Search Results (2,409)

Background/Objectives: Platinum-resistant ovarian cancer (PROC) is a major therapeutic challenge, as it responds poorly to standard platinum-based treatment, has limited treatment options, and offers a generally unfavorable prognosis. Chemotherapeutic agents like pegylated liposomal doxorubicin (PLD), topotecan (TOPO), and gemcitabine (GEM) are used for this setting, but with varying efficacy and toxicity profiles, leading to an increasing need to understand the optimal balance between treatment effectiveness and tolerability for improving patient outcomes. This study evaluates the efficacy and side effects of PLD, TOPO, and GEM, focusing on progression-free survival (PFS), overall survival (OS), and safety profiles. Methods: We conducted a retrospective observational study that included 856 PROC patients treated with PLD (n = 383), TOPO (n = 352), or GEM (n = 121) at the OncoHelp Oncology Center from January 2018 to December 2023. Inclusion criteria encompass diagnosis, prior platinum therapy, and Eastern Cooperative Oncology Group (ECOG) status (0–2). Treatment protocols followed standard dosing, with adjustments for toxicity. Primary endpoints included PFS and OS, with safety assessed by incidence of grade 3 and 4 toxicities per CTCAE v5.0. Kaplan–Meier analysis and Cox regression were used to compare survival, and statistical significance was set at p < 0.05. Results: TOPO showed higher toxicity than PLD and GEM, including liver damage, hematological and non-hematological side effects, while PLD induced more skin toxicity. In terms of survival, minor differences were seen between the three chemotherapeutic agents, with a slight advantage for PLD for better disease control. Conclusions: Given the comparable results in OS across the regimens, treatment decisions should be based on other factors such as patient tolerance and quality of life. Full article

Background: HIV and tuberculosis (TB) co-infection poses a significant health challenge, particularly when involving the central nervous system (CNS), where it leads to severe morbidity and mortality. Current treatments face challenges such as drug resistance, immune reconstitution inflammatory syndrome (IRIS), and persistent inflammation. Glutathione (GSH) has the therapeutic potential to enhance treatment outcomes by improving antibiotic efficacy, reducing inflammation, and mitigating immune dysfunction. Methods: Relevant studies were identified through systematic searches of PubMed, Elsevier, WHO, and related databases. Inclusion criteria focused on preclinical and clinical research examining GSH or its precursors in HIV, TB, or co-infection, with emphasis on microbial control, immune modulation, and CNS-related outcomes. Results: Preclinical studies showed that GSH improves macrophage antimicrobial function, reduces oxidative stress, and limits Mycobacterium tuberculosis (M.tb) growth. Animal models demonstrated reduced bacterial burden in the lungs, liver, and spleen with GSH supplementation, along with enhanced granuloma stability. Clinical studies highlighted increased TH1 cytokine production, reduced inflammatory markers, and improved CD4+ T cell counts in HIV–M.tb co-infected patients. N-acetylcysteine (NAC), a GSH precursor, was shown to significantly enhance the efficacy of first-line TB antibiotics and mitigate treatment-associated toxicity. Discussion: GSH shows promise as an adjunct therapy for HIV–M.tb co-infection, particularly for cases involving the CNS, where it may improve immune recovery and reduce inflammation. However, evidence is limited by small sample sizes and a lack of randomized trials. Future research should focus on developing CNS-directed GSH formulations and evaluating its integration into current treatment protocols to address the dual burden of HIV and TB, ultimately improving patient outcomes. Full article

Cadmium (Cd) pollution poses an important problem, but limited information is available about the toxicology effects of Cd on freshwater invertebrates. We investigated the accumulation, oxidative stress, microbial community changes, and transcriptomic alterations in apple snails (Pomacea canaliculata) under Cd stress. The snails were exposed to the 10 μg/L Cd solution for 16 days, followed by a 16-day elimination period. Our results showed that the liver accumulated the highest Cd concentration (17.41 μg/g), followed by the kidneys (8.00 μg/g) and intestine-stomach (6.68 μg/g), highlighting these tissues as primary targets for Cd accumulation. During the elimination period, Cd concentrations decreased in all tissues, with the head-foot and shell exhibiting over 30% elimination rates. Cd stress also resulted in reduced activities of superoxide dismutase (SOD), catalase (CAT), and glutathione transferase (GST) compared to the control group. Notably, even after 16 days of depuration, the enzyme activities did not return to normal levels, indicating persistent toxicological effects. Cd exposure significantly reduced the diversity of gut microbiota in P. canaliculata. Moreover, transcriptome analysis identified differentially expressed genes (DEGs) primarily associated with lysosome function, motor proteins, protein processing in the endoplasmic reticulum, drug metabolism via cytochrome P450 (CYP450), arachidonic acid metabolism, and ECM–receptor interactions. These findings suggest that Cd stress predominantly disrupts cellular transport and metabolic processes. Overall, our study provides comprehensive insights into the toxicological impact of Cd on P. canaliculata and emphasizes the importance of understanding the mechanisms underlying Cd toxicity in aquatic organisms. Full article

Hepatic fibrosis (HF) is an important pathological state in the progression of chronic liver disease to end-stage liver disease and is usually triggered by alcohol, nonalcoholic fatty liver, chronic hepatitis viruses, autoimmune hepatitis (AIH), or cholestatic liver disease. Research on novel therapies has become a hot topic due to the reversibility of HF. Research into the molecular mechanisms of the pathology of HF and potential drug screening relies on reliable and rational biological models, mainly including animals and cells. Hence, a number of modeling approaches have been attempted based on human dietary, pathological, and physiological factors in the development of HF. In this review, classical and novel methods of modeling HF in the last 10 years were collected from electronic databases, including Web of Science, PubMed, ScienceDirect, ResearchGate, Baidu Scholar, and CNKI. Animal models of HF are usually induced by chemical toxicants, special diets, pathogenic microorganisms, surgical operations, and gene editing. The advantages and limitations of hepatic stellate cells (HSCs), organoids, and 3D coculture-based HF modeling methods established in vitro were also proposed and summarized. This information provides a scientific basis for the discovery of the pathological mechanism and treatment of HF. Full article

Hazardous heavy metals, particularly cadmium (Cd), are widely distributed in the environment and cause oxidative stress in various animal and human organs. Clove oil (CLO), a common aromatic spice, has been used as a traditional medication as it has potent anti-inflammatory, antioxidant, and hepatoprotective properties. Background/Objectives: This study aimed to investigate the antioxidant, antiapoptotic, and anti-inflammatory effects of clove oil (CLO) against hepatorenal toxicity induced by cadmium (Cd). Methods: Twenty rats were equally divided into four groups: a control group, a Cd group treated with 15 mg/kg b.wt CdCl₂, a CLO group administered 200 mg/kg b.wt CLO, and a Cd+CLO group. All groups were orally treated for 4 weeks. Results: Cadmium (Cd) exposure caused anemia and hepatorenal damage, as evidenced by increased serum levels of urea, creatinine, uric acid, total bilirubin (including its direct and indirect fractions), and elevated activities of liver enzymes such as alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP). However, total protein and albumin levels decreased. Furthermore, there was a decrease in the levels of glutathione, glutathione transferase, and catalase in the liver antioxidant profiles. Meanwhile, malondialdehyde levels increased. Cadmium toxicity caused elevated expression of liver apoptosis markers, such as tumor necrosis factor-alpha (TNF-α) and caspase-3, and inflammation. CLO ameliorated the oxidative effects of Cd through decreasing urea (27.4%), creatinine (41.6%), liver enzymes, and hepatic apoptotic markers while increasing levels of total protein, albumin, and hepatic values of SOD (60.37%), CAT (64.49%), GSH (50.41%), and GST (9.16%). Conclusions: Hematological and biochemical parameters, as well as the antioxidant system, improved following clove oil treatment, leading to a reduction in hepatorenal damage. Therefore, it is possible to conclude that CLO protects rats from inflammation, apoptosis, and hepatorenal oxidative damage caused by Cd poisoning. Comprehensive translational research is required to validate CLO’s efficacy and safety of use in humans. Future studies should focus on elucidating the precise molecular mechanisms, optimal dosing strategies, and potential synergistic effects of CLO with other therapeutic agents. Full article

A considerable quantity of microplastic debris exists in the environment and the toxicity of these materials has a notable impact on aquatic ecosystems. In this paper, 50–500 µm polystyrene microplastics (exposure concentrations were 200 µg/L, 800 µg/L, and 3200 µg/L concentrations) were selected to study the effects of polystyrene microplastics (PS-MPs) on cell morphology, detoxification enzyme activity, and mRNA expression in the liver tissues of crucian carp juveniles. The results demonstrated that: (1) Different concentrations of PS-MPs cause varying degrees of pathological and oxidative damage to liver tissue cells of crucian carp. The higher the concentration of microplastics, the lower the antioxidant enzyme (CAT, GST, SOD) activity and the greater the tissue cell damage. These results demonstrate a typical dose–effect relationship. (2) Principal component analysis and Spearman’s correlation analysis demonstrated that four components, namely glutathione S-transferase (GST) and its related genes (GSTpi, GSTα), along with catalase (CAT), contributed the most to the observed outcome. These four components demonstrated a relatively high level of responsiveness to PS-MP exposure and can be employed as ecotoxicological indicators of microplastics. (3) This experiment evaluated five genes in three treatments, which found that PS-MPs had different effects on gene expression in the liver and the tested genes were involved in different response pathways associated with virulence. In this study, the toxicity of PS-MPs to crucian carp was determined at the cellular, protein, and mRNA expression levels, and combined with principal component analysis and correlation analysis to identify response sensitivity indicators that provide a scientific basis for ecological risk assessment and the safe use of microplastics. Full article

Background/Objectives: Hyperlipidemia is a serious risk factor for cardiovascular diseases and liver steatosis. In this work, we explored the effect of an herbal formula (CBF) containing immature Ceratonia siliqua pods and Ocimum basilicum extracts on lipid metabolism disorders and lipoprotein-rich plasma (LRP) oxidation in mice. Methods: The phenolic composition was determined using HPLC-DAD analysis. The antioxidant activity was studied using various in vitro methods. Acute toxicity was evaluated in mice. Importantly, the effect of the CBF on lipid metabolism disorders was investigated in a high-fat diet (HFD) hyperlipidemia mouse model. An in silico study was carried out to predict underlying mechanisms. Results: The HPLC analysis revealed gallic acid, cinnamic acid, and naringenin as major phenolics of the carob pod aqueous extract. Concerning the basil hydro-ethanolic extract, rosmarinic, chicoric, caftaric, and caffeic acids were the main phenolics. Accordingly, the CBF prevented LRP oxidation in a concentration-dependent manner. This formula is not toxic in mice (LD₅₀ > 2000 mg/kg body weight). Moreover, animals administered the CBF at 200 mg/kg/day presented a significant decline in their body weight gain, adipose tissue weight, plasma total cholesterol, low-density lipoprotein cholesterol (LDL-C) level, and glycaemia after 10 weeks’ treatment. Accordingly, the CBF decreased the plasma atherogenic index and the LDL-C to HDL-C ratio and reduced the level of fats accumulated in the liver. The molecular docking study revealed that chicoric, rosmarinic, and caftaric acids, and naringenin bound particularly strongly to many proteins involved in the regulation of lipid and cholesterol metabolism. This includes the HMG-CoA reductase, PPARα/γ, PCSK9, Cyp7a1, and ATP-citrate lyase. Conclusions: The CBF could be a good source of natural supplements, functional foods, and pharmaceuticals effective in managing hyperlipidemia and oxidative stress and preventing their related cardiovascular disorders. Full article

It has been known since the early days of the discovery of aflatoxin B1 (AFB1) that there were large species differences in susceptibility to AFB1. It was also evident early on that AFB1 itself was not toxic but required bioactivation to a reactive form. Over the past 60 years there have been thousands of studies to delineate the role of ~10 specific biotransformation pathways of AFB1, both phase I (oxidation, reduction) and phase II (hydrolysis, conjugation, secondary oxidations, and reductions of phase I metabolites). This review provides a historical context and substantive analysis of each of these pathways as contributors to species differences in AFB1 hepatoxicity and carcinogenicity. Since the discovery of AFB1 as the toxic contaminant in groundnut meal that led to Turkey X diseases in 1960, there have been over 15,000 publications related to aflatoxins, of which nearly 8000 have addressed the significance of biotransformation (metabolism, in the older literature) of AFB1. While it is impossible to give justice to all of these studies, this review provides a historical perspective on the major discoveries related to species differences in the biotransformation of AFB1 and sets the stage for discussion of other papers in this Special Issue of the important role that AFB1 metabolites have played as biomarkers of exposure and effect in thousands of human studies on the toxic effects of aflatoxins. Dr. John Groopman has played a leading role in every step of the way—from initial laboratory studies on specific AFB1 metabolites to the application of molecular biomarkers in epidemiological studies associating dietary AFB1 exposure with liver cancer, and the design and conduct of chemoprevention clinical trials to reduce cancer risk from unavoidable aflatoxin exposures by alteration of specific AFB1 biotransformation pathways. This article is written in honor of Dr. Groopman’s many contributions in this area. Full article

Background: The emergence of multidrug-resistant hypervirulent Klebsiella pneumoniae (hvKp) has made it difficult to treat and control infections caused by this bacterium. Previously, the therapeutic effectiveness of phage-encoded depolymerase Dep_kpv74 in a mouse model of K. pneumoniae-induced thigh soft tissue infection was reported. In this study, the effect of Dep_kpv74 on blood parameters in mice, the proliferation and subpopulation composition of spleen lymphocytes, and the activity and stability of the enzyme at different pH and temperatures were further explored. Results: The stability tests showed that Dep_kpv74 remained active in the temperature range from 8 °C to 55 °C. The optimal pH value for maintaining the activity of Dep_kpv74 ranged from 5.0 to 9.0. The depolymerase was detected in the blood, spleen, and lungs of mice 10 min after intraperitoneal administration, reaching maximum activity values after 1–3 h and maintaining activity a day after administration. The introduction of Dep_kpv74 at the therapeutic dose (10 μg/mouse) or at a 10-fold higher dose did not lead to reliable changes in bloodstream cell content compared with the reference values of intact mice. The biochemical results of the studies indicated that Dep_kpv74 did not exert any toxic effects on liver and kidney functions. The results of the analysis of lymphocyte proliferative activity demonstrated that Dep_kpv74 depolymerase has a mild immunomodulatory effect. Conclusions: Thus, the results of this study provide one more confirmation that depolymerase Dep_kpv74 is a potential candidate for the treatment of infections caused by hvKp expressing K2 capsular polysaccharides. Full article

Microplastics, defined as plastic fragments smaller than 5 mm, degrade from larger pollutants, with nanoscale microplastic particles presenting significant biological interactions. This study investigates the toxic effects of polystyrene nanoplastics (PS-NPs) on juvenile mice, which were exposed through lactation milk and drinking water at concentrations of 0.01 mg/mL, 0.1 mg/mL, and 1 mg/mL. The results show that PS-NP exposure during lactation and juvenile periods caused delayed weight gain and impaired organ development, particularly in the liver and kidneys, without causing functional abnormalities or toxic injuries. The primary toxicity of PS-NPs was observed in the intestinal tract, including shortened villi, disrupted tight junctions, inhibited epithelial cell proliferation, and oxidative stress responses. These findings highlight the importance of evaluating the developmental toxicity of nanoplastics at environmentally relevant doses. Full article

Background/Objectives: New drugs are required for the treatment of liver cancers and protozoal parasite infections. Analogs of the known anticancer active and antileishmanial 2′,4′,6′-trimethoxychalcone SU086 were prepared and investigated. Methods: The chalcones were prepared according to the Claisen–Schmidt condensation protocol and analyzed. They were tested for activity against two liver cancer cell lines (HepG2 and HuH-7) and protozoal parasites (Toxoplasma gondii and Leishmania major). Unspecific toxicity and expression of Hsp90 and Hsp70 upon treatment were analyzed in liver cancer cells. Results: A new chalcone, 2′,4′,6′-trimethoxy-3-pentafluorosulfanylchalcone (246TMP-3SF5), with a pentafluorosulfanyl (SF₅) substituent showed pronounced activities against liver cancer cells and T. gondii parasites which were superior to the activities of the parent chalcone SU086 in these models. In contrast, SU086 and its anthracene analog 2′,4′,6′-trimethoxy-9-anthracenylchalcone (246TMP-Anth) were most active against L. major promastigotes. The new SF₅-substituted chalcone behaved like the known Hsp90 inhibitor 17-AAG and upregulated Hsp70 expression in liver cancer cells. Conclusions: The SF₅-substituted SU086 analog has potential to become a new drug for the therapy of hepatoma and toxoplasmosis. Full article

Phthalates are the emerging environmental toxicants derived from phthalic acid and its constituents, which are moderately present in plastics and many personal care products. Phthalate exposure occurs through various environmental factors, including air, water, and soil, with absorption facilitated via ingestion, inhalation, and dermal contact. Upon exposure, phthalates become bioavailable within the biological systems and undergo biotransformation and detoxification processes in the liver. The physicochemical properties of phthalates indicate their lipophilicity, environmental persistence, and bioaccumulation potential, influencing their absorption, distribution, and hepatic biotransformation. The prolonged exposure to phthalates adversely influences the biological redox system by altering the levels of the enzymatic and non-enzymatic antioxidants, molecular signaling pathways, and causing hepatic pathogenesis. The strategies to combat phthalate-induced toxicity include avoiding exposure to these compounds and using plant-based bioactive molecules such as polyphenols, which possess therapeutic potential as antioxidants, suppress inflammatory cascades, prevent oxidative damage, and stabilize cellular integrity. This review presents a comprehensive and updated account of the chemical, biochemical, immunological, and toxicological properties of phthalates, along with novel plant-based therapeutic strategies to mitigate the phthalate-induced adverse effects on living systems. Full article

Giant unilamellar vesicles (GUVs) are versatile cell models in biomedical and environmental research. Of the various GUV production methods, hydrogel-assisted GUV production is most easily implemented in a typical biological laboratory. To date, agarose, polyvinyl alcohol, cross-linked dextran-PEG, polyacrylamide, and starch hydrogels have been used to produce GUVs. Some leach and contaminate the GUVs, while others require handling toxic material or specialised chemistry, thus limiting their use by novices. Alternative hydrogel materials could address these issues or even offer novel advantages. To facilitate discovery, we replaced the manual spreading of reagents with controlled drop-casting in glass Petri dishes and polystyrene multi-well plates, allowing us to rapidly screen up to 96 GUV-production formulations simultaneously. Exploiting this, we rapidly evaluated assorted biomedical hydrogels, including PEG-DA, cross-linked hyaluronic acid, Matrigel, and cross-linked DNA. All of these alternatives successfully produced GUVs. In the process, we also developed a treatment for recycling agarose and polyvinyl alcohol hydrogels for GUV production, and successfully encapsulated porcine liver esterase (PLE-GUVs). PLE-GUVs offer a novel method of GUV labelling and tracing, which emulates the calcein-AM staining behaviour of cells. Our results highlight the utility of our protocol for potentiating substrate material discovery, as well as protocol and product development. Full article

The monitoring of heavy metals in aquatic ecosystems is of critical importance due to the toxic effects that these elements can have on wildlife and the potential risks that they pose to human health. Rivers situated in close proximity to agricultural regions are particularly susceptible to contamination from a combination of natural and anthropogenic sources. The study of bioaccumulation is of great importance for the early detection of environmental stressors. The combination of electrochemical techniques, such as square-wave anodic stripping voltammetry (SWASV), with automated flow-batch systems represents an efficient and cost-effective approach for the detection of trace metals in environmental samples. This study examines the bioaccumulation of cadmium and lead in Cyprinus carpio, a bioindicator of contamination in the Colorado River, Argentina. The fish were exposed to sublethal metal concentrations for 24, 48, and 96 h. Metal quantification was conducted using a novel automatic flow-batch system with SWASV and a bismuth film electrode. To the best of our knowledge, this constitutes the first application of this methodology on aquatic bioindicators for the assessment of metal accumulation in a natural environment. The technique demonstrated enhanced sensitivity and selectivity for the detection of trace metals. The bioaccumulation results demonstrated an increase in cadmium and lead concentrations in fish liver tissue after 96 h, reaching 10.5 µg g⁻¹ and 11.9 µg g⁻¹, respectively. Validation with inductively coupled plasma–atomic emission spectrometry (ICP-AES) demonstrated a satisfactory correlation, confirming the reliability of the method. This novel electrochemical approach offers enhanced accuracy and efficiency, making it a promising tool for environmental monitoring. The results indicate that Colorado River water is within safe levels for aquatic life regarding these metals. However, continuous monitoring is recommended to detect changes in contamination levels and protect ecosystem health, especially during water crises and under climate change. Full article

Background/Objectives: Metastatic colorectal cancer (mCRC) is mainly treated with 5-Fluoro-Uracil (5-FU), Oxaliplatin and Irinotecan chemotherapies and anti-Epidermal Growth Factor Receptor (EGFR) or anti-Vascular Endothelial Growth Factor (VEGF) targeted therapies. Due to chemotherapy-related toxicity, patients receive induction treatment to achieve tumour response followed by maintenance therapy with less cytotoxic molecules or a chemotherapy-free interval to reduce chemotherapy-related toxicity. In this study, the aim was to determine the patient, cancer and treatment factors that influence the duration of maintenance therapy (DMT). Methods: We collected retrospective data on a cohort of 133 patients treated at the Centre Georges François Leclerc (CGFL) cancer centre in Dijon between March 2014 and June 2022. Patients had unresectable or potentially resectable diseases. They received first-line induction treatment with chemotherapy and/or targeted therapy and maintenance treatment, defined as the interruption of at least one chemotherapy agent. Results: In the multivariate analysis, age (HR: 1.02, 95% CI 1.00–1.04, p = 0.031), N2 nodal status (HR: 1.78, 95% CI 1.09–2.89, p = 0.021) and the presence of peritoneal metastases (HR: 2.05, 95% CI 1.25–3.36, p = 0.004), as well as baseline carcino-embryonic antigen (CEA) level (HR: 1.10, 95% CI 1.00–1.20, p = 0.052), were significantly associated to poor DMT. Local treatment of liver metastases also significantly reduced the DMT (HR: 0.49, 95% CI 0.28–0.86, p = 0.013). In our cohort, induction triplet chemotherapy significantly increased the CEA delta (70% vs. 44%, p = 0.047) compared to doublet chemotherapy and led to a higher rate of liver surgery (40% vs. 21%, p = 0.014) and a trend for a higher rate of local treatment of metastases (62% vs. 45%, p = 0.059). Conclusions: Duration of maintenance therapy is determined by the initial patient and colorectal cancer characteristics. However, it is significantly increased by local treatment of liver metastases. By reducing the tumour burden, a triplet induction chemotherapy regimen increases the rate of liver metastase resection. Full article