Search Results (1,731)

Anemone baicalensis Turcz., a botanical species with a rich historical background in traditional medicine for detoxification and insecticidal applications, possesses a vast, yet largely unexplored, therapeutic potential. This study primarily focused on conducting a qualitative phytochemical analysis of the plant, determining the active ingredient content and antioxidant activity of various solvent extracts. The qualitative phytochemical analysis revealed the presence of 12 different types of phytochemicals within the plant. Utilizing ultraviolet-visible spectrophotometry, we identified 11 active ingredients in 4 solvent extracts. Notably, the methanol extract was found to contain high concentrations of total carbohydrate, total monoterpenoid, total phenolic, total tannin, and total triterpenoid. In the antioxidant experiment, the methanol extract demonstrated superior scavenging abilities against 1,1-diphenyl-2-picrylhydrazyl radical, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonicacid) diammonium salt, superoxide anion radical, and hydrogen peroxide, outperforming other extracts in chelation experiments aimed at reducing iron and metal ions. Consequently, the methanol extract was selected for further investigation. Subsequent ultrahigh-performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry analysis revealed that the methanol extract contained 39 compounds, primarily phenolic compounds and triterpenoid saponins. Three stability assessments confirmed the extract’s stability under high temperatures, varying pH levels, and simulated gastrointestinal processes. Additionally, oil stability testing demonstrated its antioxidant capacity in extra virgin olive oil and cold-pressed sunflower seed oil media. An oral acute toxicity experiment conducted on mice not only confirmed the absence of acute toxicity in the methanol extract but also provided a dose reference for subsequent gastric protection experiments. Notably, the methanol extract exhibited significant gastroprotective effects against ethanol-induced gastric lesions in rats, as evidenced by histopathological and biochemical analyses. Specifically, the extract reduced levels of malondialdehyde, alanine aminotransferase, and aspartate aminotransferase while increasing glutathione, nitric oxide, and catalase, indicating its gastroprotective mechanism. These findings suggest that the methanol extract from the aerial part of Anemone baicalensis could be a promising therapeutic agent for conditions associated with oxidative imbalances. They underscore the plant’s potential therapeutic benefits and offer valuable insights into its antioxidant properties, thereby broadening our understanding of its medicinal potential. Full article

Background/Objectives: Nintedanib (NTD), a triple tyrosine kinase receptor inhibitor, is the recommended first-line tackling option for idiopathic pulmonary fibrosis (IPF). Nevertheless, the adequacy of NTD is curtailed by issues associated with its low solubility, first-pass effect, poor bioavailability, and liver toxicity. The objective of our work was to develop a non-invasive intratracheal (i.t.) nanoparadigm based on NTD-loaded polymeric mixed micelles (NTD-PMMs) that can effectively treat IPF by sustaining the release of NTD, and snowballing its bioavailability, solubility, and efficacy. Methods: Design-Expert^® software was used to optimize various NTD-PMMs formulations via Box–Behnken design adopting the thin-film hydration technique. The optimum formulation was chosen and in vivo tested in a rat model to explore its comparative bioavailability and toxicity. Results: The formulation composition with 309.217 mg of Soluplus, 150 mg of Tween 80, and 40 mg of sodium deoxycholate was found to fulfill the requisites of an optimum NTD-PMMs formulation. The optimum NTD-PMMs formulation divulged 90.26% entrapment efficiency with a surface charge of −14.72 mV and a nanoscale diameter of 61.36 nm. Also, it substantially sustained the release of NTD by 66.84% after 24 h and manifested a pronounced stability. In vivo histopathology investigations verified the safety of NTD-PMMs delivered intratracheally. Moreover, pharmacokinetic analyses disclosed accentuated relative bioavailability of the optimized NTD-PMMs by 2.4- and 3.82-fold as compared with both the i.t. and oral crude NTD suspensions, respectively. Conclusions: Overall, the current results elicited the potential of PMMs to serve as a promising pulmonary nanovector for the targeted delivery of NTD. Full article

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, and oral squamous cell carcinoma (OSCC) is one of the most common types. There is strong evidence that ryanodine receptor 2 (RYR2) plays an important role in different types of cancer according to previous studies. Its expression is associated with survival in patients with HNSCC, but it is unknown whether altered RYR2 expression contributes to tumorigenesis. Therefore, we examined how RYR2 polymorphisms affect OSCC susceptibility and clinicopathological characteristics. Five single nucleotide polymorphisms (SNPs) of RYR2, rs12594, rs16835904, rs2779359, rs3765097, and rs3820216, were analyzed in 562 cases of OSCC and 332 healthy controls using real-time PCR. We demonstrated that RYR2 SNP rs12594 was significantly different between the case and control groups, but this difference was not significant after adjusting for personal habits. In contrast, we found that different genotypes of SNP rs2779359 were significantly associated with the characteristics of clinical stage and tumor size in OSCC patients, according to the odds ratios and the adjusted odds ratios; specifically, patients with the T genotype had 1.477-fold (95% CI, 1.043 to 2.091; p = 0.028) and 1.533-fold (95% CI, 1.087–2.162; p = 0.015) increases in clinical stage and tumor size, respectively, compared with patients with the C allele. The results of our study, in which RYR2 SNPs associated with OSCC progression and development were examined for the first time, suggest that clinicopathological characteristics may alter OSCC susceptibility. Finally, RYR2 SNP rs2779359 not only plays a role in both the prognosis and diagnosis of oral cancer but is also likely an important predictive factor for recurrence, response to treatment, and medication toxicity. Full article

Betaine, known as trimethylglycine, is a non-toxic natural substance reported to affect cancer cell responses. This study delves into the impact of betaine on the survival, proliferation, and invasion of oral squamous cell carcinoma (OSCC) cells in vitro. Human OSCC cells (HSC-4 and HSC-7) were subjected to varying concentrations of betaine, and their viability and proliferation were assessed through colourimetric MTT and colony-forming unit assays. Cell cycle progression and cell apoptosis were also investigated using flow cytometry, while cell migration and invasion were examined using a transwell migration assay, and the mRNA expression was evaluated by a quantitative polymerase chain reaction. Finally, proteomic analysis was conducted through liquid chromatography-tandem mass spectrometry on the extracted protein component of the cells. Results indicate that betaine effectively suppressed OSCC proliferation and colony formation. It triggered early apoptosis without disrupting cell cycle progression, reduced cell migration, and inhibited invasion. Betaine exposure led to significantly decreased mRNA levels of MMP1, MMP2, and MMP9 while downregulating FN1, a gene linked to epithelial-to-mesenchymal transition. Proteomic analysis revealed 9240 differentially expressed up/downregulated proteins in cells treated with betaine. The significantly upregulated proteins were associated with ATP-binding cassette (ABC) transporters, while the down-regulated proteins were associated with G protein-coupled receptors (GPCR) ligand binding. In conclusion, betaine exhibits potent anti-cancer properties by attenuating OSCC cell proliferation and mitigating invasion. Exploring this natural product as an adjunct for managing oral squamous cell carcinoma shows promise, although further investigations are needed to fully elucidate its functionality. Full article

The coffee pulp, a significant by-product of coffee processing, is often discarded but has potential for recycling and high-value uses. This study aimed to investigate the chemical composition of two coffee pulp ingredients, a flour (CPF) and an aqueous extract (CPE), and conducted acute and sub-chronic toxicity assays to determine their safety. The proximate composition revealed the high fiber content of both ingredients; the CPF mainly contained insoluble fiber, while CPE consisted exclusively of soluble pectic polysaccharides. The CPF had higher concentrations of amino acids and a better balance of essential/non-essential amino acids, whereas the CPE exhibited higher concentrations of free amino acids, ensuring higher bioavailability. Both ingredients showed elevated mineral content, while heavy-metal concentrations remained within acceptable limits. This study established the bioactive potential of the CPF and the CPE, demonstrating the high content of caffeine and gallic, protocatechuic, and 4-caffeoylquinic acids. The toxicity studies revealed that the CPF and the CPE exhibited safety when orally administered to mice. Administered doses were non-toxic, as they did not induce lethality or adverse effects in the mice or produce significant histopathological or biochemical adverse changes. This study represents a first step in valorizing the CPF and the CPE as safe novel food ingredients with health benefits for functional and nutritional foods. Full article

The fruit of Morinda citrifolia, also known as the noni tree, has been extensively used in Polynesian culture as an alternative medicine to various diseases. Recent studies have pointed out its anxiolytic activity in vitro and in mouse models. Despite the effectiveness of developed anxiolytic drugs in the market, the potential side effects of these medications have led people to resort to traditional medicine such as M. citrifolia. However, evidence regarding its anti-anxiety characteristics is still lacking to this day. Hence, this preliminary study implemented combined network pharmacology and molecular docking to validate its anti-anxiety claims. This study highlighted the bioactive compounds of the M. citrifolia fruit part to have excellent absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, particularly their outstanding oral bioavailability and blood–brain barrier penetration, both of which are essential considerations to ensure the effectiveness of anxiolytic drugs to arrive at the site of action. Moreover, noni fruit metabolites target genes involved in glutamatergic synapse pathways, which have been significantly associated with anxiety. Through molecular docking, selected compounds exhibited a strong binding affinity towards GRIA2 and PRKCA, both of which have connections with glutamatergic pathways. With all things considered, the results established that the noni fruit potentially contains therapeutic agents that elicit anti-anxiety potential. Through this, the promotion of a more sustainable, accessible, and affordable treatment of anxiety could be developed. Full article

Miltefosine, an orally administered drug, is an important component of the therapeutic arsenal against visceral and mucosal forms of leishmaniasis. However, data regarding the safety and tolerability of miltefosine treatment for cutaneous leishmaniasis (CL) are relatively limited. The aim of this study was to evaluate the tolerability, safety, and adverse events (AEs) of miltefosine treatment in patients with CL. In this cohort study, we reviewed the medical records of all miltefosine-treated patients between 1 January 2016 and 31 December 2022, at Israel Defense Forces military dermatology clinics and the dermatology and Tropical Medicine Clinics at Chaim Sheba Medical Center, Ramat-Gan, Israel. A total of 68 patients (54 males, 79%) with a median age of 30.3 ± 15.6 years (range: 18–88) were included in this study. Leishmania species were identified as L. major (n = 37, 54.4%), L. tropica (n = 12, 17.6%), L. braziliensis (n = 18, 26.5%), and L. infantum (n = 1, 1.5%) using polymerase chain reaction (PCR). Miltefosine tablets were administered orally at a dose of 50 mg, three times daily, for 28 days. Overall, 44 patients (65%) completed the 28-day treatment, and the remaining patients required dose reduction or early discontinuation of treatment. AEs (of any degree) were common, reported in 91% of patients. Both previously reported and previously unreported AEs were documented. Gastrointestinal symptoms (66.1%) and malaise (23.5%) typically occurred during the first two weeks of treatment and tended to subside. Other AEs, including acute renal failure (20.6%), sudden and severe pleuritic chest pain (7.6%), acne exacerbation (11.8%), suppuration of CL lesions (17.8%), and AEs related to the male genitourinary system (39.6% of males), typically occurred towards the end of treatment. The latter included testicular pain, epididymitis, diminution or complete absence of ejaculate, inability to orgasm, and impotence. Severe AEs necessitated treatment discontinuation (29.4%) or hospitalization (10.3%). URTI-like symptoms, arthritis, cutaneous eruption, pruritus, and laboratory abnormalities were also observed. Overall, the cure rate (for all patients combined) evaluated 3 months after the completion of treatment was 60%. The tolerability of miltefosine treatment for CL is low. Close clinical and laboratory monitoring is required during treatment, as severe AEs are not uncommon. As new insights regarding its toxicities emerge, further studies are required to define the role of miltefosine in the treatment of CL. Full article

Cardiovascular disease is the first cause of death worldwide and kills more people each year than any other cause of death. N, N-dimethylaniline-heliamine (DH), a synthetic tetrahydroisoquinoline alkaloid, has shown notable antiarrhythmic activity. However, the metabolic processes and pharmacokinetic characteristics of DH in rats have not been studied. This study aims to identify its metabolites, as well as develop and validate a rapid and efficient bioanalytical method for quantifying DH in rat plasma over a wide range of concentrations. Its metabolites were characterized in silico, in vitro, and in vivo. A series of 16 metabolites were identified, of which 12 were phase I metabolites and 4 were phase II metabolites. A low probability of DH binding to DNA, protein, and glutathione is predicted by the in silico model. The main metabolic processes of DH were demethylation, dehydrogenation, glucuronidation, and sulfation. Concentration–time profiles were generated by analyzing the plasma, and the outcomes were analyzed via non-compartmental analysis to identify the pharmacokinetic parameters. Among the detected parameters were the volume of distribution, estimated at 126,728.09 ± 56,867.09 mL/kg, clearance at 30,148.65 ± 15,354.27 mL/h/kg, and absolute oral bioavailability at 16.11%. The plasma distribution volume of DH was substantially higher than the overall plasma volume of rats, which suggests that DH has a specific tissue distribution in rats. This study suggests that DH is appropriately bioavailable and excreted via a variety of routes and has low toxicity. Full article

Drug Delivery Systems (DDSs) of known drugs are prominent candidates for new and more effective treatments of various diseases, as they may increase drug solubility, dissolution velocity, and bioavailability. Mitotane (o,p′-dichlorodimethyl dichloroethane [o,p′-DDD]) is used for the treatment of adrenocortical cancer and, occasionally, Cushing’s syndrome. However, the efficacy of mitotane is limited by its low oral bioavailability, caused by its extremely poor aqueous solubility. This research explores the development of a new powder self-emulsifying drug delivery system (P-SEDDS) for mitotane to improve its oral bioavailability. The study focuses on the new concept of a mitotane-loaded P-SEDDS to overcome the challenges associated with its limited solubility and high logP, thereby improving its therapeutic efficacy, reducing off-target toxicity, and avoiding first-pass metabolism. The P-SEDDS formulations were meticulously designed using only α-cyclodextrin and oil, with the goal of achieving a stable and efficient P-SEDDS. The optimized formulation was characterized for pharmaceutical properties, and its pharmacokinetic behavior was examined in rats. The results demonstrated a significant enhancement in the bioavailability of mitotane when delivered through the P-SEDDS, attributed to the increased dissolution velocity and improved absorption of the poorly water-soluble drug. The results suggest that a mitotane-loaded P-SEDDS has distinctly enhanced in vitro and in vivo performance compared with conventional mitotane formulations (Lysodren^®), which leads to the conclusion that the P-SEDDS formulation could be a viable and effective strategy for improving the dissolution rate and bioavailability of poorly aqueous-soluble ingredients. Full article

Colorectal cancer (CRC) is one of the top 10 most common cancers worldwide and caused approximately 10 million deaths in 2022. CRC mortality has increased by 10% since 2020 and 52.000 deaths will occur in 2024, highlighting the limitations of current treatments due to ineffectiveness, toxicity, or non-adherence. The widely used chemotherapeutic agent, 5-fluorouracil (5-FU), is associated with several adverse effects, including renal, cardiac, and hepatic toxicity; mucositis; and resistance. Taurine (TAU), an essential β-amino acid with potent antioxidant, antimutagenic, and anti-inflammatory properties, has demonstrated protective effects against tissue toxicity from chemotherapeutic agents like doxorubicin and cisplatin. Taurine deficiency is linked to aging and cancers such as breast and colon cancer. This study hypothesized that TAU may mitigate the adverse effects of 5-fluorouracil (5-FU). Carcinogenesis was chemically induced in rats using 1,2-dimethylhydrazine (DMH). Following five months of cancer progression, taurine (100 mg/kg) was administered orally for 8 days, and colon tissues were analyzed. The results showed 80% of adenocarcinoma (AC) in DMH-induced control animals. Notably, the efficacy of 5-FU showed 70% AC and TAU 50% while, in the 5-FU + TAU group, no adenocarcinoma was observed. No differences were observed in the inflammatory infiltrate or the expression of genes such as K-ras, p53, and Ki-67 among the cancer-induced groups whereas APC/β-catenin expression was increased in the 5FU + TAU-treated group. The mitotic index and dysplasia were increased in the induced 5-FU group and when associated with TAU, the levels returned to normal. These data suggest that 5-FU exhibits a synergic anticancer effect when combined with taurine. Full article

Tumor cells produce excessive reactive oxygen species (ROS) but cannot detoxify ROS if they are due to an external agent. An agent that produces toxic levels of ROS, specifically in tumor cells, could be an effective anticancer drug. CMC-2 is a molecular hybrid of the bioactive polyphenol curcumin conjugated to dichloroacetate (DCA) via a glycine bridge. The CMC-2 was tested for its cytotoxic antitumor activities and killed both naïve and multidrug-resistant (MDR) bladder cancer (BCa) cells with equal potency (<1.0 µM); CMC-2 was about 10–15 folds more potent than curcumin or DCA. Growth of human BCa xenograft in mice was reduced by >50% by oral gavage of 50 mg/kg of CMC-2 without recognizable systemic toxicity. Doses that used curcumin or DCA showed minimum antitumor effects. In vitro, the toxicity of CMC-2 in both naïve and MDR cells depended on increased intracellular ROS in tumor cells but not in normal cells at comparable doses. Increased ROS caused the permeabilization of mitochondria and induced apoptosis. Further, adding N-Acetyl cysteine (NAC), a hydroxyl radical scavenger, abolished excessive ROS production and CMC-2’s cytotoxicity. The lack of systemic toxicity, equal potency against chemotherapy -naïve and resistant tumors, and oral bioavailability establish the potential of CMC-2 as a potent drug against bladder cancers. Full article

Polybrominated dibenzofurans (PBDFs) are major brominated dioxins in the environment, but information on their bioaccumulation potential and toxicokinetics is limited. This study conducted oral exposure experiments with C57BL/6J mice to investigate the uptake ratios, distribution in the liver, plasma and brain, metabolism, and elimination kinetics of four bromine/chlorine-substituted dibenzofurans (TrBDF: 2,3,8-tribromo, TeBDF: 2,3,7,8-tetrabromo, PeBDF: 1,2,3,7,8-pentabromo, TrBCDF: 2,3,7-tribromo-8-chloro) in comparison with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The hepatic uptake ratios of 2,3,7,8-substituted dibenzofurans were lower than that of TCDD (up to 84% of the administered doses) and decreased with the number of Br substitutions (42%, 33%, and 29% for TrBCDF, TeBDF, and PeBDF, respectively). The brain uptake ratios of these dibenzofurans were less than 0.05%, and the plasma-to-brain transfer ratio also decreased with the Br number. All 2,3,7,8-substituted compounds were eliminated from the liver following first-order kinetics, with half-times in the order of TrBCDF (5.6 days) < TeBDF (8.8 days) ≈ TCDD (8.7 days) < PeBDF (13 days). The non-2,3,7,8-substituted TrBDF was poorly retained in the liver (<0.01% of the dose at 1 day) and rapidly eliminated following two-phase kinetics. All dibenzofurans were metabolised into monohydroxylated products in the liver, but the contribution of this metabolic pathway to hepatic elimination was only significant for TrBDF. As the toxic effects of dioxin-like compounds are influenced by their biological persistence, the slow elimination of TrBCDF, TeBDF, and PeBDF observed in this study suggests that exposure risk of brominated dibenzofurans may be underestimated using the toxic equivalency factors of the less persistent chlorinated analogues. Full article

Background: The safety of oral hygiene products is a growing concern, particularly regarding the toxicity of specific ingredients used in their formulations. The purpose of this study was to evaluate the knowledge and attitudes of dentists, physicians, pharmacists, and the general public regarding ingredients in oral hygiene products, especially fluoride. Additionally, this study aimed to identify which ingredients may exhibit potential toxicity based on historical records of any adverse effects being induced by a material/component. Methods: A self-administered questionnaire was used in an online cross-sectional observational study to collect data on sociodemographic characteristics, knowledge of fluoride in dental medicine, fluoride usage practices in oral hygiene products, opinions on ingredient toxicity in oral hygiene products, and personal experiences of adverse reactions to products and their components. The collected data underwent descriptive and regression analyses to reveal patterns and relationships within the dataset. Results: The study found a moderate overall knowledge level regarding fluoride usage in dentistry among participants (Md = 5.00, IQR 2.50–7.00). Healthcare professionals exhibited significantly higher knowledge scores compared to the general population (p ≤ 0.001), with dental professionals displaying the highest scores. Regarding concerns about the usage of fluoride, the majority of respondents (77.0%) did not express any concerns. Minor concerns included the risk of ingestion (6.0%) and dental fluorosis (4.6%). Among the other ingredients in oral hygiene products, respondents named alcohol as the most toxic ingredient (70.3%), followed by artificial colors (53.1%), artificial sweeteners (50.4%), and parabens (50.1%). It is noteworthy that the majority of participants (61.6%) stated that they had never experienced any side effects associated with the use of oral hygiene products. Conclusion: This study underscores disparities in fluoride knowledge between healthcare professionals and the general population in Croatia, with dental experts exhibiting a superior understanding. Despite lingering misconceptions about fluoride content and potential toxicity, the majority of participants acknowledge its oral health benefits and use fluoride products regularly. Full article

Micro- and nano-plastics (MNPLs) can move along the food chain to higher-level organisms including humans. Three significant routes for MNPLs have been reported: ingestion, inhalation, and dermal contact. Accumulating evidence supports the intestinal toxicity of ingested MNPLs and their role as drivers for increased incidence of colorectal cancer (CRC) in high-risk populations such as inflammatory bowel disease (IBD) patients. However, the mechanisms are largely unknown. In this review, by using the leading scientific publication databases (Web of Science, Google Scholar, Scopus, PubMed, and ScienceDirect), we explored the possible effects and related mechanisms of MNPL exposure on the gut epithelium in healthy conditions and IBD patients. The summarized evidence supports the idea that oral MNPL exposure may contribute to intestinal epithelial damage, thus promoting and sustaining the chronic development of intestinal inflammation, mainly in high-risk populations such as IBD patients. Colonic mucus layer disruption may further facilitate MNPL passage into the bloodstream, thus contributing to the toxic effects of MNPLs on different organ systems and platelet activation, which may, in turn, contribute to the chronic development of inflammation and CRC development. Further exploration of this threat to human health is warranted to reduce potential adverse effects and CRC risk. Full article

(1) Background: Oral cavity cancer represents the most common site of origin of head and neck mucosal malignancies. A few limited studies have suggested that chronic irritation, particularly in non-healing ulcers, and fibrotic tissue from poor dentition or ill-fitting dentures had a role in developing mouth cancer. This scoping review aims to evaluate the existing evidence concerning Oral Cavicty Cancer (OCC) in non-smokers/non-drinkers and the relationship with dental trauma. (2) Methods: A scoping review of the PubMed, Embase, and Web of Science databases was completed in adherence with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews checklist. (3) Results: Of the 33 articles that met inclusion, in 6 of them authors discussed the role of topography in dental trauma, in 11 articles authors discussed the carcinogenesis mechanism involved in chronic mucosal trauma, in 17 articles data on ill-fitting dentures was included, 4 studies dealt with the effect of broken/sharp teeth on mucosal damage, and in 7 studies the role of oral hygiene was covered. Less frequently discussed topics included gender, risk of neck nodes, and the role of potentially malignant oral disorders. (4) Conclusions: The available literature suggests a potential connection between chronic dental trauma and the development of OCC. Studies have highlighted factors such as denture use and ill-fitting dental appliances as contributors to an increased risk of oral cancer. Interestingly, we still miss data to support the hypothesis that women, particularly those without toxic habits like smoking or alcohol consumption, appear to be disproportionately affected by oral cancer related to chronic dental trauma. Full article