating characteristic analyses helped evaluate the diagnostic performance of the selected biomarkers in predicting relapse and mortality. Univariate and multivariate logistic regression analyses were conducted to identify the independent predictors. Results: The mean OS and mean relapse-free survival (RFS) were 71.6 ± 7.4 and 38.7 ± 2.9 months, respectively. SUVmax^liver ≤ 22 and HI2 > 62.3 were associated with a significantly shorter OS. High lactate dehydrogenase (LDH) levels and HI2 > 87.9 were significantly associated with a reduced RFS. LDH, SUVmax^liver, and HI2 had a significant predictive value for relapse. SUVmax^liver and HI2 levels were also predictive of mortality; SUVmax^liver ≤ 22 and HI2 > 62.3 independently predicted mortality, while HI2 > 87.9 independently predicted relapse. MTV was not significantly associated with survival. Conclusions: Metabolic tumor burden and inflammation-based markers, particularly SUVmax^liver and HI2, are significant prognostic indicators of DLBCL and may enhance risk stratification and aid in identifying patients with an increased risk of relapse or mortality, potentially guiding personalized therapy. Full article

This study included 221 patients with COVID-19 who were admitted to the emergency department of Avicenne Hospital in Rabat between August 2020 and August 2021. Patients were divided into three groups according to their D-dimer levels (<1, 1–2, and >2 µg/mL). Adjusted and unadjusted logistic regression analyses were performed to assess the association between elevated D-dimer levels and in-hospital mortality. Pearson’s correlation analysis was performed to explore the relationship between D-dimer levels and various biological and clinical parameters. The results revealed a statistically significant difference in the mean (SD) age among the three groups (p = 0.006). Analysis showed a statistically significant difference in the means (SD) of oxygen saturation, duration of hospital stay, and breathing rate among the three independent groups of COVID-19 patients. Patients with elevated D-dimer levels (greater than 2 µg/mL) experienced worse outcomes than those in the other groups, with severity, transfer to intensive care, and in-hospital mortality of 55 (40.7%), 35 (16%), and 24 (11%) patients, respectively, with p-values of 0.048, 0.002, and 0.002, respectively. Patients in the D-dimer > 2 µg/mL group had significantly higher C-reactive protein (CRP), lactate dehydrogenase, urea, cardiac troponin, B-type natriuretic peptide, and ferritin levels than those in the other two groups. The p-value was significant among the three groups (p = 0.044, p = 0.001, and p < 0.001). Age and elevated D-dimer levels (greater than 2 µg/mL) were associated with mortality in patients diagnosed with COVID-19. Correlation analysis indicated that D-dimer in COVID-19 patients is associated with worsening respiratory, hepatic, cardiac, and coagulation parameters, suggesting their utility as an integrative marker of disease severity. D-dimer levels > 2 µg/mL were identified as an independent risk factor for COVID-19 in-hospital mortality. Measuring and monitoring D-dimer levels can assist clinicians in taking timely actions and predicting the prognosis of patients with COVID-19. Full article

Lactate dehydrogenase (LDH) catalyzes the reversible interconversion of pyruvate and lactate, coupled with the redox cycling of NADH and NAD⁺. While LDHA has been extensively studied as a therapeutic target, particularly in cancer, due to its role in the Warburg effect, LDHB remains underexplored, despite its involvement in the metabolic reprogramming of specific cancer types, including breast and lung cancers. Most known LDH inhibitors are designed against the LDHA isoform and act competitively at the active site. In contrast, LDHB exhibits distinct kinetic properties, substrate preferences, and structural features, warranting isoform-specific screening strategies. In this study, 115 natural compounds previously reported as LDHA inhibitors were systematically evaluated for LDHB inhibition using an integrated in silico and in vitro approach. Virtual screening identified 16 lead phytochemicals, among which luteolin and quercetin exhibited uncompetitive inhibition of LDHB, as demonstrated by enzyme kinetic assays. These findings were strongly supported by molecular docking analyses, which revealed that both compounds bind at an allosteric site located at the dimer interface, closely resembling the binding mode of the established LDHB uncompetitive inhibitor AXKO-0046. In contrast, comparative docking against LDHA confirmed their active-site binding and competitive inhibition, underscoring their isoform-specific behavior. Our findings highlight the necessity of assay conditions tailored to LDHB’s physiological role and demonstrate the application of a previously validated colorimetric assay for high-throughput screening. This work lays the foundation for the rational design of selective LDHB inhibitors from natural product libraries. Full article

Objectives: This study investigated the properties of a neutral exopolysaccharide (EPS-LP1) with an average molecular weight of 55,637 Da, isolated from Lactiplantibacillus plantarum DMDL 9010 (LP9010). Results: The composition of EPS-LP1 includes galactose (Gal), glucose (Glu) and mannose (Man) in a molar ratio of 5.35:86.25:8.40. Notably, EPS-LP1 exhibits a smooth and rod-like surface along with thermal stability. Methylation combined with nuclear magnetic resonance analysis revealed that EPS-LP1 structured as t-Galp(1→, →6)-Glcp(1→, 4)-Glcp(1→ and →4,6)-Galp(1→), with relative molar ratio of 1.016:9.874:4.355:78.693:6.062, respectively. In the concentration range of 50 to 400 mg/mL, we observed the absence of cytotoxic effects from EPS-LP1 on RAW264.7 cells. Furthermore, EPS-LP1 demonstrated protective effects on RAW264.7 cells against oxidative damage by reducing the production of reactive oxygen species (ROS), malondialdehyde (MDA), and lactate dehydrogenase (LDH) release. Conversely, an increase in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and concentrations of glutathione (GSH) was observed. Immunoreactivity assays indicated that EPS-LP1 can effectively reduce the production of nitric oxide (NO) and inhibit the secretion of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Additionally, it inhibited the activation of the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B gene binding (NF-kB) signaling pathway. Conclusions: This research provides a foundation basis for further investigations into the neutral exopolysaccharide derived from LP9010. Full article

At weaning, piglets deal with numerous changes and stressors, which can lead to reduced feed intake, digestive disturbances, and gut inflammation. In this context, there is a compelling need to develop new and innovative nutritional strategies aimed at restoring intestinal balance in piglets after weaning and controlling the weaning-associated intestinal inflammation. This study investigated the effect of a diet, including a synbiotic additive (a mix of grape seed and camelina meals as the prebiotic and a lactobacilli mixture as the probiotic) on intestinal inflammation in piglets after weaning. An acute inflammation was induced by the intraperitoneally challenge with Escherichia coli lipopolysaccharide (LPS). The experimental groups were as follows: Control group (piglets fed a conventional corn-soybean meal-based diet), LPS group (piglets fed the Control diet and challenged with 80 µg/b.w. of LPS), SYN group (piglets fed a basal diet, including 5% prebiotic mix and 0.1% probiotic mix, SYN diet), and SYN+LPS group (piglets fed the SYN diet and challenged with 80 µg/b.w. of LPS). Using genomic and proteomic techniques, genes and proteins related to intestinal inflammation were measured in both the jejunum and colon. The results showed that the LPS challenge induced an exacerbated inflammatory response in the jejunum and colon of piglets, inducing an overexpression of a large palette of inflammation-related mediators, including lactate dehydrogenase (LDH) activity, cytokines (e.g., interleukin (IL)—IL-1β, IL-6, tumor necrosis factor alpha—TNF-α), and chemokines (e.g., monokine induced by interferon-gamma—MIG, regulated on activation, normal T cell expressed and secreted—RANTES). All these effects are prevented by the SYN diet, which controls the amplitude of intestinal inflammation induced by the LPS challenge in piglets. Overall, these results suggested that piglets, after weaning, fed the synbiotic diet are less susceptible to the LPS challenge. This diet might be used as a nutritional strategy to alleviate intestinal inflammation in piglets after weaning. Full article

Porcine reproductive and respiratory syndrome (PRRS) is aworldwide spread disease. This study analyzed the changes in saliva analytes of pigs infected with PRRS virus (PRRSV) in different clinical conditions that can appear in PRRSV-positive farms. Biomarkers for inflammation (haptoglobin, total proteins), immune response (adenosine deaminase), tissue damage (lactate dehydrogenase), stress (alpha-amylase), and sepsis (calprotectin, aldolase, Serpin B12) were measured in pigs under three clinical scenarios: (1) no evident clinical signs, (2) clinical signs indicating PRRSV activation, and (3) secondary bacterial infection by Streptococcus suis. Haptoglobin and lactate dehydrogenase showed significant increases in pigs with PRRSV activation compared to pigs without clinical signs. Additionally, the levels of Serpin B12, aldolase, calprotectin, total proteins, and the activity of adenosine deaminase significantly increased in pigs with meningitis compared to pigs without clinical signs, but did not show significant differences between healthy pigs and those with PRRSV clinical signs without bacterial infection. In summary, PRRSV-infected pigs can show differences in selected saliva analytes depending on their clinical condition. These findings may have practical applications for detecting PRRSV infections and differentiating cases with associated meningitis. Full article

Background: Immune checkpoint inhibitors (ICIs) used for the treatment of advanced melanoma have yielded significant results, with long-term responses and improved survival rates, but not for all treated patients. Therefore, predictive biomarkers of response to ICI therapy have been intensively explored. Our study aimed to evaluate the dynamics of peripheral blood lymphocyte variation and their correlation with a set of related inflammatory factors in Nivolumab-treated advanced melanoma patients. Methods: The immunophenotypic assessment of peripheral blood immune cell subpopulations (CD3⁺, CD4⁺, and CD8⁺ T cells; CD19⁺ B cells; CD16⁺CD56⁺ NK cells; and CD4⁺/CD8⁺ ratio) was performed by the flow cytometry technique, concomitantly with a complete blood count; levels of S100, IL-6, and TNF-α proteins were quantified in serum by immunoassays, and lactate dehydrogenase (LDH) by a chemiluminescence assay. Results: Approximately 85% and 79% of patients recorded a trend of increasing levels of CD8⁺ lymphocytes and NK cells, respectively, during therapy. The percentage of NK cells negatively correlated with CD3⁺, CD4⁺, and CD19⁺ cells; the last three cell populations also established negative correlations with the inflammatory neutrophile/lymphocyte ratio (NLR). Furthermore, CD19⁺ cells were negatively correlated with the systemic inflammatory response index (SIRI) and systemic immune-inflammation index (SII). The evaluation of progression biomarkers showed that LDH levels directly correlated with IL-6 and S100 proteins, but no correlation was found with TNFα; IL-6 levels negatively correlated with percentages of CD3⁺, CD4⁺, and CD8⁺ lymphocytes. Conclusions: Variation in lymphocyte subpopulations during immunotherapy of advanced melanoma patients, associated with other cellular and/or molecular inflammatory markers, might provide insights about immune system response, but additional prospective studies are needed. Full article

Background: Lactate dehydrogenase (LDH) activity, producing high levels of lactate from pyruvate in cancer cells, is often associated with poor patient prognosis. We previously showed enhanced LDH/lactate levels in estrogen receptor (ER) compared to ER + breast cancer cells; lactate or pyruvate supplementation to ER + cells significantly enhanced their motile ability, while LDHB gene knockout (KO) or treatment with LDH inhibitors reduced the motility of the highly aggressive ER breast cancer cells. Aims: To investigate the molecular mechanisms by which lactate, LDHB KO, or treatment with LDH inhibitors can modulate the motile capabilities of breast cancer cell lines. Methods: KO experiments were performed using siRNA, and global expression was determined by proteomic profiling with Proteome Profiler Human XL Oncology arrays, Western blot, and immunofluorescence. Results: Lactate supplementation to ER + breast cancer cells enhanced expression of vimentin, N-cadherin, and snail, while reducing the expression of JAM-A, E-cadherin, and nectin-4. This expression profile was reversed with LDHB KO in ER cells. LDHB KO, or treatment with LDH inhibitors in ER cells, also reduced the expression of IL-6, IL-8, and MMP-2. The expressions of other markers such as PECAM-1, CCL20, and ENPP-2 were differentially modulated with LDH B KO in de novo ER cells (MDA-MB-231) vs. those that had ER knockout (pII). Conclusions: Our data show a novel role for lactate in modulating the EMT status in breast cancer cells and highlight the important role of lactate in breast cancer motility in part through modulating EMT status and the expression profile of cytokines, adhesion molecules, MMP-2, and nectin-4. Full article

We used the data from a successful therapeutic assay that used icatibant in patients with hypoxemic COVID-19 pneumonia (the ICAT·COVID trial) to explore pathophysiological mechanisms. We performed concurrent-type, criterion-related validity analyses to assess the discriminative ability of a panel of nine potential serum markers (interleukin 6, ferritin, lactate dehydrogenase, C reactive protein, fibrin fragment D (D-dimer), complement 1 esterase inhibitor (antigenic and functional), complement 4 factor, and lymphocyte count) to predict the clinical milestones. Consistent with previous research, we evidenced a significant relationship between interleukin 6, lactate dehydrogenase and the lymphocyte count, and the clinical events. Furthermore, exposure to icatibant, a bradykinin B2 receptor antagonist (which improved pneumonia and mortality in the aforementioned randomised trial), attenuated this relationship, although this effect faded over time. The results reinforce the key role that the angiotensin-converting enzyme 2 has on COVID-19 pathophysiology as a point of convergence between the renin–angiotensin and kallikrein–kinin systems. This was shown clinically by the successful blocking of inflammatory pathways by icatibant at the bradykinin effector loop level early during the acute hyperinflammatory stage of the disease. Full article

Dairy cows are highly susceptible to mastitis caused by Klebsiella pneumoniae, and treating these infections poses a challenge due to the resistance of the bacterium to common antibiotics. This study aimed to evaluate the safety of W. cibaria SDS2.1 and investigate its protective effects against K. pneumoniae-induced mastitis. The safety of W. cibaria SDS2.1 was assessed through comprehensive analyses, including antibiotic resistance profiling, hemolysis assays, cell cytotoxicity tests, and whole-genome sequencing. Furthermore, its ability to protect against cellular and tissue damage caused by K. pneumoniae-induced mastitis was evaluated using both in vitro and in vivo models. Our results revealed that W. cibaria SDS2.1 was non-hemolytic, non-cytotoxic, and significantly inhibited the growth of K. pneumoniae (p < 0.05). Additionally, W. cibaria SDS2.1 effectively reduced the adhesion and invasion of K. pneumoniae. In the K. pneumoniae-induced mouse mastitis model, W. cibaria SDS2.1 significantly reduced myeloperoxidase (MPO) activity, mammary tissue damage, and the expression of inflammatory cytokines (IL-6, IL-1β, and TNF-α) (p < 0.05). In K. pneumoniae-infected bovine mammary epithelial cells (bMECs), W. cibaria SDS2.1 significantly decreased lactate dehydrogenase (LDH) release, indicating reduced cellular damage. These findings demonstrate that W. cibaria SDS2.1 exhibits anti-inflammatory properties in experimental models, suggesting its potential role in mitigating K. pneumoniae-induced mastitis. Full article

Endurance athletes frequently experience muscle damage and inflammation due to prolonged, high-intensity exercise, which can impair recovery and hinder performance. This review examines the role of branched-chain amino acid (BCAA) supplementation in muscle repair, inflammation modulation, and immune regulation. BCAAs—particularly leucine and isoleucine—activate key molecular pathways, including the mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK), to promote muscle protein synthesis and enhance energy metabolism. They also attenuate inflammatory responses by modulating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), mitogen-activated protein kinase (MAPK), and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways, reducing levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). In addition, BCAAs influence immune function via mechanistic target of rapamycin complex 1 (mTORC1) signaling, enhance autophagy, and mitigate exercise-induced apoptosis. These molecular effects result in reduced muscle soreness, lower muscle damage biomarker levels (e.g., creatine kinase, lactate dehydrogenase), and improved recovery. Practical considerations such as optimal dosage, timing, and co-supplementation with carbohydrates, proteins, or omega-3s are also addressed. While BCAAs show promise as a nutritional strategy for enhancing recovery and controlling inflammation in endurance athletes, further research is needed to refine personalized protocols and clarify long-term effects. Full article

Background/Objectives: Inflammatory bowel disease significantly impairs the patient’s quality of life. In young individuals, both the disease and the drugs used for the treatment may impact fertility. Our study aimed to assess the action of new 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone on the rat testes in a model of TNBS-induced colitis in rats. Methods: In the current study, testes from eight randomly chosen rats were taken from each of the following groups: the control group (K), the colitis group (C), and the groups receiving compounds 7b, 10b, and 13b in higher doses (20 mg/kg). Results: Colitis did not affect the testicular index (expressed as a percentage of the body weight), but in group 13b, this parameter was significantly higher than in group K. No significant differences between groups were noticed in malondialdehyde, superoxide dismutase, interleukin-1, or metalloproteinase 9 levels. In the colitis group, lactate dehydrogenase activity in the testes was not increased; however, the administration of compound 10b significantly increased this parameter when compared to both groups K and C. Histological evaluation also did not reveal abnormalities, and the morphology of the testicular tissues was comparable in all groups. Conclusions: The results may suggest that the new 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone did not exert significant testicular toxicity. Full article

After weaning, piglets no longer consume breast milk, and their immune system is not yet fully developed. At this time, if weaned piglets are infected with E. coli, their subsequent growth will be seriously affected. In the present study, 48 healthy 28-day-old weaned piglets (6.65 ± 1.19 kg, Duroc × Landrace × Large White) were randomly divided into an LPS group and control group. Piglets in the LPS group were intraperitoneally injected with an LPS solution (LPS was dissolved in sterile saline to form a solution of 100 μg/mL and injected at a dose of 1 mL per kilogram of body weight) for 13 consecutive days. Piglets in the control group were injected with the same volume of sterile saline. On days 1, 5, 9, and 13 of the experiment, six piglets from each group were randomly selected for dissection, the blood and heart samples were collected, and then cardiac function-related indicators were detected. A portion of the heart tissue was fixed in 4% paraformaldehyde and further used to make paraffin sections; then, hematoxylin–eosin (H&E) staining was performed. Masson staining was used to detect the changes in collagen fibers in the hearts. The other parts of the heart tissues were frozen in liquid nitrogen and stored in a refrigerator at −80 °C for the detection of tissue antioxidant indices. The mRNA expression levels of the toll-like receptor 4 (TLR4) signaling pathway, transforming growth factor-β (TGF-β) signaling pathway, and inflammatory cytokines in heart tissues were detected by real-time PCR. The results showed that catalase (CAT) and superoxide dismutase (SOD) contents in the heart tissue homogenates increased significantly on days 1 and 5 in LPS-induced piglets (p < 0.01, p < 0.05), while total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) contents decreased significantly on day 5 (p < 0.05). On day 5, the contents of serum cardiac function indicators lactate dehydrogenase (LDH), creatine kinase isoenzymes (CK-MB), and cardiac troponin I (cTn-I) were significantly increased in LPS-induced piglets (p < 0.01). On the 1st and 5th days, the heart tissue showed obvious pathological damage, which was manifested as the disordered arrangement of myocardial fibers, depression of myocardial cells, infiltration of inflammatory factors, congestion of capillaries, and significant increase in cardiac collagen fibers. On the 1st day, the mRNA expression levels of tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6) were significantly increased in LPS-induced piglets with heart injury (p < 0.01). On the 5th day, the mRNA expression levels of the TLR4 signaling pathway [TLR4, myeloid differentiation primary response gene 88 (MyD88), nuclear factor kappa-B (NF-κB)], TNF-α, and interleukin 10 (IL-10) were also significantly increased in LPS-induced piglets with heart injury (p < 0.01, p < 0.05). The mRNA expression levels of the TGF-β signaling pathway (TGF-β, Smad2, and Smad4) in cardiac fibrosis-related genes were significantly increased on days 5 and 9 (p < 0.01, p < 0.05). The mRNA expression levels of Smad3 and Smad7 in cardiac fibrosis-related genes were also significantly increased on day 9 (p < 0.01). These results indicate that oxidative stress occurs in the heart tissue of LPS-induced piglets on the 1st and 5th days, leading to cardiac tissue damage. However, on the 9th and 13th days, the degree of heart damage in the piglets was less than that on the 1st and 5th days, which may be due to the tolerance of piglets’ tissues and organs because of multiple same-dose LPS stimulations. Full article

K. pneumoniae is a major cause of bovine mastitis worldwide, making it difficult to control due to its resistance to multiple drugs. L. paraplantarum has been explored as a promising new approach to fighting bovine mastitis. In this study, the probiotic potential and safety of L. paraplantarum SDN1.2, as well as its ex vivo and in vivo anti-inflammatory effects against K. pneumoniae-induced mastitis, were comprehensively investigated using bioinformatics analyses and experimental validation methods. The results revealed that L. paraplantarum SDN1.2 exhibits non-hemolytic activity, is not cytotoxic, lacks virulence genes (e.g., adhesion factors, toxins, and invasion factors) and antibiotic resistance genes (e.g., beta-lactamases and tetracycline resistance genes), as supported by whole-genome sequencing, and significantly inhibits the growth of K. pneumoniae, as evaluated by antimicrobial tests. Following further validation in vitro, L. paraplantarum SDN1.2 demonstrated the capability to inhibit the adhesion and invasion of K. pneumoniae to bMECs. In a mouse model of K. pneumoniae-induced mastitis, L. paraplantarum SDN1.2 reduced the extent of neutrophil infiltration and inflammatory lesions. Furthermore, L. paraplantarum SDN1.2 pretreatment significantly reduced myeloperoxidase (MPO) activity and the expression of inflammatory cytokines (IL-6, IL-1β, and TNF-a) in mouse mammary gland tissue. In K. pneumoniae-infected bMECs, L. paraplantarum SDN1.2 significantly lowered lactate dehydrogenase (LDH) levels and expression of inflammatory cytokines such as IL-6, IL-1β, and TNF-α. The results demonstrated that the newly isolated L. paraplantarum SDN1.2 from bovine sources exhibits promising characteristics as a safe probiotic for the alleviation of bovine mastitis due to its safety profile and anti-inflammatory and antibacterial properties. Full article