Toxic Damage Research Articles

Effect of Silymarin on Gentamicin Induced Nephrotoxicity in Rats

Background: As oxidative stress is an important factor in producing nephrotoxicity by a variety of drugs and chemicals; so, it may be assumed that agents having antioxidant property may protect the kidney from oxidative damage and can improve renal function. Objective: In the present study the ameliorative effect of silymarin was determined in a gentamicin-induced nephrotoxic model of rat. Methodology: This experimental animal study was carried out in the Department of Pharmacology at Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh from January 2014 to January 2015 for a period of one year. In this study nephrotoxicity was induced by administering gentamicin (80 mg/kg/day for 7 days) intraperitoneally. Silymarin was administered (500 mg/kg/day for 14 days) orally concomitantly with gentamicin (7 days) and sacrificed on 15th day. To determine nephrotoxicity and amelioration of nephrotoxicity as well as the status of oxidative stress and lipid peroxidation; serum creatinine, serum urea, renal cortical reduced glutathione and malondialdehyde levels were estimated. Changes in renal architecture were estimated by histopathology of renal tissues. Results: Group (II) rats were injected gentamicin intraperitoneally for 7 days and sacrificed on 15th day showed significant (P< 0.001) increase of serum creatinine and urea level while there was significant (P< 0.001) reduction of renal cortical glutathione and increase (P< 0.001) in malondialdehyde concentration when compared to the control group (group I). This was supported by histological observations of H&E and PAS stained transverse section of renal cortex which suggested significant (P< 0.001) level of structural damage of renal cortex as evidenced from glomerular atrophy, tubular degeneration, presence of desquamated cellular debries and cast in the tubular lumen, mononuclear inflammatory cell infiltration. Statistically significant amelioration was observed in all the biochemical parameters which were supported by histology of renal cortex in silymarin treated group. Conclusion: The results from biochemical and histological observations of the present study indicate that silymarin was probably effective to ameliorate the signs of toxic damage to the renal cortex. Bangladesh Journal of Infectious Diseases, December 2023;10(2):71-76

Експериментальне дослідження гепатопротекторної дії комплексу n-оксид-2,6-диметил піридину з бурштиновою кислотою (Потейтіну) на моделі токсичного гепатиту, спричиненого тетрахлорметаном

Plant growth regulators (PGR), in particular, methyl derivatives of pyridine N-oxide, reduce the acute toxicity of pesticides, reduce the hepatotoxic effects of chlorpyrifos and ease the course of intoxication under long-term exposure. The role of the body’s defence systems under the combined effects of PGR and pesticides has not yet been sufficiently elucidated. The study of the protective effect of PGR Poteitin under the conditions of toxic damage to the liver by carbon tetrachloride (CCl4) will allow finding out the mechanisms of its combined action. The results of the research will be used to develop preventive measures for pesticide poisoning. Aim. Investigate the hepatoprotective properties of the 2.6-dimethylpyridine N-oxide complex with succinic acid (Poteitin) on the model of acute hepatitis caused by carbon tetrachloride. Materials and Methods. Acute hepatitis was modelled on male Wistar Han rats with subcutaneous injection of CCl4 (pure substance) in petroleum jelly oil (0.8 ml/100 g of body weight) for 2 days. Poteitin was administered at the doses of 23 and 0.23 mg/kg, reference substance Silybor 35 – at the dose of 5 mg/kg. Intact rats received petroleum jelly oil in the same volumes. Poteitin and Silybor were administered in a treatment-prophylactically regimen, orally 1 hour pre- and 2 hours post-CCl4. The activity of enzymes of cytolysis and cholestasis, indicators reflecting liver function, the content of lipid peroxidation (LP) products and antioxidant activity were determined in blood serum. Histological studies of liver tissue were carried out. The index of effectiveness of the protective effect of Poteitin was calculated The results were statistically processed using the one-way ANOVA followed by Fisher's LSD post-hoc test. Results and Discussion. CCl4 caused acute liver damage: increased activity of markers of cytolysis and cholestasis, decrease in a number of functional tests, activity of catalase, LP products accumulation, fatty and balloon dystrophy of hepatocytes, lympho-leukocyte infiltration. Poteitin on the background of CCl4 contributed to the normalization of the activity of markers of cytolysis and cholestasis, the restoration of functional indicators, reduced the content of LP products, increased the activity of catalase, and reduced liver damage. The protective effect of Poteitin was not inferior to Silybor. Conclusions. 1. Under the conditions of acute hepatitis, carbon tetrachloride causes moderate liver damage. 2. Poteitin at the doses of 23 and 0.23 mg/kg has a pronounced hepatoprotective effect: it normalizes the activity of enzymes of cytolysis and cholestasis, functional indicators – the level of glucose, cholesterol, total protein and bilirubin, urea; reduces the intensity of LP and activation of the antioxidant system. 3. The protective effect of Poteitin at both tested doses as cytolysis and cholestasis indicators, functional tests and morphostructural changes in the liver is comparable to the reference drug Silybor. The protective effect of Poteitin, determined by the intensity of LP, is greater than that of Silybor. Keywords: acute hepatitis, carbon tetrachloride, hepatoprotective effect, 2.6-dimethylpyridine N-oxide complex with succinic acid.

Pan-metagenome reveals the abiotic stress resistome of cigar tobacco phyllosphere microbiome.

The important role of microbial associations in mediating plant protection and responses to abiotic stresses has been widely recognized. However, there have been limited studies on the functional profile of the phyllosphere microbiota from tobacco (Nicotiana tabacum), hindering our understanding of the mechanisms underlying stress resilience in this representative and easy-to-cultivate model species from the solanaceous family. To address this knowledge gap, our study employed shotgun metagenomic sequencing for the first time to analyze the genetic catalog and identify putative plant growth promoting bacteria (PGPB) candidates that confer abiotic stress resilience throughout the growth period of cigar tobacco in the phyllosphere. We identified abundant genes from specific bacterial lineages, particularly Pseudomonas, within the cigar tobacco phyllospheric microbiome. These genes were found to confer resilience against a wide range of stressors, including osmotic and drought stress, heavy metal toxicity, temperature perturbation, organic pollutants, oxidative stress, and UV light damage. In addition, we conducted a virome mining analysis on the metagenome to explore the potential roles of viruses in driving microbial adaptation to environmental stresses. Our results identified a total of 3,320 scaffolds predicted to be viral from the cigar tobacco phyllosphere metagenome, with various phages infecting Pseudomonas, Burkholderia, Enterobacteria, Ralstonia, and related viruses. Within the virome, we also annotated genes associated with abiotic stress resilience, such as alkaline phosphatase D (phoD) for nutrient solubilization and glutamate-5-semialdehyde dehydrogenase (proA) for osmolyte synthesis. These findings shed light on the unexplored roles of viruses in facilitating and transferring abiotic stress resilience in the phyllospheric microbiome through beneficial interactions with their hosts. The findings from this study have important implications for agricultural practices, as they offer potential strategies for harnessing the capabilities of the phyllosphere microbiome to enhance stress tolerance in crop plants.

Variations in the oral microbiome and metabolome of methamphetamine users.

Drug addiction can seriously damage human physical and mental health, while detoxification is a long and difficult process. Although studies have reported changes in the oral microbiome of methamphetamine (METH) users, the role that the microbiome plays in the process of drug addiction is still unknown. This study aims to explore the function of the microbiome based on analysis of the variations in the oral microbiome and metabolome of METH users. We performed the 16S rRNA sequencing analysis based on the oral saliva samples collected from 278 METH users and 105 healthy controls (CTL). In addition, the untargeted metabolomic profiling was conducted based on 220 samples. Compared to the CTL group, alpha diversity was reduced in the group of METH users and the relative abundances of Peptostreptococcus and Gemella were significantly increased, while the relative abundances of Campylobacter and Aggregatibacter were significantly decreased. Variations were also detected in oral metabolic pathways, including enhanced tryptophan metabolism, lysine biosynthesis, purine metabolism, and steroid biosynthesis. Conversely, the metabolic pathways of porphyrin metabolism, glutathione metabolism, and pentose phosphate were significantly reduced. It was speculated that four key microbial taxa, i.e., Peptostreptococcus, Gemella, Campylobacter, and Aggregatibacter, could be involved in the toxicity and addiction mechanisms of METH by affecting the above metabolic pathways. It was found that with the increase of drug use years, the content of tryptamine associated with neuropsychiatric disorders was gradually increased. Our study provides novel insights into exploring the toxic damage and addiction mechanisms underlying the METH addiction.IMPORTANCEIt was found that with the increase of drug use years, the content of tryptamine associated with neuropsychiatric disorders gradually increased. The prediction models based on oral microbiome and metabolome could effectively predict the methamphetamine (METH) smoking. Our study provides novel insights into the exploration of the molecular mechanisms regulating the toxic damage and addiction of METH as well as new ideas for early prevention and treatment strategies of METH addiction.

Mitochondrial transplantation attenuates oligomeric amyloid-beta-induced mitochondrial dysfunction and tight junction protein destruction in retinal pigment epithelium

Transplantation of mitochondria derived from mesenchymal stem cells (MSCs) has emerged as a new treatment method to improve mitochondrial dysfunction and alleviate cell impairment. Interest in using extrinsic mitochondrial transplantation as a therapeutic approach has been increasing because it has been confirmed to be effective in treating various diseases related to mitochondrial dysfunction, including ischemia, cardiovascular disease, and toxic damage. To support this application, we conducted an experiment to deliver external mitochondria to retinal pigment epithelial cells treated with oligomeric amyloid-beta (oAβ). Externally delivered amyloid-beta internalizes into cells and interacts with mitochondria, resulting in mitochondrial dysfunction and intracellular damage, including increased reactive oxygen species and destruction of tight junction proteins. Externally delivered mitochondria were confirmed to alleviate mitochondrial dysfunction and tight junction protein disruption as well as improve internalized oAβ clearance. These results were also confirmed in a mouse model in vivo. Overall, these findings indicate that the transfer of external mitochondria isolated from MSCs has potential as a new treatment method for age-related macular degeneration, which involves oAβ-induced changes to the retinal pigment epithelium.

Patulin induces ROS-dependent cardiac cell toxicity by inducing DNA damage and activating endoplasmic reticulum stress apoptotic pathway

Patulin (PAT) is one of the mycotoxins commonly found in agricultural products and fruits, and has obvious toxic effects on animals and humans. PAT has been found to cause myocardial toxicity and oxidative damage, but the mechanism of myocardial toxicity remained to be elucidated. We investigated the toxic effects and potential mechanisms of PAT on human cardiomyocytes and explored the effects of reactive oxygen species (ROS) on them. The study showed that treatment with PAT for 24 h decreased cell viability and superoxide dismutase (SOD) activity, and increased ROS and lactate dehydrogenase (LDH) levels. Moreover, in addition to detecting increased γ-H2AX expression and observing nuclear damage, the comet assay also showed increased DNA tail distance in the PAT-treated group, followed by an increase in phosphorylation of the p53 protein and p21 protein expression, and a decrease in CDK1 and Cyclin B1 protein expression, and G2/M phase arrest. In addition, PAT induced endoplasmic reticulum stress (ERS) and induced apoptosis, as evidenced by Ca2+ increase, ER enlargement and swelling, and upregulation of ERS-related genes and proteins expression, and increased expression of three apoptotic pathway proteins under ERS, including CHOP, JNK, and caspase-12. Meanwhile, N-acetylcysteine (NAC, a ROS scavenger) reversed the negative effects of PAT treatment on cells. These results clarify that excessive ROS production by PAT-treated AC16 cells not only causes DNA damage, leading to cell cycle arrest, but also causes ERS, which triggers apoptotic pathways to cause apoptosis.

Glycogen for lysosome-targeted CpG ODNs delivery and enhanced cancer immunotherapy

CpG oligodeoxynucleotides (ODNs) strongly activate the immune system after binding to toll-like receptor 9 (TLR9) in lysosome, which demonstrated significant potential in cancer immunotherapy. However, their therapeutic efficacy is limited by drawbacks such as rapid degradation and poor cellular uptake. Although encouraging progress have been made on developing various delivery systems for CpG ODNs, safety risks of the synthetic nanocarriers as well as the deficient CpG ODNs release within lysosome remain big obstacles. Herein, we developed a novel nanovector for lysosome-targeted CpG ODNs delivery and enhanced cancer immunotherapy. Natural glycogen was simply aminated (NH2-Gly) through grafting with diethylenetriamine (DETA), which was spherical in shape with diameter of approximately 40 nm. NH2-Gly possessed good biocompatibility. Cationic NH2-Gly complexed CpG ODNs well and protected them from nuclease digestion. NH2-Gly significantly enhanced the cellular uptake of CpG ODNs. Efficient CpG ODNs release was observed in the presence of α-glucosidase that mimicking the environment of lysosome. Consequently, NH2-Gly/CpG complexes triggered potent antitumor immunity and effectively inhibit the tumor growth without causing any toxic effect or tissue damages. This work highlights the promise of glycogen for lysosome-targeted on-command delivery of CpG ODNs, which brings new hope for precision cancer immunotherapy.

INOCULAÇÃO E APLICAÇÃO DE DIFERENTES DOSES DE Azospirillum brasilense E SUA INFLUÊNCIA NO DESENVOLVIMENTO DA CULTURA DO MILHO

Benefits in grain productivity, with low economic cost, ease of application, without causing toxic damage to the environment and with high potential for crop response, are target points in research involving the cultivation of corn. In this context, the present study aimed to evaluate the effect of inoculation of Azospirillum brasilense on the vegetative structures of the corn crop, envisioning an increase in the development of the plant. The experimental design used was completely randomized, with six treatments and four replications, totaling 24 experiments. Seeds were inoculated with A. brasilense in different doses of the commercial product (0 - 1000 mL), where the plant height (AP), ear insertion height (AIE), stem diameter (DC), total number of leaves (NTF) and number of leaves below the first ear (NFAE), were evaluated. The inoculation of corn seeds based on A. brasilense strain Ab-V5 promoted influence on some biometric variables, with an increase in the total number of leaves (NTF), plant height (AP) and height of ear insertion (AIE) for the evaluated hybrid, resulting in increments in its vegetative development. The dosage of 549 mL per hectare was considered as favorable to result in greater amounts of total leaves (NTF) in the plant, according to the adjustment of the proposed model. The results emphasized that inoculation with this strain is a valid technique and is increasingly used by farmers, and its study is a contributing factor for improvements in agronomic parameters.

Abstract B059: Identification of cohesin RAD21 as a novel aneuploidy-associated marker driving prostate cancer progression by mitigating toxic DNA damage

Abstract Prostate cancer (PCa) is one of the most common cancers among men, leading to the second cause of death for men with cancers in the US. Aneuploidy, featured by imbalanced chromosome numbers, is a hallmark of cancer. Epidemiology studies on primary PCa cohorts of Physicians' Health Study and Health Professionals Follow-up Study (PHS and HPFS) have shown that high levels of whole-genome aneuploidy correlate with lethal progression in PCa. However, the detail mechanisms of how aneuploidy drives aggressiveness of PCa are still unclear. Here, we used the case of chromosome 8q (chr 8q, the long arm of chr 8) gain to study aneuploidy-associated prostatic malignancies. Chr 8q gains are the most frequently gain events that occur in around 23% of PCa cases. By using the PHS and HPFS cohorts, we modeled the increased expression of each gene located on chr 8q, for predicting the risks for lethal progression, and obtained the odds ratio (OR) for each. Then, we ranked the ORs for lethal progression and identified several important genes highly associated with lethality when overexpressed. Among them, the cohesin subunit gene, RAD21, is one of the top associators. Increased RAD21 mRNA level, per se, is highly correlated with lethality in all PCa cases, and the lethality is synergistically aggravated in the cases with both increased RAD21 expression and chr 8q gains. indicating that RAD21 cooperates with other chr 8q genes to drive cancer progression and chr 8q gains. To determine how RAD21 overexpression promotes PCa, we studied the effect of overexpression of RAD21 in early prostatic oncogenic events. We utilized the isogenic mouse prostate organoid models carrying an inducible the fusion-oncogene, TMPRSS2-ERG (T-ERG), which 50% of PCa cases harbor. We found that induction of T-ERG leads to a strong oncogenic replication stress at an early stage. Such stress results in an increase in apoptosis and growth impairment in these primary organoids. Overexpression of RAD21, mimicking the chr 8q gain situation, mitigates such replication stress and rescues the growth defect caused by T-ERG. These data suggest the role of increased RAD21 in promoting oncogenic growth of PCa cells by reducing oncogenic toxicity at an early stage. In addition, we showed that such role of RAD21 overexpression sustains in the more advanced cancerous organoid (ERG positive and PTEN loss) and promotes the growth of the cancer organoids. Consistently, increased RAD21 expression correlates with increase proliferative markers in human prostate cancer cases. In conclusion, we identified that overexpression of multiple chr 8q genes are correlated with lethal progression in primary PCa, and RAD21 is one of such genes. Increased RAD21 plays a fundamental role in reducing toxic DNA damage caused by prostatic oncogenesis. Citation Format: Xiaofeng A Su, Konrad H Stopsack, Daniel R Schmidt, Duanduan Ma, Zhe Li, Thomas Janas, Matthew G Vander Heiden, Kathryn L Penny, Paul A Scheet, Tamara L Lotan, Angelika Amon, Lorelei A Mucci. Identification of cohesin RAD21 as a novel aneuploidy-associated marker driving prostate cancer progression by mitigating toxic DNA damage [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B059.

A Review of the Effectiveness of Homoeoprophylaxis: SARS-CoV-2 Compared to Pre-COVID-19 Infectious Diseases

AbstractFrom Hahnemann's use in 1799 of Belladonna 30 to prevent scarlet fever, to the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2023, appropriate potencies of similarly 'similar' remedies have been used to prevent targeted infectious diseases. This is known to many as homeoprophylaxis (HP) or 'similar prevention.' Data from recent surveys suggest that the effectiveness of HP remedies against SARS-CoV-2 is lower compared to other infectious diseases. This review examines relevant evidence and suggests possible explanations for the emerging difference and ways to improve HP effectiveness. Evidence of HP's effectiveness against a range of infectious diseases from 1974 to 2014 is compared with evidence of HP's effectiveness against SARS-CoV-2 collected from 2020 to 2022. A summary of the evidence, describing the use of over 247,000,000 doses of HP medicines against various infectious diseases, suggests an average effectiveness of around 88%. Another summary of the evidence, describing the use of HP by several authors in 2020, 2021, and 2022 against SARS-CoV-2, shows a range of effectiveness around 70%. The reasons for apparent differences in HP effectiveness between 'traditional' infectious diseases and SARS-CoV-2 are discussed. It is suggested that these differences could have been expected, particularly due to the quality of most nosodes against SARS-CoV-2. The value of HP in comparison to coronavirus disease 2019 vaccines is also discussed, and conclusions are drawn. Appropriate HP against SARS-CoV-2 offers an option that appears to be at least as effective as vaccination, without any risk of toxic damage, but there is room for improvement.

Effect of climate change on hematotoxicity/hepatoxicity oxidative stress, Oncorhynchus mykiss, under controlled conditions.

Described as the 'main ecological factor', temperature, strongly affects the physiological stress responses of fish. In order to evaluate the effects of temperature variations on fish culture and food value chain, the present study was designed as a climate change model. Furthermore, the present study provides a theoretical basis for a better understanding of the mechanisms of the environmentally induced changes. In this direction, we examined the blood physiology and oxidative stress responses induced by temperature variation in the rainbow trout, a temperature-sensitive cold-water fish. The obtained results showed that climate changes promoted the inhibited activities' expressions and the development of potential tissue and hematological defense mechanisms against temperature-induced toxic damage. This study showed that climate change could be a subset of the studies on the stress physiology in aquaculture, which can be developed for new experimental designs and research collaborations. Furthermore, it highlights knowledge gaps to guide future research in this emerging field.

Liver failure after treatment with inotuzumab and polychemotherapy including PEG-asparaginase in a patient with relapsed Philadelphia chromosome–negative acute lymphoblastic leukemia

We present the case of a 58-year-old female patient who presented with an extramedullary B-ALL relapse after prior allogenic HSCT and blinatumomab therapy. The patient died from complications of a drug-induced acute liver failure after a salvage therapy combining inotuzumab ozogamicin (InO)-based induction followed by consolidation with high dose MTX and pegaspargase based on the GMALL protocol for older ALL patients. After a diagnosis of the extramedullary relapse in the form of a retro vesical chloroma, the patient received an individualized multi-agent chemotherapy based on induction chemotherapy for older patients in combination with InO. After four administrations of InO, in combination with vincristine, dexamethasone, cytarabine, and cyclophosphamide, CT-imaging showed a reduction in volume of the chloroma and response to therapy. Consolidation with high-dose methotrexate and pegaspargase was administered. The patient developed toxic liver damage manifested by hyperbilirubinemia and progressive hepatic encephalopathy. The diagnostic criteria for VOD were met, and therapy with defibrotide was initiated. Liver biopsy revealed no histological signs of VOD but instead steatohepatitis indicative of drug-induced toxicity. The patient ultimately died of hemorrhagic shock through postinterventional hemorrhage after liver biopsy. In conclusion, although InO shows promising results in the therapy of r/r ALL with and without additional chemotherapy, the combination with MTX and pegaspargase in an intensively pretreated patient with relapse after HCST may impart an increased risk for liver-related toxicity. Special caution is required when assessing fitness for further liver toxic regimens. A key takeaway is also the reminder that InO can cause liver damage not only in the form of VOD but also through direct hepatocellular toxicity.

Selenium reduces acrylamide-induced testicular toxicity in rats by regulating HSD17B1, StAR, and CYP17A1 expression, oxidative stress, inflammation, apoptosis, autophagy, and DNA damage.

This study investigated the effects of Selenium (Se) on testis toxicity induced by Acrylamide (ACR) in rats. In our study, 50 male adult rats were used, and the rats were divided into five groups; control, ACR, Se0.5 + ACR, Se1 + ACR, and Se1. Se and ACR treatments were applied for 10 days. On the 11th day of the experimental study, intracardiac blood samples from the rats were taken under anesthesia and euthanized. Sperm motility and morphology were evaluated. Dihydrotestosterone, FSH, and LH levels in sera were analyzed with commercial ELISA kits. MDA, GSH, TNF-α, IL-6, and IL-1β levels and SOD, GPx, and CAT, activities were measured to detect the level of oxidative stress and inflammation in rat testis tissues. Expression analysis of HSD17B1, StAR, CYP17A1, MAPk14, and P-53 as target mRNA levels were performed with Real Time-PCR System technology for each cDNA sample synthesized from rat testis RNA. Testicular tissues were evaluated by histopathological, immunohistochemical, and immunofluorescent examinations. Serum dihydrotestosterone and FSH levels decreased significantly in the ACR group compared to the control group, while LH levels increased and a high dose of Se prevented these changes caused by ACR. A high dose of Se prevented these changes caused by ACR. ACR-induced testicular oxidative stress, inflammation, apoptosis, changes in the expression of reproductive enzymes, some changes in sperm motility and morphology, DNA, and tissue damage, and Se administration prevented these pathologies caused by ACR. As a result of this study, it was determined that Se prevents oxidative stress, inflammation, apoptosis, autophagy, and DNA damage in testicular toxicity induced by ACR in rats.

Osmotic response during kidney perfusion with cryoprotectant in isotonic or hypotonic vehicle solution.

Organ cryopreservation would revolutionize transplantation by overcoming the shelf-life limitations of conventional organ storage. To prepare an organ for cryopreservation, it is first perfused with cryoprotectants (CPAs). These chemicals can enable vitrification during cooling, preventing ice damage. However, CPAs can also cause toxicity and osmotic damage. It is a major challenge to find the optimal balance between protecting the cells from ice and avoiding CPA-induced damage. In this study, we examined the organ perfusion process to shed light on phenomena relevant to cryopreservation protocol design, including changes in organ size and vascular resistance. In particular, we compared perfusion of kidneys (porcine and human) with CPA in either hypotonic or isotonic vehicle solution. Our results demonstrate that CPA perfusion causes kidney mass changes consistent with the shrink-swell response observed in cells. This response was observed when the kidneys were relatively fresh, but disappeared after prolonged warm and/or cold ischemia. Perfusion with CPA in a hypotonic vehicle solution led to a significant increase in vascular resistance, suggesting reduced capillary diameter due to cell swelling. This could be reversed by switching to perfusion with CPA in isotonic vehicle solution. Hypotonic vehicle solution did not cause notable osmotic damage, as evidenced by low levels of lactate dehydrogenase (LDH) in the effluent, and it did not have a statistically significant effect on the delivery of CPA into the kidney, as assessed by computed tomography (CT). Overall, our results show that CPA vehicle solution tonicity affects organ size and vascular resistance, which may have important implications for cryopreservation protocol design.

Effect of atrazine on testicular toxicity involves accommodative disorder of xenobiotic metabolizing enzymes system and testosterone synthesis in European quail (Coturnix coturnix)

Due to the wide use of atrazine (ATR), the concern has increased regarding the negative impact of ATR on reproduction. Nevertheless, the reproductive effects caused by different exposure concentrations and the severity of toxic damage are poorly understood. In organisms, ATR is metabolized and degraded through phase II enzyme systems, and changes in cytochrome P450 (CYP) enzymes may have a regulatory role in the harm of ATR. However, less information is available on the induction of CYPs by ATR in avian organisms, and even less on its effects on the testis. Birds are exposed to ATR mainly through food residues and contaminated water, the purpose of this study was to examine reproductive toxicity by different exposure concentrations and elaborate metabolic disorders caused by ATR in European quail (Coturnix coturnix). In this study, the quail were given ATR at 50 mg/kg, 250 mg/kg and 500 mg/kg by oral gavage for 45 days, and the testicular weight coefficients, histopathology and ultrastructure of testes, primary biochemical functions, sex steroid hormones, critical protein levels in the testosterone synthesis pathway, the expression of genes involved CYPs, gonad axis and nuclear receptors expression were investigated. Altogether, testicular coefficient decreased significantly in the high-dose group (1.22%) compared with the control group (3.03%) after 45 days of ATR exposure, and ATR is a potent CYP disruptor that acts through the NXRs and steroid receptor subfamily (APND, CAR, ERND and ERα) without a dose-dependent manner. Notably, ATR interfered with the homeostasis of hormones by triggering the expression of hormones on the gonad axis (LH and E2). These results suggest that exposure to ATR can cause testicular toxicity involving accommodative disorder of phase II enzyme and testosterone synthesis in European quail.

Food-grade titanium dioxide and zinc oxide nanoparticles induce toxicity and cardiac damage after oral exposure in rats

BackgroundMetallic nanoparticles (NPs) are widely used as food additives for human consumption. NPs reach the bloodstream given their small size, getting in contact with all body organs and cells. NPs have adverse effects on the respiratory and intestinal tract; however, few studies have focused on the toxic consequences of orally ingested metallic NPs on the cardiovascular system. Here, the effects of two food-grade additives on the cardiovascular system were analyzed.MethodsTitanium dioxide labeled as E171 and zinc oxide (ZnO) NPs were orally administered to Wistar rats using an esophageal cannula at 10 mg/kg bw every other day for 90 days. We evaluated cardiac cell morphology and death, expression of apoptotic and autophagic proteins in cardiac mitochondria, mitochondrial dysfunction, and concentration of metals on cardiac tissue.ResultsHeart histology showed important morphological changes such as presence of cellular infiltrates, collagen deposition and mitochondrial alterations in hearts from rats exposed to E171 and ZnO NPs. Intracellular Cyt-C levels dropped, while TUNEL positive cells increased. No significant changes in the expression of inflammatory cytokines were detected. Both NPs altered mitochondrial function indicating cardiac dysfunction, which was associated with an elevated concentration of calcium. ZnO NPs induced expression of caspases 3 and 9 and two autophagic proteins, LC3B and beclin-1, and had the strongest effect compared to E171.ConclusionsE171 and ZnO NPs induce adverse cardiovascular effects in rats after 90 days of exposure, thus food intake containing these additives, should be taken into consideration, since they translocate into the bloodstream and cause cardiovascular damage.

Влияние гепатопротекторного фитокомплекса на выраженность эндогенной интоксикации у лабораторных крыс при экспериментальной патологии печени, вызванной гидразином

Abstract. The purpose is to study the influence of the hepatoprotective phytocomplex on the severity of endogenous intoxication in laboratory rats with experimental liver pathology caused by hydrazine. Methods. The studies were carried out on non-linear rats, formed into 3 groups (n = 10). Toxic damage to the liver in rats of groups 1 and 2 was modeled by a single intragastric administration of hydrazine at a dose of 200 mg/kg of body weight. Immediately after intoxication and for the next three weeks in 1st group, the drug fitosomin was used – daily orally in the form of boluses at a dose of 0.5 g/kg of body weight, 2nd group after intoxication received empty cereal boluses, 3rd group was intact. In dynamics, the degree of endogenous intoxication was studied by the concentration of medium mass molecules (MMM) in the blood of animals at λ = 254 and 280 nm. Scientific novelty. Experimentally new data on the pharmacological effects of the hepatoprotective phytocomplex was obtained, which includes lecithin, dihydroquercetin, extracts of milk thistle, agrimony and golden boletus. For the first time, the effectiveness of the drug fitosomin was determined to reduce the severity of the endogenous intoxication syndrome in laboratory rats with experimental liver pathology caused by hydrazine. Results. It has been determined that hydrazine-induced liver pathology in laboratory rats is accompanied by the development of endogenous intoxication syndrome with a more pronounced increase in the blood fraction of MMM 254 relative to MMM 280. The use of fitosomin leads to a weakening of the toxic effect of hydrazine both on the liver and on the body of animals as a whole. The course application of the hepatoprotective phytocomplex increases the survival rate of rats, improves their clinical condition and leads to a decrease in the concentration of MMM in the blood. The obtained results outlined the prospects for the use of the drug fitosomin in veterinary practice in case of liver damage, as well as intoxication of animals.

Incidence of hypoxic hepatitis in patients with cardiogenic shock and association with mortality

Abstract Background Shock of any cause leads to hypoxic and toxic organ damage, especially in perfusion-sensitive organs such as the liver. In septic shock, hypoxic hepatitis is defined as an increase of ASAT and ALAT to >700 U/l and is associated with increased mortality. However, pathophysiology, dynamics and treatment differ between septic and cardiogenic shock (CS). Thus, the definition of hypoxic hepatitis derived from patients with septic shock may not be suitable in CS. Purpose To evaluate incidence and impact of hypoxic hepatitis in patients with CS based on existing as well as on novel CS-specific cut-offs. Methods Unselected patients >18 years treated for cardiogenic shock at a tertiary care centre between 2009 and 2019 were analysed for presence and prognostic impact of hypoxic hepatitis. Receiver operating curve analyses/Youden Index Method were used to determine optimal ASAT/ALAT cut-off values for hypoxic hepatitis. Multivariable adjusted logistic regressions models were constructed to compare different ASAT/ALAT cut-offs for the prediction of in-hospital mortality. Results This analysis included 698 patients [mean age 69 years, 212 (29.9%) female]. A total of 386 (55.3%) patients died. Liver enzyme elevation >700 U/l was present in 135 (19.1%) patients and not associated with in-hospital mortality (OR 1.1, 95% CI: 0.69, 1.75, p-value 0.69). Mortality was best predicted by new cut-offs with a >34% increase for ASAT and a >51% increase for ALAT. Using these criteria, hypoxic hepatitis was found in 36% (254/698 patients), most commonly during early disease trajectory (74% within first 3 days, Figure 1). Hypoxic hepatitis using this definition was associated with in-hospital mortality (OR 2.46, 95% CI: 1.67, 3.64, p-value <0.001). Conclusion Using novel, CS-specific cut-offs, defines hypoxic hepatitis as a relevant marker of excess mortality in patients with CS. These findings identify hypoxic hepatitis as a relevant disease modifier in CS and emphasises the need for further investigation of therapies reducing its occurrence and impact.Figure 1

T1rho and T2rho based myocardial tissue characterisation in small animals at high-field MRI

Abstract Introduction Cardiac tissue characterisation using T2-based MRI promises non-invasive diagnosis or monitoring of inflammatory heart disease, toxic heart damage after chemotherapy and myocardial infarction or post-infarction patients. T2 relaxation is also an indicator for the detection of myocardial oedema or intramyocardial haemorrhage [1]. However, accurate T2 quantification is challenging due to motion, blood flow and field inhomogeneities, especially in high-field MRI [2]. In this work, we present an alternative to T2 imaging that uses spin-locking (SL) to provide a robust measurement of T2ρ relaxation. It is known from relaxation theory that T2ρ has a sensitivity almost identical to T2 [3]. In the small animal study presented here, cardiac T2ρ quantification is tested for the first time using a newly developed pulse sequence and compared with established methods. Methods All measurements were performed on a preclinical 7T MRI. T2 contrast was prepared using a CPMG (Carr-Purcell-Meiboom-Gill) sequence. T2ρ contrast was conventionally generated by a balanced-SL (BSL) preparation [4]. Furthermore, a new approach for T2ρ was developed based on a MLEV sequence (Malcolm-Levitt, [2]). In contrast to [2], all pulse delays were minimised here, producing pure T2ρ contrast (Fig. 1). The new method was first validated in phantom experiments and then tested in three mice with radial image acquisition accelerated for cardio-MRI. Results The results of the phantom study are shown in figure 2. No significant differences were found between BSL and MLEV for T2ρ quantification (mean deviation 0.74%). In vivo, significant artefacts were observed for T2 (Fig. 3), while both T2ρ methods showed improved image quality. For the evaluation of relaxation times in the left ventricle, the mean across all animals was: T2=22.9±2.6ms (R2=0.979), BSL-T2ρ=51.4±5.4ms (R2=0.983) and MLEV-T2ρ=60.0±3.4ms (R2>0.99). Thus, the MLEV-T2ρ method achieves the most robust quantification with a mean R2>0.99 and provides relaxation time maps with diagnostic image quality. Discussion: In the present study, myocardial T2ρ mapping was tested at 7T. While no significant differences between BSL and MLEV appeared in phantom experiments, significant difference was found in vivo. Here, only the MLEV technique could achieve robust quantification. One reason for the improved performance is the continuous refocusing and minimisation of free dephasing of the transverse magnetisation. The results also show that MLEV-T2ρ has improved image quality and more robust quantification compared to CPMG-T2. Conclusion Cardiac T2ρ quantification is a robust alternative to established T2 imaging and can be applied under high-field conditions. A combined measurement of T1ρ and T2ρ relaxation time could be used for native detection of myocardial fibrosis and oedema.Figure 1)Comparison of image qualityFigure 2)Results in a knockout model

Acute iucterine hepatitis as a manifestation of severe autoimmune hepatitis

In the article, on the example of a clinical case, a variant of the course of severe acute autoimmune hepatitis type II in a 20-year-old woman is analyzed. The prevalence of this disease are presented. Possible types of autoimmune hepatitis course are discussed. The main diagnostic criteria that indicate the likelihood of autoimmune hepatitis and the tactics of managing these patients are described.
 This clinical case demonstrates that in the absence of epidemiological, anamnestic data indicating a possible viral or toxic liver damage, it is necessary to think and exclude autoimmune liver damage. It is believed that the level of gamma globulin exceeding more than 1.5 times the upper limit of normal and the absence of viral hepatitis are independent predictors of the presence of autoimmune hepatitis, and the earlier immunosuppressive therapy is started, the more favorable the prognosis of the disease.