Aspects Of Toxicity Research Articles

A green approach for delignification of corn husks and their application as an unpowered thermo-responsive sensor

The world is adopting biodegradable materials to replace existing petroleum-based plastics, owing to their toxicity and unfriendly environmental aspects. Biodegradable corn husk (CH) is considered a promising alternative due to its environmental friendliness and widespread availability as agricultural waste. In this work, a green process for the delignification of corn husk was developed and preparation of CH-based reversible thermo-responsive delignified corn husk (RTDCH) sensors was done which exhibit different colors corresponding to particular temperature ranges. These RTDCH sensors employed with reversible thermo-responsive nanoparticles (RTNPs) were characterized thoroughly using X-ray Diffraction (XRD), scanning electron microscopy (SEM), thermo-gravimetric analysis (TGA), and Fourier transform spectroscopy (FTIR), which ensures their successful synthesis. Upon deploying them for sensing temperatures from 20 to 80℃, different color displays appeared rapidly within 5seconds, which helps to identify the particular temperature range. The RTDCH exhibited excellent reusability for several cycles and maintained consistency in color displays at certain exposed temperatures. The RTDCH, being unpowered, fast responsive, accurate, biodegradable, economical, and scalable production feasibilities, has the necessary traits to become practical at the industrial level. Such materials have tremendous potential for the food industry, scientific laboratories, and monitoring the temperature of industrial processes. The strategy adopted in this work is crucial since it is paving the way for the development of advanced functional materials from natural wastes through green synthesis approaches.

Cyclodextrins: Advances in Chemistry, Toxicology, and Multifaceted Applications

Cyclodextrins (CDs) have garnered significant attention in various scientific and industrial fields due to their unique ability to form inclusion complexes with a wide range of guest molecules. This review comprehensively explores the latest advancements in cyclodextrin chemistry, focusing on the synthesis and characterization of cyclodextrin derivatives and their inclusion complexes. This review examines the biological activities of cyclodextrins, highlighting their pharmacological properties and pharmacokinetics, and discussing their promising applications in drug delivery systems. Furthermore, the industrial utilization of cyclodextrins, including their role in nanomaterials and nanostructured coatings, as well as their potential in environmental remediation, are explored. The present research also addresses the critical aspect of toxicity, particularly concerning cyclodextrin inclusion complexes, providing an overview of the current understanding and safety considerations. Through a multidisciplinary approach, the aim is to present a complete view of cyclodextrins, underscoring their versatility and impact across various domains.

Transgenerational response of glucose metabolism in Caenorhabditis elegans exposed to 6-PPD quinone

In Caenorhabditis elegans, 6-PPD quinine (6-PPDQ) could cause several aspects of toxicity together with alteration in glucose metabolism. However, transgenerational alteration in glucose metabolism remains still unknown after 6-PPDQ exposure. In the current study, we further observed transgenerational increase in glucose content induced by 6-PPDQ (1–10 μg/L). After 1–10 μg/L 6-PPDQ exposure, although expressions of genes controlling gluconeogenesis were not changed in the offspring, expressions of hxk-1, hxk-3, pyk-1, and pyk-2 controlling glycolysis could be decreased in the offspring. Meanwhile, transgenerational decrease in expressions of daf-16 encoding FOXO transcriptional factor and aak-2 encoding AMPK was detected in the offspring of 6-PPDQ (1–10 μg/L) exposed nematodes. RNAi of daf-16 and aak-2 led to more severe transgenerational increase in glucose content and reduction in expressions of hxk-1 and hxk-3 induced by 6-PPDQ. Moreover, RNAi of daf-16, aak-2, hxk-1, hxk-3, pyk-1, and pyk-2 caused susceptibility to transgenerational 6-PPDQ toxicity on locomotion and reproduction. Additionally, 6-PPDQ induced activation of SOD-3 and HSP-6 reflecting anti-oxidation and mitochondrial UPR responses could be inhibited by RNAi of daf-16, aak-2, hxk-1, hxk-3, pyk-1, and pyk-2. Therefore, exposure to 6-PPDQ potentially resulted in transgenerational alteration in glucose metabolism, which provided the possible link to induction of transgenerational 6-PPDQ toxicity in organisms.

Toxicity and environmental aspects of surfactants

Abstract As the single largest class of specialty chemicals, surfactants are consumed in huge quantities in our daily life and in many industrial areas. In the past, the attention was focused entirely on technical performance. However, starting from the 1970s and 80s, surfactant related environmental concerns have become the main driving force to upgrade surfactant production technology to make more benign or “greener” products. For this reason, environmental issues, dermatological effects, and oral toxicity are the main priorities when surfactants are considered for a specific purpose. In this paper, we present five cases to demonstrate how the surfactant industry tackles these challenges to mitigate the environmental and health effects associated with surfactant consumption. We also discuss the important role played by surfactants in a current carbon capture and storage (CCS) strategy to reduce the CO2 level in the atmosphere. Surfactant-based stable CO2 foam flooding is a well-established enhanced oil recovery technique. It has been considered to be an economically realistic procedure to sequester large amounts of CO2 in geological formations.

Discovery of novel protective agents for infection-related delirium through bispectral electroencephalography

Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.

Evaluating the Effects of BSA-Coated Gold Nanorods on Cell Migration Potential and Inflammatory Mediators in Human Dermal Fibroblasts.

Albumin-coated gold nanoparticles display potential biomedical applications, including cancer research, infection treatment, and wound healing; however, elucidating their interaction with normal cells remains an area with limited exploration. In this study, gold nanorods (GNR) were prepared and coated with bovine serum albumin (BSA) to produce GNR-BSA. The functionalized nanoparticles were characterized based on their optical absorption spectra, morphology, surface charge, and quantity of attached protein. The interaction between GNR-BSA and BSA with normal cells was investigated using human dermal fibroblasts. The cytotoxicity test indicated cell viability between ~63-95% for GNR-BSA over concentrations from 30.0 to 0.47 μg/mL and ~85-98% for BSA over concentrations from 4.0 to 0.0625 mg/mL. The impact of the GNR-BSA and BSA on cell migration potential and wound healing was assessed using scratch assay, and the modulation of cytokine release was explored by quantifying a panel of cytokines using Multiplex technology. The results indicated that GNR-BSA, at 10 μg/mL, delayed the cell migration and wound healing 24 h post-treatment compared to the BSA or the control group with an average wound closure percentage of 6% and 16% at 6 and 24 h post-treatment, respectively. Multiplex analysis revealed that while GNR-BSA reduced the release of the pro-inflammatory marker IL-12 from the activated fibroblasts 24 h post-treatment, they significantly reduced the release of IL-8 (p < 0.001), and CCL2 (p < 0.01), which are crucial for the inflammation response, cell adhesion, proliferation, migration, and angiogenesis. Although GNR-BSA exhibited relatively high cell viability towards human dermal fibroblasts and promising therapeutic applications, toxicity aspects related to cell motility and migration must be considered.

Convergent Active Site Evolution in Platinum Single Atom Catalysts for Acetylene Hydrochlorination and Implications for Toxicity Minimization.

Platinum single atoms anchored onto activated carbon enable highly stable Hg-free synthesis of vinyl chloride (VCM) via acetylene hydrochlorination. Compared to gold-based alternatives, platinum catalysts are in initial phases of development. Most synthetic approaches rely on chloroplatinic acid, presenting opportunities to explore other precursors and their impact on catalyst structure, reactivity, and toxicity aspects. Here, we synthesize platinum single atom catalysts (Pt SACs, 0.2-0.8 wt % Pt) employing diverse Pt2+ and Pt4+ complexes with ammine, hydroxyl, nitrate, and chloride ligands, following a scalable impregnation protocol on activated carbon extrudates. X-ray absorption spectroscopy (XAS) reveals that Pt4+ species reduce to Pt2+ upon deposition onto the support. Despite similar oxidation states, the initial activity is precursor dependent, with tetraammine-derived Pt SACs displaying 2-fold higher VCM yield than chlorinated counterparts, linked to superior hydrogen chloride binding abilities by density functional theory (DFT) simulations. Their activity gradually converges due to dynamic active site restructuring, delivering remarkable precursor-independent stability over 150 h. Operando XAS and DFT studies uncover reaction-induced ligand exchange, generating common active and stable Pt-Cl x (x = 2-3) species. Convergent active site evolution enables flexibility in metal precursor selection and thus toxicity minimization through multiparameter assessment. This study advances safe-by-design catalysts for VCM synthesis, highlighting the importance of toxicity analyses in early-stage catalyst development programs.

In silico Investigation of the Interactions of Thymol and Carvacrol on the Spike Protein of Omicron Variant and MPro Enzyme of Coronavirus

Many drug studies have been conducted against the coronavirus disease, which has affected the whole world since December 2019, and some studies have been carried out on natural treatment methods. Many ideas for curing coronavirus disease of T. vulgaris known as thyme plant have been presented, although there are gaps in the literature on the subject. In this work, the anti-severe acute respiratory syndrome coronavirus 2 potential of the major compounds of the T. vulgaris plant’s essential oil was investigated in silico. The major components of the T. vulgaris plant's essential oil are thymol and carvacrol. Using molecular docking experiments, we evaluated the effects of thymol and carvacrol in thyme essential oil on Omicron variant spike protein and main protease enzyme (Mpro) of severe acute respiratory syndrome coronavirus 2. We also used online databases to investigate the adsorption, distribution, metabolism, absorption, and toxic (ADMET) aspects of these two compounds. It was determined that thymol and carvacrol have strong binding affinity to the spike protein of the Omicron variant and the main protease enzyme. The compounds interact with target proteins through electrostatic, hydrogen bonds, and hydrophobic interactions. More promising findings are obtained when the contacts of carvacrol with target proteins are assessed in terms of the structure-activity relationship.

Effects of changed water regime on the toxicity of silver nanoparticles (AgNPs) in tadpoles of Fejervarya limnocharis.

Climate change is viewed as one of the important causes of the amphibian population decline. Aspects of climate change like increase in water temperature and drying up of habitats have been underrepresented. The expanding production and usage of metal nanoparticles like silver nanoparticles (AgNPs) make them likely to end up in aquatic ecosystems. To arrive at a realistic assessment of the impact of AgNPs in a warming world, we have investigated the effects of temperature on the acute toxicity of AgNPs in tadpoles of Fejervarya limnocharis at 24, 48, 72 and 96h of exposure. The various aspects of sub-lethal toxicities of AgNPs with increase in temperature were also investigated. Besides, the effects of habitat desiccation on the sub-lethal toxicities of AgNPs in the tadpoles were analysed. The LC50 values of AgNPs at four different time points were found to be significantly different between the two different temperatures. Alterations in survival pattern, life history traits, amplifications in genotoxic potential and oxidative stress were observed with increased water temperature following AgNP exposure. The phenomenon of habitat desiccation was also found to significantly affect the toxicity of AgNPs with respect to alterations in mortality rate, time to metamorphosis and morphometric parameters of metamorphosed tadpoles. The findings suggest that changed water regime such as increased water temperature as well as reduction in water level accelerated the toxic effects of AgNPs in F. limnocharis tadpoles which is likely to affect their natural populations.

N-Benzyl piperidine Fragment in Drug Discovery.

The N-benzyl piperidine (N-BP) structural motif is commonly employed in drug discovery due to its structural flexibility and three-dimensional nature. Medicinal chemists frequently utilize the N-BP motif as a versatile tool to fine-tune both efficacy and physicochemical properties in drug development. It provides crucial cation-π interactions with the target protein and also serves as a platform for optimizing stereochemical aspects of potency and toxicity. This motif is found in numerous approved drugs and clinical/preclinical candidates. This review focuses on the applications of the N-BP motif in drug discovery campaigns, emphasizing its role in imparting medicinally relevant properties. The review also provides an overview of approved drugs, the clinical and preclinical pipeline, and discusses its utility for specific therapeutic targets and indications, along with potential challenges.

Cellular and subcellular effects of chronic low-dose Lambda-cyhalothrin pesticide exposure modulated by medicinal plant methanol extract in rat

The extensive use of Lambda-cyhalothrin (LCT) has been associated with the various toxicities that non-target organisms can undergo including mammals. However, the mechanism of LCT-induced cytotoxicity in animal brain cells is still elusive, particularly in brain regions, notably the hippocampus, an area directly involved in cognitive function. This study aimed to investigate the neurotoxic effects in the rat hippocampus chronically exposed to LCT (0.18 mg/kg and 0.36 mg/kg), and the neuroprotective potential of Melissa officinalis L methanol extract (MOE) (200 mg/kg) against this toxicity. After experimental period (90 days), the redox status, the functional and structural integrity of the hippocampus mitochondria as well as the apoptotic signaling pathway were evaluated. The current findings suggest that LCT induces an imbalance of mitochondrial redox status characterized by, on one side, an increase of stress markers such as protein carbonyls (PCO), malondialdehyde (MDA), and hydrogen peroxide (H2O2) levels; and on the other side, a decline in the potential of antioxidant systems, namely the level of mitochondrial enzymatic activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD) and glutathione (GSH).This study also showed an increase in mitochondrial permeability, along with mitochondrial edema and considerable decrease in its O2 consumption. Moreover, the same results recorded an increase in caspase-3 and cytosolic cytochrome-c. Conversely, this study proved that all these toxic aspects induced by LCT were significantly mitigated when the administration of this synthetic pyrethroid was associated with MOE. Taken together, data of this study shed light on mitochondrial damage and apoptosis stimulation under the toxic effect of LCT and suggests that MOE is endowed with potent neuroprotective effects, possibly via its antioxidant and antiapoptotic properties.

Enhanced Skin Penetration and Efficacy: First and Second Generation Lipoidal Nanocarriers in Skin Cancer Therapy.

Skin carcinoma remains one of the most widespread forms of cancer, and its global impact continues to increase. Basal cell carcinoma, melanoma, and squamous cell carcinoma are three kinds of cutaneous carcinomas depending upon occurrence and severity. The invasive nature of skin cancer, the limited effectiveness of current therapy techniques, and constraints to efficient systems for drug delivery are difficulties linked with the treatment of skin carcinoma. In the present era, the delivery of drugs has found a new and exciting horizon in the realm of nanotechnology, which presents inventive solutions to the problems posed by traditional therapeutic procedures for skin cancer management. Lipid-based nanocarriers like solid lipid nanoparticles and nanostructured lipid carriers have attracted a substantial focusin recent years owing to their capability to improve the drug'ssite-specific delivery,enhancing systemic availability,and thus its effectiveness. Due to their distinct structural and functional characteristics, these nanocarriers can deliver a range of medications, such as peptides, nucleic acids, and chemotherapeutics, via different biological barriers, such as the skin. In this review, an effort was made to present the mechanism of lipid nanocarrier permeation via cancerous skin. In addition, recent research advances in lipid nanocarriers have also been discussed with the help of in vitro cell lines and preclinical studies. Being a nano size, their limitations and toxicity aspects in living systems have also been elaborated.

A review on the enantioselective distribution and toxicity of chiral pesticides in aquatic environment.

Chiral pesticides account for about 40% of the total pesticides. In the process of using pesticides, it will inevitably flow into the surface water and even penetrate into the groundwater through surface runoff and other means, as a consequence, it affects the water environment. Although the enantiomers of chiral pesticides have the same physical and chemical properties, their distribution, ratio, metabolism, toxicity, etc. in the organism are often different, and sometimes even show completely opposite biological activities. In this article, the selective fate of different types of chiral pesticides such as organochlorine, organophosphorus, triazole, pyrethroid and other chiral pesticides in natural water bodies and sediments, acute toxicity to aquatic organisms, chronic toxicity and other aspects are summarized to further reflect the risks between the enantiomers of chiral pesticides to non-target organisms in the water environment. In this review, we hope to further explore its harm to human society through the study of the toxicity of chiral pesticide enantiomers, so as to provide data support and theoretical basis for the development and production of biochemical pesticides.

Financial Toxicity Among Patients With Metastatic Prostate Cancer: A Mixed Methods Approach to Identify Effective Interventions.

Financial toxicity associated with treatments for metastatic prostate cancer remains poorly defined. We sought to understand aspects of financial toxicity not captured in a commonly employed financial toxicity questionnaire and identify potential interventions to help alleviate financial toxicity through a convergent mixed methods approach. Patients seen at our institution's advanced prostate cancer clinic were approached for completion of the Comprehensive Score for Financial Toxicity (COST-FACIT) questionnaire (quantitative analysis). A maximal variation purposive sample was chosen to participate in focus group discussions (qualitative analysis). Conventional content analysis was performed using an inductive approach. COST-FACIT scores were compared between patients experiencing high and low financial toxicity using Wilcoxon rank sum test. Three themes were identified through qualitative analysis: (1) workload, (2) coping strategies, and (3) communication. We found alignment with the existing theory of financial capacity across our findings. Two unique aspects of financial toxicity emerged that were not assessed quantitatively and deemed to be significant. Specifically, cost transparency (including health care teams knowledgeable about and willing to discuss costs) and inclusion of informal caregivers in financial toxicity screening and decision-making may guide future interventions aimed at limiting financial toxicity in this population. Prolonged treatment courses involving multiple lines of treatment with varying costs result in distinct financial toxicity components for patients with metastatic prostate cancer that are not assessed with COST-FACIT. Improving cost transparency, health care team knowledge and engagement, and providing resources to support informal caregivers may have a significant impact on the financial toxicity experienced by these patients.

Visualization of renal rotenone accumulation after oral administration and in situ detection of kidney injury biomarkers via MALDI mass spectrometry imaging.

The examination of drug accumulation within complex biological systems offers valuable insights into the molecular aspects of drug metabolism and toxicity. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) is an innovative methodology that enables the spatial visualization and quantification of biomolecules as well as drug and its metabolites in complex biological system. Hence, this method provides valuable insights into the metabolic profile and any molecular changes that may occur as a result of drug treatment. The renal system is particularly vulnerable to adverse effects of drug-induced harm and toxicity. In this study, MALDI MSI was utilized to examine the spatial distribution of drug and renal metabolites within kidney tissues subsequent to a single oral dosage of the anticancer compound rotenone. The integration of ion mobility spectrometry with MALDI MSI enhanced the data acquisition and analysis, resulting to improved mass resolution. Subsequently, the MS/MS fragment ions of rotenone reference drug were detected and characterized using MALDI HDMS/MS imaging. Notably, drug accumulation was observed in the cortical region of the representative kidney tissue sections treated with rotenone. The histological examination of treated kidney tissues did not reveal any observable changes. Differential ion intensity of renal endogenous metabolites was observed between untreated and rotenone-treated tissues. In the context of treated kidney tissues, the ion intensity level of sphingomyelin (D18:1/16:0), a sphingolipid indicator of glomerular cell injury and renal damage, was found to be elevated significantly compared to untreated kidney tissues. Conversely, the ion intensities of choline, glycero-3-phosphocholine (GPC), inosine, and a lysophosphatidylcholine LysoPC(18:0) exhibited a significant decrease. The results of this study demonstrate the potential of MALDI MSI as a novel technique for investigating the in situ spatial distribution of drugs and renal endogenous molecules while preserving the anatomical integrity of the kidney tissue. This technique can be used to study drug-induced metabolism and toxicity in a dynamic manner.

Beyond Chemoimmunotherapy in Advanced Non-Small Cell Lung Cancer: New Frontiers, New Challenges.

Chemoimmunotherapy is currently the preferred first-line treatment option for the majority of patients with advanced non-small cell lung cancer without driver genetic alterations. Most of these patients, however, will experience disease progression within the first year after treatment initiation and both patients and their physicians will be confronted with the dilemma of the optimal second-line treatment. Identification of molecular targets, such as KRASG12C, BRAFV600X, METexon14, and human epidermal growth factor receptor 2 mutations, and RET rearrangements offer therapeutic opportunities in pretreated patients with corresponding alterations. For those tumors that do not harbor oncogenic drivers, second-line treatment with docetaxel remains the current standard of care despite modest efficacy. Strategies to challenge docetaxel include the combination of immune checkpoint inhibitors (ICIs) with tyrosine inhibitors of multiple kinases or with DNA damage response inhibitors, antibody-drug conjugates, and locoregional treatments for oligoprogressive disease. Next-generation immunotherapy strategies, such as T-cell engagers, immune-mobilizing monoclonal T-cell receptors, chimeric antigen receptor cell therapy, tumor infiltrating lymphocytes, and T-cell receptor cell therapy are being currently investigated in the quest to reverse resistance to ICIs. Importantly, the advent of these new agents heralds a novel spectrum of toxicities that require both the physician's and the patient's education. Herein, we review current and future strategies aiming to outperform docetaxel after chemoimmunotherapy failure, and we provide practical information on how to best communicate to our patients the unique toxicity aspects associated with immunotherapy.

Life cycle assessment of lead‐free potassium sodium niobate versus lead zirconate titanate: Energy and environmental impacts

AbstractOver the years, lead‐based piezoelectric ceramics found extensive use in vital fields such as sensors and actuators. Despite their exceptional electromechanical properties, lead‐containing materials pose severe environmental risks and foster a new era of lead‐free piezoelectric materials after decades of research. However, recent comparative assessments of potassium sodium niobate (KNN) versus lead zirconate titanate (PZT) piezoelectric materials proposed that the environmental damage already presented before use due to raw material extraction and processing, invoking concerns on the true greenness of the lead‐free alternatives. Nevertheless, many other factors deserve further consideration, for example, reference geometry and life cycle stage. Herein, the comprehensive life cycle assessment is undertaken on PZT and KNN‐based ceramics with a unit volume of 0.001 m3 from cradle to gate. Results show that PZT exhibits higher negative impacts than KNN‐based counterparts, attributed to lead extraction, processing, and associated environmental emissions. Across primary quantitative impact indicators from toxicity, environmental, and resource aspects, KNN‐based ceramics impose fewer risks on the environment and human health, with the overall impact being only 28% of PZT ceramics. Still, more efficient methods are required for KNN‐based ceramics to reduce the high energy consumption and emission during extraction and purification of raw material Nb2O5. This work not only offers critical insights for material development but also serves as a multifaceted reference for advanced fabrication technologies.image

Comparative steroidogenic effects of hexafluoropropylene oxide trimer acid (HFPO-TA) and perfluorooctanoic acid (PFOA): Regulation of histone modifications

As a widely used alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been detected in the environment and humans; however, little is known regarding its male reproductive toxicity. To compare the effects of HFPO-TA on steroid hormone synthesis with PFOA, we exposed Leydig cells (MLTC-1) to non-lethal doses (0.1, 1, and 10 μM) of PFOA and HFPO-TA for 48 h. It was found that the levels of steroid hormones, 17α-hydroxyprogesterone (OHP), androstenedione (ASD), and testosterone (T) were significantly increased in 1 and 10 μM of PFOA and HFPO-TA groups, with greater elevation being observed in the HFPO-TA groups than in the PFOA groups at 10 μM. We further showed that the two rate-limiting steroidogenic genes (Star and Cyp11a1) were up-regulated, while Hsd3b, Cyp17a1, and Hsd17b were down-regulated or unchanged after PFOA/HFPO-TA exposure. Moreover, PFOA exposure significantly up-regulated histone H3K4me1/3 and H3K9me1, while down-regulated H3K4me2 and H3K9me2/3 levels. By contrast, H3K4me2/3 and H3K9me2/3 were enhanced, while H3K4me1 and H3K9me1 were repressed after HFPO-TA treatment. It was further confirmed that H3K4me1/3 were increased and H3K9me2 was decreased in Star and Cyp11a1 promoters by PFOA, while HFPO-TA increased H3K4me2/3 and decreased H3K9me1 in the two gene promoters. Therefore, we propose that low levels of PFOA/HFPO-TA enhance the expression of Star and Cyp11a1 by regulating H3K4 and H3K9 methylation, thus stimulating the production of steroid hormones in MLTC-1 cells. Collectively, HFPO-TA exhibits stronger effects on steroidogenesis compared to PFOA, which may be ascribed to the distinct regulation of histone modifications. These data suggest that HFPO-TA does not appear to be a safer alternative to PFOA on the aspect of male reproductive toxicity.

In silico Studies of Cilnidipine Degradation Products for Structure Confirmation, Toxicity Prediction and Molecular Docking

In this study, a comprehensive analysis of cilnidipine and its degradation products (KD1-KD4 and CD1-CD3) with three main objectives viz. (i) toxicity prediction for bacterial mutagenicity, (ii) assessment of pharmacological activity and (iii) density functional theory (DFT) calculations were performed for structure confirmation. For bacterial mutagenicity prediction, in silico assessments were performed following ICH M7 guidelines. Using rule-based and statistical-based methodologies, predictions revealed an alerting group in CD1-CD3, while no alerting group was observed in KD1-KD4 for bacterial mutagenicity. To assess pharmacological activity, docking studies were conducted to identify the mode of binding and interaction types of cilnidipine and its degradation products with N-type and L-type calcium channel subunits 7VFS and 7UHF, respectively. Additionally, 20 drugs acting as calcium channel blockers were considered for docking analysis to correlate the affinities of binding. The interaction energies revealed that molecule CD3 shows the highest binding affinity with the ligand molecules, with a binding energy of -9.2 (kcal/mol) with 7VFS and -8.7 (kcal/mol) with 7UHF proteins, followed by KD3 with a binding energy of -8.7 (kcal/mol) (7VFS) and -7.9 (kcal/mol) (7UHF). Furthermore, DFT calculations were employed to reassess the structures of degradation products CD1 and CD2 proposed in the literature. Simulating 1H and 13C NMR spectra, the obtained data demonstrated good agreement with experimental results, confirming the proposed stereo-configurations in the literature. Based on in silico bacterial mutagenicity predictions and docking studies, KD3 emerged as a promising compound for receptor binding. Additionally, DFT calculations provided structural insights, affirming stereo-configurations proposed in the existing literature. This multifaceted approach contributed valuable insights into the toxicity, pharmacology and structural aspects of cilnidipine degradation products.

Research progress on the antitumor effects of harmine.

Harmine is a naturally occurring β-carboline alkaloid originally isolated from Peganum harmala. As a major active component, harmine exhibits a broad spectrum of pharmacological properties, particularly remarkable antitumor effects. Recent mechanistic studies have shown that harmine can inhibit cancer cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle regulation, angiogenesis, and the induction of tumor cell apoptosis. Furthermore, harmine reduces drug resistance when used in combination with chemotherapeutic drugs. Despite its remarkable antitumor activity, the application of harmine is limited by its poor solubility and toxic side effects, particularly neurotoxicity. Novel harmine derivatives have demonstrated strong clinical application prospects, but further validation based on drug activity, acute toxicity, and other aspects is necessary. Here, we present a review of recent research on the action mechanism of harmine in cancer treatment and the development of its derivatives, providing new insights into its potential clinical applications and strategies for mitigating its toxicity while enhancing its efficacy.