Severe Toxicity Research Articles

Topical Losartan Dosage Response and Corneal Toxicity at Higher Concentrations.

The purpose of this study was to evaluate the efficacy and safety of higher dosages of topical losartan in an alkali-burn fibrosis model in rabbits. In total, 18 rabbits had standardized alkali burns that trigger stromal fibrosis. Six eyes per group were treated with topical losartan (0.8 mg/mL, 8 mg/mL, or 40 mg/mL) 6 times per day. Slit-lamp photographs were obtained, and multiplex immunohistochemistry was performed for myofibroblast marker alpha-smooth muscle actin (α-SMA), mesenchymal cell marker vimentin, and basement membrane marker laminin alpha-5. Topical losartan at 40 mg/mL 6 times per day produced severe discomfort and ocular surface toxicity in all rabbits, and treatment was discontinued at nine days in this group. Topical losartan at 8 mg/mL 6 times per day caused less rabbit discomfort on application, but there were persistent epithelial defects and marked stromal opacity in 5 of 6 eyes after 1 month of treatment. Topical losartan 0.8 mg/mL was well tolerated by rabbits, and corneal opacity was markedly reduced at 1 month in 5 of 6 corneas compared with corneas in the 8 mg/mL and 40 mg/mL losartan groups. A persistent epithelial defect with opacity was noted in 1 cornea in the 0.8 mg/mL losartan group. Both total SMA-positive stromal cells per section (14.5 ± 2.8 vs. 3.5 ± 0.7, P = 0.04) and total stromal vimentin intensity units (310 ± 64 vs. 132 ± 35, P = 0.02) were significantly greater after 1 month of treatment in corneas treated with 8 mg/mL than corneas treated with 0.8 mg/mL of topical losartan. Topical losartan dosages over 0.8 mg/mL should be used cautiously in patient eyes. In eyes with a current epithelial defect, it is recommended that 0.2 mg/mL losartan 6 times per day be used until the epithelium closes.

Current Insights into Therapeutic Potential of Terpenoids as Anticancer Agents.

Cancer is regarded as one of the main causes of death globally. Future predictions indicate that the death rate from cancer will keep rising, which may reach 11.4 million in 2030. Carcinogenesis refers to the phenomenon of transforming a normal cell into a cancer cell. Cancer is characterized by unregulated and uncontrolled cell division due to alterations at the molecular and genetic levels. Gene mutations can speed up the rate of cell division, which leads to cancer. Metastasis entails the dissemination of cancer cells from the primary site to distant regions of the body via the circulatory or lymphatic systems. This review is mainly focusing on the anticancer properties of terpenoids. In the case of human beings, several types of cancers can be treated clinically based on the form and phase of the cancer. So, there are different types of treatment regimens available for the management of cancer, such as immunotherapy, hormonal therapy, radiation therapy, and chemotherapy. Several problems are associated with cancer therapy, including chemoresistance, severe toxicity, relapse, and metastasis. To minimize these complications, natural products like terpenoids seem to be beneficial for the effective management of cancer. Experimental results revealed that the anticancer potential of terpenoids is due to activation of apoptosis and stimulation of cell cycle arrest. Some of the terpenoids exhibit anticancer effects by inhibiting angiogenesis and metastasis via the regulation of several signaling pathways intracellularly. Certain terpenoids have been shown to work in concert with anticancer medications (doxorubicin, cisplatin, paclitaxel, and 5-fluorouracil) to provide synergistic effects. These terpenoids have also been shown to be effective against cancer cells that are resistant to several drug therapies. The current study will focus on signaling pathways and mode of action of several types of terpenoids as anticancer agents. Further, it will provide insights into the ongoing clinical trials and prospective pathways for the advancement of terpenoids as possible anti-cancer agents.

Antibody-targeted T cells and natural killer cells for cancer immunotherapy

BackgroundAdoptive cell cancer therapies aim to re-engineer a patient’s immune cells to mount an anti-cancer response. Chimeric antigen receptor T and natural killer cells have been engineered and proved successful in treating some cancers; however, the genetic methods for engineering are laborious, expensive, and inefficient and can cause severe toxicities when they over-proliferate.ResultsWe examined whether the cell-killing capacity of activated T and NK cells could be targeted to cancer cells by anchoring antibodies to their cell surface. Using metabolic glycoengineering to introduce azide moieties to the cellular surface, we covalently attached a dibenzocyclooctyne-modified antibody using the strain-promoted alkyne azide cycloaddition reaction, creating antibody-conjugated T and NK cells. We targeted the immune cells to tumors possessing the xenoantigen, N-glycolyl neuraminic acid GM3 ganglioside, using the 14F7hT antibody. These activated T and NK cells are “armed” with tumour-homing capabilities that specifically lyses antigen-positive cancer cells without off-target toxicities. Moreover, when exposed to target cells, 14F7hT-conjugated T cells that are not preactivated exhibit increased perforin, granzyme, CD69, and CD25 expression and specific cell killing.ConclusionsThis research shows the potential for a non-genetic method for redirecting cytotoxic immune cells as a feasible and effective approach for tumor-targeted cell immunotherapy.Graphical

Programmable bacteria synergize with PD-1 blockade to overcome cancer cell-intrinsic immune resistance mechanisms.

Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ-producing bacteria was sufficient to drive systemic tumor antigen-specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3-CD4+ and CD8+ T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ-producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.

In-situ and ex-situ preparation of Bi2S3 on the BiVO4/TiO2 to construct Bi2S3/BiVO4/TiO2 heterojunction for efficient Cr(VI) reduction

The environmentally friendly and rapid removal of hexavalent chromium (Cr(VI)) from wastewater has garnered significant attention, driven by the severe acute toxicity and carcinogenic properties associated with Cr(VI). The design and synthesis of heterojunctions are recognized as effective solutions for enhancing the photocatalytic performance of TiO2 based materials. BiVO4/TiO2 and Bi2S3/BiVO4/TiO2 composite films (BVT) were prepared via a simple hydrothermal method. The influence of Bi2S3 preparation methods (In-situ and Ex-situ) on the morphology, structure and properties of BVT was studied. The relative crystallinity of TiO2, BiVO4/TiO2, BVT(In-situ) and BVT(Ex-situ) were 50 %, 62 %, 72 % and 92 %, respectively. SEM shows that the morphology of Bi2S3 in BVT(In-situ) was nanoribbon and that of Bi2S3 in BVT(Ex-situ) was radioactive sphere. Compared with pure TiO2 and BiVO4/TiO2, the light absorption range of BVT composite material has been expanded from the ultraviolet light region to the visible region, the bandgap has been significantly narrowed, and the photocurrent density has been increased. The BVT(In-situ) shows stronger photoelectrical performance and reduction efficiency of Cr (VI) compared to BVT(Ex-situ), reaching 93.9 %. The photocatalytic reaction rate of BVT(In-situ) and BVT(Ex-situ) are 0.0291 min−1 and 0.0266 min−1, respectively. Density functional theory (DFT) calculations indicate that the work function of BiVO4 is higher than that of Bi2S3, and electrons will transfer from Bi2S3 to BiVO4 at the heterojunction interface. The BVT(In-situ) heterojunction constructed in this experiment greatly improves the separation and transport efficiency of photo-generated carriers, laying the foundation for the wide application of BVT heterojunction in the field of optoelectronics and providing a strategy for photocatalytic reduction of Cr(VI). The BVT(In-situ) with FTO conductive glass, it also can be applied to photovoltaic fields such as solar cells, photocatalysis and photodetectors.

Modulating the Anticancer Activity of Square‐Planar Platinum (II) Complex by Its Chelated Diphosphine

ABSTRACTThis work reports the preparations and anticancer activities of a set of platinum (II) complexes. Two types of bidentate ligands, azadiphosphine (PNP) and diphosphine (PP), were applied to afford different kinds of platinum centers, the homoleptic complexes, [Pt (PNP)2]2+ (1 and 2) and [Pt (PP)2]2+ (4), and the hybrid complex, [Pt (PNP)(PP)]2+ (3). All these complexes are characterized by various analytical techniques, and their structures were validated using single‐crystal X‐ray diffraction analysis. Notably, the stability of the complexes 1–4 is differentiated both in phosphate‐buffered saline (PBS) and in the culture media (RPMI‐1640), relative to the type of coordinated diphosphine ligands, specifically, the more PNP ligands, the less stability. The bite angles of P‐Pt‐P bonds in 1–4 would be reliant on their stability, so that complexes 1 and 2 with small bite angles tend to be labile. A mechanistic understanding on the decomposition of 2 is proposed with the aid of mass analysis. As a result, their anticancer activities should be also associated with their stability so that the chelated ligands, with more PNP ligands, lead to more cytotoxicity. Mechanistically, the poisonous platinum (II) derivatives of complex 2 should interact with the nucleus DNA, whereas the intact complex 4 is not traceable, confirming from a γ‐H2AX‐related immunofluorescence staining kit. Additionally, complex 2 exhibits severe toxicity toward several cancer cells as well as a normal cell. Furthermore, complex 2 has inhibited the formation and viability of three‐dimensional T24 mammospheres, reminding it of a promising candidate for anticancer treatments. Overall, the present work provides a way for the systematic investigation to elucidate how a bidentate diphosphine ligand modulates the stability and the anticancer activities of the corresponding square‐planner platinum (II) complex.

Revolutionizing cancer treatment: an in-depth exploration of CAR-T cell therapies.

Cancer is a leading cause of fatality worldwide. Due to the heterogeneity of cancer cells the effectiveness of various conventional cancer treatment techniques is constrained. Thus, researchers are diligently investigating therapeutic approaches like immunotherapy for effective tumor managements. Immunotherapy harnesses the inherent potential of patient's immune system to achieve desired outcomes. Within the realm of immunotherapy, CAR-T (Chimeric Antigen Receptor T) cells, emerges as a revolutionary innovation for cancer therapy. The process of CAR-T cell therapy entails extracting the patient's T cells, altering them with customized receptors designed to specifically recognize and eradicate the tumor cells, and then reinfusing the altered cells into the patient's body. Although there has been significant progress with CAR-T cell therapy in certain cases of specific B-cell leukemia and lymphoma, its effectiveness is hindered in hematological and solid tumors due to the challenges such as severe toxicities, restricted tumor infiltration, cytokine release syndrome and antigen escape. Overcoming these obstacles requires innovative approaches to design more effective CAR-T cells, which require a competent and diverse team to develop and implement. This comprehensive review addresses numerous therapeutic issues and provides a strategic solution while providing a deep understanding of the structural intricacies and production processes of CAR-T cells. In addition, this review explores the practical aspects of CAR-T cell therapy in clinical settings.

Bombesin-Targeted Delivery of β-Carboline-Based Ir(III) and Ru(II) Photosensitizers for a Selective Photodynamic Therapy of Prostate Cancer.

Despite advances in Ir(III) and Ru(II) photosensitizers (PSs), their lack of selectivity for cancer cells has hindered their use in photodynamic therapy (PDT). We disclose the synthesis and characterization of two pairs of Ir(III) and Ru(II) polypyridyl complexes bearing two β-carboline ligands (N^N') functionalized with -COOMe (L1) or -COOH (L2), resulting in PSs of formulas [Ir(C^N)2(N^N')]Cl (Ir-Me: C^N = ppy, N^N' = L1; Ir-H: C^N = ppy, N^N' = L2) and [Ru(N^N)2(N^N')](Cl)2 (Ru-Me: N^N = bpy, N^N' = L1; Ru-H: N^N = bpy, N^N' = L2). To enhance their selectivity toward cancer cells, Ir-H and Ru-H were coupled to a bombesin derivative (BN3), resulting in the metallopeptides Ir-BN and Ru-BN. Ir(III) complexes showed higher anticancer activity than their Ru(II) counterparts, particularly upon blue light irradiation, but lacked cancer cell selectivity. In contrast, Ir-BN and Ru-BN exhibited selective photocytoxicity against prostate cancer cells, with a lower effect against nonmalignant fibroblasts. All compounds generated ROS and induced severe mitochondrial toxicity upon photoactivation, leading to apoptosis. Additionally, the ability of Ir-Me to oxidize NADH was demonstrated, suggesting a mechanism for mitochondrial damage. Our findings indicated that the conjugation of metal PSs with BN3 creates efficient PDT agents, achieving selectivity through targeting bombesin receptors and local photoactivation.

Sublethal concentration of λ-cyhalothrin inhibits insulin-like peptides and leads to reproductive toxicity in Chrysoperla sinica.

Insulin-like peptides (ILPs) act as crucial reproductive neuropeptides in insects, regulating insect reproduction through the insulin signaling pathway (ISP). Our previous studies have found that the sublethal concentrations (LC1 and LC10) of lambda-cyhalothrin (λCy) could induce severe reproductive toxicity in the lacewing, Chrysoperla sinica (Tjeder), but the toxicological mechanism remains unclear. This study discovered that λCy could inhibit CsILP transcription, leading to a decrease in insulin content and downregulation of C. sinica insulin receptor (CsInR) and C. sinica forkhead box O (CsFOXO) expression in ISP. Interference with CsILP expression resulted in downregulation of C. sinica vitellogenin (CsVg) and decreasing fecundity, while exogenous injection of bovine insulin promoted upregulation of CsVg expression and facilitated reproduction in female adults of C. sinica. Meanwhile, interference with FOXO of ILP downstream transcription factor could lead to downregulation of CsVg, hindering ovarian development and resulting in a decrease in egg production. However, exogenous injection of bovine insulin could remedy the effects caused by FOXO interference. In addition, ILP mediates juvenile hormone and 20-hydroxyecdysone biosynthesis by acting on their synthetic regulatory enzymes and influences the signal transduction of the 2 reproductive endocrine hormones, thereby regulating the reproductive endocrine environment in C. sinica. In conclusion, λCy inhibits CsILP expression, leading to disorder of ISP, leading to the reduced fecundity of C. sinica.

Fatal Case of Immune-Related Myocarditis and Myositis Due to Treatment with Immune Checkpoint and Tyrosine Kinase Inhibitors.

Immune checkpoint inhibitor and tyrosine kinase inhibitor combinations have become the new standard of care in the first-line treatment of metastatic clear cell renal cell carcinoma. However, there is a growing concern regarding severe immune-related adverse events. A 78-year-old man with metastatic clear cell renal cell carcinoma, treated with pembrolizumab and axitinib, was admitted to the emergency department 30 days after initiating treatment due to rapidly progressive myositis. Myocarditis with severe ventricular dysfunction was identified. Muscular biopsy findings were compatible with inflammatory myopathy associated with immune checkpoint inhibitors. Initial treatment with high-dose corticosteroids showed an insufficient response. Therapeutic escalation on the third day with methylprednisolone, immunoglobulin, and abatacept resulted in clinical improvement. On the eleventh day, a sudden malignant arrhythmia occurred, followed by cardiac arrest. This represents one of the first case reports describing myocarditis and myositis during treatment with pembrolizumab-axitinib. While immune checkpoint inhibitor may play a major role, it is also possible that the tyrosine kinase inhibitor, while attempting to promote immune modulation, also increases severe toxicities.

Gingerol acts as a potent radiosensitizer in head and neck squamous cell carcinoma

Treatment options for advanced head and neck squamous cell carcinoma (HNSCC) are limited and often cause severe toxicity and debilitating long-term impacts. Developing effective and safer treatments is warranted. Several plant extracts have shown their effectiveness, but a comprehensive comparison between plant extracts in HNSCC has not been reported. Our aim was to investigate the effect of different plant extracts on the proliferation and viability of HNSCC cell lines. In addition, we investigated the efficacy of combining cytotoxic plant extracts with radiation. Since RT is a cornerstone in the treatment and management of HNSCC, it is desirable to enhance its efficacy through combination with cytotoxic agents that have minimal side effects. HNSCC cell lines were treated with various plant extracts at different concentrations. MTT assays were performed to identify the most potent anti-tumor plant extract. Colony-formation assays were performed to determine the radiosensitization effect. To investigate the effect on migration, transwell migration assays were performed. Annexin V staining was performed to analyze cell apoptosis. 6-gingerol resulted in the most significant dose-dependent inhibition in all cell lines compared to other plant extracts. Colony-formation assays showed a significant radiosensitizing effect when 6-gingerol was combined with radiation. In addition, the combination of 6-gingerol with radiation resulted in a significant decrease in HNSCC cell migration. Mechanistically, Annexin V staining showed that the combination of 6-gingerol and RT induces a synergistic apoptotic effect in MOC1, MOC2 and SCC9 cells compared to RT alone. In conclusion, 6-gingerol enhances the effect of radiation in HNSCC cell lines and could be a suitable candidate for combination therapy in HNSCC.

Healing and Hallucinations: A Comprehensive Look at Datura

The Solanaceae plant family is a large clade that includes Datura, a genus of plants with many species recognized for their severe pharmacological effects via tropane alkaloids like atropine, hyoscyamine and scopolamine. These alkaloids act as antagonists of muscarinic acetylcholine receptors with leading to a truly diverse pharmacological action, ranging from anticholinergic effects all the way through hallucinogenic properties. Datura plants have been used historically in traditional medicine and rituals worldwide but are infamous for poisoning due to the risk of severe anticholinergic toxicity, including death. Nevertheless, their pharmacology has become of interest for research due to potential therapeutic applications: specifically in controlling nauseousness and perhaps neurological disorders. In this review, we provide a summary of the botanical description and cultivation methods in addition to those on traditional use practices concerning phytochemistry, pharmacology and toxicology as compared with evidence-based information together emphasizing cautions against availability without stringent regulatory consideration for its modern medical uses or ritualistic purposes.

Flavor compound geraniol induces inhibited nutrient utilization and developmental toxicity on embryonic–larval zebrafish

AbstractFlavors are widely utilized in the food and oral pharmaceutical industry, particularly in products for children, to enhance palatability and promote ingestion willingness. The complex compositions of flavors potentially induce severer toxicity especially in children. In this study, zebrafish embryos are applied for toxicity screening of flavor and its compounds by immersing in flavor solutions followed by the assessment of morphology of zebrafish larvae. Geraniol is identified as the prominent toxic compound and is considered highly toxic to zebrafish embryo. In further toxicology study, geraniol demonstrates the concentration‐dependent developmental toxicity as the obvious reduction of body and eye lengths, as well as the increased prevalence of tail deformities, pericardial edema, and spine deformation. Zebrafish larvae treated with geraniol exhibit reduction in liver area and exocrine pancreas length, increase in yolk sac area, as well as elevation of triglycerides and total cholesterol, which indicate the inhibited nutrient utilization. Transcriptome analysis reveals that under geraniol treatment, 248 differentially expressed genes (DEGs) are downregulated, whereas 23 DEGs are upregulated, and 110 DEGs are related to metabolic process. Biological processes of lipid metabolism, carbohydrate metabolism, protein hydrolysis, and transmembrane transport, including their involved functional genes, are all downregulated. These findings reveal the developmental toxicity of geraniol by affecting the nutrient utilization‐related organs development and biological processes. This study establishes an efficient screening model for identifying toxic flavor compounds during developing stages, thereby elucidating the potential safety risks of geraniol exposure in zebrafish and providing a comprehensive understanding of its potential toxicity mechanism.

Efficacy and safety of Anlotinib based neoadjuvant chemotherapy for locally advanced triple negative breast cancer (TNBC)

BackgroundAnlotinib, an oral multitarget tyrosine kinase inhibitor, has shown the ability to inhibit tumor angiogenesis. This study aimed to assess the effectiveness and safety of anlotinib plus docetaxel, epirubicin, and cyclophosphamide (TEC) as a neoadjuvant chemotherapy regimen for locally advanced TNBC.MethodsLocally advanced TNBC patients who had received no prior systemic treatment were eligible for this study. The enrolled patients were scheduled to undergo six cycles of anlotinib (12 mg, d1-14, q3w) plus docetaxel (75 mg/m2, d1, q3w), epirubicin (75 mg/m2, d1, q3w) and cyclophosphamide (600 mg/m2, d1, q3w) prior to surgery, unless there was disease progression or severe toxicity. The primary objective of this study was the safety of this therapeutic regimen, and the secondary objective was the tumor response. The safety of this regimen was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the efficacy of this treatment was measured using the Response Evaluation Criteria in Solid Tumors version 1.1.ResultsA total of 18 patients were included in this study. Participants completed an average of 5.56 neoadjuvant treatment cycles. The objective response rate (ORR) was 83.33%, and the disease control rate was 100%, respectively. The pCR was 55.6%. No patients discontinued therapy because of Adverse effects (AEs). Grade 3 or 4 AEs were observed in 5 cases (27.8%), with neutropenia and palmar-plantar erythrodysesthesia syndrome being the most common.ConclusionsAnlotinib combined with TEC as neoadjuvant therapy demonstrated manageable toxicity and promising antitumor activity for locally advanced TNBC. Further investigation of this combination regimen is warranted.

Cyanide Medical Countermeasure Development: Assessing the Efficacy of Intramuscular Sodium Tetrathionate for the Treatment of Acute, Severe Cyanide Toxicity in Swine (Sus scrofa).

Given its availability and lethality, cyanide has potential for weaponization and thus has the attention of several governmental agencies. In large scale exposure scenarios, an effective countermeasure that can be administered quickly and in low volume intramuscularly may prove valuable because IV medications may have limited practical applications in these situations. Sodium tetrathionate, a potential cyanide antidote, is a compound that provides sulfur to rhodanese, the enzyme that detoxifies cyanide endogenously. Additionally, sodium tetrathionate has been reported to directly react with cyanide and is effective when administered intramuscularly. In this study, we assess the efficacy of sodium tetrathionate, when administered intramuscularly for the treatment of acute, oral cyanide poisoning in swine. We conducted a prospective trial approved by the 59th Medical Wing Institutional Animal Care and Use Committee comparing intramuscular sodium tetrathionate (n=6) to no treatment control (n=4) in animals (Sus scrofa) exposed to a lethal dose of oral potassium cyanide. Survival at 120 minutes was the primary outcome. Lactate, a cyanide toxicity biomarker, was measured. At the study end, all animals were euthanized in compliance with the Animal Welfare Act and the American Association for Accreditation of Laboratory Animal Care. Survival between groups was summarized using a Kaplan-Meier survival curve after comparing survival by log-rank, Mantel-Cox analysis. The Mann-Whitney U test was used for comparison of other variables between groups. At baseline animals were similar. There was 100% survival in the treatment group and 0% survival in the control group (P=0.0011). Serum lactate significantly increased in the control group (control: 5±0.9 vs. treatment: 2.1 ± 0.5 mmol/L at 20 minutes). Sodium tetrathionate (intramuscular) significantly improved survival in a large, swine model of acute, oral cyanide poisoning. Future studies will be directed at further assessing sodium tetrathionate as a potential medical countermeasure for cyanide poisoning.

BCL-XL-targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors.

Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-XL) is associated with drug resistance and disease progression in numerous cancers. The compelling nature of this protein as a therapeutic target prompted efforts to develop selective small-molecule BCL-XL inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-XL inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-XL-targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts and did not cause cardiovascular toxicity nor dose-limiting thrombocytopenia in monkeys. While an unprecedented BCL-XL-mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-XL-targeting agent to enter human clinical trials.

Identification of compounds from Origanum compactum and Origanum elongatum using HPLC/UV-ESI-MS and comparative analysis of their antioxidant, antimicrobial, anticoagulant, and antidiabetic properties

The aim was to assess the phytochemical composition, phenolic component levels, and biological properties of the flowering tops of Origanum compactum and Origanum elongatum. The study employed phytochemical assays, spectrophotometric techniques for quantitative analysis of polyphenols, flavonoids, and tannins, and compound identification using HPLC/UV-ESI-MS. The antimicrobial, antioxidant, anticoagulant, and antidiabetic properties were examined both in vitro and in vivo. The results showed that the O. compactum extract had significantly high levels of total polyphenols, measuring 47.368 mg gallic acid equivalents per gram, and flavonoids, measuring 14.839 mg quercetin equivalents per gram. The phytochemical examination of O. compactum revealed that lithospermic acid accounted for 36.82 % of the chemicals detected, followed by salvianolic acid C at 12.57 % and ros-marinic acid at 6.01 %. The main constituents of O. elongatum are salvianolic acid C (14.46 %), luteolin-3-O-glucuronide (13.51 %), salvianolic acid B (12.24 %), rosmarinic acid (7.83 %), and rutin (6.18 %). The results demonstrated different levels of effectiveness against the investigated microorganisms, with the extract from O. compactum exhibiting better activity, particularly against Gram-negative bacteria, certain yeasts, and the fungus Aspergillus niger. The aqueous extracts of both Origanum species demonstrate significant antioxidant activity. O. compactum has a higher total antioxidant capacity (IC50 of 35.083 μg/mL) compared to O. elongatum (IC50 of 77.080 μg/mL). However, O. elongatum has a higher reducing power (35.697 μg/mL) compared to O. compactum (42.563 μg/mL). In vivo evaluations revealed that the aqueous extracts of O. compactum and O. elongatum possess significant antihyperglycemic and anticoagulant properties. The extracts demonstrated a marked reduction in blood glucose levels during the oral glucose tolerance test (OGTT) in Wistar rats and effectively prolonged both prothrombin time (PT) and activated partial thromboplastin time (aPTT), highlighting their ability to inhibit coagulation pathways. Moreover, their comparable efficacy to standard antihyperglycemic medications and absence of severe toxicity, even at high doses, underscore their therapeutic potential for safe and effective treatment applications. Between the two species, O. compactum exhibited superior efficacy in key biological activities such as antioxidant, antimicrobial, and anticoagulant properties, making it a strong candidate for therapeutic applications. This study underscores the value of Origanum species as a rich source of bioactive compounds, offering significant potential in pharmaceuticals, nutraceuticals, and agri-food industries. The findings pave the way for further exploration of their diverse applications.

Comparing robust proton versus online adaptive photon radiotherapy for short-course treatment of rectal cancer

Background and purposeImage-guided proton beam therapy (IG-PBT) and cone-beam CT (CBCT)-based online adaptive photon radiotherapy (oART) have potentials to restrict radiation toxicity. They are both hypothesised to reduce therapy limiting bowel toxicity in the multimodality treatment of locally advanced rectal cancer (LARC). This study aimed to quantify the difference in relevant dose-volume metrics for these modalities. Material and MethodsSix-degrees-of-freedom IG-PBT and oART short-course radiotherapy (SCRT) were simulated for 18 LARC patients. Relative biological effectiveness (RBE) was 1.1 for IG-PBT. Delivered dose was evaluated using post-CBCTs. Target coverage was considered robust if average dose to 99 % of the clinical target volume was ≥ 95 % of the prescription. Organ at risk (OAR) doses were compared using dose-volume histograms and severe bowel toxicity estimated using dose–response modelling. ResultsTarget coverage was robust in all patients for oART and all but one patient for IG-PBT. For the main OARs, IG-PBT increased the volume exposed to ≥ 15 Gy (RBE), but reduced volumes exposed to lower doses. Both low- and high-dose exposure to bowel loops were significantly different between the modalities (median (interquartile range) IG-PBT-V8.9Gy(RBE) = 92 cm3 (51–156), oART-V8.9Gy(RBE) = 166 cm3 (107–234), p < 0.001; IG-PBT-V23Gy(RBE) = 62 cm3 (25–106), oART-V23Gy(RBE) = 38 cm3 (18–75), p < 0.001), translating into similar total grade ≥ 3 bowel toxicity risk. ConclusionIG-PBT and oART delivered comparable and satisfying target coverage in SCRT for LARC with similar estimated risk of severe bowel toxicity. Volumes of OAR exposed to 15 Gy (RBE) or more were reduced by oART, while IG-PBT reduced the volumes receiving doses below this level.

Exploration of Novel “Ferroxazide/Ferrazone” Derivatives as Antitrypanosomatid Agents: Design, Synthesis, and Biological Efficacy

ABSTRACTTrypanosomatids are the etiologic agents of numerous parasitic diseases that cause significant morbidity and mortality in millions of people and animals around the world. Approved antitrypanosomatid agents are limited by several drawbacks, such as severe toxicity, lengthy treatment, need for hospitalization, and susceptibility to drug resistance. Consequently, parasitic diseases remain a substantial public health problem, and new drugs are required, especially drugs suitable for rural health systems that have limited resources. In an attempt to find antitrypanosomatid agents to address this problem, we report here on the synthesis and biological efficacy of ferrocene derivatives of nifuroxazide and nitrofurazone, which were designed by replacing the nitrofuran scaffold within their structures with the ferrocene moiety. The 1,2‐disubstituted ferrocene intermediates 8 and 9, featuring amine and carboxaldehyde groups, exhibited the best in vitro antiamastigote activity against Leishmania major strain NIH S and Leishmania donovani strain 9515, respectively. Ferroxazide derivative 15 was revealed as a mammalian cell nontoxic hit compound against Trypanosoma congolense strain IL3000 trypomastigotes; however, no in vivo treatment efficacy was observed against T. congolense strain IL3000‐infected BALB/c mice during a preliminary animal study. The synthesized ferrocene derivatives were poorly soluble in the in vitro and in vivo testing media, hindering uniform sampling and dosing. This study's outcome indicates that replacing the 5‐nitrofuran moiety with ferrocene did not increase antitrypanosomatid activity compared to the nitrofuran parent drugs nifuroxazide and nitrofurazone.

Investigations into the occurrence of polycyclic aromatic hydrocarbons in surface waters of the Narok and Bomet counties of Kenya

Polycyclic aromatic hydrocarbons (PAHs) are a group of emerging chemical pollutants that pose severe health challenges and toxicity to people and aquatic organisms exposed to these pollutants. This study sought to assess the types and levels of PAHs and their eco-toxicity indices in surface waters of Narok and Bomet counties of Kenya, which have witnessed an increase in charcoal-burning activities and vehicular emissions near water bodies. Sampling was done in eight regions of the two counties based on their proximity to PAH sources. Extraction of the water samples was done via a solid-phase mmethod. Seven US Environmental Protection Agency (US EPA) priority PAHs were detected. The concentrations of these PAHs varied from below the limits of detection up to 31.42 µg l −1 for dibenzo[ a,h ]anthracene. The majority of the PAHs from Narok County were pyrogenic, while those from Bomet were petrogenic based on PAH diagnostic ratios. The surface waters were significantly polluted with dibenzo[ a,h ]anthracene, with risk quotients above 1.0 in the surface waters, and were found to be hazardous, with hazard quotients above 10.0, thus indicating potential environmental risks. The findings indicate the need for stringent measures to be put in place to mitigate the risks posed by these PAHs.