Toxic Effects In Liver Research Articles

Abstract 735: Mitigation of liver toxicity effects of bispecific T cell engagers in immune-competent liver-tumor co-culturing high-throughput platform

Abstract The remarkable clinical therapeutic effects and wide-ranging applications of bispecific T cell engagers (BiTEs) have revolutionized the treatment approaches in the field of oncology. While the advantages of these innovative immunotherapies are undeniable, it is imperative to thoroughly investigate their safety aspects. With increasing use of biologics for treatment of various cancers, the incidence of immune-related adverse events (irAEs) will undoubtedly increase. Therefore, there is a compelling need to develop measures to effectively prevent or manage irARs already on the stage of the development of new clinical candidates. To address this need, we have created a high-throughput, automation friendly, 384-well-format platform in which 3D spheroid models are co-cultured in units interconnected by microfluidic channel. The tissue-tissue interaction was facilitated by a gravity-driven, tubeless flow system. The design allows for the simultaneous evaluation of the anti-tumor efficacy and liver safety of immunotherapeutics. In our system, we employed 3D spheroids comprised of primary human hepatocytes and Kupffer cells to model the liver, ensuring the preservation of their metabolic and inflammatory functions. Additionally, we established a solid tumor model using human cancer cell lines (HCT116-GFP) and primary cancer-associated fibroblasts, effectively mimicking the complex tumor microenvironment We treated 3D spheroid models with runimotamab (HER2xCD3 BiTE), catumaxomab (EPCAMxCD3), nivatrotamab (GD2xCD3) and control bispecific antibodies in the presence of peripheral blood mononuclear cells (PBMCs). Tumor viability and growth was assessed by fluorescence measurements, while liver toxicity and function were monitored by release of liver aminotransferases ALT and microscopy. To mitigate potential liver toxicity, we co-treated spheroid co-cultures with adalimumab (anti-TNF), tocilizumab (anti-IL-6R), raleukin (IL-1R antagonist) (each 100ug/ml), desatanib, dexamethasone or ruxolitinib (each 100nM). The treatment with all bispecific antibodies resulted in a significant decrease of fluorescence and size of tumor spheroids in comparison to control antibody. At the same time increased ALT concentrations were observed after the treatment with BiTEs. The application of small molecular drugs protected against liver damage, but also severely disrupted tumor killing. Interestingly, adalimumab revealed liver protective actions without affecting tumor killing, suggesting TNF-mediated mechanism of toxicity. In summary, we have developed a relevant, high-throughput platform for the evaluation of novel immunotherapies closely reflecting clinical scenarios. High throughput of the assay represents a powerful screening tool for clinical candidate development. Citation Format: Michal Rudnik, Lisa Hölting, Tamara Häfeli, Özlem Yavaş Grining, Frauke Greve, Daniela Ortiz Franyuti, Ramona Matheis, Laure-Anne Ligeon, Ekaterina Breous-Nystrom, Olivier Frey. Mitigation of liver toxicity effects of bispecific T cell engagers in immune-competent liver-tumor co-culturing high-throughput platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 735.

Targeted Therapy of Acute Liver Injury via Cryptotanshinone-Loaded Biomimetic Nanoparticles Derived from Mesenchymal Stromal Cells Driven by Homing.

Acute liver injury (ALI) has the potential to compromise hepatic function rapidly, with severe cases posing a considerable threat to human health and wellbeing. Conventional treatments, such as the oral administration of antioxidants, can inadvertently lead to liver toxicity and other unwanted side effects. Mesenchymal stromal cells (MSCs) can target therapeutic agents directly to inflammatory sites owing to their homing effect, and they offer a promising avenue for the treatment of ALI. However, the efficacy and feasibility of these live cell products are hampered by challenges associated with delivery pathways and safety concerns. Therefore, in this work, MSC membranes were ingeniously harnessed as protective shells to encapsulate synthesized PLGA nanoparticle cores (PLGA/MSCs). This strategic approach enabled nanoparticles to simulate endogenous substances and yielded a core-shell nano-biomimetic structure. The biomimetic nanocarrier remarkably maintained the homing ability of MSCs to inflammatory sites. In this study, cryptotanshinone (CPT)-loaded PLGA/MSCs (CPT@PLGA/MSC) were prepared. These nanoparticles can be effectively internalized by LO2 cells. They reduced cellular oxidative stress and elevated inflammatory levels. In vivo results suggested that, after intravenous administration, CPT@PLGA/MSCs significantly reduced uptake by the reticuloendothelial system and immune recognition compared to PLGA nanoparticles without MSC membrane coatings, subsequently resulting in their targeted and enhanced accumulation in the liver. The effectiveness of CPT@PLGA/MSCs in alleviating carbon tetrachloride-induced oxidative stress and inflammation in a mouse model was unequivocally demonstrated through comprehensive histological examination and liver function tests. This study introduces a pioneering strategy with substantial potential for ALI treatment.

Association of Age With Treatment-Related Adverse Events and Survival in Patients With Metastatic Colorectal Cancer

While the incidence of early-onset metastatic colorectal cancer (mCRC) has been increasing, studies on the age-related disparity in this group of patients are limited. To evaluate the association of age with treatment-related adverse events and survival in patients with mCRC and explore the potential underlying factors. This cohort study included 1959 individuals. Individual data on 1223 patients with mCRC who received first-line fluorouracil and oxaliplatin therapy in 3 clinical trials, and clinical and genomic data of 736 patients with mCRC from Moffitt Cancer Center were used to assess genomic alterations and serve as an external validation cohort. All statistical analyses were conducted from October 1, 2021, through November 12, 2022. Metastatic colorectal cancer. Survival outcomes and treatment-related adverse events were compared among patients in 3 age groups: younger than 50 (early onset), 50 to 65, and older than 65 years. In the total population of 1959 individuals, 1145 (58.4%) were men. Among 1223 patients from previous clinical trials, 179 (14.6%) in the younger than 50 years group, 582 (47.6%) in the 50 to 65 years group, and 462 (37.8%) in the older than 65 years group had similar baseline characteristics except for sex and race. The younger than 50 years group had significantly shorter progression-free survival (PFS) (hazard ratio [HR], 1.46; 95% CI, 1.22-1.76; P < .001) and overall survival (OS) (HR, 1.48; 95% CI, 1.19-1.84; P < .001) compared with the 50 to 65 years group after adjustment for sex, race, and performance status. Significantly shorter OS in the younger than 50 years group was confirmed in the Moffitt cohort. The younger than 50 years group had a significantly higher incidence of nausea and vomiting (69.3% vs 57.6% [50-65 years] vs 60.4% [>65 years]; P = .02), severe abdominal pain (8.4% vs 3.4% vs 3.5%; P = .02), severe anemia (6.1% vs 1.0% vs 1.5%; P < .001), and severe rash (2.8% vs 1.2% vs 0.4% P = .047). The younger than 50 years group also had earlier onset of nausea and vomiting (1.0 vs 2.1 vs 2.6 weeks; P = .01), mucositis (3.6 vs 5.1 vs 5.7 weeks; P = .05), and neutropenia (8.0 vs 9.4 vs 8.4 weeks; P = .04), and shorter duration of mucositis (0.6 vs 0.9 vs 1.0 weeks; P = .006). In the younger than 50 years group, severe abdominal pain and severe liver toxic effects were associated with shorter survival. The Moffitt genomic data showed that the younger than 50 years group had a higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%; P = .047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%; P = .005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%; P = .05), but lower prevalence of BRAF mutation (7.7% vs 8.5% vs 16.7%; P = .002). In this cohort study of 1959 patients, those with early-onset mCRC showed worse survival outcomes and unique adverse event patterns, which could be partially attributed to distinct genomic profiles. These findings may inform individualized management approaches in patients with early-onset mCRC.

Phosphorothioated amino-AS1411 aptamer functionalized stealth nanoliposome accelerates bio-therapeutic threshold of apigenin in neoplastic rat liver: a mechanistic approach

Hepatocellular carcinoma (HCC) is a leading cause of death globally. Even though the progressive invention of some very potent therapeutics has been seen, the success is limited due to the chemotherapeutic resistance and recurrence in HCC. Advanced targeted treatment options like immunotherapy, molecular therapy or surface-engineered nanotherapeutics could offer the benefits here owing to drug resistance over tumor heterogenicity. We have developed tumor-sensing phosphorothioate and amino-modified aptamer (AS1411)-conjugated stealth nanoliposomes, encapsulating with apigenin for precise and significant biodistribution of apigenin into the target tumor to exploit maximum bio-therapeutic assistances. The stable aptamer functionalized PEGylated nanoliposomes (Apt-NLCs) had an average vesicle size of 100–150 nm, a smooth surface, and an intact lamellarity, as ensured by DLS, FESEM, AFM, and Cryo-TEM. This study has specified in vitro process of optimum drug (apigenin) extrusion into the cancer cells by nucleolin receptor-mediated cellular internalization when delivered through modified AS1411 functionalized PEGylated nanoliposomes and ensured irreversible DNA damage in HCC. Significant improvement in cancer cell apoptosis in animal models, due to reduced clearance and higher intratumor drug accumulation along with almost nominal toxic effect in liver, strongly supports the therapeutic potential of aptamer-conjugated PEGylated nanoliposomes compared to the nonconjugated formulations in HCC. The study has established a robust superiority of modified AS1411 functionalized PEGylated nanoliposomes as an alternative drug delivery approach with momentous reduction of HCC tumor incidences.Graphical

HPB P24 Comparison of outcomes of Deb-TACE in patients with HCC larger than 5cm compared with HCC less than 5cm

Abstract Background Transarterial chemoembolization (TACE) improves survival in cirrhotic patients with intermediate-stage hepatocellular carcinoma (HCC). Drug-eluting bead (Deb)-TACE is associated with a reduction in liver toxicity and drug-related adverse effects compared with chemotherapy-TACE. This retrospective paired cohort study compares the outcomes of DEB-TACE in patients with HCC greater than and less than 5 centimeters. Methods Sixty-nine patients had Deb-TACE as the primary treatment for HCC over a 3-year period from May 2019 -to May 2022. Patients were paired into two unmatched groups according to tumour size. Group A; tumour size &amp;gt; 5cm and group B tumour size &amp;lt; 5cm. Each group was then compared following a single or repeated treatment of Deb-TACE. Tumour response was evaluated using the standardised modified Response Evaluation Criteria in Solid Tumours (mRECIST) to detect evidence of tumour size regression. Patients were classified as having either a complete response (CR), partial response (PR), stable disease (SD),or progressive disease (PD). Also, any adverse outcomes including hepatic decompensation were recorded Results Group A,(34.48%) 10 patients had a single session of Deb-TACE. Post-treatment surveillance showed that 4 patients (44.44%) showed CR, PR in 2 patients (22.22%), SD in 1 patient (11.11%), 2 patients (22.22%) had PD, one patient was still waiting for his follow-up surveillance. On the other hand,(65.52%)19 patients had repeated sessions, CR was evident in 2 patients (10.5%), PR in 1 patient (5.2%), SD in 3 patients (15.7%), PD in 2 patients (10.5%), 7 patients (36.84%) had initial PR followed by CR, 2 patients (10.5%) showed initial SD then PD and finally 2 patients (10.5%) were PR and became PD. Group B, 18 (45%) patients had single Deb-TACE, Patients showing CR were 7(58.3%), PR was detected in 2 patients (16.67%), one patient (8.33%) had SD, 2 patients (16.67%%) showed PD, and 6 patients were still waiting for their surveillance, no response recorded for them. (55%) 22 patients had repeated Deb-TACE sessions. 3 patients(13.6%) showed CR, PR were 4 patients (18.18%), one patient (4.5%) had SD, PD were 6 patients (27.27%). However, 3 patients (13.6%) were PR then showed CR,3 patients (13.6%) were PR became PD and finally 2 patients (9%) were PD became CR. Conclusions DEB-TACE is effective for HCCs &amp;gt; 5cm with a response rate of 66.67% in patients who had a Single DEB-TACE dose as their first treatment and it increased to 79% in patients who had repeated deb-TACE; however, that was not statistically significantly different (P = 0.48). The Patients group who had HCC &amp;lt;5 cm showed responses up to 83% with single-dose compared to 59% for repeated DEB-TACE, this was not statistically significant with (P = 0.25) . There was no difference in complications between the two groups.

Trimethyltin induces apoptosis and necroptosis of mouse liver by oxidative stress through YAP phosphorylation

Trimethyltin (TMT) is widely used as a major component of plastic stabilizers in agriculture and industry, and can accumulate in large quantities in the liver. To investigate the relationship between liver tissue damage induced by TMT exposure and YAP phosphorylation in mice, we gave the mice drinking water containing 0.01 mg/mL TMT for 14 days to establish an in vivo experimental model, and continuously treated AML12 cells with 20 μM TMT for 24 h to establish an in vitro experimental model. Transcriptomics revealed that TMT exposure altered 62,466 apparently diversely expressed genes, including 1197 upregulated and 899 downregulated genes, and that enrichment of the Hippo pathway occurred. Moreover, western blotting (WB) and quantitative real-time PCR (qRTPCR) results showed that TMT exposure triggered an increase in the expression of P-YAP, apoptosis and necroptosis-interrelated genes, and a decrease in Bcl-2 expression in mouse livers tissues and AML12 cells. The expression of P-YAP was significantly suppressed in the TRULI-treated TMT-exposed AML12 cells, while oxidative stress levels and damage were also significantly attenuated. In conclusion, TMT triggers YAP phosphorylation to induce oxidative stress inducing apoptosis and necroptosis in mouse livers tissues. Our results confirm the liver toxic effect and specific mechanism of TMT.

Toxicity Profiles of Systemic Therapies for Advanced Hepatocellular Carcinoma

The recent development of targeted therapy and immunotherapy has made neoadjuvant therapy an attractive option for patients with hepatocellular carcinoma (HCC). However, surgeons are concerned that adverse effects of neoadjuvant therapy with these agents could lead to delayed or even cancelled surgeries. To summarize the current evidence regarding toxicity profiles for tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) among patients with HCC. Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from January 1990 and December 2021. Single-group, placebo-controlled, and dual-agent clinical trials comparing TKIs and ICIs in patients with HCC were eligible for inclusion. Following the Preferred Reporting Items in Systematic Reviews and Meta-analysis guideline, 2 reviewers independently extracted data. A random-effects model was used. The primary outcome was the proportion of patients with clinically significant liver-related adverse events. Secondary outcomes included the proportion of patients who experienced clinically relevant (grade 3 or higher) adverse events and significant adverse events (ie, those that were life threatening, required hospitalization, or prolonged disability) as well as the risk ratio (RR) of these complications. Overall, 30 studies with 12 921 patients were included. Patients had a mean (range) age of 62 (18-89) years; a mean (SD) 84% (3) were male; a mean (SD) 82% (16) had Barcelona Clinic Liver Cancer stage C HCC; and a mean (SD) 97% (6) had Childs A cirrhosis. Overall, 21% (95% CI, 16%-26%) of patients receiving TKIs had liver toxic effects compared with 28% (95% CI, 21%-35%) of patients receiving ICIs. Severe adverse events occurred in 46% (95% CI, 40%-51%) of patients receiving TKIs compared with 24% (95% CI, 13%-35%) of patients receiving ICIs. Compared with patients receiving sorafenib, other TKIs were associated with similar rates of liver toxic effects (RR, 1.06; 95% CI, 0.92-1.24) but higher rates of severe adverse events (RR, 1.24; 95% CI, 1.07-1.44). Comparing ICIs with sorafenib, there were similar rates of liver toxic effects (RR, 1.10; 95% CI, 0.86-1.40) and severe adverse events (RR, 1.19; 95% CI, 0.95-1.50). In this systematic review and meta-analysis, serious adverse events were lower with ICIs than with TKIs, while liver toxic effects were similar. Combination therapy with novel ICIs is an appealing option in trials of neoadjuvant therapy for patients with HCC, requiring evaluation in preoperative trials.

Targeted Lipidomics Reveal the Effect of Perchlorate on Lipid Profiles in Liver of High-Fat Diet Mice.

Perchlorate, commonly available in drinking water and food, acts on the iodine uptake by the thyroid affecting lipid metabolism. High-fat diets leading to various health problems continually raise public concern. In the present study, liver lipid metabolism profiles and metabolic pathways were investigated in C57BL/6J mice chronically exposed to perchlorate using targeted metabolomics. Mice were fed a high-fat diet and treated orally with perchlorate at 0.1 mg/kg bw (body weight), 1 mg/kg bw and 10 mg/kg bw daily for 12 weeks. Perchlorate induced disorders of lipid metabolism in vivo and hepatic lipid accumulation confirmed by serum biochemical parameters and histopathological examination. There were 34 kinds of lipid in liver detected by UHPLC-MS/MS and key metabolites were identified by multivariate statistical analysis evaluated with VIP > 1, p-value < 0.05, fold change > 1.2 or < 0.8. Perchlorate low, medium and high dose groups were identified with 11, 7 and 8 significantly altered lipid metabolites compared to the control group, respectively. The results of the metabolic pathway analysis revealed that the differential metabolites classified into different experimental groups contribute to the glycerophospholipid metabolic pathway. These findings provide insights into the effects of perchlorate on lipid metabolism during long-term exposure to high-fat diets and contribute to the evaluation of perchlorate liver toxic mechanisms and health effects.

Possible effects of some anaesthetic agents in rat hepatotoxicity: Histological and biochemical study

Selectively steroidal neuromuscular blocking agents, such as rocuronium, are required to maintain surgical procedures. It is a sugammadex γ-cyclodextrin-derived drug that encapsulates these drugs and reverses its effects. In the present study, it was aimed to investigate the effects of sugammadex rocuronium complex on liver and possible toxic effects on hepatocytes using histopathological and biochemical methods. In the current study, 32 adult Sprague - Dawley male rats were used. Four groups were designed as pure control, control group, sugammadex and sugammadex-rocunorium. Following the experimental procedures, liver tissues extracted from rats were stained after routine histological procedures. The images were taken from the sections for histopathological evaluation. For biochemical analysis, glutathione (GSH) and malondialdehyde (MDA) enzymes were analyzed in the liver tissues. In the group treated with the sugammadex-rocunorium complex, caspase-3 expressions were observed to be higher than in other groups. In addition, while the amount of GSH belonging to sugammadex and sugammadex-rocunorium groups decreased compared to the control group, an increase in MDA amount was found. Sugammadex-rocunorium can lead to oxidative stress in the hepatocytes. However, more studies are needed to reveal the toxic effects of sugammadex and sugammadex and rocunorium complex in the liver.

Co-administration of CSL112 (apolipoprotein A-I [human]) with atorvastatin and alirocumab is not associated with increased hepatotoxic or toxicokinetic effects in rats

CSL112 (apolipoprotein A-I, apo AI [human]) is an investigational drug in Phase 3 development for risk reduction of early recurrent cardiovascular events following an acute myocardial infarction (AMI). Although CSL112 is known to be well tolerated with a regimen of four weekly 6 g intravenous infusions after AMI, high doses of reconstituted apo AI preparations can transiently elevate liver enzymes in rats, raising the possibility of additive liver toxicity and toxicokinetic (TK) effects upon co-administration with cholesterol-lowering drugs, i.e., HMG-CoA reductase and proprotein convertase subtilisin/kexin type 9 inhibitors. We performed a toxicity and TK study in CD rats assigned to eleven treatment groups, including two dose levels of intravenous (IV) CSL112 (140 mg/kg, low-dose; 600 mg/kg, high-dose) administered as a single dose, alone or with intravenous alirocumab 50 mg/kg/week and/or oral atorvastatin 10 mg/kg/day. In addition, control groups of atorvastatin and alirocumab alone and in combination were investigated. Results showed some liver enzyme elevations (remaining <2-fold of baseline) related to administration of CSL112 alone. There was limited evidence of an additive effect of CSL112 on liver enzymes when combined, at either dose level, with alirocumab and/or atorvastatin, and histology revealed no evidence of an increased incidence or severity of hepatocyte vacuolation compared to the control treatments. Co-administration of the study drugs had minimal effect on their respective exposure levels, and on levels of total cholesterol and high-density lipoprotein cholesterol. These data support concomitant use of CSL112 with alirocumab and/or atorvastatin with no anticipated negative impact on liver safety and TK.

Laboratory, Clinical, and Survival Outcomes Associated With Peptide Receptor Radionuclide Therapy in Patients With Gastroenteropancreatic Neuroendocrine Tumors

Peptide receptor radionuclide therapy (PRRT) is approved in the US for treatment of gastroenteropancreatic neuroendocrine tumors (NETs), but data on PRRT outcomes within US populations remain scarce. To analyze the first 2 years of PRRT implementation at a US-based NET referral center. This cohort study was conducted using medical records of patients with metastatic NET receiving PRRT from 2018 through 2020 in a NET program at a tertiary referral center. Included patients were those at the center with metastatic NETs who received at least 1 dose of PRRT over the study period. Laboratory toxic effects were assessed using Common Terminology Criteria for Adverse Events version 5.0. Tumor response was determined using Response Evaluation Criteria in Solid Tumors 1.1. Survival analysis was conducted to identify factors associated with progression-free survival (PFS) and overall survival. Data were analyzed from August 2018 through August 2020. Receiving 4 cycles of lutetium-177-dotatate infusion, separated by 8-week intervals targeted to 7.4 GBq (200 mCi) per dose. Data were compared from before and after PRRT to determine hematologic, liver, and kidney toxic effects and to assess tumor progression and patient survival. Among 78 patients receiving at least 1 dose of PRRT, median (interquartile range) age at PRRT initiation was 59.8 (53.5-69.2) years and 39 (50.0%) were men. The most common primary NET sites included small bowel, occurring in 34 patients (43.6%), and pancreas, occurring in 22 patients (28.2%). World Health Organization grade 1 or 2 tumors occurred in 62 patients (79.5%). Among all patients, 56 patients underwent pretreatment with tumor resection (71.8%), 49 patients received nonsomatostatin analogue systemic therapy (62.8%), and 49 patients received liver-directed therapy (62.8%). At least 1 grade 2 or greater toxic effect was found in 47 patients (60.3%). Median PFS was 21.6 months for the study group, was not reached by 22 months for patients with small bowel primary tumors, and was 13.3 months for patients with pancreatic primary tumors. Having a small bowel primary tumor was associated with a lower rate of progression compared with having a pancreatic primary tumor (hazard ratio, 0.19; 95% CI, 0.07-0.55; P = .01). Median overall survival was not reached. This cohort study of patients with metastatic NETs found that PRRT was associated with laboratory-measured toxic effects during treatment for most patients and an overall median PFS of 21.6 months. Patients with small bowel NETs had longer PFS after PRRT compared with patients with pancreatic NETs.

Melatonin alleviates the deterioration of oocytes and hormonal disorders from mice subjected to glyphosate

Glyphosate (Gly) is the herbicide widely used in agricultural fields and landscaping. Mammalian exposure to glyphosate could cause neurotoxicity, blood, liver, kidney, endocrine, reproductive, genetic and other toxic effects. Melatonin (MT) is a neuroendocrine hormone secreted mainly by the pineal gland. It is unknown whether MT can improve reproductive defects and hormonal disorders in mice exposed to Gly. In this study, mice were exposed to 250 and 500 mg/kg Gly by intragastric administered and 15 mg/kg MT was treated via intraperitoneal injection for 7 days. Our results shown that the weight gain of mice, the ovarian coefficient and the ATP content in the ovaries were decreased significantly. Gly-treated oocytes showed that the first polar body extrusion failed, the level of oxidative stress increased, and the mitochondrial membrane potential (MMP) decreased. Subsequently, our results showed that increased expression level of BAX protein, reduced expression of BCL-2 protein, ATG12 and LC3 protein expression increased in ovaries after Gly treatment. At the same time, Gly exposure led to abnormal expression of Hypothalamic-Pituitary-Thyroid (HPT) axis-related genes and disrupted hormone homeostasis. After the injection of 15 mg/kg MT, the oocytes showed decreased oxidative stress level, increased mitochondrial membrane potential, incremental ATP content in the ovaries and the hormone levels were approached to the control group. Thus, our results demonstrated that melatonin can improve oocyte quality and maintain hormone homeostasis in mice exposed to glyphosate.

Real-world experience with 5-aminolevulinic acid for the photodynamic diagnosis of bladder cancer: Diagnostic accuracy and safety.

5-Aminolevulinic acid (ALA)-mediated photodynamic diagnosis (PDD) has recently been approved in Japan for the management of non-muscle invasive bladder cancer. As such, the current study aimed to investigate the real-world diagnostic accuracy and safety of ALA-PDD-assisted transurethral resection of bladder tumor (TURBT). A total of 76 patients who underwent PDD-assisted TURBT were enrolled. ALA (20 mg/kg body weight) was orally administered before TURBT. Fluorescence observation and tissue collection were performed during surgery, after which diagnostic accuracy was determined. Potential side effects of ALA, including vomiting, hypotension, and liver toxicity, were carefully monitored. The sensitivity, specificity, positive predictive value, and negative predictive value for detecting urothelial carcinoma were 90.1 %, 61.2 %, 55.1 %, and 92.2 % for fluorescence light (FL) and 65.4 %, 88.9 %, 75.7 %, and 83.9 %, for white light (WL) respectively. The mean number of tumors detected per patient was 1.92 and 1.39 for FL and WL (p < 0.05), respectively. No significant differences in the FL sensitivity and specificity were observe among the three patient groups classified according to ALA exposure time after oral administration (2-3, 3-4, and >4 h). ALA-related adverse effects included vomiting (seven cases), hypotension (seven cases, two of which were severe), and liver toxicity (four cases). All side effects disappeared shortly after standard treatment. ALA-PDD showed sufficient diagnostic accuracy even after more than 4 h of ALA exposure prior to surgery, as well as acceptable safety profiles.

Melatonin inhibits Benzo(a)pyrene-Induced apoptosis through activation of the Mir-34a/Sirt1/autophagy pathway in mouse liver.

Benzo(a)pyrene (BaP), an important environmental pollutant, is produced as the result of incomplete combustion of organic materials in many industries and food cooking process. It has been purposed that BaP induces hepatotoxicity through oxidative stress and apoptosis. Several studies have shown that melatonin can protect against chemical-induced apoptosis through autophagy pathway. In this study, we assessed the modulating effect of melatonin, a well-known antioxidant, on BaP-induced hepatotoxicity through induction of autophagy. Thirty male mice were treated daily for 28 consecutive days. BaP (75mg/kg; oral gavage) and melatonin (10 and 20mg/kg, i.p.) were administered to mice. The liver histopathology and the levels of apoptosis and autophagy proteins as well as the expression of miR-34a were determined. The BaP exposure induced severe liver histological injury and markedly enhanced AST, ALT and MDA level. Also, apoptosis proteins and hepatic miR-34a expression increased. However, the level of Sirt1 and autophagy markers such as LC3 II/I ratio and Beclin-1 reduced. The co-administration of melatonin reversed all changes caused by BaP. In summary, melatonin appears to be effective in BaP-induced hepatotoxicity maybe through the miR-34a/Sirt1/autophagy molecular pathway.

PENGARUH PEMBERIAN EKSTRAK ETANOL RIMPANG LENGKUAS (ALPINIA GALANGA) TERHADAP GAMBARAN HISTOPATOLOGI HEPAR MENCIT (MUS MUSCULUS L.) YANG DIINDUKSI MONOSODIUM GLUTAMATE

ABSTRACT&#x0D; Background: Long term consumption of Monosodium Glutamate (MSG) in excess isreported induced liver damage. Toxic effect in liver are due to the degeneration andnecrosis of hepatocytes, which also increases lipid peroxidation. Antioxidant in galangal rhizome is expected to repair liver damage caused by free radicals in MSG. &#x0D; Method: This study is an experimental research with Post Test Only Control Group Design. The samples in this study are 25 mice divided into 5 groups which are, negative control (not given any treatment), positive control (given MSG 4 mg/gBW for 14 days), treatment 1 (given MSG 4 mg/gBW for 14 days continued with ethanol extract of galangal rhizome 14 mg/20 gBW for7 days), treatment 2 (given MSG 4 mg/gBW for 14 days continued with ethanol extract of galangal rhizome 28 mg/20 gBW for 7 days), and treatment 3 (given MSG 4 mg/gBW for 14 days continued with ethanol extract of galangal rhizome 56 mg/20 gBW for 7 days). Then surgery was needed for histopathological examination. &#x0D; Results: Based on mean scoring results, the results showed calculation of liver cell degeneration for positive control (11,8), negative control (5,2), treatment 1 (10,6), treatment 2 (8,4), and treatment 3 (7,6). Based on the test results One Way ANOVA, the result showed the value of p=0,001 for liver histopathological appearance of mice. &#x0D; Conclusion: There is an effect of ethanol extract of galangal rhizome to the liver histopathological appearance of male mice.

Synthesis of Cobalt Hydroxide Nano-flakes Functionalized with Glutamic Acid and Conjugated with Thiosemicarbazide for Anticancer Activities Against Human Breast Cancer Cells.

In recent years, researchers were attracted to nanomaterials components for their potential role in cancer treatment. This study aimed to develop a novel and biocompatible cobalt hydroxide (Co(OH)2) nano-flakes that is functionalized by glutamic acid (Glu) and conjugated to thiosemicarbazide (TSC) for anticancer activities against human breast cancer MCF-7 cells. Physico-chemical properties of the Co(OH)2@Glu-TSC nanomaterial are characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), energy dispersive X-ray (EDX) analysis, and Fourier-transform infrared (FT-IR) spectroscopy. MTT assay, flow cytometry, and caspase-3 activity analysis used for evaluating anticancer properties of the Co(OH)2@Glu-TSC nanomaterial. The MTT assay result showed cellular uptake of Co(OH)2@Glu-TSC and cell viability loss in a concentration-dependent. Results of flow cytometry and caspase-3 activity analysis indicated the stimulation of apoptosis through an increase in Caspase-3 and nucleus fragmentation. In general, our findings indicate the anticancer activities of Co(OH)2@Glu-TSC nanomaterial and so it can be considered as a new treatment for breast cancer. However, further in vivo studies are required to evaluate the accumulation of Co(OH)2@Glu-TSC nanomaterial in healthy organs, such as the liver, kidneys, brain, and testes, and potential toxic effects.

Hemophilia A ameliorated in mice by CRISPR-based in vivo genome editing of human Factor VIII

Hemophilia A is a monogenic disease with a blood clotting factor VIII (FVIII) deficiency caused by mutation in the factor VIII (F8) gene. Current and emerging treatments such as FVIII protein injection and gene therapies via AAV-delivered F8 transgene in an episome are costly and nonpermanent. Here, we describe a CRISPR/Cas9-based in vivo genome editing method, combined with non-homologous end joining, enabling permanent chromosomal integration of a modified human B domain deleted-F8 (BDD-F8) at the albumin (Alb) locus in liver cells. To test the approach in mice, C57BL/6 mice received tail vein injections of two vectors, AAV8-SaCas9-gRNA, targeting Alb intron 13, and AAV8-BDD-F8. This resulted in BDD-F8 insertion at the Alb locus and FVIII protein expression in the liver of vector-, but not vehicle-, treated mice. Using this approach in hemophilic mice, BDD-F8 was expressed in liver cells as functional human FVIII, leading to increased plasma levels of FVIII and restoration of blood clotting properties in a dose-dependent manor for at least 7 months, with no detectable liver toxicity or meaningful off-target effects. Based on these findings, our BDD-F8 genome editing approach may offer an efficacious, long-term and safe treatment for patients with hemophilia A.

Tebuconazole induced oxidative stress related hepatotoxicity in adult and larval zebrafish (Danio rerio).

Tebuconazole is widely used as fungicide and has frequently been detected at elevated concentrations in environmental media. To characterize the potential toxicity of tebuconazole on vertebrate and humans. Using zebrafish as a vertebrate model, the toxic effects in liver that produced by low-toxic concentrations of tebuconazole were assessed in adult zebrafish. We further focused on tebuconazole-induced toxicity and its possible mechanism in larval zebrafish using a hepatotoxicity assay. The induction of oxidative stress in adult fish was evaluated by superoxide dismutase (T-SOD), catalase (CAT), peroxidase (POD), glutathione S-transferase (GST) activity, and the increased aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio. Significantly increased enzyme activity was observed in the liver of male and female fish at both exposure and depuration stage. Exposure to maximum non-lethal (MNLC) concentration of tebuconazole from 72 to 120 h post-fertilization (hpf) affected the liver size and yolk retention in larval zebrafish. Decreased fluorescence intensity was observed in larval Tg(Apo14:GFP) zebrafish, indicating liver degeneration after tebuconazole treated. Histopathological examination confirmed the alterations in liver histoarchitecture in exposed zebrafish. Significant 1.28-fold and 1.65-fold increases in reactive oxygen species levels were observed in juveniles exposed to MNLC and lethal concentration 10 (LC10) group, respectively. The acridine orange staining assay showed that apoptotic cells occurred in the liver regions. These results indicated that tebuconazole exposure resulted in impacts on the ecological risk in fish and vertebrate. Overall, the present study suggested further research in needed to better understand the tebuconazole-induced toxicity mechanism that associated with oxidative stress.

Study on liver protection and hepatotoxicity of saikosaponin a based on zebrafish model

Bupleuri Radix has both liver protection and hepatotoxicity. Saponins are the main pharmacodynamic and toxic components of Bupleuri Radix. Based on zebrafish physical model and the model of alcoholic fatty liver( AFL) pathology,the liver toxic and protective effect of saikosaponin a( SSa) were assessed. The results indicated that 1. 77 μmol·L-1 SSa showed protective effect to AFL zebrafish. 5. 30 μmol·L-1 SSa was hepatotoxic to healthy zebrafish,but it showed protective effect to AFL zebrafish. 5. 62 μmol·L-1 SSa was hepatotoxic to healthy and AFL zebrafish. This study is benefit for clinical safety of saikosaponin a.

Ameliorative impact of cold-pressed Rosmarinus officinalis oil against liver toxicity and genotoxic effects in streptozotocin-induced diabetic rats and their offspring.

Diabetes mellitus (DM) is a chronic, lifelong condition threatening human health. Rosmarinus officinalis oil (RO) could have a future role in DM therapy. This study evaluated the composition and antioxidative potential of RO. Antidiabetic traits of RO in streptozotocin (STZ)-induced diabetic rats was also studied considering the ameliorative impact against embryogenesis defects using in vitro and in vivo biochemical, histological, and genetic assays. RO was investigated for fatty acids and bioactive compounds (tocols and total phenolic compounds), and antiradical potential against DPPH• radicals. The genetic effects were investigated using comet assay and DNA fragmentation test. DM was induced to albino rats by injecting 60mg/kg of STZ, while RO (100mg/kg b.w.) was administered. The pregnant animals were divided into four groups; control (C), RO-treated (RO), diabetic (D), and combined diabetic with RO-treated (D-RO). The study was conducted for 180days. In RO, the contents of polyunsaturated fatty acids, monounsaturated fatty acids, and saturated fatty acids were 42.3%, 41.7%, and 15.8%, respectively. The levels of α-, β-, γ-, and δ-tocopherols were 280, 20, 1,025, and 35mg/100g RO, respectively. RO contained 7.2mg GAE/g of total phenolic compounds (TPC), while RO quenched 70% of DPPH• radicals. While glucose levels reached the highest in DM rats, treating STZ-induced diabetic animals with RO-resoluted serum glucose levels. RO reduced the highest levels of serum chemistry parameters were recorded in DM animals. Histological photographs of maternal and fetus liver exhibited degenerated hepatic cells and congestion central vein. Comet cells and DNA fragments were significantly decreased in D-RO group comparing to the DM group. RO exhibited antidiabetic capabilities, and thus, it could be utilized as a functional ingredient in novel foods, nutraceuticals, and dietary supplements for diabetic patients. PRACTICAL APPLICATIONS: RO is rich in bioactive phytochemicals (tocols and phenolic compounds) with antiradical and antihyperglycemic capabilities. Tocols and phenolics are active in radical scavenging of reactive nitrogen species (i.e., peroxynitrite and nitrogen dioxide), and in the prevention of DNA bases nitration. Our results demonstrated that RO could improve the disturbed metabolism of carbohydrate in STZ-diabetic animals. The potential mode of action of bioactive compounds in RO most likely encompasses the intracellular pathway involved in glucose homeostasis or insulin signaling. In addition, the suppression of oxidative stress by phenolic compounds could provide to the antidiabetic impacts of RO. Our data supported that RO could be utilized to ameliorate DM. Protection with RO directed high protection of the maternal organs and offspring against the oxidative stress of diabetes due to the antihyperlipidemic effects and the antioxidant capabilities of RO.