Significant Toxicity Research Articles

Single-cell genomics details the maturation block in BCP-ALL and identifies therapeutic vulnerabilities in DUX4-r cases

AbstractB-cell progenitor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy and is driven by multiple genetic alterations that cause maturation arrest and accumulation of abnormal progenitor B cells. Current treatment protocols with chemotherapy have led to favorable outcomes but are associated with significant toxicity and risk of side effects, highlighting the necessity for highly effective, less toxic, targeted drugs, even in subtypes with a favorable outcome. Here, we used multimodal single-cell sequencing to delineate the transcriptional, epigenetic, and immunophenotypic characteristics of 23 childhood BCP-ALLs belonging to the BCR::ABL1+, ETV6::RUNX1+, high hyperdiploid, and recently discovered DUX4-rearranged (DUX4-r) subtypes. Projection of the ALL cells along the normal hematopoietic differentiation axis revealed a diversity in the maturation pattern between the different BCP-ALL subtypes. Although the BCR::ABL1+, ETV6::RUNX1+, and high hyperdiploidy cells mainly showed similarities to normal pro-B cells, DUX4-r ALL cells also displayed transcriptional signatures resembling mature B cells. Focusing on the DUX4-r subtype, we found that the blast population displayed not only multilineage priming toward nonhematopoietic cells, myeloid, and T-cell lineages, but also an activation of phosphatidylinositol 3-kinase (PI3K)/AKT signaling that sensitized the cells to PI3K inhibition in vivo. Given the multilineage priming of DUX4-r blasts with aberrant expression of myeloid marker CD371 (CLL-1), we generated chimeric antigen receptor T cells, which effectively eliminated DUX4-r ALL cells in vivo. These results provide a detailed characterization of BCP-ALL at the single-cell level and reveal therapeutic vulnerabilities in the DUX4-r subtype, with implications for the understanding of ALL biology and new therapeutic strategies.

Simultaneous determination of lead and cadmium in water by metal oxide framework complex-modified glassy carbon electrodes

Lead (Pb) and cadmium (Cd) are pervasive environmental pollutants known for their significant biological toxicity. The traditional methods for detecting these ions often necessitate large-scale instruments and complex procedures. In contrast, electrochemical detection methods offer advantages such as rapidity, portability, and sensitivity, making them suitable for the simultaneous detection of heavy metals. Metal-organic frameworks (MOFs), characterized by their exceptional adsorption and enrichment capabilities for heavy metal ions, have shown promise in this regard. Nevertheless, the poor conductivity of most MOFs has limited their electrochemical applications. In this study, glassy carbon electrodes (GCEs) were modified using the MOF ZIF-8, in combination with a bismuth complex and carboxylated multi-walled carbon nanotubes, resulting in the fabrication of Bi@ZIF-8/CMWCNTs/GCE electrochemical sensors. Leveraging the porous nature and large specific surface area of ZIF-8, the lead and cadmium ion adsorption by bismuth akin to mercury, and the conductivity of carboxylated multi-walled carbon nanotubes, the sensor developed in this study exhibits excellent capability for simultaneous detection of lead and cadmium ions in water. Under optimized conditions, Pb2+ and Cd2+ showed good linear relationships with the peak current in the concentration range of 2.0–50.0 μg/L. In the concentration range studied, the regression equations for Pb2+ and Cd2+ were determined as follows: y = 0.2982x + 0.4553 (r = 0.9962) for Pb2+ and y = 0.3631x + 0.1242 (r = 0.9949) for Cd2+. The detection limits for Pb2+ and Cd2+ were 0.76 μg/L and 0.87 μg/L, respectively. The relative standard deviations (RSDs) for 50 μg/L mixed standard solution of Pb and Cd were 1.89 % and 1.23 %, respectively. Furthermore, the RSDs for the same modified electrode tested with 50 μg/L Pb2+ and Cd2+ mixed standard solution over seven consecutive days were 2.27 % and 1.42 %, respectively, under identical conditions. In practice, the lead and cadmium concentrations of a lake were found to range from 4.42 μg/L to 5.60 μg/L, while the lead and cadmium concentrations of effluent from a wastewater plant ranged from 11.83 μg/L to 14.49 μg/L. This research not only describes a new electrochemical platform for the simultaneous determination of lead and cadmium in water but also provides a new method for the simultaneous determination of lead and cadmium in water. This research is valuable for promoting the application of MOFs in the field of electrochemistry.

The efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of hemophagocytic lymphohistiocytosis in adult patients: an open-label, single-center study.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by hyperinflammation and organ failure, with a high mortality rate. Current first-line treatments for adult patients have limited efficacy and significant toxicity. The novel selective histone deacetylase inhibitor (HDACi), chidamide, has shown promise in preclinical studies for the potential treatment of HLH. An open-label, single-center study was conducted to evaluate the efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of HLH in adult patients. Seventeen patients who fulfilled at least five of the eight HLH-2004 criteria were enrolled and treated with the combination therapy. The primary outcome was overall response rate (ORR), and secondary outcomes included survival, safety and tolerability, and changes in laboratory indicators. A total of 17 HLH patients who met the inclusion criteria were enrolled in this study, with a male to female ratio of 1.8:1. The age range at enrollment was 31 to 71 years old, with a median age of 52 years old. The ORR was 76.5% (13/17 patients), with a complete response (CR) rate of 17.6% (3/17 patients) and a partial response (PR) rate of 58.8% (10/17 patients). The median overall survival (OS) was not achieved, with OS at 6 months and 12 months being 81% and 65%, respectively. The median progression free survival (PFS) was not achieved, with PFS at 6 months and 12 months being 68% and 55%, respectively. Hematologic toxicities is the most common. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. The results showed that the levels of sCD25, platelets, aspartate aminotransferase, lactate dehydrogenase, and albumin in these patients were significantly improved 3 weeks after treatment. The addition of chidamide to etoposide and glucocorticoids may be a promising new treatment option for patients with HLH, with a high ORR, manageable safety profile, and significant improvement in laboratory indicators. Further research is needed to confirm these findings and determine the optimal dosing and duration of therapy.

Evaluation of the Antibacterial, Anti-Inflammatory, And Bone-Promoting Capacity of UiO-66 Loaded with Thymol or Carvacrol.

Oral infectious diseases have a significant impact on the health of oral and maxillofacial regions, as well as the overall well-being of individuals. Carvacrol and thymol, two isomers known for their effective antibacterial and anti-inflammatory properties, have gained considerable attention in the treatment of oral infectious diseases. However, their application as topical drugs for oral use is limited due to their poor physical and chemical stability. UiO-66, a metal-organic framework based on zirconium ion (Zr4+), exhibits high drug loading capability. Carvacrol and thymol were efficiently loaded onto UiO-66 with loading rates of 79.60 ± 0.71% and 79.65 ± 0.76%, respectively. The release rates of carvacrol and thymol were 77.82 ± 0.87% and 76.51 ± 0.58%, respectively, after a period of 72 h. Moreover, Car@UiO-66 and Thy@UiO-66 demonstrated excellent antibacterial properties against Candida albicans, Escherichia coli, and Staphylococcus aureus with minimum bactericidal concentrations (MBC) of 0.313 mg/mL, 0.313 mg/mL, and 1.25 mg/mL, respectively. Furthermore, based on the results of the CCK8 cytotoxicity assay, even at concentrations as high as 1.25 mg/mL, Car@UiO-66 and Thy@UiO-66 exhibited excellent biocompatibility with a relative cell survival rate above 50%. These findings suggest that Car@UiO-66 and Thy@UiO-66 possess favorable biocompatibility properties without significant toxicity towards periodontal membrane cells. Additionally, in vivo studies confirmed the efficacy of Car@UiO-66and Thy@UiO-66 in reducing inflammation, promoting bone formation through inhibition of TNF-a and IL6 expression, enhancement of IL10 expression, and acceleration of bone defect healing. Therefore, the unique combination of antibacterial, anti-inflammatory, and osteogenic properties make Car@UiO-66 and Thy@Ui O-66 promising candidates for the treatment of oral infectious diseases and repairing bone defects.

Toxicological evaluation of porcine bile powder in Kunming mice and Sprague-Dawley rats.

Background: Porcine bile powder (PBP) is a traditional Chinese medicine that has been used for centuries in various therapeutic applications. However, PBP has not previously undergone comprehensive component analysis and not been evaluated for safety through standard in vivo toxicological studies. Methods: In our study, we characterized the component of PBP by liquid chromatography-mass spectrometry. The acute and subchronic oral toxicity, genotoxicity, and teratogenicity studies of PBP were designed and conducted in Kunming mice and Sprague-Dawley (SD) rats. Results: The chemical analysis of PBP showed that the main components of PBP were bile acids (BAs), especially glycochenodeoxycholic acid. There were no signs of toxicity observed in the acute oral test and the subchronic test. In the genotoxicity tests, no positive results were observed in the bacterial reverse mutation test. Additionally, in the mammalian micronucleus test and mouse spermatocyte chromosomal aberration test, no abnormal chromosomes were observed. In the teratogenicity test, no abnormal fetal development was observed. Conclusion: Our findings demonstrate that PBP, composed mainly of BAs, is non-toxic and safe based on the conditions tested in this study.

Toxicity of New Psychoactive Substance (NPS): Threo-4-methylmethylphenidate (4-Mmph) – Prediction of toxicity using in silico methods

This study represents the first application of in silico methods to evaluate the toxicity of 4-methylphenidate (4-Mmph), a new psychoactive substance (NPS). Using advanced in silico toxicology tools, it was feasible to anticipate key aspects of 4-Mmph's toxicological profile, including acute toxicity (LD50), genotoxicity, cardiotoxicity, and possible endocrine disruption. The findings indicate significant acute toxicity with variability among species, a high potential for adverse effects in the gastrointestinal system and lungs, a low genotoxic potential, a significant likelihood of skin irritation, and a notable cardiotoxicity risk associated with hERG channel inhibition. Evaluation of endocrine disruption revealed a low likelihood that 4-Mmph interacts with the estrogen receptor alpha (ER-α), indicating minimal estrogenic activity. These insights, derived from in silico studies, play a crucial role in improving the comprehension of 4-Mmph in forensic and clinical toxicology. These initial toxicological inquiries establish the foundation for future investigations and help formulate risk assessment and management strategies regarding the use and abuse of NPS. This article is part of a larger project funded by the Polish Ministry of Education and Science, titled “Toxicovigilance, Poisoning Prevention, and First Aid in Poisoning with Xenobiotics of Current Clinical Importance in Poland” (Grant Number SKN/SP/570184/2023).

Stereotactic Body Proton Therapy Versus Conventionally Fractionated Proton Therapy for Early Prostate Cancer: A Randomized, Controlled, Phase 3 Trial

We aimed to determine if ultra-hypofractionated proton therapy delivered via stereotactic body proton therapy (SBPT) is non-inferior to conventionally fractionated proton therapy (CFPT) in patients with early prostate cancer. This study was a multicenter, randomized, controlled, non-inferiority phase 3 trial that included patients with histologically confirmed low-risk prostate adenocarcinoma defined by Gleason score grouping 1, PSA <10 ng/mL, and clinical stage T1-2a N0 M0 according to AJCC 7th ed. Eligible participants were randomly assigned initially at a 1:1 ratio and later at a 2:1 ratio to SBPT (38 Gy in 5 fractions) or CFPT (79.2 Gy in 44 fractions). The primary endpoint was freedom from failure (FFF) at 2 years from the date of randomization. Non-inferiority for FFF was determined based on one-sided confidence intervals. Toxicities were compared at different time points using Fisher's Exact test. Health-related quality-of-life (HRQoL) was analyzed at different time points using a mixed-effects linear model. This trial is registered with ClinicalTrials.gov, NCT01230866, and is closed to accrual. Between December 10, 2010, and September 29, 2020, 144 patients were enrolled and 135 were randomly assigned (90 to the SBPT group and 45 to the CFPT group). The median follow-up was 5 years (IQR 3.9-5.2). The 2-year FFF was 100% for both groups, with the one-sided 5-year risk difference in FFF between groups reported as 2.63% (90% CI: -1.70%-6.96%), favoring the SBRT arm, thus fulfilling the pre-specified criteria for non-inferiority of SBPT compared to CFPT. Rates of gastrointestinal (GI) and genitourinary (GU) G2 and G3 toxicities did not differ significantly between groups but the the study was not powered to detect significant toxicity differences. Also, HRQoL metrics did not differ significantly between groups over the study median follow up. SBPT is non-inferior to CFPT regarding FFF, with similar long-term GU and GI toxicity rates and minimal impact in patient reported HRQoL over time.

Gemcitabine versus Bacillus Calmette-Guérin (BCG) in Non Muscle Invasive Transitional Cell Carcinoma of the Bladder after Trans-Urethral Resection

Abstract Background To overcome Bacillus Calmette–Guérin (BCG) shortage and its side effect several studies have compared the safety and efficacy of intravesical gemcitabine with (BCG) for non-muscle invasive bladder cancer. The aim of this work is to evaluate the efficacy of Gemcetabine as a local intravesical treatment of superficial TCC in reducing the risk of recurrence and progression after TURBT in comparison to BCG. Patients and Methods This single blind controlled randomized study Included 82 patients which randomly divided into 2 groups by 1:1 method.Each group included 41 patients, group I will receive gemcitabine. Group II will receive BCG.These patients were diagnosed with superficial bladder tumor (TCC) after TURBT. These patients were followed in the out-patient clinic in the Department of Urology Ain Shams University Hospital and 6th October Health Insurance Hospital during the period from 2017 till 2021. Results After 1 year of follow up 67.6% of group I on the other hand 63.4% of group II were free of tumors. As regard tumor progression, only 2.7% of group I patient had tumor progression while 4.9% of group II had tumor progression but all of these results were statistically not-significant with P. value 0.475. As regard side effects after 1 year of follow up. Regarding dysuria 24 patients 96% in group (I) complained of mild dysuria. On the other hand, 39 patients 95.1 % in group (II) complained of dysuria, 9 of them 21.9 % had sever dysuria and 30 patients 73.2 % had mild dysuria. which was statistically not significant with P. value 0.078. Urine analysis was done after treatment. 33 patients (89.2%) had pus cells in the patients of group I while in group II, all patients had pus cells in urine analysis, which was statistically significant with (P. value 0.046). Conclusion Gemcitabine was associated with nearly similar efficacy and a clinically significant better toxicity profile compared with BCG. Intravesical gemcitabine is a promising drug that may be an option in treating patients with non muscle invasive bladder cancer.

Tolerance of radiotherapy with concomitant glofitamab in diffuse large Bcell lymphoma: acase report.

Glofitamab, an anti-CD20 antibody, is approved as a third-line treatment for relapsed or refractory (r/r) diffuse large-cell B lymphoma (DLBCL), achieving a complete response in nearly 40% of patients. This humanized IgG1 bispecific monoclonal antibody binds to CD20 on malignant B lymphocytes and to CD3 on cytotoxic T cells. This dual binding forms an immunological synapse, activating T lymphocytes and leading to the lysis of tumor cells. Salvage radiotherapy is also effective for r/r DLBCL, but its combination with systemic treatments like glofitamab may increase radiation-induced toxicity. We report the first case of a patient with r/r DLBCL receiving concurrent salvage radiotherapy and glofitamab. A 68-year-old female diagnosed with stage IV DLBCL underwent initial treatment with R-CHOP, then Car-T cell therapy, followed by glofitamab for recurrence. Upon early metabolic progression detected by 18FDG-PET/CT, salvage radiotherapy was administered to the refractory site concurrently with glofitamab. The patient experienced mild para-spinal pain post-radiotherapy but no other significant toxicities. Three months post-treatment, she showed a complete metabolic response with no radiotherapy toxicity, as evidenced by PET-CT, and no signs of radiation pneumonitis. This case indicates that combining glofitamab with salvage radiotherapy is tolerable and suggests potential efficacy, warranting further investigation in prospective studies for r/r DLBCL.

Acute ellipsoid zone thickening: A sign of probable digoxin toxicity?

A 62-year-old gentleman presented with blurred vision in both eyes associated with excessive sleepiness and headache for 5 days. Optical coherence tomography (OCT) showed thickening of ellipsoid zone (EZ) with subtle separation from retinal pigment epithelium in both eyes. Patient was on digoxin 0.25 mg once daily for the past 2 years. As OCT was suggestive of photoceptor involvement, we sought an opinion from the cardiologist to consider withholding digoxin. Patient reported visual improvement at 1 week. At 6 months, OCT showed normalization of EZ. We propose that acute EZ thickening would be a sign of digoxin toxicity.

Targeting the mSWI/SNF complex in POU2F-POU2AF transcription factor-driven malignancies

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

Green Formulation of Descurainia sophia Aqueous Extract Mediated Ag NPs and Determination of Its Anti-Hemangioma Effects

Hemangioma is a common cancer with severe clinical signs. Finding a new anti-hemangioma supplement or drug inside of the chemotherapeutic drug is valuable. We synthesized silver nanoparticles containing Descurainia sophia leaf for investigating the anti-hemangioma, cytotoxicity, and antioxidant effects. Characterization of AgNPs was performed by Field Emission Scanning Electron Microscopy (FE-SEM), UV–Visible Spectroscopy (UV-Vis), and X-Ray diffraction analysis (XRD). The plain peak in the wavelength 449 nm revealed the AgNPs synthesis. TEM and FE-SEM analyses showed that synthesized AgNPs were found to be 16.9 to 48.43 nm mean particle size. For investigating the antioxidant efficacy, the DPPH assay was conducted. AgNPs prevented 50% of DPPH in the dilation of 40 μg/mL. To measure the anti-hemangioma efficacy of AgNPs, MTT assay was applied on SK HEP-1 and HAEND cell lines. AgNPs had high anti-hemangioma efficacy on above tumor cells without any significant toxicity on HUVEC. The best finding of anti-hemangioma properties of AgNPs was seen in the case of the HAEND cell line. This study indicated significant anti-hemangioma and antioxidant potentials of AgNPs containing Descurainia sophia.

1,3,5-Triaza-7-phosphaadamantane and Cyclohexyl Groups Impart to Di-Iron(I) Complex Aqueous Solubility and Stability, and Prominent Anticancer Activity in Cellular and Animal Models.

Using a multigram-scalable synthesis, we obtained nine dinuclear complexes based on nonendogenous iron(I) centers and featuring variable aminocarbyne and P-ligands. One compound from the series (FEACYP) emerged for its strong cytotoxicity in vitro against four human cancer cell lines, surpassing the activity of cisplatin by 3-6 times in three cell lines, with an average selectivity index of 6.2 compared to noncancerous HEK293 cells. FEACYP demonstrated outstanding water solubility (15 g/L) and stability in physiological-like solutions. It confirmed its superior antiproliferative activity when tested in 3D spheroids of human pancreatic cancer cells and showed a capacity to inhibit thioredoxin reductase (TrxR) similar to auranofin. In vivo treatment of murine LLC carcinoma with FEACYP (8 mg kg-1 dose) led to excellent tumor growth suppression (88%) on day 15, with no signs of systemic toxicity and only limited body weight loss.

Pharmacological mechanisms involved in the diuretic activity of the ethanol-soluble fraction of Baccharis milleflora (Less.) DC. - An ethnopharmacological investigation

Baccharis milleflora (Less.) DC. is a plant native to Brazil that is frequently used in traditional medicine as a diuretic and antihypertensive. However, even though it is traditionally used for these purposes, its diuretic and hypotensive effects have not been fully elucidated. Investigate the cardiorenal effects of the ethanol-soluble fraction (ESBM) of Baccharis milleflora in normotensive rats. Cladodes of B. milleflora were analyzed using light and scanning electron microscopy to provide anatomical data to support quality control. Subsequently, the ESBM was obtained and analyzed using LC-DAD-MS, and its components were annotated. The acute toxicity of ESBM was assessed in female Wistar rats. The acute and prolonged diuretic and hypotensive effects were then studied in Wistar rats. Finally, we assessed the mechanisms responsible for the diuretic effects of ESBM, including the activity of renal Na+/K+/ATPase, angiotensin-converting enzyme, and erythrocyte carbonic anhydrase. Additionally, we also investigated the involvement of bradykinin, prostaglandins, and nitric oxide. From LC-DAD-MS data, thirty-three metabolites were identified from ESBM, including chlorogenic acids, glycosylated phenolic derivatives, C-glycosylated flavones, and O-glycosylated flavonols. No signs of acute toxicity were observed in female rats. The findings showed that ESBM had significant diuretic and natriuretic effects, as well as a potassium-sparing effect. The treatment with ESBM was able to significantly decrease serum levels of creatinine and malondialdehyde, and also significantly increase levels of nitrite, an indirect marker of nitric oxide bioavailability. Furthermore, pre-treatment with L-NAME abolished all diuretic effects induced by ESBM. This study presented important morpho-anatomical and phytochemical data that support the quality control of Baccharis milleflora. The ESBM exhibited a significant diuretic and natriuretic effect following acute and seven-days repeated treatment in Wistar rats, without affecting renal potassium elimination. These effects appear to be dependent on the activation of the nitric oxide-cyclic GMP pathway. This study suggests the potential use of B. milleflora preparations in clinical situations where a diuretic effect is needed.

Acute oral toxicity and safety assessment of Morus alba L. (Moraceae) methanol fruit extract in mice

Mulberry or Morus alba fruits, belonging to the Moraceae family, are well recognized for their distinct taste and high nutritional content. Nevertheless, studies revealing the toxic effects of fruits are scanty. This study aimed to examine the adverse effects of methanolic fruit extract (MFME) derived from M. alba on mice following OECD 425 guidelines. The female Swiss albino mice were divided into two distinct categories. One group was designated as the control group (administered vehicle), while the other was assigned as the test group (administered 2000 mg/kg MFME orally). Subsequently, behavioral changes were monitored daily, and body weights, relative organ weights, and biochemical and hematological parameters were measured. Additionally, liver, kidney, heart, brain, and ovary assessments were conducted on the 14th day to detect any signs of toxicity. A histopathological investigation was conducted on the anesthetized animals’ vital organs (heart, liver, kidney, brain, and ovary). The study’s findings indicate that the oral administration of MFME did not result in any mortality. Additionally, no significant changes were seen in behavior, food and water intake, biochemical parameters, hematological investigations, and organ weights. Furthermore, the histological analysis revealed no notable pathological alterations in the separated essential organs of mice treated with MFME. The results of this study indicate that the oral administration of MFME is deemed safe up to the maximum test dosage of 2000 mg/kg.

Polyimidazole ligands: Copper(II) complexes and antiproliferative activity in cancer cells

The design of novel chelators for therapeutic applications has been the subject of extensive research to address various diseases. Many chelators can manipulate the levels of metal ions within cells and effectively modulate the metal excess. In some cases, chelators show significant toxicity to cells.We investigated polyimidazole ligands by potentiometry and UV–Vis spectroscopy for their ability to form copper(II) complexes. We also compared the antiproliferative activity of the polyimidazole ligands and their copper(II) complexes with polypyridine ligands in CaCo-2 (colorectal adenocarcinoma), SH-SY5Y (neuroblastoma) and K562 (chronic myelogenous leukemia) cells and normal HaCaT (keratinocyte) cells.Polyimidazole ligands are less cytotoxic than their analogous polypyridine ligands. All polyimidazole ligands, except the tetraimidazole ligand for K562 cells, did not show any significant effect on the viability of cancer and normal cells. In contrast, the cytotoxic activity of polypiridine ligands was also observed in normal cells with IC50 values similar to those of cancer cells.Tetra imidazole ligand, the only ligand active on the leukemic K562 cell line, induced caspase-dependent apoptosis and increased intracellular reactive oxygen species production with mitochondrial damage.The low cytotoxicity of the polyimidazole ligands, even if it limits their use as anticancer agents, could make them useful in other medical applications, such as in the treatment of metal overload, microbial infections, inflammation or neurodegenerative disorders.

Discovery of a novel inhibitor of macropinocytosis with antiviral activity

Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a molecule with antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using High-Throughput Microscopy, where we identified chemical entities capable of preventing infection with a pseudotype virus expressing the spike (S) protein from SARS-CoV-2. Subsequent experiments confirmed the capacity of virapinib to inhibit infection by SARS-CoV-2, as well as by additional viruses, such as Monkeypox virus and TBEV. Mechanistic analyses revealed that the compound inhibited macropinocytosis, limiting this entry route for the viruses. Importantly, virapinib has no significant toxicity to host cells. In summary, we present the discovery of a molecule that inhibits macropinocytosis, thereby limiting the infectivity of viruses that use this entry route such as SARS-CoV2.

PHARMACOLOGY OF SPONDIAS MOMBIN IN LIVER CANCER TREATMENT AND TOXICITY EVALUATION

Cancer is among the major causes of death in the world. Spondias mombin is a natural product being accepted as medication for many diseases. This research aimed at evaluating the toxicity potential and pharmacology properties of Spondias mombin leaves in liver cancer treatment. Spondias mombin leaves were shade dried at room temperature and size reduced to powder and extracted using cold maceration. Phytochemical screening of the plant extract was conducted. Six weeks of healthy mice; weighing 22-25g were used. For acute toxicity studies, ten mice were grouped into a normal control group and another group received 2000mg/kg of the extract. The animals were observed closely for 14 days. Twenty-four mice were divided into 4 groups. One group served as control and received only saline at 10mls/kg and the other groups received one percent diethylnitrosamine (DEN) given via peritoneal injection to the mice weekly at a dose of 35mg/kg for six weeks. The remaining three groups received 250 mg/kg, 500 mg, and doxorubicin 2 mg/kg after four weeks of induction. The treatment commenced with the extract while still giving the DEN for cancer induction. The phytochemical analysis shows the presence of alkaloids, cardiac glycosides, saponins, tannins, phenolic compounds, steroids, flavonoids, and terpenoids, and the absence of carbohydrates anthraquinones. Animals exposed to the extract and observed for 14 days exhibited no obvious sign of toxicity with zero mortality during the period of observation. There is a slight weight change among the control group between 20.8±3.56 to 25.63 2.60.The creatinine, CL, and HCO3 of the control significantly (P˂0.005) differed from the study groups. There was a slight increase in weight after the first dose, though a steady decrease was noticed following the second, third, and fourth doses of DEN in the mice. ALT and AST were higher in the extract-treated groups compared to both Dox-treated and saline-treated groups. The extract was shown to have no obvious physical sign of toxicity and it doesn’t cause mortality in all the tested animals. Ethanol extract of the plant reversed the loss in weight, deterioration in liver enzymes, and protein production to an extent similar to that of standard anti-cancer agents.

Evaluation of Acute and Repeated Dose Oral Toxicity of Phoenix dactylifera L. Pollen Methanolic Extract in Rats

Pollen of the date palm (Phoenix dactylifera L.) has been used for thousands of years as a traditional herbal medicine for improving fertility. However, safety of plant-derived materials is an important concern to human health, and herbal remedies should be taken with adequate knowledge about their toxicity, adverse effects, purity, appropriate dosage and dose limits. The current work was undertaken to evaluate the safety of date palm pollen (DPP) and to classify it according to its oral toxicity in rats. The experiments were done according to the reported guidelines of the Organization for Economic Co-operation and Development (OECD) to assess the acute and repeated dose oral toxicity in rats. The obtained results showed neither death nor sign of toxicity or abnormality in any of the animals throughout the experimental period regarding acute and repeated dose oral toxicity. Also the results of the hematological and clinical biochemistry determinations showed no significant differences between the control and DPP-treated rat groups. It could be concluded that, the tested plant material is a relatively safe substance and its approximate LD50 defined by 2000mg/kg &lt; LD50 &lt; 5000mg/kg according to the OECD tests guidelines.

A Novel Piezo1 Agonist Promoting Mesenchymal Stem Cell Proliferation and Osteogenesis to Attenuate Disuse Osteoporosis

Disuse osteoporosis (OP) is a state of bone loss due to lack of mechanical stimuli, probably induced by prolonged bed rest, neurological diseases, as well as microgravity. Currently the precise treatment strategies of disuse OP remain largely unexplored. Piezo1, a mechanosensitive calcium (Ca2+) ion channel, is a key force sensor mediating mechanotransduction and it is demonstrated to regulate bone homeostasis and osteogenesis in response to mechanical forces. Using structure‐based drug design, a novel small‐molecule Piezo1 agonist, MCB‐22‐174, which can effectively activate Piezo1 and initiate Ca2+ influx, is developed and is more potent than the canonical Piezo1 agonist, Yoda1. Moreover, MCB‐22‐174 is found as a safe Piezo1 agonist without any signs of serious toxicity. Mechanistically, Piezo1 activation promotes the proliferation of bone marrow mesenchymal stem cells by activating the Ca2+‐related extracellular signal‐related kinases and calcium–calmodulin (CaM)‐dependent protein kinase II (CaMKII) pathway. Importantly, MCB‐22‐174 could effectively promote osteogenesis and attenuate disuse OP in vivo. Overall, the findings provide a promising therapeutic strategy for disuse OP by chemical activation of Piezo1.