DRUG AND CHEMICAL TOXICOLOGY

Toxicological evaluation of LivLonga, a polyherbal combination, in rodents
Majeed A, Pandey A, Thazhathidath S and Bani S
There has been keen interest on herbs and phytoconstituents with hepatoprotective property to help restore healthy liver function. Ayurveda, the ancient Indian traditional system of medicine mentions about , and which are reported to have hepatoprotective activity. Apart from supporting metabolism, liver plays pivotal role in numerous bodily processes, immune functions to digestion, detoxification, and storage of nutrients. Factors such as sedentary lifestyle, viral infections, drugs/chemicals, high calorie diet, excess intake of alcohol etc have adverse impact on normal functioning of liver. Development of novel herbal combination with standards of safety and efficacy can help manage liver ailments and protect liver health. LivLonga is a polyherbal combination of scientifically validated ingredients- curcuminoids, garcinol and piperine to support healthy liver function. The present work was conducted to evaluate toxicity of LivLonga using models when administered orally. The acute, subacute, and subchronic toxicity studies were carried out in accordance with the test guidelines established by the Organization for Economic Cooperation and Development. A single-dose acute oral toxicity produced no toxic effects after 14 days of treatment. Four-week (subacute) and 3-months (subchronic) oral toxicity studies were conducted and observed no abnormal clinical signs, no alterations in the body weight, hematology and biochemical parameters or gross and histopathological changes. Thus, oral administration of LivLonga showed no signs of toxicity when dosed orally to rats, with a no observed adverse effect level (NOAEL) of 600 mg/kg/day.
Aprepitant mitigates paclitaxel-induced neuropathic pain in rats via suppressing inflammatory pathways in dorsal root ganglia
Khalilzadeh M, Ghasemi M, Faghir-Ghanesefat H, Ghafouri Esfahani M, Dehpour AR and Shafaroodi H
Neuropathic pain is the crucial dose-limiting side effect of paclitaxel in chemotherapy patients that negatively impacts the quality of life and survival. Currently, no effective treatment option is available. Aprepitant, a well-established chemotherapy antiemetic performing neurokinin-1 receptor antagonism, shows analgesic effects in some pain models. We studied aprepitant analgesic effects on the paclitaxel-induced neuropathic pain model in rats besides inflammatory markers assessment. Rats intraperitoneally received paclitaxel, reaching the cumulative paclitaxel dose of 8 mg/kg. Aprepitant was orally administered every alternate day between days 2 and 14, with a prescribed dosage of 10 or 20 mg/kg. The evaluation of mechanical allodynia and cold hyperalgesia involved the measurement of paw withdrawal threshold and acetone test score on days 0, 7, and 14. On day 14, paw licking latency was measured using a hot plate test before scarification and tissue collection for interleukin 1β, tumor necrosis factor α, and nuclear factor kappa B (NF-kB) evaluation. Paclitaxel induced neuropathy as indicated by a lowered hind paw withdrawal threshold in the Von Frey test, a higher score in the acetone test, and shortened hot plate latency. Aprepitant effectively alleviated cold and thermal hyperalgesia as well as mechanical allodynia. Moreover, aprepitant administration significantly reversed paclitaxel-mediated elevation of proinflammatory cytokines levels in dorsal root ganglia. In addition, aprepitant application suppressed the protein expression of NF-kB in the dorsal root ganglia of paclitaxel-treated rats, as revealed by western blot analysis. Aprepitant treatment ameliorates neuropathy induced by paclitaxel, which is associated with decreasing proinflammatory cytokines and NF-kB expression.
Taurine and enzymatically modified isoquercitrin synergistically protect against the methotrexate-induced cardiotoxicity in rats: antioxidant and antiapoptotic effects
Mahmoud MM, Hegazy R and El-Sayed WM
This study aimed to evaluate the protective potential of taurine (Tau) and enzymatically modified isoquercitrin (EMIQ), both individually and in combination, against MTX-induced cardiotoxicity in male rats. A total of 36 rats were randomly divided into six groups (six animals each): control (vehicle), MTX alone (20 mg/kg, single dose), EMIQ+MTX (EMIQ at 26 mg/kg, p.o. for 16 days, with a single dose of MTX on the 13th day), Tau + MTX (Tau at 500 mg/kg, p.o. for 16 days, with a single dose of MTX on the 13th day), (EMIQ+Tau)+MTX, and (EMIQ+Tau)½+MTX. MTX treatment resulted in elevated levels of cardiac creatine phosphokinase-myocardial band, troponin I, nitric oxide, malondialdehyde, and serum IL-6, while decreasing levels of cardiac myeloperoxidase, catalase, and superoxide dismutase. MTX also reduced expression of , induced DNA laddering and fragmentation, and increased cleaved caspase-3 protein expression in cardiac tissue. Both Tau and EMIQ showed equivalent effectiveness in protecting the heart against MTX-induced damage due to their antioxidant, anti-inflammatory, and antiapoptotic properties. Notably, combined treatment with half-doses of Tau and EMIQ offered superior protection compared to full doses of each agent alone. The full-dose combination showed similar efficacy to the half-dose combination, with a few exceptions. Overall, these results suggest a synergistic effect of Tau and EMIQ in mitigating MTX-induced cardiotoxicity, warranting further investigation into the underlying mechanisms.
Mitigating aluminum chloride-induced toxicity in with peptide fractions from species
Akano JM, Molik ZA, Abolaji AO and Ogbole OO
This study assessed the antioxidative and protective effects of peptide extracts from selected species on Aluminum Chloride (AlCl)-induced toxicity in (EHU), (EHI), and (EHG) were screened for bioactive peptides. The crude peptide extract and partially purified peptide fractions of all the plants were subjected to preliminary antioxidants activities through 2, 2-diphenyl-1-picrylhyhdrazyl (DPPH), and nitric oxide (NO) scavenging activities. The most active peptide fraction was subjected to biochemical studies using Flies were treated with AlCl (100 mg/kg diet), peptide fraction (5 and 10 mg/kg diet), and cotreatment of AlCl and the fraction, respectively. After treatment, flies were homogenized for the determination of total thiol and Glutathione (non-protein thiol) content, catalase and Glutathione-S-transferase activities, and nitric oxide (nitrite/nitrate) and hydroperoxide levels. The antioxidant screening revealed that the peptide fraction from (PEHU) was the most significant compared to the control (ascorbic acid). The PEHU (5 and 10 mg/kg diet) maintained the redox status of the flies in the biochemical study. The PEHU significantly counteracted AlCl-induced reduction in antioxidants (catalase, GST, GSH and Total thiol), increased nitric oxide levels, and acetylcholinesterase activity and prevented behavioral deficits flies. Hence, the peptide fraction of may shield against the life-threatening effects of free radicals associated with aluminum chloride toxicity.
Carvacrol modulates antioxidant enzymes, DNA integrity, and apoptotic markers in zearalenone-exposed fetal rat liver
Eleyan M, Zughbur MR, Hussien M, Ayesh BM and Ibrahim KA
Maternal exposure to zearalenone (ZEA), a mycotoxin, can impact fetal liver development. This study investigated the protective effects of carvacrol (CRV) against ZEA-induced fetal liver damage. Thirty-two pregnant rats were allocated to four groups (eight rats/group); control, CRV (75 mg/kg), ZEA (5 mg/kg), and co-treated group (ZEA + CRV). The animals were given their doses during the gestation period. Maternal exposure to ZEA revealed a significant increase in the malondialdehyde (MDA) level in the fetal liver. In contrast, glutathione S-transferase (GST), superoxide dismutase (SOD), and catalase (CAT) activities, besides glutathione (GSH) levels, were decreased in ZEA-intoxicated rats. Additionally, ZEA increased the expression of pro-apoptotic genes (P53, Bax, and caspase-9), elevated the immunoreactivity of caspase-3, decreased anti-apoptotic Bcl-2, and induced severe fatty degeneration, congestion, and necrosis in the fetal liver. The comet assays revealed significant DNA damage, as evidenced by reduced head DNA content and increased tail DNA content and tail moment in the ZEA-exposed rats. Surprisingly, co-treatment with CRV significantly mitigated fetal hepatic lipid peroxidation, antioxidant disturbance, apoptosis, and DNA damage after maternal exposure to ZEA. These findings highlight the potential of CRV as a promising approach to mitigate ZEA-associated developmental hepatotoxicity.
Ascorbic acid regulates and toxicogenetic effects of hydroxyurea on eukaryotic cells
Aguiar RPS, Souza JMT, de Menezes APM, do Nascimento MLLB, de Castro E Sousa JM, Cavalcante AACM, Ferreira PMP, Araújo AJ and Marinho-Filho JDB
Hydroxyurea (HU) exerts unique and diverse biological effects as an anti-leukemic agent, irradiation sensitizer, and HbS inducer in patients with sickle cell anemia. Herein, we assessed the potential toxicogenic and/or oxidant effects of hydroxyurea associated with ascorbic acid by examinations in and human cancer cells and systemically on mice tissues. Growing roots and HCT-116 colorectal tumor cells were examined after HU and HU plus ascorbic acid exposure. DNA damage and antioxidant enzymatic activity were quantified in peripheral blood mononuclear cells (PBMC), bone marrow leukocytes and livers of mice after 7 day-HU treatment (7.5, 15 and 30 mg/kg/day) and Vitamin C 2 μM. Hydroxyurea presented toxic effects on meristematic cells, causing chromosomal abnormalities and reduction of mitotic index, killed HCT-116 colorectal carcinoma cells and induced DNA injuries upon mice cells (hepatocytes, bone marrow leukocytes and PBMC). Simultaneously, hydroxyurea decreased levels of CAT and GSH activities and expand lipid peroxidation. All these biochemical and physiological changes were ameliorated when associated with ascorbic acid, indicating it restored antioxidant enzymes, decreased MDA levels, removed peroxides and, consequently, presented cytoprotection against HU-provoked cellular damage in normal cells. On the other hand, antioxidants compounds may interfere on effectiveness of HU during anticancer chemotherapies.
Molecular docking, ADME properties and synthesis of thiophene sulfonamide derivatives
Jebamani J, Shivalingappa J, Pranesh S, Pasha M and Pawar C
This study investigates the drug-like properties of target molecules containing thiophene sulfonamide groups using computational molecular docking techniques. The binding interactions of these derivatives were assessed using protein 2NSD (Enoyl acyl carrier protein reductase InhA, complexed with N-(4-methylbenzoyl)-4-benzylpiperidine, PDB DOI: 10.2210/pdb2NSD/pdb) as the receptor. Molecular docking results revealed notable docking scores for all compounds, ranging from -6 to -12 kcal/mol. Compounds and in particular, demonstrated impressive glide scores (>11 kcal/mol) and were selected for further analysis through molecular dynamics simulations, which provided deeper insights into their dynamic behavior and stability. The drug-like properties of these molecules were evaluated based on Lipinski's Rule of Five and ADME (Absorption, Distribution, Metabolism, and Excretion) criteria and compared with known drugs. Additionally, we synthesized these target molecules using Suzuki-Miyaura coupling with a nickel catalyst replacing palladium. The chemical structures of the synthesized compounds were confirmed through elemental analysis, LC-MS,H-NMR, and C-NMR spectroscopy.
Fumaric acid protects rats from ciprofloxacin-provoked depression through modulating TLR4, Nrf-2, and p190-rho GTP
Khalaf MM, Mahmoud HM, Kandeil MA, Mahmoud HA and Salama AA
Depression is a persistent illness affecting health, behavior, and performance in life. Worldwide morbidity and mortality are caused by depression. The current study intended to explore fumaric acid's potential protective effect against ciprofloxacin-provoked depression in rats and to determine its mechanism of action by studying its antioxidant and anti-inflammatory properties. Five groups of male Wistar albino rats (120 g ± 20) were employed; the first group received physiological saline, the second group received fumaric acid (80 mg/kg/day; orally) for 3 weeks, the third group was administered ciprofloxacin (50 mg/kg/day; orally) for 3 weeks to induce depression, the fourth group received a daily low dose of fumaric acid (40 mg/kg; orally) concurrent with ciprofloxacin and the fifth group received a daily high dose of fumaric acid (80 mg/kg; orally) concurrent with ciprofloxacin for 21 days. Then, behavior tests, oxidative stress indicators, inflammatory biomarkers, neurotransmitters, p190 Rho GTP, and histopathological examination were evaluated. Ciprofloxacin significantly increased oxidative stress biomarkers [malondialdehyde (MDA) as a lipid peroxidation marker and nitric oxide (NO)] and biomarkers of inflammation (TLR-4)] and tumor necrosis factor-alpha (TNF-α) with reduction in the activities of the nuclear factor erythroid 2-related factor 2 (Nrf-2) and catalase as well as brain contents of neurotransmitters and P190-RHO GTP. In addition, it causes necrosis of neurons and mild loss of Purkinje cells. Fumaric acid eliminates these effects of ciprofloxacin. Fumaric acid has beneficial effects as an anti-depressant in Wistar albino male rats that received ciprofloxacin.
Probiotics modulation of the endotoxemic effect on the gut and liver of the lipopolysaccharide challenged mice
Babu G and Mohanty B
The multistrain probiotics' efficacy in ameliorating the endotoxemic effect in Lipopolysaccharide (LPS) challenged mice was evaluated with the agonist of anti-inflammatory peptide, neurotensin (NTS), especially targeting the inflammation of the gut and liver. Swiss Albino Mice (Female, 8 weeks old) were maintained in eight groups: Group I as Control, Group II-Group V were exposed to intraperitoneal (i.p.) LPS (1 mg/kg bw) for 5 days. After that, Group III and Group VI were administered probiotics orally (0.6 gm/kg bw/day), Group IV and Group VII with NTS receptor 1 (NTSR1) agonist PD149163 (50 µg/kg bw/day i.p.), and Group V and Group VIII co-administered with probiotics and PD149163 for 28 days. Group II (LPS-exposed) was maintained without any further treatment; mice of all the groups were sacrificed at day 34. In the LPS-exposed mice, endotoxemia was distinct from a significant ( < 0.001) increase of plasma pro-inflammatory cytokines (TNF-α; IL-6), a decrease of anti-inflammatory cytokine (IL-10), oxidative stress, and inflammation of the gut and liver. Increased serum transaminases indicated hepatic inflammation. A decreased population of the and increased indicated microbiota dysbiosis. Probiotics when used as an adjunct along with PD149163 have shown better efficacy in inflammation modulation as reflected in the significantly decreased ( < 0.001) inflammatory mediators, oxidative stress, restoration of the beneficial bacterial population, along with a significant reduction in histopathological scores of the gut and the liver than when used alone. This study suggests probiotics could be used as an adjunct in clinical practice along with anti-inflammatory drugs for better therapeutic efficacy.
Exploring health beneficial effects of poisonous mushroom Batsch Fr
Petrović J, Glamočlija J, Cvetković S, Nikolić B, Gašić U and Robajac D
In the present study, phenolic and flavonoid composition and biological properties of methanolic extract of wild growing collected in Serbia have been investigated. Ellagic acid was the most abundant phenolic compound (34.92 µg g-), followed by 5-O-caffeoylquinic acid (4.51 µg g-), whereas isoorientin was the most abundant flavonoid (3.42 µg g-). turned out to be a rich source of phenolic compounds (74.67 mg GAE g- d.w.), whereas total flavonoid content was significantly lower (4.05 mg QE g- d.w.). As for the various investigated biological activities, methanolic extract exerted high level of antioxidant, antimicrobial and antibiofilm activities. The highest antioxidative potential was measured by TAC (350 TE mg g- d.w.), whereas evaluation of antimicrobial properties showed selective antimicrobial potential toward tested pathogenic microorganisms, with resistant strain of being the most susceptible to the activity of the extract (MIC 0.08 mg mL-, MBC 0.16 mg mL-). Furthermore, methanolic extract of demonstrated genotoxicity, severe hemolysis effects and selective cytotoxicity against colon cancer cells. From the obtained data, it may be concluded that investigated mushroom albeit being toxic for human consumption, may be considered as a source of highly bioactive components with potential application in drug development.
Unraveling the hepatoprotective and anti-pancreatic cancer potential of : a comprehensive and in silico evidence
Amrati FE, Lim A, Slighoua M, Chebaibi M, Mssillou I, Drioiche A, Di Cristo F, Al-Sheikh YA, Aboul-Soud MAM, Edderkaoui M and Bousta D
Guss. () is a medicinal plant used for cancer treatment. However, these treatments may be associated with complications that need to be investigated. This work aims to evaluate not only the chemical composition but also the hepatoprotective and anticancer properties of extracts. The chemical constitution of the hydroethanolic extract was explored using gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC). The hydroethanolic extract, flavonoids, and polyphenols-rich extract at 100, 15, and 50 mg/kg, respectively, were administered to acetaminophen-treated rats for seven days. We used Western blotting and Real-Time quantitative Polymerase Chain Reaction (RT-qPCR) to determine the protein and the mRNA levels of cancer stemness markers in pancreatic cancer cell lines MIA PaCa-2 and BxPC-3 exposed to increasing doses of extracts. analysis was used to evaluate the effects of phenolic compounds revealed in on caspase-3 and HSP90, and on liver damage on CYP2E1. The primary phenolics detected by GC-MS and HPLC were ferulic acid and benzofurazan. The positive control group showed an increase in AST, ALT, ALP, triglycerides, and VLDL levels. extracts demonstrated hepatoprotective effects by ameliorating acetaminophen-induced alterations of biochemical and hispathological parameters. Immunoblotting and RT-qPCR profiling of cancer stemness markers indicated a reduction in the expression levels of Oct-4 and Nanog proteins, as well as a reduction in the mRNA levels of CD133 by 50-60% and Sox2 by 80-90% in pancreatic cancer cells. Molecular docking showed that naringenin presented the highest docking Gscore on CYP2E1 (-8.199) and HSP90 (-7.742). In conclusion, extracts could be considered as a safe and promising therapeutic strategy to sensitize pancreatic cancer cells to chemotherapy.
Evaluation of acute and subacute dermal toxicity of antibacterial bioactive glass-infused surgical cotton gauze in Wistar rats
Dattaray D, L R, Roy P, Chakraborty J and Mandal TK
Mesoporous bioactive glass, with its versatile characteristics and morphology, holds significant potential as an ideal hemostatic material. However, limited data is available regarding its toxicity levels. Consequently, this research intends to assess the acute and repeated dose dermal toxicity of Mesoporous antibacterial bioactive glass microsphere impregnated nonwoven surgical cotton gauze (MABGmscg) dressing in albino Wistar rats, following the standards set by the Organization for Economic Cooperation and Development. In the acute dermal toxicity study, the impact of MABG (@2000mg/kg BW) mscg dressing was assessed following a single dermal application in both male and female Wistar rats (n = 10). Mortality, clinical signs, body weight fluctuations and gross observations were consistently monitored over a14 day period following the single dose. The results indicated that, MABG (@2000mg/kg BW) mscg dressing upon dermal exposure did not cause any adverse effect in acute dermal toxicity study in Wistar rats compared to control group. Given that 2000 mg/kg BW of MABG was deemed a nontoxic dose, a repeated dose dermal toxicity study of MABGmscg dressing was subsequently conducted at three dose levels (@200, 500, 1000 mg/kg BW) over 28 consecutive days in Wistar rats. During the study period, no unscheduled deaths occurred, and there were no clinical signs associated with treatment, body weight variations or abnormal gross findings at necropsy in any groups. The analysis concluded that, MABGmscg dressing is safe to be considered as a hemostatic dressing at the various tested dose levels in Wistar rats.
Toxicity of pesticide cocktails in amphibian larvae: understanding the impact of agricultural activity on aquatic ecosystems in the Salado River basin, Argentina
Cuzziol Boccioni AP, Lajmanovich RC, Attademo AM, Lener G, Lien-Medrano CR, Simoniello MF, Repetti MR and Peltzer PM
Aquatic communities are increasingly exposed to complex mixtures of contaminants, mainly pesticides due to the impact of agricultural activity. The aim of this study was to evaluate the toxicity of an eight-pesticide cocktail on larvae of the South American common toad, . The cocktail represents a realistic mixture of insecticides (cypermethrin, chlorpyrifos and lambda-cyhalothrin), herbicides (glyphosate, glufosinate ammonium, prometryn and metolachlor), and a fungicide (pyraclostrobin) previously found in aquatic organisms () from the Salado River Basin, an area with strong agricultural pressure. Computational simulations through the Density Functional Tight-Binding method indicated a strong spontaneous trend toward the formation of the cocktail, suggesting that it may act as a novel xenobiotic entity in the environment. The cocktail effects were evaluated in early-developing and premetamorphic larvae, at feasible concentrations found in real scenarios. The mixture led to high mortality and teratogenicity in early-developing larvae. Premetamorphic larvae showed endocrine disruption, oxidative stress, and impairments in detoxification and hepatic functioning. Neurotoxicity, genotoxicity, cardiotoxicity and high mortality under stress conditions were also observed in exposed larvae. This novel evaluation highlights the ecotoxicological risk for aquatic organisms exposed to complex mixtures and underscores the need to consider cocktail effects in studies regarding ecosystems health.
Reproductive and developmental toxicity of α-terpineol in Wistar rats
Hegde SS and Malashetty VB
Alpha-terpineol (α-T) is a type of monoterpenoid alcohol commonly present in essential oils, it contributes to a pleasant floral fragrance similar to that of lilacs. This research aimed to evaluate the impact of α-terpineol on the reproductive functions of both male and female rats, including gonadal activity, mating behavior, conception, conceptus development and parturition. Six male and female Wistar rats per group received α-terpineol through gavage at doses of 0, 75, 150 and 300 mg/kg/day. The study revealed changes in body weight gain inhibition, food consumption, azoospermia, decreased testosterone levels (0.7 ± 1.61 ng/mL, 0.7 ± 2.30 ng/mL) as well as histopathological variations in testis and epididymis among males exposed to doses of 150 and 300 mg/kg/day. Moreover, this exposure led to significantly decreased serum T4 levels in both adult males (21.85 ± 12.68 ng/mL, 16.20 ± 9.15 ng/mL) and dams (11.24 ± 12.37 ng/mL, 9.48 ± 11.74 ng/mL) at the dose range of 150 and 300 mg/kg/day without affecting TSH concentrations. In summary, the present study showed that α-terpineol induced reproductive toxicities in male rats. Therefore, a detailed toxicological assessment is highly recommended.
and anti-inflammatory activity of and β-caryophyllene oxide in carrageenan-induced paw edema in Wistar rats
Kumar GS, Sholapuri P, K D, Shaily Enugonda M and B P G
This study is aimed to evaluate the impact of methanolic extract of and isolated plant compound, β-Caryophyllene oxide against carrageenan-induced paw edema in rat model and its therapeutic potential compared with reference drug, Indometacin. Methanolic extract of was characterized using FTIR, LC-MS, NMR spectral studies. Paw edema was induced by sub-plantar injection of 100 µl of 1% carrageenan. Oxidative enzymes, such as super oxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione reductase (GR), lipid peroxidation and C-reactive protein levels were measured in paw tissue. evaluation of anti-inflammatory activity of plant compounds was evaluated against the molecular targets of inflammation. C-reactive protein and lipid-peroxidation levels were significantly increased whereas the activity levels of oxidative enzymes were significantly decreased in inflammation-induced rats. The recovery of oxidative enzyme levels was seen in treated groups in a dose dependent manner. C-reactive protein and lipid-peroxidation levels were significantly decreased in treated groups, indicating the anti-inflammatory activity of the plant extract and the plant compound. Computational analysis rationalizes the inhibitory ability of plant derived compound possibly by altering the inflammatory signaling pathway.
Population pharmacokinetics and pharmacodynamics of L-asparaginase and its impact on the development of pancreatitis and hypersensitivity reactions in children with leukemia under treatment
Gándara-Mireles JA, Lares-Asseff I, Espinoza EAR, Loera-Castañeda V, Reyes Gutiérrez FM, Sandoval-Cabrera A, Hurtado LPC, Muñoz CM, Villanueva Fierro I, Payan Gandara H, Patrón-Romero L and Almanza-Reyes H
L-asparaginase (L-Asp) is an essential enzyme in the treatment of patients with Acute Lymphoblastic Leukemia (ALL), commonly associated with adverse events (AE). Knowing the pharmacokinetic and pharmacodynamic (PK/PD) parameters of L-Asp as well as its relationship with the development of AE is an important strategy in the search to improve the efficacy and safety of the treatment. Seventy-four children with ALL that were being treated with L-Asp, were included. One to three blood samples were randomly obtained from each patient, at times from 0 to 30 hours, until completing a total of 211 samples. The L-Asp activity and the Asparagine (Asp) concentration were quantified, in addition, the presence of anti-L-Asp antibodies (Anb) was determined. A population PK/PD model of L-Asp was developed to determine the association of covariates with PK/PD parameters. The presence of Anb was associated with the increase in L-Asp clearance (CL) and with the decrease of volume of distribution 1 (V1). On the other hand, female sex was significantly associated with the increase of V1, while the age from 1 to 6 years was significantly associated with the increase of V1. The presence of Anb as well as the female sex were related to the increase IC50 (concentration-needed to deplete-50% of Asp). Patients who presented Asp depletion before the first 24 hours after administration presented pancreatitis, this could be a risk marker. Significant results were found in this study, use of these results may contribute to the safe and effective use of L-Asp.
Linolenic acid stimulates eryptosis and hemolysis through oxidative stress and CK1α/MLKL: protective role of melatonin, urea, and polyethylene glycol
Alharthy FH, Alsughayyir J and Alfhili MA
Anticancer medications cause anemia in patients through ill-defined mechanisms, including hemolysis and eryptosis. Although α-linolenic acid (ALA) possesses anticancer properties against a variety of cancer cells, there is a dearth of evidence regarding how it modulates red blood cell (RBC) physiology. RBCs from healthy donors were subjected to anticancer concentrations of ALA (2.5, 5, 10, 20, 40, 80, and 100 μM) at 37 °C for 24 h, and colorimetric tests were used to determine hemolysis and acetylcholinesterase (AChE) activity. Meanwhile, flow cytometry was employed to identify eryptotic cells using annexin-V-FITC and forward scatter (FSC), Fluo4/AM to detect Ca, and HDCFDA to assess oxidative stress. ALA significantly increased hemolysis and eryptosis in a concentration-dependent manner, along with elevated Fluo4 and DCF fluorescence, and erythrocyte sedimentation rate, and reduced FSC and AChE activity. Moreover, the addition of D4476, necrosulfonamide, melatonin, isosmotic urea, and polyethylene glycol 8000 - but not sucrose - significantly inhibited ALA toxicity. In conclusion, ALA stimulates hemolysis and eryptosis through Ca buildup, oxidative stress, anticholinesterase activity, casein kinase 1α (CK1α), and mixed lineage kinase domain-like protein (MLKL). The anticancer activity of ALA may be potentiated by the use of Ca channel blockers and chelators, antioxidants, and CK1α and MLKL inhibitors to ameliorate its toxicity to RBCs.
Mitochondrial toxicity of selected natural compounds: assessment and molecular docking and dynamics simulation
Ergüç A, Albayrak G, Muhammed MT, Karakuş F and Arzuk E
Boiss & Hausskn stands out for its rich bioactive constituents including prantschimgin (PRA), imperatorin (IMP), suberosin (SUB), adicardin (ADI), and oxypeucedanin hydrate (OPH) in the Apiaceae family. Although these molecules contribute to several biological activities, their mitochondrial toxicity were not illuminated in depth with the appropriate and models. Cell viability studies investigated the cytotoxic activities of molecules in HepG2 cells by replacing glucose with galactose due to Warburg effects. Mitochondrial toxicity (mitotoxicity) parameters such as cellular adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) levels were assessed with cytotoxic concentrations of selected molecules. Molecular docking and dynamics studies were also conducted against mitochondrial electron transport chain (ETC) complexes (I-V) with selected compounds. results showed that PRA, SUB, and IMP reduced cell viability more in galactose media compared to high glucose media in a dose-dependent manner. PRA, IMP, and SUB decreased ATP levels and MMP, especially in the galactose medium. The study revealed that PRA, IMP, and SUB might bind to complexes I-V at different levels. The docking study demonstrated that PRA had the highest binding potential with the complexes, higher than the standard ligands in some cases. The molecular dynamics (MD) simulation study showed that PRA formed stable complexes with complexes II, III, and IV. In addition, PRA was anticipated to remain inside the binding site of complex II most stably during the 230 ns simulation period. Our study suggests that PRA, IMP, and SUB exhibit mitotoxicity.
Vitamin E improves oxidative stress, apoptosis, and steroidogenesis impairment in glyphosate-induced mice
Shafiee Mehr M, Haeri SMJ, Barzroodi Pour M and Bayat M
Glyphosate (Gly) is a nonselective pesticide with high potential to toxic effects on the reproductive system. Recent studies suggest that Vitamin E can indeed have a positive impact on the reproductive system, while Gly, a nonselective pesticide, has been linked to significant risks of toxicity on reproductive health. It's crucial to be mindful of the potential impacts of such substances on the reproductive system.
Single acute and repeated subacute toxicity evaluations of leaf extract with anti-inflammatory potential
Sohn E, Kim YJ, Lim HS and Jeong SJ
The nutraceutical and biological potential of , a fruiting plant, has been reported. We and others have demonstrated that leaf extract (AAL) has various pharmacological properties, such as antioxidant, antimicrobial, and neuroprotective effects. However, knowledge about the safety and potential toxicity of AAL remains limited. We aimed to assess the potential toxicity of AAL using acute and repeated subacute oral toxicity tests in rats. In both acute and repeated subacute toxicity test, no AAL-related behavioral abnormalities or changes in mortality, food intake, body weight were observed up to a dosage of 2000 mg/kg, indicating that the median lethal dose of AAL is higher than 2000 mg/kg. In subacute toxicity tests, no significant changes in hematological and biochemical parameters, urinalysis results, and histopathological variables were observed. Therefore, the no-observed-adverse-effect level (NOAEL) of orally administered AAL was estimated to be 2000 mg/kg/day in male and female rats. We also examined the effect of AAL on the inflammatory reaction in lipopolysaccharide (LPS)-stimulated BV-2 cells. AAL treatment significantly inhibited the LPS-stimulated increases in the levels of nitric oxide (NO) and inflammatory cytokines, implying that AAL has an anti-inflammatory effect. Quality control analysis revealed that two marker compounds, rutin and isoquercitrin, were present at 27.570 and 4.322 mg/g, respectively, in a freeze-dried AAL sample and were completely eluted within 27 min. The extraction recovery was 99.47-103.80%, and the precision was ≤2.79%. Overall, these findings suggest the safety, anti-inflammatory activity, and standardization of AAL.
Toxicity optimization of green zinc oxide quantum dots in zebrafish using Box-Behnken design: a novel approach for safer nanoparticle synthesis
R MNF, M C, R S and S P
Zinc oxide quantum dots, also known as ZnO QDs, are highly desirable due to their numerous favorable characteristics, such as their beneficial photoluminescence, solubility in water, along with sunlight absorption. They are well-suited for use in biomedical applications, drugs, and bioimaging. However, study on the toxicology of these QDs is needed before they can be used in humans. Zebrafish () are cheap, fast-growing, and similar to humans, which makes them ideal as in vivo model for studying the toxicity of nanomaterials. The toxicity investigations involving zinc oxide QDs (ZnO QDs) and zinc oxide bionanocomposite (ZnO BC) in zebrafish that were concentration-dependent are evaluated, and the Box-Behnken design (BBD) was utilized to optimize the results. To determine the proper dosage, a study on cell line as well as hemocompatibility was carried out prior to testing the toxic effects of ZnO QDs along with ZnO BC upon zebrafish. When administered at 2.5 μg/l of ZnO BC and 2 μg/l of ZnO QDs, neither ZnO BC nor ZnO QDs appeared to be toxic to embryos during hatching and development. The testing of larval behavior in visible light revealed a dose-dependent decrease in both the total diving distance as well as speed. Nevertheless, at ZnO BC and ZnO QDs levels >250 μg/l and >200 μg/l, respectively, notable effects were seen in zebrafish embryos. Hence, ZnO QDs and BC at low concentrations were notably nontoxic. In order to guarantee the safety of nanomaterials in bio applications, this research supports upcoming imaging investigations on their harmful effects.