Search Results (3,842)

Purpose: The liver is susceptible to adverse effects from radiation therapy (RT) and systemic therapy (ST) for breast cancer, given its anatomical proximity. Thus, we evaluated hepatotoxicity after RT and ST for breast cancer. Methods: This multicenter retrospective study included breast cancer patients treated with RT in 2021 and underwent a liver function test (LFT) before and after RT. Patients with bilateral breast cancer or a history of thoracic or abdominal RT and liver disease were excluded. Changes in Common Terminology Criteria for Adverse Events (CTCAE) grading of liver enzyme elevation (LEE) of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) and its associations with Dose-volume histogram (DVH) parameters and other clinical factors were analyzed. Results: In total, 529 patients were included in the analysis. Median values of mean liver dose, V5Gy, V10Gy, and V20Gy dose to the liver were 1.37 Gy, 4.3%, 2.1%, and 0.9%, respectively. In the post-RT LFT, 6 (1.1%), 9 (1.7%), and 25 (4.7%) patients showed CTCAE grade elevation of AST, ALT and ALP, respectively, with most cases being grade 1. Three patients (0.6%) met the diagnostic criteria for radiation-induced liver disease (RILD). In multivariate logistic regressions including various DVH parameters, neoadjuvant therapy was associated with LEE. Conclusions: The incidences of LEE and RILD after multimodal therapy for breast cancer were limited, suggesting that RT and ST can be considered safe in terms of hepatotoxicity. Nevertheless, caution in treating patients who underwent neoadjuvant therapy, especially to those with underlying liver disease, might help minimize LEE. Full article

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting the joints, with neurogenic inflammation involving the nervous system being a hallmark of the condition. Treatments include medications such as disease-modifying antirheumatic drugs (DMARDs), corticosteroids, and biologics targeting inflammatory pathways. Yet, these treatments are not curative for RA. Heat Shock Proteins (HSPs) are molecular chaperones with immunoregulatory properties; however, their role is not yet fully understood, as these molecules may play a dual, pro- and anti-inflammatory role. In this study, we evaluated the protein expression levels of HSPs 27, 60, 70, and 90 in the synovial membrane and spinal cord of the RA rats’ model to determine their roles during the disease course, both on the neurological and immunological levels. Furthermore, HSP levels have been evaluated in the spinal cord of control and RA rats’ model after high and low doses of ketamine injection. Significant changes in Hsp60, 70, and 90 expression levels were observed only in the spinal cord of RA rats. We demonstrated that blocking N-methyl-D-aspartate receptors with ketamine can modulate spinal cord HSPs expression in RA rats and subsequently impact neurogenic inflammation and adult neurogenesis. This suggests that HSPs may be a promising target for RA treatment due to their complex immunomodulatory effects and potential interactions with the nervous system. Further research is needed to explore their therapeutic potential and develop effective interventions for RA. Full article

Sepsis is a life-threatening condition driven by a dysregulated host response to infection, with high mortality and few treatment options. Decades of failed drug development underscore the urgent need for therapies with novel mechanisms of action. Vimentin, an intermediate filament protein, acts as a network hub that senses and integrates cellular signals. Its involvement in key sepsis pathologies, including infection, hyperinflammation, immunosuppression, coagulopathy and metabolic dysregulation, positions it as a potential therapeutic target. This study evaluated the efficacy of ALD-R491, a novel small-molecule vimentin modulator, in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice received ALD-R491 prophylactically or therapeutically, alone or with ceftriaxone. The treatment significantly reduced serum levels of key biomarkers of sepsis, including C-reactive protein (CRP), lactate (Lac), tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), and dose-dependently improved the survival of septic mice. Organ-specific analysis confirmed the effects of ALD-R491 in mitigating hyperinflammation and multi-organ injury. The treatment reduced pulmonary edema and inflammation; preserved liver tissue architecture and improved hepatic function with lowered alanine aminotransferase/aspartate aminotransferase (ALT/AST); decreased kidney tubular damage; and improved renal function with lowered creatinine/blood urea nitrogen (BUN). These preclinical findings indicate that the vimentin-targeting agent ALD-R491 represents a promising therapeutic candidate for sepsis and merits further clinical investigation. Full article

Dihydroorotase (DHOase) catalyzes the reversible cyclization of N-carbamoyl-L-aspartate to dihydroorotate, a key step in de novo pyrimidine biosynthesis. A flexible active site loop in DHOase undergoes conformational switching between loop-in and loop-out states, influencing substrate binding, catalysis, and inhibitor recognition. In this study, we identified 5-fluoroorotate (5-FOA) and myricetin as inhibitors of Saccharomyces cerevisiae DHOase and systematically analyzed 97 crystal structures and AlphaFold 3.0 models of DHOases from 16 species representing types I, II, and III. Our results demonstrate that loop conformation is not universally ligand-dependent and varies markedly across DHOase types, with type II enzymes showing the greatest flexibility. Notably, S. cerevisiae DHOase consistently adopted the loop-in state, even with non-substrate ligands, restricting accessibility for docking-based inhibitor screening. Docking experiments with 5-FOA and myricetin confirmed that the loop-in conformation prevented productive active-site docking. These findings highlight the importance of selecting appropriate loop conformations for structure-based drug design and underscore the need to account for loop dynamics in inhibitor screening. Full article

Feedlots rely on corn-based total mixed rations (TMR) to finish yaks. However, corn is markedly deficient in lysine and, therefore, we hypothesized that feedlot yaks supplemented with rumen-protected lysine (RPLys) would improve performance. To test this hypothesis, twelve 2.5-year-old male yaks (122 ± 5.3 kg) were selected, and divided into a control (CON) and RPLys-supplemented (RPL) group. All yaks were provided with a pelleted diet that consisted of 25.0% corn stalk, 31.6% corn grain, and 24.0% corn by-products; while RPL yaks were supplemented with 37.0 g/d RPLys. Dry matter intake was not affected (p = 0.671) by RPLys supplementation, but the average daily gain was greater (p < 0.05; 1.46 vs. 1.25 kg/d) and the feed-to-gain ratio was lesser (p < 0.01; 3.39 vs. 3.90) in RPL than CON yaks. Serum urea nitrogen concentration and aspartate aminotransferase were greater (p < 0.05) in the CON than the RPL group. However, plasma lysine concentration was greater (p < 0.05), while threonine tended to be greater (p = 0.065) in RPL than CON yaks. Rumen ammonia-N concentration was lesser (p < 0.05) in RPL than CON yaks, but pH and volatile fatty acids concentration did not differ (p > 0.10) between groups. The relative abundances of the ruminal bacterial phyla of Firmicutes and Elusimicrobiota were greater (p < 0.05), whereas of the phylum Bacteroidota and genus Butyrivibrio were lesser (p < 0.05) in RPL than CON yaks. In general, the rumen microbiota was altered toward more abundant N utilization taxa in RPLys-supplemented yaks. RPLys-supplemented yaks had elevated plasma lysine and improved feed conversion ratio, providing the first evidence that bypass lysine improves the growth performance of yaks on corn-based diets in feedlots. Full article

The aim of the present study is to evaluate the impact of chromium (Cr) supplementation on glucose and lipid metabolism in breast muscle in broilers under heat stress. A total of 220 day-old broiler chicks were reared in cages. At 29 days old, 180 birds were randomly assigned to three treatments (0, 400, and 800 µg Cr/kg, as chromium picolinate) and transferred to climate chambers (31 ± 1 °C, 60 ± 7% humidity) for 14 days. Growth performance, carcass traits, serum biochemical indices, fasting glucose and insulin, homeostasis model assessment of insulin resistance (HOMA-IR), as well as muscle metabolomic profiles and gene expression related to energy and lipid metabolism were analyzed. The results showed that, compared with the heat stress group, the groups supplemented with 400 and 800 µg Cr/kg showed higher dry matter intake and average daily gain, breast muscle ratio, and lower feed conversion ratio and abdominal fat ratio; chickens supplemented with 400 and 800 µg Cr/kg showed significantly lower serum corticosterone (CORT), free fatty acids, and cholesterol levels compared with the heat stress (HS) group (p < 0.05). Fasting blood glucose and HOMA-IR were also significantly reduced, while fasting insulin was significantly increased in the Cr-supplemented groups (p < 0.05). Metabolomic analysis revealed that Cr supplementation regulated lipid and amino acid metabolism by altering key metabolites such as citric acid, L-glutamine, and L-proline, and modulating pathways including alanine, aspartate, and glutamate metabolism, and glycerophospholipid metabolism. Furthermore, Cr supplementation significantly upregulated the expression of Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1 α (PGC-1α), ATP Binding Cassette Subfamily A Member 1 (ABCA1), Peroxisome Proliferator-Activated Receptor α (PPARα), and ATP Binding Cassette Subfamily G Member 1 (ABCG1) in both the hepatic and muscle tissue. This paper suggested that chromium supplementation may enhance energy metabolism and lipid transport like the findings of our study suggested. Full article

Background/Objectives: Stroke is the second leading cause of death worldwide. There is an unmet need to manage stroke pathophysiology, including L-glutamate (L-Glu)-mediated neurotoxicity. The acai berry (Euterpe sp.) contains phytochemicals with potentially nutraceutical content. The aim of this study was to assess the ability of acai berry extracts to counter L-Glu neurotoxicity using human differentiated TE671 cells. Methods: The cytotoxicity of L-Glu and acai berry extracts was quantified using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial function was examined by a quantitation of cellular ATP levels, the maintenance of the mitochondrial membrane potential (MMP), and the production of reactive oxygen species (ROS). Whole-cell patch-clamp recordings monitored the activation of N-methyl-D-aspartate receptors (NMDARs). Candidate phytochemicals from acai berry extracts were modeled in silico for NMDAR binding. Results: L-Glu significantly reduced cell viability, ATP levels, the MMP, and increased cellular ROS. Generally, acai berry extracts alone were not cytotoxic, although high concentrations were detrimental to ATP production, maintenance of the MMP, and elevated ROS levels. Whole-cell patch-clamp recordings revealed that the combined addition of 300 µM L-Glu and 10 µM glycine activated currents in differentiated TE671 cells, consistent with triggering NMDAR activity. Acai berry extracts ameliorated the L-Glu-induced cytotoxicity, mitochondrial dysfunction, elevated ROS levels, and limited the NMDAR-mediated excitotoxicity (p < 0.001–0.0001). Several virtual ligands from acai berry extracts exhibited high-affinity NMDAR binding (arginine, 2,5-dihydroxybenzoic acid, threonine, protocatechuic acid, and histidine) as possible candidate receptor antagonists. Conclusions: Acai berry phytochemicals could be exploited to reduce the L-Glu-induced neurotoxicity often observed in stroke and other neurodegenerative diseases. Full article

Objectives: This study aimed to evaluate the association between adherence to the Mediterranean diet and blood trimethylamine-N-oxide (TMAO) levels. Methods: This randomized clinical trial enrolled 53 healthy adults with normal or overweight body mass index (BMI) who were recruited from a cardiology outpatient clinic in Istanbul, Turkey. Dietary patterns and Mediterranean diet adherence (assessed using the MEDAS) were evaluated alongside anthropometric and biochemical parameters, including fasting glucose, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Twenty individuals with low adherence underwent a 4-week Mediterranean dietary intervention with daily dietary monitoring. To assess changes, pre- and postintervention data were compared. Results: The results revealed that individuals adhering to the Mediterranean diet exhibited significantly lower blood TMAO levels (p < 0.001). In males, total cholesterol, LDL, triglyceride, and ALT levels significantly decreased compared with those at baseline (p < 0.05), whereas fasting blood glucose, HDL, and AST levels showed no significant changes (p > 0.05). In females, only blood TMAO levels exhibited significant reduction, with no other biochemical parameters indicating significant differences (p > 0.05). Additionally, males demonstrated significant improvements in anthropometric measures, including weight, BMI, fat mass, muscle mass, waist, and hip circumference, compared with pre-intervention values (p < 0.05), whereas females exhibited no significant changes in these measures (p > 0.05). Conclusions: Our findings demonstrate that implementing the Mediterranean diet in individuals with initially low adherence causes significantly reduced blood TMAO levels even within a short intervention period of 4 weeks. Full article

To assess the influence of dietary bile acid (BA) on the phenotype associated with hepatic lipid metabolism and its regulation of lipid homeostasis in gibel carp (Carassius auratus gibelio) under high-fat diet (HFD) conditions, five HFDs were designed using soybean oil (SO) as the single lipid source and supplemented with 0, 200, 400, 600, and 800 mg/kg BA (designated as BA0, BA200, BA400, BA600, and BA800, respectively). Juvenile fish (32.37 ± 0.13 g) were fed five BA-added HFDs (12% SO) for 8 weeks. Considerably lower levels of aspartate transaminase, alanine aminotransferase, low-density lipoprotein, triglyceride, and total cholesterol in the serum were observed in gibel carp fed with HFDs with 400–600 mg/kg BA (p < 0.05). The hepatocytes of the BA400 and BA600 groups were intact without abnormal architecture or histopathological changes, compared to other groups. The presence of most genes related to fatty acid biosynthesis decreased significantly with the addition of 400–600 mg/kg BA (p < 0.05), while the gene expressions of hormone-sensitive lipase, adiponectin receptor 2, and peroxisome proliferator-activated receptor α were variably up-regulated, along with the elevation of dietary BA (p < 0.05). Critical genes involved in bile acid and cholesterol synthesis were obviously down-regulated in gibel carp receiving 600–800 mg/kg dietary BA (p < 0.05), despite the sterol 27-hydroxylase (cyp27a1) gene in the BA800 group (p < 0.05). Moreover, hepatopancreas from the BA0 and BA600 groups were isolated for transcriptome sequencing, identifying 7040 differentially expressed genes (DEGs). The enriched KEGG pathways of DEGs mainly included steroid biosynthesis, protein digestion and absorption, etc. Seven randomly selected DEGs were validated using qRT-PCR and were in agreement with the RNA-seq results. Consequently, the appropriate supplementation of dietary BA for juvenile gibel carp is recommended at doses of 400–600 mg/kg in SO-based HFDs, which could contribute to the amelioration of HFD-induced excessive fat deposition in the hepatopancreas of gibel carp by both inhibiting fatty acid intake, biosynthesis, and steroid production and enhancing lipid decomposition. The findings may elucidate the physiological role of exogenous BA in fish and its underlying mechanism, providing references for the reasonable application of BA in aquafeeds and the prevention of HFD-induced metabolic dysfunction in fish. Full article

Autoimmune encephalitis (AE) is an autoantibody-mediated central nervous system disorder with diverse neuropsychiatric and neurological manifestations, and should be considered in the differential diagnosis of acute and subacute neurological or psychiatric syndromes. In this retrospective study, we analyzed 65 patients: 54 with AE (47 antibody-positive, seven antibody-negative) and 11 antibody-positive without AE. The most frequently detected antibodies targeted N-methyl-D-aspartate receptor (NMDAR), leucine-rich glioma-inactivated protein 1 (LGI1), and contactin-associated protein-like 2 (CASPR2)—key synaptic and axonal membrane proteins involved in excitatory neurotransmission, neuronal signaling, and synaptic plasticity. Clinical presentations were heterogeneous, ranging from common neuropsychiatric, cognitive, and seizure manifestations to atypical brainstem or cerebellar features. Symptom distribution analysis further demonstrated distinct patterns among Ab-positive AE, Ab-negative AE, and Ab-positive non-AE groups, with specific symptom–antibody associations providing potential diagnostic clues. Diagnostic complexity was underscored by unusual age at onset, overlap with multiple sclerosis, cases preceded by herpes labialis, and dual-antibody detection. A subset of antibody-positive patients had alternative diagnoses, highlighting the need for careful clinical correlation and cautious interpretation of antibody results. These findings illustrate the diagnostic challenges and broad clinical spectrum of AE, emphasizing the importance of integrating serological, clinical, and imaging data to improve diagnostic accuracy and guide management. Full article

During the grain and cereal production process, whether during harvesting, processing, or storage, errors can occur, compromising product quality and potentially leading to contamination by fungi, which produce toxic substances known as mycotoxins. When fed to animals, these contaminated grains and cereals can cause several negative effects on animal health, impacting their production performance, including immunosuppression, hepatotoxicity, nephrotoxicity, and reproductive problems. To minimize the problems caused by mycotoxins, anti-mycotoxin additives, also known as adsorbents, are used. These are inert materials that bind to mycotoxins and are excreted in feces, preventing their action within the animal’s body. Therefore, the objective of this study was to evaluate the effectiveness of an anti-mycotoxin product based on bentonite, activated charcoal, milk thistle extract, and yeast cell wall in the diet of mycotoxin-contaminated lambs on animal health and performance. Thirty lambs were divided into three homogeneous groups: control (without mycotoxins or additives), mycotoxin (with mycotoxins), and anti-mycotoxin (mycotoxins and additive). The mycotoxins used for feed contamination were aflatoxin (AFLA) (200 ppb), fumonisin (FUMO) (15 ppm), zearalenone (ZEA) (500 ppb), and deoxynivalenol (DON) (1.5 ppm). The anti-mycotoxin additive was used at a dose of 1 kg/ton of concentrate. Parameters of zootechnical performance, hematological profile, serum biochemistry, and oxidative status were evaluated. The group that ingested the contaminated concentrate with mycotoxin had a lower average daily weight gain (ADG) when compared to the control and anti-mycotoxin groups. Ingestion of a mycotoxin-contaminated diet increased the activity of aspartate aminotransferase and gamma-glutamyltransferase, which are indicators of liver damage. However, when the anti-mycotoxin additive was used, the increase in these enzymes was modest and lower than in the mycotoxin group. Ingestion of a mycotoxin-containing concentrate increased levels of oxidative stress biomarkers such as reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), myeloperoxidase (MPO), and reduced glutathione (GST), demonstrating that the mycotoxin challenge was effective in causing oxidative stress. However, when the diet was contaminated with mycotoxins and supplemented with the anti-mycotoxin additive, the levels of ROS and TBARS were similar to those of the negative control group. We concluded that adding the anti-mycotoxin product to the lambs’ diets prevented or minimized the problems caused by mycotoxin consumption, allowing these lambs to have ADG, and feed efficiency similar to the control group. Full article

Background: Shentong Zhuyu Decoction (STZYD) is a traditional Chinese medicine formula that has shown promise in alleviating neuropathic pain (NPP), yet its central mechanisms remain unclear. Methods: We investigated the STZYD effects on NPP using network pharmacology, in vivo assays, and analytical chemistry, focusing on molecular pathways and GABAergic neuronal modulation. Results: Network pharmacology revealed 254 potential STZYD targets enriched in calcium signaling and GABAergic synapse pathways, especially the NMDAR-2B/CaMKII/CREB axis. High-dose STZYD (1.25 g·mL⁻¹) and ifenprodil (6 mg·kg⁻¹) reversed hyperalgesia and anxiety-like behaviors in spared nerve injury (SNI) mice, and microdialysis showed that STZYD and ifenprodil reduced the glutamate, D-serine, aspartate, glycine, and gamma-aminobutyric acid levels in the interpeduncular nucleus (IPN). Immunofluorescence and fiber photometry showed reduced c-Fos expression and suppressed GCaMP signals in IPN GABAergic neurons, with chemogenetic experiments confirming their role in pain modulation. Multimodal molecular biology experiments demonstrated that STZYD and ifenprodil significantly downregulated the GluN2B, p-CaMKII, and p-CREB expressions within the IPN. We identified 145 constituents in STZYD through high-resolution mass spectrometry analysis, among which 40 were absorbed into plasma and 7 were able to cross the blood–brain barrier and accumulate in the IPN. Molecular docking revealed the strong binding of licoricesaponin K2 and senkyunolide F to NMDAR-2B. Conclusions: STZYD exerts dose-dependent antinociceptive effects by modulating IPN GABAergic neuronal activity through the inhibition of the NMDAR-2B-mediated CaMKII/CREB pathway. Full article

The cryopreservation of Chengde polled goat semen plays a critical role in conserving genetic resources, enhancing the utilization efficiency of superior breeding bucks, and advancing artificial insemination techniques. However, spermatozoa are vulnerable to oxidative stress during the freezing process, which can significantly compromise sperm motility. In this study, pooled ejaculates from multiple bucks were divided into six groups, including a control group cryopreserved with conventional extender and five treatment groups supplemented with sericin at concentrations of 0.2%, 0.4%, 0.6%, 0.8%, and 1.0% (w/v). The results demonstrated that supplementation of the semen cryoprotectant with 0.6% sericin significantly improved post-thaw sperm viability to 65.25% in Chengde hornless goats, while concurrently reducing both the sperm abnormality rate (p < 0.05) and intracellular ROS levels (p < 0.05). Integrated TMT proteomics and LC/MS metabolomics further compared the 0.6% sericin group with the frozen control group and identified 162 differentially expressed proteins and 109 differential metabolites between the sericin supplementation and frozen control groups. Functional analysis revealed the significant enrichment of differential metabolites, such as glutamine, in the alanine, aspartate, and glutamate metabolism pathway, concomitant with the marked upregulation of antioxidant proteins including LRP8, GSTM3, and SIRT2. Thus, 0.6% sericin enhances cryotolerance primarily by improving sperm viability, reducing oxidative damage, and sustaining energy metabolism. These findings indicate that sericin enhances cryotolerance by reducing oxidative damage and supporting metabolic function, providing preliminary molecular insights for improving goat semen cryopreservation. Full article

The large yellow croaker (Larimichthys crocea) is an economically important marine fish in China, whose growth rate in aquaculture has yet to meet the industry’s demands. Understanding the mechanism underlying inter-individual growth differences will create a favorable condition for selective breeding. In combined transcriptome and metabolome analyses, this study collected muscle tissues from four groups of croakers categorized based on sex and growth rate: fast-growing males, slow-growing males, fast-growing females, and slow-growing females. We identified 2344 differentially expressed genes (DEGs) and 198 differentially expressed metabolites (DEMs). Three genes, bpgm, mstnb, and mylpfb, played a crucial role in the growth regulation of large yellow croaker. The pathway enrichment analysis showed that “Aminoacyl-tRNA biosynthesis”, “Alanine, aspartate and glutamate metabolism”, “Inositol phosphate metabolism” and “Retrograde endocannabinoid signaling” pathways were involved in growth regulation. This study provides new clues for future research on the molecular mechanisms of growth regulation in large yellow croaker and builds a theoretical basis for improving the growth quality of this species. Full article

Parkinson’s disease (PD) is a progressive neurological disorder that affects movement, causing symptoms such as tremors, stiffness, slowness, and balance problems due to the degeneration of dopamine-producing neurons in the brain. Nowadays there is no cure for PD. Alpha synuclein (α-syn) aggregates, which are a hallmark of PD, are known to induce microglial activation, specifically the detrimental M1 microglial phenotype, which contributes to neuroinflammation and disease progression. Cannabinoid receptor 2 (CB₂R) activation has been shown to counteract neuroinflammation. CB₂R is able to interact with N-methyl-D-aspartate (NMDA) receptors (NMDAR), which has also attracted attention in PD research due to its role in excitotoxicity. Here we aimed to study the interaction between CB₂R and NMDAR in a PD context in rat tissue. We observed that α-syn fibrils alter CB₂R activation and CB₂R-NMDAR heteromerization in a heterologous expression system. Furthermore, activation of CB₂R counteracted NMDAR signaling. In microglia, α-syn fibrils decreased CB₂R-NMDAR heteromer expression while increasing CB₂R signaling. Importantly, CB₂R activation counteracted the α-syn fibrils-induced increase in M1-activated microglia, while it favored the polarization of microglia to the beneficial M2 phenotype. These results reinforce the idea of using cannabinoids for treating PD, as they provide not only the anti-inflammatory effects of cannabinoids but also counteract the detrimental increase in NMDAR signaling present in this disease. Full article