Significant Toxicity Research Articles

Fabrication of bamboo nanocellulose fibril-based food packaging with dual-antimicrobial property

The development of cellulose-based packaging films with excellent antimicrobial properties and biocompatibility has garnered significant attention. In this work, nanocellulose fibrils (NCFs) derived from from bamboo parenchyma cells were utilized to fabricate nanocomposite film with antimicrobial properties. This system exhibited distinct release behaviors for two antimicrobial agents, with the slow release of Ag nanoparticle (AgNP) in the initial stage contributed to delaying food spoilage, while the subsequent pH change in the microenvironment facilitated the release of essential oil of sour orange blossoms (SEO) for secondary antimicrobial activity. Additionally, the composite film demonstrated improved thermal stability and UV blocking capacity. Moreover, AgNP has been proven to enhance the mechanical properties, with the tensile strength of the novel composite film increasing by 34.85 % compared to control group. The water vapor permeability and oxygen permeability of the novel composite film were reduced, which could potentially reduce weight loss and slow down the rate of after-ripening. Following the acidification treatment, the films containing EO@MPN (essential oil encapsulated with metal-polyphenol network) component performed different antimicrobial patterns, indicating their pH-responsive antimicrobial capabilities, and they are effective against both Gram-positive and Gram-negative bacteria. After a 24-h exposure to a food simulant, the release amount of Ag was measured at 67.6 μg/dm2, within the acceptable limit, and the release profile of Ag was characterized. Cytotoxicity and Live/Dead staining tests confirmed that the novel composite film film had no significant toxicity, thus making it safe for application in food preservation. Furthermore, in a 15-day preservation experiment with mangoes, the novel composite film demonstrated the best performance, underscoring its potential as a sustainable antimicrobial packaging material.

Targeted delivery of letrozole-loaded Mg-doped cobalt ferrite nanoparticles for breast cancer treatment

Breast cancer is the most common cancer in women globally. Letrozole is an aromatase inhibitor used as an anticancer drug. Conventional Letrozole therapies for breast cancer often cause adverse effects when administered orally or parenterally. Efforts have been made to develop an advanced drug delivery system for breast cancer treatment, aiming to improve drug release accuracy and therapeutic efficacy while minimizing side effects. This study focuses on magnesium-doped cobalt ferrite nanoparticles (Mg-doped CFNPs) as potential drug delivery carrier for breast cancer treatment. Mg-doped CFNPs with the chemical formula Co1-xMgxFe2O4 (where x = 0.0, 0.05, 0.10, 0.15, 0.20 and 0.25) were synthesized with different concentrations of 5 %, 10 %, 15 %, 20 %, and 25 % by the sol gel method with a fine size of 30–70 nm and their characteristics such as surface morphology, structural properties, chemical composition, and charge were investigated using scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and zeta potential analysis respectively. After synthesis, the Mg-doped CFNPs were coated with Poly ethylene glycol (PEG) and encapsulated with Letrozole, which exhibited <10 % hemolytic activity across all concentrations, as well as minimal cytotoxic effects on non-cancerous cells (HEK-293) but exhibited significant toxicity towards breast cancer cell lines (MCF-7, MDA-MB-231).The best results were obtained at a concentration of 25 % in both the hemolytic assay and the MTT assay, which indicated that increasing the amount of magnesium in cobalt decreased the toxicity and increased the drug release efficiency of nanoparticles.

Safety assessment of novel oxadiazole derivatives in acute and sub-acute toxicity studies.

1,3,4-Oxadiazole is a fascinating heterocyclic compound with a unique five-membered ring structure containing nitrogen and oxygen atoms. It has garnered significant attention for its interactions and activities within biological systems. This versatility has led to the production of several ligands using this compound as a pharmacophore. This study evaluates the acute toxicity of three oxadiazole derivatives (1,3,4-Bromo, Chloro, and Iodo) followed by a 28days sub-acute study involving four different doses of each derivative. The study followed the guideline, the Organization for Economic Cooperation and Development (OECD) outlined, specifically OECD Guidelines 425 for the acute toxicity study and OECD Guidelines 407 for the sub-acute study. In the acute toxicity study, a high dose of 2000 mg/kg was administered to male and female rats to establish lethal dose 50 (LD50) values, and the rats were closely monitored for 14 days. The subsequent sub-acute study involved the administration of four different doses (1.25, 2.5, 5, and 10 mg/kg) of each derivative to male and female rats for 28 days. Throughout both studies, careful monitoring for signs of toxicity and comprehensive hematological, biochemical, and histological analysis were carried out thoroughly. The results of the acute toxicity study indicated that all three derivatives had LD50 values exceeding 2000 mg/kg, and the rats did not display significant signs of toxicity. Similarly, no organ or systemic toxicity was observed in the repeated dose sub-acute study for any of the three derivatives. In conclusion, based on the findings of these studies, it was determined that the derivatives are safe for further investigation of their pharmacological activity.

A Mechanistic Approach on Structural, Analytical and Pharmacological Potential of Beta-sitosterol: A Promising Nutraceutical

Abstract: Phytosterols are bioactive substances that are found spontaneously in the cell membranes of plants and have an atomic composition similar to cholesterol produced by vertebrate cells. They are widely distributed in dietary lipids from plants such as nuts, seeds, and beans with olive oil. β-sitosterol has a variation of pharmacological belongings, with analgesic, immunomodulatory, antiseptic, antineoplastic, anti-inflammatory, cholesterol decreasing, hepatoprotective, and protecting action concerning respiratory and non-alcoholic fatty liver disease illnesses, antioxidant, and anti-diabetic activity. Clinical studies on humans have shown that it works against prostate cancer and has anti-inflammatory and anti-cancer properties. Pharmacological testing of β-sitosterol demonstrated a range of actions including antibacterial, anti-inflammatory, antinociceptive, anticancer, antifertility, angiogenic, antioxidant, immunomodulatory, diabetes-fighting, and anticancer without significant toxicity. Several formulations have been created by numerous authors, but there are few scholarly reviews of the analytical, pharmacology, and phytochemistry methodologies for this molecule. In this review the literature on β-sitosterol, its biosynthesis, pharmacology, nutraceutical applications, toxicity, formulations, and analytical techniques are all highlighted.

Prevalence and spectrum of manifestations of tamoxifen retinopathy as assessed by multimodal and ultra-widefield retinal imaging

Background/ObjectivesTamoxifen has well-known retinal toxicity, but the epidemiology of this toxicity is poorly defined. This study aims to 1) evaluate the prevalence of tamoxifen retinopathy in a major northeastern metropolitan area based on multimodal retinal imaging and 2) determine whether the additional peripheral retina captured in ultra-widefield (UWF) imaging aids in the diagnosis of tamoxifen retinopathy. MethodsThis retrospective cohort study examined female patients initiated on tamoxifen for at least 12 months prior to their first retinal exam. Two independent graders performed blinded review of spectral-domain optical coherence tomography (OCT) images for evidence of macular toxicity and UWF images for signs of central and peripheral toxicity. A one-tailed two-proportion Z-test determined whether peripheral pigmentary changes were more prevalent in the tamoxifen cohort than age- and gender-matched controls. Results241 eyes from 123 patients were included in the tamoxifen cohort, and 258 eyes from 132 patients were included in the control cohort. Two patients demonstrated definitive tamoxifen retinopathy, for a prevalence of 1.6%. One patient demonstrated crystalline maculopathy on OCT and UWF imaging, while another demonstrated pseudocystic cavitations on OCT imaging. Neither patient had peripheral findings on UWF imaging. Peripheral pigmentary changes were not significantly more prevalent in the tamoxifen cohort. ConclusionsThese findings suggest that UWF imaging does not contribute to diagnosis of tamoxifen retinopathy, and OCT may be the most valuable tool in diagnosing tamoxifen retinopathy. Our prevalence (1.6%) diverges from higher rates in studies screening with similarly advanced retinal imaging. Further large population studies are needed.

PREVALENCE OF DIDANOSINE-RELATED RETINAL TOXICITY AT AN URBAN ACADEMIC CENTER AS DIAGNOSED WITH ULTRA-WIDEFIELD IMAGING.

Antiretroviral therapy has revolutionized HIV treatment with didanosine (DDI) as a pioneering drug. However, DDI has been associated with retinal toxicity, characterized by peripheral chorioretinal degeneration with macular sparing. Despite its clinical recognition, the prevalence and risk factors for didanosine-induced retinopathy are not well described. This retrospective case series analyzed 127 DDI-treated patients at Weill Cornell Medicine Department of Ophthalmology. Inclusion criteria included at least 6 months of DDI use and available ultra-widefield imaging. Patients were categorized as affected or unaffected based on retinal imaging assessed by two reviewers. The affected group was further divided into "probable" or "possible" retinopathy. Patient demographics, DDI usage characteristics, and imaging findings were analyzed with statistical comparisons drawn between affected and unaffected cohorts. Of the 127 patients, 9 (7%) showed signs of didanosine-induced retinal toxicity. On average, the affected group was older compared with the unaffected group (65.1 vs. 56.5 years, P = 0.025), with lower BMI (23.2 vs. 27.4, P = 0.04), and older at the start of the treatment (51.6 vs. 40.8 years, P = 0.026). Mild phenotypes with peripheral pigmentary changes were also identified using ultra-widefield imaging. This pioneering academic study highlighted a notable prevalence of DDI-induced retinal toxicity. Statistical analysis demonstrated age, BMI, and age at treatment initiation as potential risk factors. Ultra-widefield autofluorescence emerged as a valuable tool in detecting and delineating findings. Follow-up studies are needed to determine the necessity of regular screening for individuals on or with a history of didanosine use.

A multifunctional self-reinforced injectable hydrogel for enhancing repair of infected bone defects by simultaneously targeting macrophages, bacteria, and bone marrow stromal cells

Injectable hydrogels (IHs) have demonstrated huge potential in promoting repair of infected bone defects (IBDs), but how to endow them with desired anti-bacterial, immunoregulatory, and osteo-inductive properties as well as avoid mechanical failure during their manipulation are challenging. In this regard, we developed a multifunctional AOHA-RA/Lap nanocomposite IH for IBDs repair, which was constructed mainly through two kinds of reversible cross-links: (i) the laponite (Lap) crystals mediated electrostatic interactions; (ii) the phenylboronic acid easter bonds between the 4-aminobenzeneboronic acid grafted oxidized hyaluronic acid (AOHA) and rosmarinic acid (RA). Due to the specific structural composition, the AOHA-RA/Lap IH demonstrated superior injectability, self-recoverability, spatial adaptation, and self-reinforced mechanical properties after being injected to the bone defect site. In addition, the RA molecules could be locally released from the hydrogel following a Weibull model for over 10 days. Systematic in vitro/vivo assays proved the strong anti-bacterial activity of the hydrogel against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Moreover, its capability of inducing M2 polarization of macrophages (Mφ) and osteogenic differentiation of bone marrow stromal cells (BMSCs) was verified either, and the mechanism of the former was identified to be related to the JAK1-STAT1 and PI3K-AKT signaling pathways and that of the latter was identified to be related to the calcium signaling pathway, extracellular matrix (ECM) receptor interaction and TGF-β signaling pathway. After being implanted to a S. aureus infected rat skull defect model, the AOHA-RA/Lap IH significantly accelerated repair of IBDs without causing significant systemic toxicity. Statement of significanceRosmarinic acid and laponite were utilized to develop an injectable hydrogel, promising for accelerating repair of infected bone defects in clinic. The gelation of the hydrogel was completely driven by two kinds of reversible cross-links, which endow the hydrogel superior spatial adaption, self-recoverability, and structural stability. The as-prepared hydrogel demonstrated superior anti-bacterial/anti-biofilm activity and could induce M2 polarization of macrophages and osteogenic differentiation of BMSCs. The mechanism behind macrophages polarization was identified to be related to the JAK1-STAT1 and PI3K-AKT signaling pathways. The mechanism behind osteogenic differentiation of BMSCs was identified to be related to the ECM receptor interaction and calcium signaling/TGF-β signaling pathways.

Efficacy and Tolerance of First-Line Afatinib in Elderly NSCLC Patients with EGFR Mutations in Vietnam: A Multicenter Real-World Study.

Afatinib, a second-generation epidermal growth factor receptor(EGFR) tyrosine kinase, has proven effective for non-small-cell lung cancer (NSCLC) patients with EGFR mutations through randomized controlled trials and real-world studies. Elderly patients exhibit unique characteristics in terms of physical condition and comorbidities, leading to differences in clinical practice for selecting the initial dosage and making dose adjustments compared to younger patients. This study aims to evaluate the effectiveness and adverse effects of first-line Afatinib treatment in elderly patients with NSCLC harboring EGFR mutations in Vietnam in a real-world context. We conducted a retrospective analysis of 135 patients, aged 65 years and older, across nine cancer centers in Vietnam. These patients, who harbored drug-sensitive EGFR mutations (excluding de novo T790M), received first-line Afatinib treatment between April 2018 and June 2022. The primary endpoints, time to treatment failure (TTF), and overall survival (OS) were assessed using the Kaplan-Meier method, and comparisons were conducted using the log-rank test. Secondary endpoints included the overall response rate (ORR) according to RECIST 1.1 and adverse effects as classified by CTCAE 4.0. The median age was 71.2 years (SD ± 5.3). Comorbidities included cardiovascular disease (20.7%), diabetes (5.2%), chronic obstructive pulmonary disease (2.2%), and hepatitis B (0.7%). Common mutations constituted 71.9% of cases, with uncommon mutations representing 28.1%. Brain metastases were observed in 24.4% of patients. Initial treatment doses were 40 mg for 35.6% of patients and 30 mg for 62.2%. With a median follow-up of 34.3 months, the median TTF was 16.3 months (95% CI: 15.4-19.5), and the median OS was 32.9 months (95% CI: 28.9-37.5). Factors associated with decreased OS included poor performance status, current smoking, and the presence of uncommon mutations. The ORR was 77.8%, with a complete response of 11.1% and a disease control rate of 94.1%. The most common toxicities were dermatologic and mucosal, including diarrhea (55.6%), rash (48.9%), and stomatitis (40.7%), predominantly in grades 1 and 2. Initiating treatment at doses below 40 mg significantly reduced most toxicities compared to the 40 mg dose. The presence of brain metastases did not significantly affect ORR, TTF, or OS. Starting treatment at doses below 40 mg significantly lowered the response rate but did not impact TTF or OS. First-line treatment with Afatinib in elderly patients with NSCLC and EGFR mutations demonstrates significant efficacy and manageable toxicity in a Vietnamese multicenter real-life setting. The effectiveness of Afatinib was confirmed, with known and well-controlled adverse effects, supporting its use in this patient population.

Characterization of food color additives and evaluation of their acute toxicity in Wistar albino rats

Background and Aim: The use of food dyes can cause certain diseases, such as anemia and indigestion, along with other disorders, tumors, and even cancer. Therefore, this study aimed to determine the chemical nature and toxicity of some commercial dyes locally used in processed foods compared with standard food dyes. Materials and Methods: Three types of standard and commercial food color additives (Sunset Yellow, Tartrazine, and Carmoisine) were extensively examined. The chemical structures and functional groups of the dyes were evaluated by Fourier-transform infrared (FTIR) spectroscopy. The melting temperatures of the dyes were also determined by chemical thermal analysis. The acute toxicity test to evaluate the standard and commercial food color safety was estimated by a range-finding study using 150 Wistar albino rats. Sub-groups were administered one of the three colors under study at doses of 2, 3, 4, and 5 g/kg body weight (BW) orally for 7 days. When no mortality was observed, an additional 15 g/kg BW was administered. Concerning the median lethal dose 50 (LD50), 38 rats were exploited using the up-and-down method. Results: Commercial dyes had lower melting points than standard colors. Regarding the range-finding study, rats receiving different doses of the dyes exhibited no signs of toxicity, no deaths, and no clinical or gross pathological signs throughout the 7 days of the experiment. However, the animals that were dosed with 15 g/kg BW of each dye showed signs of loss of appetite, tachycardia, drowsiness, and eventual death. The LD50 values of the commercial food dyes, particularly Sunset Yellow and Carmoisine, were lower than those of the standard dyes. Conclusion: Commercial food colors were more toxic to rats than standard food colors. Differences were observed between the purity of the standard and commercial dyes, and the latter ones contained different percentages of salt, indicating the occurrence of fraud in commercial markets. Keywords: acute toxicity, food colors, Fourier-transform infrared spectroscopy, lethal dose 50, range-finding study.

Chemical Characterization, Evaluation of Acute Oral Toxicity, and Anti-Diabetic Activity of Aloe sabaea Flowers Extract on Alloxan-Induced Diabetic Rats.

The study aimed to conduct chemical profiling, acute in-vivo toxicity evaluation, and the potential anti-diabetic effect of standardized Aloe sabaea flowers ethanolic extracts (ASFEE) on alloxan-induced diabetic rats. The chemical composition was analyzed using GC-MS and TLC techniques. The oral acute toxicity study was performed according to the WHO 2000 and the OECD 420 guidelines. Furthermore, anti-diabetic activity was investigated using two doses of ASFEE (0.2 and 0.5 g/kg/day BW, p.o.) compared with glibenclamide (5 mg/kg/day, p.o.). A molecular docking investigation of the identified components with the PTPN9 enzyme was performed to figure out the proposed anti-diabetic mechanism. GC-MS analysis displayed the existence of 18 compounds; mostof the compoundswere fatty acids and theiresters, and phytosterols. Total phenolic and flavonoid contents were 42.00±1.26 mg GAE/g DW and 22.21±1.55 mg QE/g DW, respectively. The results of the in-vivo toxicity study revealed the absence of noticeable signs of toxicity or mortality at various doses establishing the safety of the tested extract. The estimated LD50 value was higher than 10 g/kg. Antidiabetic action exhibited a noticeable decline in fasting blood glucose (FBG) levels comparable to glibenclamide with no inducing intense hypoglycemia and considerable excess weight.

Colonic targeting insulin-loaded trimethyl chitosan nanoparticles coated pectin for oral delivery: In vitro and In vivo studies

Colon-targeted delivery offers several benefits for oral protein delivery, such as low proteolytic enzyme activity, natural pH, and extended residence time, which improve the bioavailability of the encapsulated protein. Therefore, we hypothesize that developing a novel colonic nanocarrier system based on modified chitosan, which enhances solubility at natural pH and is coated with a colon-degradable polymer, will provide an effective delivery system for oral insulin. This study aims to synthesize insulin-loaded pectin-trimethyl chitosan nanoparticles (Ins-P-TMC-NPs) as an oral insulin delivery system and evaluate their efficacy both in vitro and in streptozotocin-induced diabetic male rats. N-trimethyl chitosan (TMC), synthesized via a methylation method, was used to prepare insulin-TMC nanoparticles coated with pectin via the ionic gelation method. The nanoparticles were characterized for their physicochemical properties, cumulative release profile, and surface morphology. In vitro biological cytotoxicity and cellular uptake of the nanoparticles were evaluated against HT-29 cells using an MTT assay and fluorescent microscopy, respectively. The in vivo blood glucose-lowering effect was assessed in diabetic male Sprague–Dawley rats, with in vivo toxicity evaluated in the liver, spleen, duodenum, pancreas, and kidney through histological studies (H&E staining). The results showed that Ins-P-TMC-NPs were spherical, with an average size of 379.40 ± 40.26 nm, a polydispersity index of 24.10 ± 1.03 %, a zeta potential of +17.20 ± 0.52 mV, and a loading efficiency of 83.21 ± 1.23 %. Compared to uncoated TMC nanoparticles, Ins-P-TMC-NPs reduced insulin loss in simulated gastrointestinal fluid by approximately 67.23 ± 0.97 % and provided controlled insulin release in simulated colonic fluid. In vitro bioactivity studies revealed that Ins-P-TMC-NPs were non-toxic, with cell viability of 91.12 ± 0.91 %, and exhibited high cellular uptake in the HT-29 cell line with a fluorescence intensity of 37.80 ± 2.40. Furthermore, in vivo studies demonstrated a sustained reduction in blood glucose levels after oral administration, peaking after 8 h with a glucose reduction of 87 ± 1.03 %. Histological sections showed no signs of toxicity. Overall, the developed colon-targeted oral insulin delivery system shows great potential as a candidate for oral insulin administration.

Fumaric acid per se and in combination with methotrexate arrests inflammation via moderating inflammatory and oxidative stress biomarkers in arthritic rats

Objective: Fumaric acid is a dicarboxylic acid that belongs to the phenolic class enriched in fruits and vegetables that are traditionally used for the treatment of various ailments. The research was planned to find out the anti-inflammatory and anti-arthritic activities of fumaric acid using in-vitro and in-vivo assays. Moreover, safety study was also done. Materials and methods: The 0.1 ml complete Freund’s adjuvant was injected in left hind paw in all Wistar rats except normal rats at day 1 to induced arthritis. The treatment with fumaric acid at 10, 20, 40, and fumaric acid 40 mg/kg together with methotrexate (MTX) was administered to immunized rats at 8th day via oral gavage and continued till 28th day though, MTX was administered as standard control. Results: The fumaric acid notably (p < 0.0001) lessened the paw edema and arthritic scoring, reinstated body and immune organ weight, and oxidation status in treated rats. Fumaric acid notably restored altered C-reactive protein, rheumatoid factor, liver function tests, ESR, WBCs, RBCs and Hb levels in treated rats. The fumaric acid in combination noticeably (p < 0.01–0.0001) suppressed the expression of TNF- α, IL-6, IL-1β, NF-kβ, and COX-2, and over expressed IL-4, and IL-10 in contrast to other treated groups. Fumaric acid had presented a dose-dependent antioxidant, anti-inflammatory and anti-arthritic activities while notable activity exhibited by fumaric acid in combination with MTX. The fumaric acid exhibited non-significant clinical signs of toxicity and mortality in acute toxicity study. The LD50 was more than 2000 mg/kg. Conclusion: Fumaric acid in combination can be used as disease-modifying anti-rheumatic drug but it will need extensive pre-clinical and clinical studies.

KS18, a Mcl-1 inhibitor, improves the effectiveness of bortezomib and overcomes resistance in refractory multiple myeloma by triggering intrinsic apoptosis.

Despite a record number of clinical studies investigating various anti-myeloma treatments, the 5-year survival rate for multiple myeloma (MM) patients in the US is only 55%, and almost all patients relapse. Poor patient outcomes demonstrate that myeloma cells are "born to survive" which means they can adapt and evolve following treatment. Thus, new therapeutic approaches to combat survival mechanisms and target treatment resistance are required. Importantly, Mcl-1, anti-apoptotic protein, is required for the development of MM and treatment resistance. This study looks at the possibility of KS18, a selective Mcl-1 inhibitor, to treat MM and overcome resistance. Our investigation demonstrates that KS18 effectively induces cell death in MM by dual regulatory mechanisms targeting the Mcl-1 protein at both transcriptional and post-translational levels. Specifically, KS18 suppresses Mcl-1 activation via STAT-3 pathway and promotes Mcl-1 phosphorylation/ubiquitination/proteasome-dependent protein degradation (UPS). Significantly, KS18 triggered caspase-dependent apoptosis in MM patient samples and bortezomib-resistant cells, synergizing with venetoclax to boost apoptosis. KS18 promises to overcome bortezomib and venetoclax resistance and re-sensitize myeloma cells to chemotherapy. Furthermore, the study shows the tremendous impact of KS18 in inhibiting colony formation in bortezomib-resistant cells and demonstrates significant tumor shrinkage in KS18-treated NSG mice without notable toxicity signs after 4weeks of therapy with a single acceptable dose each week, indicating its powerful anti-neoplastic and anti-resistance characteristics. This study strongly implies that KS18 may treat MM and provide new hope to patients who are experiencing recurrence or resistance.

Assessment of oxidative stress biomarkers in Palaemon varians exposed to deep eutectic systems.

In recent years, there has been extensive research within the scientific community on deep eutectic systems due to their remarkable versatility in solubilizing diverse substances and serving as effective solvents in catalytic processes. While initially regarded as non-toxic, a comprehensive toxicological assessment is essential to comprehend their behavior within organisms. In this study, seven distinct systems, composed of N,N,N-triethyl-N-(2,3-dihydroxypropyl)ammonium chloride (N00Cl) and glycerol-derived ethers with alkyl chains of varying lengths (100, 200, 3F00, 300, 3i00, and 400), in a 1:2 molar ratio were investigated for their aquatic toxicity in shrimp (Palaemon varians). The assessment involved analyzing oxidative stress biomarkers such as glutathione S-transferase, glutathione peroxidase, catalase, superoxide dismutase, total antioxidant capacity (TAC), and lipoperoxidation (MDA content). Results show an odd-even effect for LC50 values being N00Cl-300, the system showing higher values. Regarding oxidative stress, an imbalance between reactive oxygen species (ROS) and antioxidant capacity in the organisms has been observed, suggesting significant toxicity to shrimps due to the changes in oxidative stress biomarkers at high concentrations. However, at 100mg/l all systems can be considered environmentally safe, and no negative impacts are expected on aquatic ecosystems.

Anxiolytic and Anticonvulsant Potential of Biosynthetic Limonene Derivatives in Adult Zebrafish.

This study investigated the anxiolytic and anticonvulsant effects and safety profile of limonene enantiomers and their oxidized derivatives.The toxicity test was performed by monitoring the animals for 96 hours, with no deaths or significant toxicity observed up to the highest dose, which allowed the determination of the LD50. Doses of 4, 20 and 40 mg/kg were tested, with no toxicity observed up to 96h (LD50 > 40 mg/kg). Anxiolytic activity was measured in a preference test for light and dark areas, and the effect of the compounds was evaluated in the presence of serotonergic antagonists. The (S)-(-)-LIM and (R)-(+)-LIM enantiomers showed anxiolytic effects, with (S)-(-)-LIM being effective at all doses. In the anticonvulsant test, the oxidized derivatives, such as perilyl acid (PAC), significantly delayed PTZ-induced seizures, an effect blocked by flumazenil (FMZ). The oxidized derivatives, especially perilyl acid (PAC), showed anxiolytic effects at all doses and significantly delayed the three PTZ-induced seizure events. This effect was blocked by FMZ, suggesting a relationship between PAC and the GABAergic pathway. PAC, being the most oxidized derivative, was the most effective for both anxiety and delaying seizure progression, suggesting that oxidation of limonene compounds may increase their therapeutic efficacy.

Photothermally reinforced chemodynamic therapy in the treatment of osteosarcoma by polydopamine-modified, copper peroxide loaded ZIF8 nanoparticles

Chemodynamic therapy (CDT) has played an important role in osteosarcoma (OS) treatment. However, the insufficient content of endogenous H2O2 and high expression of glutathione (GSH) in tumor tissues limit the antitumor efficacy of CDT. In this work, we developed polydopamine (PDA) coated and CuO2 NPs loaded ZIF8 nanoparticles (CuO2@ZIF8@PDA NPs) for thermally reinforced CDT treatment of OS. The CuO2@ZIF8@PDA NPs exhibited excellent stability in neutral solutions while degraded in weakly acidic environments to generate hydrogen peroxide (H2O2) and Cu2+. Cu2+ consumes GSH in tumor tissues to generate Cu+. Both Cu2+ and Cu+ catalyzed the decomposition of H2O2, triggering a Fenton-like reaction to produce hydroxyl radicals (•OH). The PDA coating endowed the nanosystem with photothermal conversion capabilities under near-infrared laser irradiation, further promoting the generation of •OH, and inducing tumor cell death. In vitro experiments demonstrated that CuO2@ZIF8@PDA NPs exhibited significant toxicity towards K7M2 cells while remaining non-toxic to normal cells. In vivo studies revealed that under 808 nm laser irradiation, CuO2@ZIF8@PDA NPs exhibited stronger killing ability against K7M2 cells than CuO2@ZIF8@PDA NPs alone. This system, which combines GSH depletion, intratumoral H2O2 self-generation, and photothermally enhanced CDT, holds great promise for playing a pivotal role in the treatment of osteosarcoma.

Internalization and mechanisms of toxicity of lipid nanocapsules in HepG2 and HepaRG hepatoma cells upon acute and chronic exposures

Lipid nanocapsules (LNCs) used as nanomedicine have been developed to enhance pharmacokinetics and decrease side effects of drugs, particularly for cancer therapies. After intravenous administration, LNCs possess an important hepatic tropism however, few data exist about their toxicity and even less after repeated exposure. This study aimed to assess the in vitro toxicity and internalization of unloaded LNCs, of 50 and 100 nm size, on HepG2 and HepaRG liver cell lines. Internalization of the 50 nm LNCs was slower compared to the 100 nm LNCs and both LNCs exhibited a higher toxicity on cancerous HepG2 cells compared to differentiated HepaRG cells. LNCs were mainly internalized via caveolin-mediated endocytosis in both cell lines. Upon chronic exposure, the toxicity of LNCs on HepaRG cells increased, although the pathways of internalization remained unchanged. Cell death studies have demonstrated an involvement of ferroptosis, but not of apoptosis. After acute and repeated exposures on HepaRG cells, the 100 nm LNCs showed a good safety profile. Finally, LNCs induced a more significant toxicity associated with faster internalization in the HepG2 cancerous model than in the differentiated HepaRG cells. This provides good evidence for LNCs to potentialize the cytotoxic effects of an active drug on liver cancer cells.

Curcuminoid Chalcones: Synthesis and Biological Activity against the Human Colon Carcinoma (Caco-2) Cell Line.

There are many current scientific reports on the synthesis of various derivatives modelled on the structure of known small-molecular and natural bioactive compounds. Curcuminoid chalcones are an innovative class of compounds with significant therapeutic potential against various diseases and they perfectly fit into the current trends in the search for new biologically active substances. The aim of this study was to design and synthesise a series of curcuminoid chalcones. The objective of this scientific paper was to synthesise twelve curcuminoid chalcones and confirm their structures using spectral methods. Additionally, the biological activity of three of the synthesised compounds was evaluated using various assays, and their anticancer properties and toxicity were studied. The proposed derivatives were obtained via the Claisen-Schmidt reaction of selected acetophenones and aldehydes in various conditions using both classical methods: the solutions and solvent-free microwave (MW) or ultrasound (US) variants. The most optimal synthetic method for the selected curcuminoid chalcones was the classical Claisen-Schmidt condensation in an alkaline (NaOH) medium. Spectral methods were used to confirm the structures of the compounds. The resazurin reduction assay, caspase-3 activity assay, and RT-qPCR method were performed, followed by measurements of the intracellular reactive oxygen species (ROS) level and the lactate dehydrogenase (LDH) release level. Twelve designed curcuminoid chalcones were successfully synthesized and structurally confirmed by NMR, MS, and IR spectroscopy. Examination of the anticancer activity was carried out for the three most interesting chalcone products. The results suggested that compound 3a increased the metabolism and/or proliferation of the human colon carcinoma (Caco-2) cell line, while compounds 3b and 3f showed significant toxicity against the Caco-2 cell line. Overall, the preliminary results suggested that compound 3b exhibited the most favourable anticancer activity.

Characterization and biological activity of selenium nanoparticles biosynthesized by Yarrowia lipolytica.

In this research, biogenic selenium nanoparticles were produced by the fungi Yarrowia lipolytica, and the biological activity of its nanoparticles was studied for the first time. The electron microscopy analyses showed the production of nanoparticles were intracellular and the resulting particles were extracted and characterized by XRD, zeta potential, FESEM, EDX, FTIR spectroscopy and DLS. These analyses showed amorphous spherical nanoparticles with an average size of 110 nm and a Zeta potential of -34.51 ± 2.41 mV. Signatures of lipids and proteins were present in the capping layer of biogenic selenium nanoparticles based on FTIR spectra. The antimicrobial properties of test strains showed that Serratia marcescens, Klebsiella pneumonia, Escherichia coli, Pseudomonas aeruginosa and Bacillus subtilis were inhibited at concentrations between 160 and 640 μg/mL, while the growth of Candida albicans was hindered by 80 μg/mL of biogenic selenium nanoparticles. At concentrations between 0.5 and 1.5 mg/mL of biogenic selenium nanoparticles inhibited up to 50% of biofilm formation of Klebsiella pneumonia, Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa. Additionally, the concentration of 20-640 μg/mL of these bioSeNPs showed antioxidant activity. Evaluating the cytotoxicity of these nanoparticles on the HUVEC and HepG2 cell lines did not show any significant toxicity within MIC concentrations of SeNPs. This defines that Y. lipolytica synthesized SeNPs have strong potential to be exploited as antimicrobial agents against pathogens of WHO concern.

Isolation and Characterization of Cytotoxic Compounds from Detarium microcarpum Guill. and Perr. Stem Bark.

Globally, about 8.2 million cancer-related deaths are recorded annually. Sadly, most of the deaths result from the toxicity of most chemotherapeutic agents. Hence, there are growing demands for chemotherapeutic agents with high specificity and selectivity. This study was designed to assess the cytotoxic potential of Detarium microcarpum and isolate cytotoxic compounds with better selectivity profiles. Detarium microcarpum Stem bark (DMS) was collected and authenticated at the Forest Herbarium Ibadan (FHI), and a voucher (FHI-111954) was issued. Dried DMS was pulverized and extracted into 70% methanol. The extract was partitioned into hexane, dichloromethane, and ethyl acetate fractions. The cytotoxicities of the extract, fractions, and isolated compounds were determined. The cytotoxicity of the isolated compounds was tested against different cell lines, including human breast (AU565 and MDA MB231), oral adenosquamous (CAL27), and cervical (HeLa) cancer cells, as well as healthy (3T3) non-cancer cells. Methyl gallate, eriodictyol, quercetin, quebrachitol, catechin, catechin gallate, and gallic acid, isolated from dichloromethane and ethyl acetate fractions, displayed weak cytotoxicity against breast (AU565 and MDAMD-231) and cervical (HeLa) cancer cell lines. Interestingly, all the compounds, except gallic acid (48.91±4.51% inhibition), displayed potent cytotoxicity on oral cancer cells. Methyl gallate and quercetin displayed the highest activity, with IC50 values of 89.57±1.98µM and 78.19±1.49µM, respectively. Interestingly, all the compounds were not toxic to healthy non-cancer (3T3) cells. The compounds displayed anticancer activity specific to oral cancer cells and were highly selective for cancer cells without causing significant toxicity to healthy non-cancer cells.