Search Results (25,845)

EGFR-targeted therapies are efficacious, but toxicity is common and can be severe. Urokinase type plasminogen activator receptor (uPAR)-targeted drugs are only emerging, so neither their efficacy nor toxicity is fully established. Recombinant eBAT was created by combining cytokines EGF and uPA on the same single-chain molecule with truncated Pseudomonas toxin. Its purpose was to simultaneously target tumors and their vasculature in the tumor microenvironment. In prior studies on mice and dogs, the drug proved efficacious. Here, we report the safety of eBAT in normal wildtype, uPAR knockout, and immunoreplete and immunodeficient tumor-bearing mice, as well as in dogs with spontaneous sarcoma that more closely mirror human cancer onset. In immunocompetent mice, tumor-bearing mice, uPAR knockout mice, and mice receiving species-optimized eBAT, toxicities were mild and self-limiting. Likewise, in dogs with life-threatening sarcoma given dosages found to be biologically active, eBAT was well tolerated. In mice receiving higher doses, eBAT was associated with dose-dependent evidence of liver injury, including portal biliary hyperplasia, oval cell proliferation, lymphoplasmacytic inflammation, periportal hepatocellular microvesicular change, hemorrhage, necrosis, and apoptosis. The results support continuing the clinical development of eBAT as a therapeutic agent for individuals with sarcoma and other cancers. Full article

Introduction and Literature Review: Pancreatic cancer is often diagnosed in an advanced/metastatic stage, as it is a very aggressive type of cancer. The prognosis of pancreatic cancer is extremely unfavorable. The mean survival rate for patients with metastatic pancreatic adenocarcinoma is 3–6 months. Stage IV pancreatic cancer has a five-year survival rate of 1.3% to 13%. This article presents recent data regarding the oncologic management of metastatic pancreatic cancer. Case presentation: We present the case of a female patient who was 49 years old at the time of diagnosis, in June 2021. The patient was diagnosed with stage IV pancreatic neoplasm (due to liver metastases). The diagnosis was made by histopathological and immunohistochemical examination, which corroborated imaging investigations. The patient underwent four lines of chemotherapy between July 2021 and July 2024, undergoing partial response to the disease. The patient is a long-term survivor of metastatic pancreatic cancer (3 years in July 2024). Discussions: the peculiarity of this case is long-term survival (3 years and a month at the date when this article is being written) in a patient with pancreatic cancer and liver metastases. Conclusions: histopathological type, good performance status, CEA, and CA tumor markers 19.9 within normal limits may be favorable prognostic factors for long-term survival in metastatic pancreatic carcinoma. Full article

Intrahepatic cholangiocarcinoma (ICC) is a universally lethal malignancy with increasing incidence. However, ICC patients receive limited benefits from current drugs; therefore, we must urgently explore new drugs for treating ICC. Quinolizidine alkaloids, as essential active ingredients extracted from Sophora alopecuroides Linn, can suppress cancer cell growth via numerous mechanisms and have therapeutic effects on liver-related diseases. However, the impact of quinolizidine alkaloids on intrahepatic cholangiocarcinoma has not been fully studied. In this article, the in vitro anti-ICC activities of six natural quinolizidine alkaloids were explored. Aloperine was the most potent antitumor compound among the tested quinolizidine alkaloids, and it preferentially inhibited RBE cells rather than HCCC-9810 cells. Mechanistically, aloperine can potentially decrease glutamate content by inhibiting the hydrolysis of glutamine, reducing D-2-hydroxyglutarate levels and, consequently, leading to preferential growth inhibition in isocitrate dehydrogenase (IDH)-mutant ICC cells. In addition, aloperine preferentially resensitizes RBE cells to 5-fluorouracil, AGI-5198 and olaparib. This article demonstrates that aloperine shows preferential antitumor effects in intrahepatic cholangiocarcinoma cells harboring the mutant IDH1 by decreasing D-2-hydroxyglutarate, suggesting that aloperine could be used as a lead compound or adjuvant chemotherapy drug to treat ICC harboring the mutant IDH. Full article

Background/Objectives: Terminal ileitis (TI) is often identified on CT scans in emergency settings. Diagnosing Crohn’s disease (CD) as a cause of TI is crucial due to its significant long-term implications. This study aimed to differentiate CD from other causes of acute TI and develop a predictive model for CD diagnosis. Methods: A retrospective case-control study was conducted at Shamir Medical Center including adults diagnosed with acute TI from January 2012 to December 2020. Patients with a history of inflammatory bowel disease or prior intestinal surgery were excluded. Patients were categorized into CD and non-CD groups based on their subsequent clinical course. A logistic regression model was developed and subsequently validated with additional patients hospitalized between 2021 and 2023. Results: Among 135 patients, 37 (27.4%) were diagnosed with CD. CD patients were younger (median age 27 vs. 39 years, p = 0.003), predominantly male (83.8% vs. 51%, p = 0.001), and had higher rates of chronic abdominal pain, diarrhea, anemia, and weight loss prior to hospitalization. Significant laboratory differences included higher platelet counts (p = 0.006) and lower mean corpuscular volume (MCV) (p = 0.001) in CD patients. Radiologic signs of complicated disease were more common in CD (35.1% vs. 4.1%, p < 0.001). The predictive model incorporating gender, abdominal pain history, and MCV showed an area under the curve (AUC) of 0.87, with a sensitivity of 100% and specificity of 63.6% in the validation group of 18 patients. Conclusions: This study identified key predictors of CD in patients presenting with acute TI and developed a predictive model with a substantial diagnostic capability. Use of this model for early identification and treatment of CD may potentially improve patient outcomes. Further prospective validation of this model is warranted. Full article

The experiment was conducted to investigate the effects of feeding rates on growth performance, liver glycolysis, gluconeogenesis, glycogen synthesis, and glycogen decomposition in juvenile largemouth bronze gudgeon (Coreius guichenoti). A total number of 600 fish were randomly distributed into 12 cylindrical plastic tanks with 50 fish per tank and triplicate tanks per treatment. Fish were fed with 2%, 3%, 4%, and 5% feeding rates (body weight per day) three times day⁻¹ for 8 w. The results indicated that the feeding rates significantly increased the body weight, weight gain rate, and specific growth rate (p < 0.05), while showing no significant effects on the condition factor and survival rate (p > 0.05). The feed conversion ratio was significantly enhanced by the feeding rate (p < 0.05), although no significant differences were observed when the feeding rate exceeded 3% (p > 0.05). The plasma glucose levels in the 4% and 5% groups were significantly higher than those in the 2% and 3% groups. Compared with other groups, the 5% group significantly increased the crucial rate-limiting enzyme activities and mRNA levels of glycolysis (PFKL and PK) (p < 0.05), while showing no significant differences on enzyme activities (PC, PEPCK, and G6P) and mRNA (pepck and g6p) levels of gluconeogenesis (p > 0.05). In addition, the mRNA levels of hepatic glut2 and glut4 in the 5% group reached the highest levels (p < 0.05). When the feeding rate exceeded 3%, hepatic glycogen and lipid accumulation were significantly increased, leading to a fatty liver phenotype. Meanwhile, the mRNA level of liver glycogen synthetase (gysl) was significantly increased (p < 0.05), while no significant difference was observed in glycogen phosphorylase (pygl) (p > 0.05). In summary, under the conditions of this study, a feeding rate exceeding 3% significantly accelerated hepatic glycogen and lipid accumulation, which ultimately induced fatty liver formation. Full article

The present study aimed to investigate the effects of the Gypsophila paniculata ethanol extract (GPEE) on oxidative stress, inflammation, and metabolic markers in a rat model of streptozotocin-induced diabetes mellitus (DM). Phytochemical analysis using high-performance liquid chromatography coupled with mass spectrometry was performed to measure the total phenolic and flavonoid contents. In vitro antioxidant activity was evaluated through DPPH, FRAP, H₂O₂, and NO scavenging tests, and the in vivo effects of the GPEE were assessed in streptozotocin-induced DM rats. Treatments with the GPEE, metformin, and Trolox were administrated by gavage for 10 days. On day 11, blood was collected, and serum oxidative stress (total oxidative status, oxidative stress index, malondialdehyde, advanced oxidation protein products, 8-hydroxydeoxyguanosine, nitric oxide, 3-nitrotyrosine, advanced glycation end-products, total antioxidant reactivity, total thiols), inflammatory (IL-1β, NF-κB, IL-18, and gasdermin D), metabolic (fasting glucose, total cholesterol, triglycerides, and triglyceride–glucose index), and liver injury (AST, ALT, and AST:ALT ratio) markers were measured. The GPEE was found to have a significant polyphenols content and a moderate in vitro antioxidant effect. In vivo, the GPEE lowered oxidants and increased antioxidants, decreased inflammatory markers and blood glucose, and improved lipid profiles and transaminases in a dose-dependent manner, with higher doses having a better effect, being comparable to those of metformin and Trolox. Full article

The gut microbiota constitutes a complex ecosystem, comprising trillions of microbes that have co-evolved with their host over hundreds of millions of years. Over the past decade, a growing body of knowledge has underscored the intricate connections among diet, gut microbiota, and human health. Bioactive polysaccharides (BPs) from natural sources like medicinal plants, seaweeds, and fungi have diverse biological functions including antioxidant, immunoregulatory, and metabolic activities. Their effects are closely tied to the gut microbiota, which metabolizes BPs into health-influencing compounds. Understanding how BPs and gut microbiota interact is critical for harnessing their potential health benefits. This review provides an overview of the human gut microbiota, focusing on its role in metabolic diseases like obesity, type II diabetes mellitus, non-alcoholic fatty liver disease, and cardiovascular diseases. It explores the basic characteristics of several BPs and their impact on gut microbiota. Given their significance for human health, we summarize the biological functions of these BPs, particularly in terms of immunoregulatory activities, blood sugar, and hypolipidemic effect, thus providing a valuable reference for understanding the potential benefits of natural BPs in treating metabolic diseases. These properties make BPs promising agents for preventing and treating metabolic diseases. The comprehensive understanding of the mechanisms by which BPs exert their effects through gut microbiota opens new avenues for developing targeted therapies to improve metabolic health. Full article

Furin, a serine protease enzyme located in the Golgi apparatus of animal cells, plays a crucial role in cleaving precursor proteins into their mature, active forms. It is ubiquitously expressed across various tissues, including the brain, lungs, gastrointestinal tract, liver, pancreas, and reproductive organs. Since its discovery in 1990, furin has been recognized as a significant therapeutic target, leading to the active development of furin inhibitors for potential use in antiviral, antibacterial, anticancer, and other therapeutic applications. This review provides a comprehensive overview of the progress in the development and characterization of furin inhibitors, encompassing peptides, linear and macrocyclic peptidomimetics, and non-peptide compounds, highlighting their potential in the treatment of both infectious and non-infectious diseases. Full article

The liver is a highly metabolically active organ, and one of the causes of its dysfunction is the damage caused by drugs and their metabolites as well as dietary supplements and herbal preparations. A common feature of such damage is drugs, which allows it to be defined as drug-induced liver injury (DILI). In this review, we analysed available research findings in the global literature regarding the effects of green tea and/or its phenolic compounds on liver function in the context of protective action during prolonged exposure to xenobiotics. We focused on the direct detoxifying action of epigallocatechin gallate (EGCG) in the liver, the impact of EGCG on gut microbiota, and the influence of microbiota on liver health. We used 127 scientific research publications published between 2014 and 2024. Improving the effectiveness of DILI detection is essential to enhance the safety of patients at risk of liver damage and to develop methods for assessing the potential hepatotoxicity of a drug during the research phase. Often, drugs cannot be eliminated, but appropriate nutrition can strengthen the body and liver, which may mitigate adverse changes resulting from DILI. Polyphenols are promising owing to their strong antioxidant and anti-inflammatory properties as well as their prebiotic effects. Notably, EGCG is found in green tea. The results of the studies presented by various authors are very promising, although not without uncertainties. Therefore, future research should focus on elucidating the therapeutic and preventive mechanisms of polyphenols in the context of liver health through the functioning of gut microbiota affecting overall health, with particular emphasis on epigenetic pathways. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD)—and its worse form, metabolic-associated steatohepatitis (MASH), characterised by inflammation and liver damage—corresponds to the liver’s involvement in metabolic syndrome, which constitutes an economic burden for healthcare systems. However, the biomolecular pathways that contribute to steatotic liver disease are not completely clear. Abnormalities of bone metabolism are frequent in people affected by metabolic liver disease, with reduced bone density and an increased risk of fracture. Receptor activator of NF-κB (RANK), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin(OPG) are critical regulators of bone metabolism, performing pleiotropic effects, and may have potential involvement in metabolic disorders like MASLD, resulting in a topic of great interest and intrigue. This narrative review aims to investigate this potential role and its implications in MASLD development and progression and in hepatocellular carcinoma, which represents its worst complication. Full article

Following the advent of direct-acting antivirals (DAAs), the treatment of hepatitis C virus (HCV) infection is now rarely challenging. However, data are still limited concerning DAA use in patients affected by glucose-6-phosphate dehydrogenase deficiency (G6PDd). Based on these considerations, the goal of this study was to evaluate the effectiveness and safety of DAAs in this subpopulation. A retrospective multicenter observational study (2015–2023) was conducted on all 2754 consecutive HCV-positive patients treated with first- and second-generation all-oral DAAs, and with a G6PDd diagnosis confirmed by quantitative testing (n = 38). At the treating clinician’s discretion, an enhanced clinical and laboratory follow-up was performed, generally on a monthly basis both during treatment and up to six months after the end of it. Concerning hematochemical parameters, no significant differences were found between any considered time point. In all cases, no treatment-related adverse events were reported, and virologic response rates were as expected without G6PDd. In conclusion, in a large experience which, to the best of our knowledge, is unprecedented in the literature, the treatment of HCV hepatitis with nearly all available DAAs in patients with G6PDd as a comorbidity—a common occurrence in countries such as Italy—proved to be highly effective and safe. Full article

CTHV is a non-invasive and accurate method for assessing liver volume in dogs. CTHV has not been studied in each type of extrahepatic PSS in dogs. This study aimed to use CTHV to compare liver volumes in dogs with different types of PSSs that had been confirmed by computed tomography angiography. Dogs with PSSs were retrospectively included and categorized into IH, EHPC, EHPA, or EHPP shunt groups. Manual CTHV was performed, and the normalized liver volume (nLV) and the difference in nLV from the estimated liver volume calculated based on body weight (LV%diff) was calculated. The study included 57 dogs: 20 IH, 21 EHPC, 9 EHPA, and 7 EHPP. The median nLV (cm³/kg) and LV%diff (%) for each group were as follows: IH 17.3 (−40.4%); EHPC 16.9 (−60.3%); EHPA 15.1 (−56.7%); and EHPP 17.2 (−59.2%), respectively. There were no significant differences in nLV among the PSS types. However, LV%diff was significantly more pronounced in the EHPC and EHPA groups compared with the IH group. Additionally, smaller dogs exhibited more severe microhepatia, with a significant positive correlation between LV%diff and body weight (p < 0.01). These findings suggest that microhepatia severity varies by shunt type and is more severe in smaller dogs, highlighting the need for further research to understand the underlying mechanisms. Full article

Background: Prior studies are inconclusive regarding the effect of obesity on mortality in persons with colorectal cancer (CRC). We sought to determine the association of pre-diagnosis body mass index (BMI) trajectories on mortality after CRC diagnosis. Methods: Utilizing the Multiethnic Cohort, we included adults aged 18–75 between 1 January 1993 and 1 January 2019 with a diagnosis of CRC and at least three available BMIs. The primary exposure, BMI, was subjected to group-based trajectory modeling (GBTM). We evaluated all-cause and CRC-specific mortality, using Cox proportional hazard (PH) models. Results: Of 924 persons, the median age was 60 years, and 54% were female. There was no statistically significant association between pre-cancer BMI trajectory and either all-cause or cancer-specific mortality. In competing risk analysis, the risk of CRC-specific mortality was higher for African Americans (HR = 1.56, 95% CI [1.00–2.43], p = 0.048) and smokers (HR = 1.59, 95% CI [1.10–2.32], p = 0.015). Risk of all-cause mortality was higher for Hawaiian persons (HR = 2.85, 95% CI [1.31–6.21], p = 0.009) and persons with diabetes (HR = 1.83, 95% CI [1.08–3.10], p = 0.026). Conclusions: Pre-diagnosis BMI trajectories were not associated with mortality after CRC diagnosis, whereas race/ethnicity, diabetes, and smoking were associated with an increased risk of death. Our findings suggest the obesity paradox alone does not account for mortality after CRC diagnosis. Full article

The endocannabinoid system (ECS) plays a crucial role in reproductive health, but its function in postpartum dairy cows remains poorly understood. This study investigated the expression patterns of ECS-related genes in the endometrium of postpartum dairy cows and their associations with endometrial health and the presence of fatty liver. Endometrial biopsies were collected from 22 Holstein Friesian cows at 4 and 7 weeks postpartum. Gene expression was analyzed using RT-qPCR, focusing on key ECS components including CNR2, MGLL, FAAH1, NAAA, NAPEPLD, PADI4 and PTGDS. The results reveal dynamic changes in ECS gene expression associated with endometritis and fatty liver. MGLL expression was significantly upregulated in cows with endometritis at 7 weeks postpartum, while NAAA expression was consistently downregulated in cows with fatty liver. CNR2 showed a time-dependent pattern in endometritis, and PTGDS expression was elevated in clinical endometritis at 4 weeks postpartum. The presence of fatty liver was associated with altered expression patterns of several ECS genes, suggesting a link between metabolic stress and endometrial ECS function. These findings indicate a potential role for the ECS in postpartum uterine health and recovery, offering new insights into the molecular mechanisms underlying reproductive disorders in dairy cows and paving the way for novel therapeutic approaches. Full article

Recent studies suggest that lactate intake has a positive effect on glycogen recovery after exercise. However, it is important to verify the effect of lactate supplementation alone and the timing of glycogen recovery. Therefore, in this study, we aimed to examine the effect of lactate supplementation immediately after exercise on glycogen recovery in mice liver and skeletal muscle at 1, 3, and 5 h after exercise. Mice were randomly divided into the sedentary, exercise-only, lactate, and saline-treated groups. mRNA expression and activation of glycogen synthesis and lactate transport-related factors in the liver and skeletal muscle were assessed using real-time polymerase chain reaction. Skeletal muscle glycogen concentration showed an increasing trend in the lactate group compared with that in the control group at 3 and 5 h after post-supplementation. Additionally, exogenous lactate supplementation significantly increased the expression of core glycogen synthesis enzymes, lactate transporters, and pyruvate dehydrogenase E1 alpha 1 in the skeletal muscles. Conversely, glycogen synthesis, lactate transport, and glycogen oxidation to acetyl-CoA were not significantly affected in the liver by exogenous lactate supplementation. Overall, these results suggest that post-exercise lactate supplement enables glycogen synthesis and recovery in skeletal muscles. Full article