Toxic Effects In Mice Research Articles

Antivenom potential of the latex of Jatropha mutabilis baill. (Euphorbiaceae) against Tityus stigmurus venom: Evaluating its ability to neutralize toxins and local effects in mice

Ethnopharmacological relevanceSpecies of the Jatropha genus (Euphorbiaceae) are used indiscriminately in traditional medicine to treat accidents involving venomous animals. Jatropha mutabilis Baill., popularly known as “pinhão-de-seda,” is found in the semi-arid region of Northeastern Brazil. It is widely used as a vermifuge, depurative, laxative, and antivenom. Aim of the studyObtaining the phytochemical profile of the latex of Jatropha mutabilis (JmLa) and evaluate its acute oral toxicity and inhibitory effects against the venom of the scorpion Tityus stigmurus (TstiV). Materials and methodsThe latex of J. mutabilis (JmLa) was obtained through in situ incisions in the stem and characterized using HPLC-ESI-QToF-MS. Acute oral toxicity was investigated in mice. The protein profile of T. stigmurus venom was obtained by electrophoresis. The ability of latex to interact with venom components (TstiV) was assessed using SDS-PAGE, UV–Vis scanning spectrum, and the neutralization of fibrinogenolytic and hyaluronidase activities. Additionally, the latex was evaluated in vivo for its ability to inhibit local edematogenic and nociceptive effects induced by the venom. ResultsThe phytochemical profile of the latex revealed the presence of 75 compounds, including cyclic peptides, glycosides, phenolic compounds, alkaloids, coumarins, and terpenoids, among others. No signs of acute toxicity were observed at a dose of 2000 mg/kg (p.o.). The latex interacted with the protein profile of TstiV, inhibiting the venom's fibrinogenolytic and hyaluronidase activities by 100%. Additionally, the latex was able to mitigate local envenomation effects, reducing nociception by up to 56.5% and edema by up to 50% compared to the negative control group. ConclusionsThe latex of Jatropha mutabilis exhibits a diverse phytochemical composition, containing numerous classes of metabolites. It does not present acute toxic effects in mice and has the ability to inhibit the enzymatic effects of Tityus stigmurus venom in vitro. Additionally, it reduces nociception and edema in vivo. These findings corroborate popular reports regarding the antivenom activity of this plant and indicate that the latex has potential for treating scorpionism.

The Agonistic Activity of the Human Epidermal Growth Factor is Reduced by the D46G Substitution.

Resistance to anti-tumor agents targeting the epidermal growth factor receptor (EGFR) reduces treatment response and requires the development of novel EGFR antagonists. Mutant epidermal growth factor (EGF) forms with reduced agonistic activity could be promising agents in cancer treatment. EGF D46G affinity to EGFR domain III was assessed with affinity chromatography. EGF D46G acute toxicity in Af albino mice at 320 and 3200 μg/kg subcutaneous doses was evaluated. EGF D46G activity in human epidermoid carcinoma cells at 10 ng/mL concentration in serum-free medium and in subcutaneous Ehrlich ascites carcinoma mice model at 320 μg/kg dose was studied. The D46G substitution decreases the thermal stability of EGF complexes with EGFR domain III by decreasing the ability of the C-terminus to be released from the intermolecular β- sheet. However, with remaining binding sites for EGFR domain I, EGF D46G effectively competes with other EGF-like growth factors for binding to EGFR and does not demonstrate toxic effects in mice. EGF D46G inhibits the proliferation of human epidermoid carcinoma cells compared to native EGF. A single subcutaneous administration of EGF D46G along with Ehrlich carcinoma cells injection inhibits the proliferation of these cells and delays tumor formation for up to seven days. EGF D46G can be defined as a partial EGFR agonist as this mutant form demonstrates reduced agonistic activity compared to native EGF. The study emphasizes the role of the EGF C-terminus in establishing interactions with EGFR domain III, which are necessary for EGFR activation and subsequent proliferation of cells.

Inula britannica ameliorates alcohol-induced liver injury by modulating SIRT1-AMPK/Nrf2/NF-κB signaling pathway

ObjectiveInula britannica is a traditional Chinese medicinal and functional food with various effects such as anti-liver injury, hypoglycemia, antioxidants, and anti-tumor. This study aimed to investigate the protective effects and mechanisms of the ethanolic extract of I. britannica (EEIB) on alcohol-induced liver injury in mice. MethodsFifty-six female C57BL/6 mice were randomly divided into seven groups: control group (Con), ethanol feeding model group (EtOH), Silibinin positive treatment group (EtOH + Silibinin 100 mg/kg), EEIB treatment group (EtOH + EEIB 100, 200, and 400 mg/kg), and EEIB control group (EEIB 400 mg/kg). The National Institute on Alcohol Abuse and Alcoholism (NIAAA) ethanol-feeding model was used to study the effects of EEIB on alcohol-induced lipid metabolism, inflammation, oxidative stress, and fibril formation in mice by histopathological evaluation, immunofluorescence staining, Western blotting analysis and molecular docking. ResultsEEIB reduced liver indices to different degrees to normal levels and improved liver morphology in mice. EEIB inhibited alcohol-induced liver injury by activating the sirtuin 1 (SIRT1)-adenosine monophosphate-activated protein kinase (AMPK) signaling pathway in the liver of alcohol-fed mice, in which sesquiterpenes may be the potential active ingredients, and also down-regulated the expression of alpha-smooth muscle actin (α-SMA), collagen alpha (Collagen I), tumor necrosis factor-alpha (TNF-α) and attenuated alcohol-induced liver injury. In addition, EEIB also activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway, which alleviated alcohol-induced liver injury at the level of oxidative stress. Notably, the EEIB control group demonstrated that EEIB had no toxic effects in mice. EEIB reduced alcoholic liver injury in a dose-dependent manner. Its therapeutic efficacy was comparable to, if not better than, that of Silibinin when administered at a dose of 400 mg/kg. ConclusionEEIB showed significant therapeutic effects on alcohol-induced liver injury in mice, and its mechanism of action was related to the SIRT1-AMPK, nuclear factor-kappa B (NF-κB), and Nrf2 signaling pathways, in which sesquiterpenes may be the potential active ingredients.

In vivo anthelmintic potentials of Gongronema latifolium and Picralima nitida against gastrointestinal parasite (Heligmosomoides bakeri).

Gastrointestinal parasites which are responsible for soil-transmitted helminthiases cause illness globally. The control of helminthiasis depends on mass distribution of anthelmintics which has been reported for its resistance, toxicity and low efficacy. In this study, anthelmintic potentials of Gongronema latifolium and Picralima nitida which have wide application in traditional medicine were determined in vivo using Heligmosomoides bakeri a naturally occurring gastro-intestinal parasite of rodents that is closely related to highly prevalent human nematode parasites. Extracts of P. nitida at 500 mg/kg had higher (p< 0.05) chemosuppression (92.45 %) than extracts of G. latifolium (65.82 %) and was highly comparable to albendazole (92.61 %). As the dose of the extracts increased from 300 to 500 mg/kg body weight, chemosuppression of 84.91 % and 92.45 % (P. nitida) and 43.54 % and 65.82 % (G. latifolium) respectively were produced. The extract of P. nitida gave deparasitization rates (p<0.05) of 72.60 % and 77.16 % at 300g/kg and 500mg/kg of body weight respectively. The glucose level and protein content reduced (p<0.05) in mice treated with extract of P. nitida when compared with extract of G. latifolium and untreated mice. Phytochemical screening revealed that P. nitida and G. latifolium contained flavonoids, alkaloids, saponins, tannins and polyphenols. Acute toxicity studies showed that Gongronema latifolium and Picralima nitida have no apparent toxic effect in mice even at the dose of 5000 mg/kg. Extracts of P. nitida and G. latifolium have anthelmintic properties that are dose-dependent, and this could offer potential lead for the development of safe, effective and affordable anthelmintics.

Giloy (Tinospora cordifolia) Extract Mediated Biochemical, Haematological and Histological Alterations in Mice

Tinospora cordifolia (TC), a medicinal plant deeply integrated into India's folklore and Ayurvedic medical tradition, has been a reliable remedy for addressing various health concerns. Despite its proven efficacy in managing diseases, it is essential to exercise prudence regarding its dosage, as excessive consumption may result in undesirable consequences. This present study seeks to ascertain if the methanolic extract of TC triggers any adverse effects on organ function, haematological parameters, or biochemical profiles. The extract was administered intra peritoneally (IP) into the Swiss albino mice at a concentration of 300mg/kg body weight and observations were taken on 7th and 14th day. In comparison to control groups, the levels of haemoglobin (Hb), packed cell volume (PVC), red blood corpuscles (RBC), red cell distribution width (RCW), and platelet count increase. However, significant decrease was also observed in the levels of erythrocyte sedimentation rate (ESR) and lymphocytes. Blood biochemical analysis reveals a significant increase in urea but a subsequent decrease in blood sugar levels. The findings unequivocally illustrate the disruption in the seminiferous tubules of the testis, accompanied by a decrease in spermatid count. Furthermore, observable damage to kidney tissues was noted. Based on these observations, it can be inferred that, despite its multifaceted therapeutic applications, TC extract may exert toxic effects in mice.

Targeting GLI1 and GLI2 with small molecule inhibitors to suppress GLI-dependent transcription and tumor growth

Aberrant activation of Hedgehog (HH) signaling in cancer is the result of genetic alterations of upstream pathway components (canonical) or other oncogenic mechanisms (noncanonical), that ultimately concur to activate the zinc-finger transcription factors GLI1 and GLI2. Therefore, inhibition of GLI activity is a good therapeutic option to suppress both canonical and noncanonical activation of the HH pathway. However, only a few GLI inhibitors are available, and none of them have the profile required for clinical development due to poor metabolic stability and aqueous solubility, and high hydrophobicity. Two promising quinoline inhibitors of GLI were selected by virtual screening and subjected to hit-to-lead optimization, thus leading to the identification of the 4-methoxy-8-hydroxyquinoline derivative JC19. This molecule impaired GLI1 and GLI2 activities in several cellular models interfering with the binding of GLI1 and GLI2 to DNA. JC19 suppressed cancer cell proliferation by enhancing apoptosis, inducing a strong anti-tumor response in several cancer cell lines in vitro. Specificity towards GLI1 and GLI2 was demonstrated by lower activity of JC19 in GLI1- or GLI2-depleted cancer cells. JC19 showed excellent metabolic stability and high passive permeability. Notably, JC19 inhibited GLI1-dependent melanoma xenograft growth in vivo, with no evidence of toxic effects in mice. These results highlight the potential of JC19 as a novel anti-cancer agent targeting GLI1 and GLI2.

Toxicity assessment of Phlogacanthus thyrsiflorus, a traditionally used anthelmintic plant of India

BackgroundThe leaves of Phlogacanthus thyrsiflorus are used as an anthelmintic remedy by the tribes of upper Assam. This study evaluates its toxic effects in laboratory bred mice and rats. Mice were orally dosed for 5 days, whereas rats were dosed for 28 days and variations in behaviour, feeding habits and blood parameters were recorded. The vital organs were processed for histopathology to observe any alternations from normal architecture.ResultsNo mortality or adverse toxic effects were manifested in this assessment. Evaluated parameters, namely feeding behaviour, body weights and relative organ weights, appeared to be similar to the control animals. Also, the haematological and serum biochemical parameters and histopathological studies revealed normal results.ConclusionsThe study indicates that P. thyrsiflorus may not be capable of causing toxic effects in mice and rats, and hence, its traditional use as an anthelmintic could be continued. However, other studies to further validate this may be carried out.

A Therapeutic Vaccine in Combination with Cyclic GMP-AMP Cures More Differentiated Melanomas in Mice.

We have identified a combinational immunotherapy termed TheraVac vaccine (TheraVac) that can cure multiple large established mouse tumors, but it failed to cure melanoma in mice. TheraVac consists of an immunostimulating arm containing an agonist (HMGN1 [N1]) for TLR4 and an agonist (R848) for TLR7/8 that synergize to activate tumor-infiltrating dendritic cells (DCs) and promote Th1 immune responses. The second arm uses an immune checkpoint blockade, anti-PDL-1, to diminish tumor-associated immunosuppression. In this study, we investigated supplementation of TheraVac by a stimulator of IFN genes (STING) agonist, cyclic GMP-AMP (cGAMP), because together they synergize in activating DCs and produced more immunostimulating IL-12p70 and TNF-α cytokines. The synergistic activation and maturation of DCs is dependent on the activation of tank binding kinase-1 (TBK1). Treatment of three different melanin-producing mouse melanomas (B16F1, M3, and M4) with intratumoral delivery of cGAMP and TheraVac eradicated 60-80% of these melanomas. Immunoprofiling of M3 tumor treated with TheraVac plus cGAMP showed an increase in CD8+ CTLs and macrophages in the tumor. There was also a marked increase of CD4, CD8 effector and memory T cells and generation of functional tumor-specific CTLs in tumor-draining lymph nodes. The resultant tumor-free mice were selectively resistant to subsequent challenge with the same tumors, indicating long-term tumor-specific protective immunity. Overall, our findings have important implications for clinical trials with a combination of these immunotherapeutics to cure melanin-producing human melanomas, without the need for exogenous tumor Ags and no clear toxic effects in mice.

Synthesis, Antidiabetic Evaluation and Molecular Docking Studies of Thiazolidine-2,4-Dione Analogues

Abstract: Introduction: Diabetes Mellitus is a disorder of metabolism described by high glucose levels. The disorder kills a larger number of individuals consistently than of malignant growth and AIDS combined. Presently available drugs have several drawbacks forcing to withdraw from treatment. The potent side effect i.e., hepatotoxicity and cardiovascular toxicity limits the use of thiazolidine-2,4-dione derivative as safe drugs. Our aim is towards the development of synthetic compounds as potential antidiabetic agents, particularly preparation and screening of new analogues of thiazolidine-2,4-dione (TZD) which are well established as oral insulin sensitizing agents that improve insulin resistance and are agonists of Peroxisome Proliferator Activated Receptor–γ (PPAR-γ). Materials and Methods: Proper substitution at C-5 position of thiazolidine-2,4-dione could produce better and potential antidiabetics with improved pharmacological properties, including toxicity. Our aim of this research work is towards this. Results: A series of C-5 substituted thiazolidine-2,4-dione analogues were synthesized. Structures of these new analogues were confirmed by IR, 1H-NMR and MASS spectroscopy. Among the synthesized compounds, three compounds: 5-(2-pyridinylbenzylidene) thiazolidine-2,4-dione, 5-(3,4-dimethoxybenzylidene) thiazolidine-2,4-dione and 5-(2,3,4-trifluorobenzylidene) thiazolidine-2,4-dione showed significant antidiabetic activity in streptozotocin induced diabetic mice comparable with Pioglitazone drug. The molecular docking studies of these compounds performed using protein target showed amino acid interactions with Leu270, Gln283 and Arg288 similar with that of Rosiglitazone and Pioglitazone. The compounds did not show any toxic effect in mice even at 2000 mg/kg of dose. Therefore, synthesis of modified and better thiazolidine-2,4-dione containing drugs other than the currently available drugs is of importance in antidiabetic drug research. Keywords: Thiazolidine-2,4-dione, Molecular docking, Antidiabetic evaluation, Swiss albino mice.

Establishing an hTERT-driven immortalized umbilical cord-derived mesenchymal stem cell line and its therapeutic application in mice with liver failure

Acute liver failure (ALF) is characterized by rapid liver cell destruction. It is a multi-etiological and fulminant complication with a clinical mortality of over 80%. Therapy using mesenchymal stem cells (MSCs) or MSCs-derived exosomes can alleviate acute liver injury, which has been demonstrated in animal experiments and clinical application. However, similar to other stem cells, different cell sources, poor stability, cell senescence and other factors limit the clinical application of MSCs. To achieve mass production and quality control on stem cells and their exosomes, transfecting umbilical cord mesenchymal stem cell (UCMSC) with lentivirus overexpressing human telomerase reverse transcriptase (hTERT) gene, the hTERT-UCMSC was constructed as an immortalized MSC cell line. Compared with the primary UCMSC (P3) and immortalized cell line hTERT-UCMSC at early passage (P10), the hTERT-UCMSC retained the key morphological and physiological characteristics of UCMSC at the 35th passage (P35), and showed no signs of carcinogenicity and toxic effect in mice. There was no difference in either exosome production or characteristics of exosomes among cultures from P3 primary cells, P10 and P35 immortalized hTERT-UCMSCs. Inoculation of either hTERT-UCMSC (P35) or its exosomes improved the survival rate and liver function of ALF mice induced by thioacetamide (TAA). Our findings suggest that this immortalized cell line can maintain its characteristics in long-term culture. Inoculation of hTERT-UCMSC and its exosomes could potentially be used in clinics for the treatment of liver failure in the future.

Eugenia gracillima essential oil has pharmaceutical applications in pain and inflammation without toxic effects in mice

Ethnopharmacological relevanceEugenia gracillima is widely used by the population in the manufacture of pulps and jellies, with popular reports of its use in the treatment of infections in the urinary system, respiratory and dermatological problems. A previous study reports that EO from E. gracillima leaves proved to be a promising antioxidant agent in combating the promastigote forms of protozoa. Despite this, this species has been little studied due to its pharmacological properties. Study objectiveIn this study, an essential oil extracted (EO) from Eugenia gracillima leaves was evaluated for its acute toxicity and anti-inflammatory, antinociceptive and behavioral effects in mice. MethodsThe EO was obtained by hydrodistillation, and the composition analysis was performed by gas chromatography coupled to mass spectrometry. Acute toxicity assessment was performed with observation of hematological parameters and histopathological evaluation, as well as tests to investigate antinociceptive, anti-inflammatory activities and behavioral effects. ResultsChromatographic analysis showed D-germacrene (16.10%), γ-muurolene-g (15.60%) and bicyclogermacrene (8.53%) as the majority of compounds. In the toxicity evaluation, no death or physiological changes were observed in mice treated with a single oral dose of up to 5000 mg/kg, and it did not lyse erythrocytes in vitro. The hematological parameters evaluated were not changed after treatment; however, 5,000 mg/kg promoted an increase in transaminase levels. In the histopathological evaluation, only the animals that received the dose of 5000 mg/kg showed discrete leukocyte infiltration around the centrilobular vein in the liver. Antinociceptive activity was detected through tests of acetic acid-induced writhing, formalin, and tail flick, promoted in part by the opioid receptor pathway. In the evaluation of anti-inflammatory activity, a reduction in inflammation was observed in the paw edema test and a decrease in the migration of leukocytes and neutrophils in the peritonitis test. The open field and elevated plus maze tests showed that EO did not affect the animals' motor functions or exploratory activity. ConclusionIt was concluded that the essential oil of E. gracillima has potential for the development of pharmaceutical formulations with analgesic and anti-inflammatory actions in non-toxic concentrations.

Biological Activity In Vitro, Absorption, BBB Penetration, and Tolerability of Nanoformulation of BT44:RET Agonist with Disease-Modifying Potential for the Treatment of Neurodegeneration.

BT44 is a novel, second-generation glial cell line-derived neurotropic factor mimetic with improved biological activity and is a lead compound for the treatment of neurodegenerative disorders. Like many other small molecules, it suffers from intrinsic poor aqueous solubility, posing significant hurdles at various levels for its preclinical development and clinical translation. Herein, we report a poly(2-oxazoline)s (POx)-based BT44 micellar nanoformulation with an ultrahigh drug-loading capacity of 47 wt %. The BT44 nanoformulation was comprehensively characterized by 1H NMR spectroscopy, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), dynamic light scattering (DLS), and cryo-transmission/scanning electron microscopy (cryo-TEM/SEM). The DSC, XRD, and redispersion studies collectively confirmed that the BT44 formulation can be stored as a lyophilized powder and can be redispersed upon need. The DLS suggested that the redispersed formulation is suitable for parenteral administration (Dh ≈ 70 nm). The cryo-TEM measurements showed the presence of wormlike structures in both the plain polymer and the BT44 formulation. The BT44 formulation retained biological activity in immortalized cells and in cultured dopamine neurons. The micellar nanoformulation of BT44 exhibited improved absorption (after subcutaneous injection) and blood-brain barrier (BBB) penetration, and no acute toxic effects in mice were observed. In conclusion, herein, we have developed an ultrahigh BT44-loaded aqueous injectable nanoformulation, which can be used to pave the way for its preclinical and clinical development for the management of neurodegenerative disorders.

Intrinsically Disordered Protein Micelles as Vehicles for Convection-Enhanced Drug Delivery to Glioblastoma Multiforme.

Lipid and micelle-based nanocarriers have been explored for anticancer drug delivery to improve accumulation and uptake in tumor tissue. As an experimental opportunity in this area, our lab has developed a protein-based micelle nanocarrier consisting of a hydrophilic intrinsically disordered protein (IDP) domain bound to a hydrophobic tail, termed IDP-2Yx2A. This construct can be used to encapsulate hydrophobic chemotherapeutics that would otherwise be too insoluble in water to be administered. In this study, we evaluate the in vivo efficacy of IDP-2Yx2A by delivering a highly potent but water-insoluble cancer drug, SN38, into glioblastoma multiforme (GBM) tumors via convection-enhanced delivery (CED). The protein carriers alone are shown to elicit minimal toxicity effects in mice; furthermore, they can encapsulate and deliver concentrations of SN38 that would otherwise be lethal without the carriers. CED administration of these drug-loaded micelles into mice bearing U251-MG GBM xenografts resulted in slowed tumor growth and significant increases in median survival times compared to nonencapsulated SN38 and PBS controls.

Optimization of endothelial growth factor receptor monoclonal antibody-gold nanorods photothermal therapy for laryngeal squamous cell carcinoma

ABSTRACT It reported that heat generated by near-infrared laser irradiation of gold nanorods (AuNRs) effectively inhibited tumor cells, and the conjugate of epidermal growth factor receptor monoclonal antibody (EGFRmAb) and gold nanorods could selectively binded to the surface of cancer cell membrane expressing EGFR. However, there are few research reports on EGFRmAb-AuNRs in laryngeal squamous cell carcinoma. Therefore, our study aimed to investigate the photothermal effect of EGFRmAb modified AuNRs in inducing tumor cell death in an animal model of laryngeal squamous cell carcinoma. We showed that the conjugates of EGFRmAb and AuNRs selectively entered laryngeal squamous cell carcinoma cells. We analyzed the parameters of laser irradiation by controlling the near-infrared to optimize the condition and procedure of targeted treatment in nude mice treated with EGFRmAb and AuNRs. In addition, we examined the safety of the combined therapy. Test results showed that EGFRmAb-AuNRs inhibited the growth of Hep-2 and CNE-2 cells but not normal epithelial cells, and the semi-inhibitor concentration of EGFRmAb in Hep-2 and CNE-2 cells was 4 pmol/ml and 2 pmol/ml, respectively. AuNRs injected into the tumor and irradiated by near-infrared laser effectively inhibited tumor growth in nude mice without toxic effect in mice. We further confirmed that the apoptosis and necrosis rates of tumor cells in mice were highest under 3 W/cm2 near-infrared laser irradiation and AuNRs minimum concentration of 280 μg/kg. In conclusion, we developed a new method of targeting EGFRmAb combined with AuNRs to achieve photothermal effect in the treatment of laryngeal squamous cell carcinoma.

An observational study conducted prospectively in a cancer specialty hospital found that drug-related issues were common among elderly cancer patients

High glucose levels are a hallmark of the metabolic condition known as diabetes mellitus and is responsible for a higher number of deaths annually than cancer and AIDS combined. Unfortunately, currently available drugs for diabetes treatment have several drawbacks and limitations, such as hepatotoxicity and cardiovascular toxicity, which limit their use as safe drugs. Therefore, our research aims to develop synthetic compounds as potential antidiabetic agents, particularly new analogues of thiazolidine-2,4-dione (TZD), which are recognised as agonists of Peroxisome Proliferator Activated Receptor- γ (PPAR- γ) and oral insulin-sensitizing drugs that reduce insulin resistance. Materials and Methods: Our research focuses on proper substitution at the C-5 position of thiazolidine-2,4-dione to produce better and more effective antidiabetic compounds with improved pharmacological properties and reduced toxicity. We created a number of thiazolidine-2,4-dione analogues with a C-5 substitution and confirmed their structures using IR, 1H-NMR, and MASS spectroscopy. Results: Among the synthesized compounds, three analogues, namely 5-(2-pyridinylbenzylidene) thiazolidine-2,4-dione, 5-(3,4-dimethoxybenzylidene) thiazolidine-2,4-dione, and 5-(2,3,4-trifluorobenzylidene) thiazolidine-2,4-dione, exhibited significant antidiabetic activity in streptozotocin-induced diabetic mice, comparable to the drug Pioglitazone. Molecular docking studies of these compounds using a protein target showed amino acid interactions with Leu270, Gln283, and Arg288, similar to Rosiglitazone and Pioglitazone. Moreover, these compounds did not show any toxic effects in mice, even at a high dose of 2000 mg/kg, indicating their safety profile. Conclusion: The synthesis of modified and improved thiazolidine-2,4-dione-containing drugs, which are safer and more effective than currently available drugs, is of utmost importance in antidiabetic drug research. Our study's findings provide a promising foundation for the development of new TZD analogues as potential antidiabetic agents with improved pharmacological properties and reduced toxicity.

Synthesis and Pharmacological Characterization of Visabron, a Backbone Cyclic Peptide Dual Antagonist of α4β1 (VLA-4)/α9β1 Integrin for Therapy of Multiple Sclerosis.

Integrins α4β1/ α9β1 are important in the pathogenesis and progression of inflammatory and autoimmune diseases by their roles in leukocyte activation and trafficking. Natalizumab, a monoclonal antibody selectively targeting α4β1 integrin and blocking leukocyte trafficking to the central nervous system, is an immunotherapy for multiple sclerosis (MS). However, due to its adverse effects associated with chronic treatment, alternative strategies using small peptide mimetic inhibitors are being sought. In the present study, we synthesized and characterized visabron c (4–4), a backbone cyclic octapeptide based on the sequence TMLD, a non-RGD unique α4β1 integrin recognition sequence motif derived from visabres, a proteinous disintegrin from the viper venom. Visabron c (4–4) was selected from a minilibrary with conformational diversity based on its potency and selectivity in functional adhesion cellular assays. Visabron c (4–4)’s serum stability, pharmacokinetics, and therapeutic effects following ip injection were assessed in an experimental autoimmune encephalomyelitis (EAE) animal model. Furthermore, visabron c (4–4)’s lack of toxic effects in mice was verified by blood analysis, tissue pathology, immunogenicity, and “off-target” effects, indicating its significant tolerability and lack of immunogenicity. Visabron c (4–4) can be delivered systemically. The in vitro and in vivo data justify visabron c (4–4) as a safe alternative peptidomimetic lead compound/drug to monoclonal anti-α4 integrin antibodies, steroids, and other immunosuppressant drugs. Moreover, visabron c (4–4) design may pave the way for developing new therapies for a variety of other inflammatory and/or autoimmune diseases.

Impact of metallic coating on the retention of 225Ac and its daugthers within core–shell nanocarriers

Currently, alpha-emitting radionuclide 225Ac is one of the most promising isotopes in alpha therapy due to its high linear energy transfer during four sequential alpha decays. However, the main obstacle preventing the full introduction of 225Ac into clinical practice is the lack of stable retention of radionuclides, leading to free circulation of toxic isotopes in the body. In this work, the surface of silica nanoparticles (SiO2 NPs) has been modified with metallic shells composed of titanium dioxide (TiO2) and gold (Au) nanostructures to improve the retention of 225Ac and its decay products within the developed nanocarriers. In vitro and in vivo studies in healthy mice show that the metallic surface coating of SiO2 NPs promotes an enhanced sequestering of radionuclides (225Ac and its daughter isotopes) compared to non-modified SiO2 NPs for a prolonged period of time. Histological analysis reveals that for the period of 3–10 d after the injections, the developed nanocarriers have no significant toxic effects in mice. At the same time, almost no accumulation of leaked radionuclides can be detected in non-target organs (e.g., in the kidneys). In contrast, non-modified carriers (SiO2 NPs) demonstrate the release of free radionuclides, which are distributed over the whole animal body with the consequent morphological changes in the lung, liver and kidney tissues. These results highlight the potential of the developed nanocarriers to be utilized as radionuclide delivery systems and offer an insight into design rules for the fabrication of new nanotherapeutic agents.

Evaluation of acute and subacute toxicity of ethanolic extract and fraction of alkaloids from bark of Aspidosperma nitidum in mice

This study investigated the acute and subacute toxicity of the ethanolic extract (EE) and alkaloid fraction (FA) from A. nitidum. The EE was obtained from trunk bark with ethanol, FA was obtained from the fractionation of EE. To test the acute toxicity, mice were divided into four groups, and the negative controls received water or aqueous solution of dimethyl sulfoxide, whereas the others received EE or FA (2000 mg/kg, orally, single dose). The same controls were used in the subacute trial. However, the animals were treated for 28 days, and the dose used was 1000 mg/kg per day of EE and FA. Daily clinical evaluations of the animals were performed. At the end of the experiment, hematological, biochemical, and histopathological assessments (liver, lung, heart, and kidney) were performed. In the acute and subacute toxicity studies, mice treated with EE and FA did not show any clinical changes, there were no changes in weight gain, hematological and biochemical parameters compared to the control groups (p > 0.05). In the histopathological examination, there was no abnormality in the organs of the treated animals. Therefore, EE and FA did not produce toxic effects in mice after acute and subacute treatment.

Exposure to perfluorooctane sulfonate reduced cell viability and insulin release capacity of β cells

Per- and polyfluoroalkyl substances (PFAS) are found to have multiple adverse outcomes on human health. Recently, epidemiological and toxicological studies showed that exposure to PFAS had adverse impacts on pancreas and showed association with insulin abnormalities. To explore how PFAS may contribute to diabetes, we studied impacts of perfluorooctane sulfonate (PFOS) on cell viability and insulin release capacity of pancreatic β cells by using in vivo and in vitro methods. We found that 28-day administration with PFOS (10 mg/(kg body weight•day)) caused reductions of pancreas weight and islet size in male mice. PFOS administration also led to lower serum insulin level both in fasting state and after glucose infusion among male mice. For cell-based in vitro bioassay, we used mouse β-TC-6 cancer cells and found 48-hr exposure to PFOS decreased the cell viability at 50 μmol/L. By measuring insulin content in supernatant, 48-hr pretreatment of PFOS (100 μmol/L) decreased the insulin release capacity of β-TC-6 cells after glucose stimulation. Although these concentrations were higher than the environmental concentration of PFOS, it might be reasonable for high concentration of PFOS to exert observable toxic effects in mice considering mice had a faster removal efficiency of PFOS than human. PFOS exposure (50 μmol/L) to β-TC-6 cells induced intracellular accumulation of reactive oxidative specie (ROS). Excessive ROS induced the reactive toxicity of cells, which eventually invoke apoptosis and necrosis. Results in this study provide evidence for the possible causal link of exposure to PFOS and diabetes risk.

Evaluation of the Antimalarial Activity of Ethanol Extracts of the Leaves of Three Plant Species Collected from Yayu Coffee Forest Biosphere Reserve, Southwest Ethiopia.

ObjectiveIn the attempt of searching for potential plant derived antimalarial medicines, the aim of the present study was to examine In vivo antimalarial efficacy of crude ethanol extracts of the leaves of Croton macrostachyus, Ruta chalepensis and Vernonia amygdalina using chloroquine (CQ) sensitive strains of Plasmodium berghei in Swiss albino mice.MethodsTo ascertain the safety level of the plant materials, crude extracts underwent oral acute toxicity assessments whereby mice received up to a single dose of 3000 mg/kg. Peter's four day standard antimalarial suppressive test was carried out to determine growth inhibition of parasitemia at tested doses of 400, 600, and 800 mg/kg of the extracts. Survival time of experimental mice and preliminary phytochemical screenings of the extracts were also done according to the standard procedures.ResultsExtracts of the plant materials did not produce severe acute toxic effects in mice that received up to 3000 mg/kg in a single dose. Although complete clearance was not recorded, extracts of the plant materials produced dose dependent suppression of the parasitemia. The highest growth inhibition recorded was by extract of V. amygdalina (61.44%) followed by C. macrostachyus (59.3%) at 800 mg/kg of tested doses. Whereas, complete parasitemia clearance was attributed in mice treated with 25 mg/kg of CQ. In addition, survival time of experimental mice was recorded and the result showed mice treated with the extracts lived longer than the corresponding negative controls. The phytochemical screening of the extracts revealed the presence of antimalarial active constituents such as alkaloids, saponins, cardiac glycosides, flavonoids, terpenoids, steroids, phenols, and tannins.ConclusionThe present study, therefore, suggests that crude ethanol extracts of C. macrostachyus, R. chalepensis, and V. amygdalina are safe and rich with active secondary metabolites which have promising antimalarial effects.