Search Results (106)

Pomacea canaliculata, as a significant invasive alien species, poses severe threats to agricultural development. Currently, chemical applications demonstrate notable efficacy in controlling this pest. However, metaldehyde exhibits overly singular toxicity towards P. canaliculata; niclosamide sulfate is not a molluscicide; and fentin acetate is a fungicide. Currently, these findings fail to elucidate the physiological and biochemical effects of the compounds after they enter the P. canaliculata’s body. In this study, we evaluated the toxicity of metaldehyde (ME), niclosamide sulfate (NS), and fentin acetate (FA) against P. canaliculata and analyzed the morphological and physiological changes in response to chemical stress. The results indicated that three chemicals exhibited potent molluscicidal activity, especially in the NS treatment group. After 12 h exposure to LC₅₀ concentrations (48 h LC₅₀), the surface area of livers was reduced significantly by 12.1%, 13.9%, and 2.8% compared to the control group, while the kidneys expanded significantly by 6.4%, 3.2%, and 16.7%, respectively. The heart showed marked enlargement by 152.1% and 44.2% under niclosamide sulfate and metaldehyde treatments. The pulmonary sac significantly contracted by 23.6% under niclosamide sulfate stress but expanded by 6.1% under fentin acetate exposure. The stomach enlarged significantly after niclosamide sulfate treatment, whereas it shrank by 2.1% and 5.7% under metaldehyde and fentin acetate treatments, respectively. Metabolomic analysis of liver tissues revealed 553, 99, and 585 differential metabolites compared to the control group, respectively. KEGG pathway enrichment analysis showed that the metabolism pathway, lysine degradation, and bile secretion are likely related to the response to chemical stress in P. canaliculata. Further examination showed a significant decrease in total protein content and the activities of malondialdehyde (MDA), acetylcholinesterase (AChE), superoxide dismutase (SOD), and catalase (CAT) under chemical stress. These findings enhance our understanding of the targeted mechanisms of molluscicides against P. canaliculata. Metaldehyde may exert neurotoxic effects on the P. canaliculata, while niclosamide sulfate may interfere with its respiratory system. Additionally, both chemicals affect metabolic pathways in the snail’s liver, including lipid metabolism and metabolic pathways associated with energy metabolism. These findings provide valuable insights for designing a novel snail control agent and formulating scientific management strategy. Full article

Background: The golden apple snail (Pomacea canaliculata), an invasive species originating from South America, has inflicted considerable agricultural and ecological harm in non-native habitats. While the molluscicide niclosamide is currently effective against P. canaliculata, its prolonged use raises environmental concerns and the risk of resistance development. Results: BAM 15 possesses strong molluscicidal activity against P. canaliculata, with 72 h LC₅₀ values of 0.4564 mg/L for adults (shell height: 20–25 mm), 0.3352 mg/L for subadults (10–15 mm), and 0.1142 mg/L for juveniles (2–3 mm). Metabolomic and proteomic profiling revealed that the altered metabolites and proteins both converged on energy metabolism and oxidative stress. Experimental validation revealed that BAM15 collapsed the mitochondrial membrane potential, drove MDA and H₂O₂ upward while depleting NADPH, boosted CAT, SOD and GPX activities, yet suppressed GR, and ultimately inflicted overt damage in the head-foot tissue of P. canaliculata. Conclusions: Our findings reveal that BAM 15 operates via a three-stage mechanism: (1) it disrupts membrane potential (ΔΨm) and impairs ATP production, severely disturbing energy metabolism; (2) energy deficits stimulate excessive electron transport chain activity, generating reactive oxygen species (ROS) and initiating oxidative stress; (3) persistent metabolic imbalance and oxidative damage culminate in extensive tissue injury. These results identify BAM 15 as a promising candidate for molluscicide development. Full article

Niclosamide has been the primary molluscicide for schistosomiasis control for over 50 years, but its chronic effects on inter-organ interactions in non-target mollusks remain poorly understood. Cipangopaludina cathayensis, a dominant species in East Asian schistosomiasis-endemic regions, was chronically exposed to environmentally relevant concentrations of niclosamide to assess its toxic effects. Digestive glands accumulated more niclosamide than the foot tissues. Prolonged exposure was associated with metabolic impairment of the digestive glands, characterized by tubular atrophy, inflammatory reactions, and depletion of nutrient components. Foot tissues exhibited epithelial lesions and muscle fiber atrophy. Alterations in foot structure were associated with changes in digestive gland nutrient status. Niclosamide exposure may weaken the metabolic coupling between these organs, thereby impairing locomotor function. At the population level, persistent niclosamide exposure may destabilize mollusk trophic-level populations, ultimately leading to ecological consequences. Our findings demonstrate the toxicological risks of niclosamide to freshwater mollusks. Full article

Background: Despite the emergence of new treatment modalities, including targeted therapies that are of benefit to patients whose tumours carry specific mutations, the prognosis for most patients with cholangiocarcinoma remains poor. Novel therapeutic approaches that can benefit the majority of patients whose tumour cells do not carry targetable mutations are urgently needed. Results: To identify mutation-agnostic treatment approaches, we screened a library of well-tolerated off-patent drugs against cholangiocarcinoma cells and normal biliary epithelial cells. The screen identified Niclosamide as a drug that reduces the viability of multiple cholangiocarcinoma cell lines but has a lesser effect on normal primary biliary epithelial cells. Moreover, Niclosamide treatment reduces the growth of cholangiocarcinoma tumour cells as tumour spheroids in vitro and reduces the growth of cholangiocarcinoma cells as tumours in a xenograft mouse model of this disease. Through a proteasome-dependent mechanism, Niclosamide treatment reduces the expression of the Proline-Rich Homeodomain (PRH) protein, a transcription factor which acts as an oncoprotein in cholangiocarcinoma cells. However, PRH knockout does not alter the sensitivity of cholangiocarcinoma cells to Niclosamide, indicating that this drug is not dependent on PRH to reduce cell viability. Interestingly, the CDK4/6 kinase inhibitor Palbociclib selectively reduces the viability of cholangiocarcinoma cell lines compared to normal biliary epithelial cells and, importantly, Palbociclib synergises with Niclosamide to reduce cholangiocarcinoma cell viability in vitro as well as to reduce tumour growth in a mouse xenograft model. Conclusion: These preclinical results suggest that the combination of Niclosamide and an inhibitor of CDK4/6 is worthy of clinical evaluation as a potential treatment for this disease. Full article

Tyrosine kinase inhibitors (TKIs), such as sunitinib and sorafenib, are standard treatments for renal cell carcinoma (RCC). However, most patients treated with these drugs eventually develop drug resistance and relapse; therefore, new treatment options for RCC are urgently required. Recent studies have focused on combination therapies targeting distinct molecular pathways that may produce synergistic effects and help overcome drug resistance in RCC. Niclosamide, an anthelmintic agent, is effective against various cancers; however, its potential in combination with sunitinib for treating RCC has not been evaluated. In this study, we assessed the therapeutic efficacy of niclosamide in combination with sunitinib against RCC and explored the underlying molecular mechanisms. Niclosamide alone inhibited RCC cell proliferation, whereas its combination with sunitinib produced a synergistic anticancer effect, both in vitro and in vivo. RNA sequencing (RNA-seq) and bioinformatic analyses showed that niclosamide modulated critical pathways, including BRIP1- and FANCA-mediated DNA repair and E2F2-regulated cell cycle progression. These findings provide proof-of-concept that niclosamide enhances TKI efficacy through modulation of DNA repair and cell cycle pathways, supporting the rationale for DNA damage response (DDR)-targeted combination strategies in RCC. Full article

Coyaima is a town in the department of Tolima, Colombia, that was prioritized in a pilot program under Colombia’s National Plan for the Control of the Taeniasis/Cysticercosis Complex, focusing on this neglected health issue. The project engaged local indigenous communities, promoting education and outreach within the One Health framework. The study included 444 randomly selected volunteers, who filled a Knowledge, Attitudes, and Practices (KAP) survey on the taeniasis/cysticercosis complex. The baseline study found no Taenia spp. eggs via microscopy on 383 stool samples examined, and no T. solium DNA was detected on human stool and soil samples by Copro-qPCR. However, seroprevalence was 8.5% for human cysticercosis and 14% for porcine cysticercosis, as detected by in-house ELISA testing for T. solium. Moreover, 57.9% of participants who provided a stool sample were positive for at least one parasite. Following the sampling and characterization activities, local health workers implemented mass treatment with Niclosamide, based on evidence of ongoing transmission, high porcine seroprevalence, poor basic sanitation, and the presence of free-roaming pigs reported in the KAP survey. These findings provide scientific evidence to apply national public health policies for controlling taeniasis/cysticercosis complex in Coyaima. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and currently is the second-leading cause of cancer-related mortality globally. Current front-line systemic therapies for advanced HCC offer only modest improvements in patient overall survival. HCC is a sexually dimorphic disease, and cancer progression is driven in part by AR activity. Here, we present novel niclosamide pro-drugs for use in advanced HCC based upon niclosamide’s known anti-AR activity and additional anti-cancer pathway efficacy. Methods: Niclosamide analogs were evaluated for their impacts on the AR protein in two HCC cell lines with different AR phenotypes. Amino acid conjugates of niclosamide were developed, and pharmacokinetic (PK) analyses were conducted to determine improvements in clearance and oral exposure. Finally, niclosamide analogs and amino acid conjugates were evaluated in an in vivo model of HCC. Results: Niclosamide analogs maintained anti-AR properties in HCC. Valine-conjugated niclosamide showed improved oral exposure, positioning it as a potential therapeutic in advanced HCC. Conclusions: Valine–niclosamide improves upon niclosamide’s poor solubility and oral bioavailability, increasing its utility for a variety of therapeutic uses. Further study of valine–niclosamide in advanced HCC and in other cancers or diseases is warranted. Full article

Rafoxanide, originally developed as a veterinary anthelmintic for the treatment of parasitic infections in livestock, has recently emerged as a promising therapeutic prospect in oncology. This compound has demonstrated notable antineoplastic effects against a variety of cancers, including skin, gastric, colorectal, and lung cancers, as well as hematological malignancies such as multiple myeloma. Rafoxanide exerts its anticancer activity through multiple complementary mechanisms, including the induction of endoplasmic reticulum stress, cell cycle arrest, apoptosis, and immunogenic cell death. Furthermore, the drug has been reported to inhibit key oncogenic signaling pathways (e.g., STAT3, NF-κB, c-FLIP, survivin) that contribute to tumor growth and metastasis. Preclinical studies in murine models have demonstrated significant reductions in tumor volume of up to 50% and a tumor-free rate exceeding 80%, with effective doses ranging from 7.5 to 40 mg/kg. This multitargeted mode of action distinguishes rafoxanide from conventional therapies and may help overcome resistance mechanisms that often limit the efficacy of cancer treatments. In this review, we summarize and discuss the growing body of evidence supporting rafoxanide’s therapeutic potential in oncology, as well as its possible applications in cancer treatment. Full article

Background/Objectives: Taeniasis, a zoonotic infection, is a common foodborne disease. Niclosamide and praziquantel have proven to be effective in treating it, but the use of the same drugs can lead to resistance, so alternative drugs need to be explored. This study investigated the anthelmintic potential of derived fractions from hydroethanolic extracts (HEs) of Aframomum melegueta (AM) and Xylopia aethiopica (XA), two medicinal plants known for their diverse bioactive properties. Methods: AM-HE fractions (dichloromethane fraction (DCMF), ether fraction (EF), aqueous fraction (AF)) and XA-HE fractions (chloroform fraction (CF), ether fraction (EF), and aqueous fraction (AF)) were used, and in vitro anthelmintic activity was assessed against Taenia spp. by using an adult motility assay for the worm’s paralysis time determination. The parasiticidal and parasitostatic activity was also tested on Taenia spp. adult worms. Cell viability was further evaluated using propidium iodide (PI) staining, with albendazole (20 mg/mL) as the reference drug. Results: The three fractions of each plant exhibited significant, dose-dependent anthelmintic activity, with AM-HE and XA-CF showing the greatest effects at 20 mg/mL. AM-EF demonstrated significant activity at 0.4% and 0.8%. Irreversibility tests revealed that most of the treated worms remained paralysis, except those exposed to the AF of both plants. PI staining confirmed the dose-dependent mortality of Taenia cells treated with HE, DCMF, and AF of AM. Conclusions: These results underscore the potential of AM and XA extracts and fractions as alternative treatments for helminth infections. Further, in vivo studies are warranted to confirm their safety and therapeutic efficacy. Full article

Background/objectives: Schistosomiasis is caused by flatworms of the genus Schistosoma, for which mollusks of the genus Biomphalaria are intermediate hosts. Niclosamide (NCL) is a molluscicide recommended by the World Health Organization (WHO) for control of Biomphalaria. Although effective, it is expensive and environmentally toxic, which raises concerns regarding its widespread use. As a result, we explored new synthetic substances as alternative strategies for controlling Biomphalaria glabrata. We evaluated the molluscicidal activity of 2-(1H-py-razol-1-yl)-1,3,4-thiadiazole and 2-(4,5-dihydro-1H-pyrazol-1-yl)-1,3,4-thiadiazole derivatives against B. glabrata snails and embryos, as well as Schistosoma cercariae (infective larvae). Methods: Adult and young snails were added to 24-well plates containing 20 synthetic compounds from the PDAN series for initial screening over 96 h at a concentration of 100 ppm. Water and NCL (2 ppm) were used as the negative and positive controls, respectively. Active compounds in the adult B. glabrata assay were selected for the tests vs. embryos and cercariae. Results: In the initial screen, only PDAN 52 (63 ± 4%) and 79 (12 ± 3%) showed molluscicidal activity at a concentration of 100 ppm up to 48 h. Consequently, we selected only PDAN 52. The LC₅₀ value found in the tests on embryos after 24 h of treatment was 20 ± 2 ppm and, after 48 h, it was 4 ± 0.5 ppm. Against cercariae, we measured an LC₅₀ value of 68 ± 5 ppm after 4 h of treatment. PDAN 52 did not induce marked toxicity against a second mollusk, Physella acuta, after 48 h of exposure. Conclusions: We highlight the promising molluscicidal activity of PDAN 52 against different developmental stages of the mollusk, B. glabrata, as well the infective larvae of Schistosoma mansoni. Full article

Background/Objectives: Non-replicating persisters (NRPs) of Mycobacterium abscessus are a bacterial subpopulation that can survive in the host under unfavorable conditions, such as hypoxia or nutrient starvation. The eradication of these bacteria is difficult, which is one reason for the long treatment duration and treatment failure. The drug discovery process should therefore contain methods to screen activity against NRPs. Methods: A hypoxic environment is used to generate NRPs of M. abscessus that are termed low-oxygen persisters (LOPs). For this, an oxidation process is used to transition a replicating culture of M. abscessus distributed in microtiter plates within a sealable box into LOPs. Colony counting, automated object counting, bactericidal activity determination of known agents, and confocal laser scanning microscopy are used to study the obtained culture. Results: The obtained culture shows typical attributes of non-replicating cells, such as significantly reduced replication, the reversibility of the LOP state under aerobic conditions, delayed regrowth on solid medium, altered morphological patterns on a single-cell level, and phenotypical resistance against a variety of clinically relevant antimycobacterial compounds. The study reveals metronidazole and niclosamide as bactericidal against M. abscessus LOPs. These compounds can be used as LOP verification compounds within the described model. Conclusions: Our model is easily implemented and quickly identifies compounds that are inactive under hypoxic conditions. It can therefore accelerate the identification of clinically effective antimycobacterial drug substances, and can be a helpful tool during the drug development process. Full article

Background/Objectives: Blepharitis is a condition often caused by Demodex folliculorum infestations, resulting in significant ocular discomfort and surface damage. Current treatments offer only temporary relief and fail to eliminate mites effectively. This study evaluates nano-niclosamide (nano-NCL), a lipophilic nanosuspension designed to enhance solubility and permeability, for targeting Demodex folliculorum. Methods: Nano-NCL was characterized by particle size, zeta potential, transmission electron microscopy, pH measurement, bacterial culture, and HPLC. Viable Demodex mites were collected from patients’ eyelashes and assigned to six treatment groups: DDW, F127, 0.15% nano-NCL, 0.3% nano-NCL, 20% TTO, and Okra. Mite survival was analyzed using Kaplan–Meier curves. The ocular surface safety was assessed via slit-lamp examination, corneal fluorescein staining, and in vivo confocal microscopy. Results: The nano-NCL particles are uniformly rod-shaped, approximately 291 nm in size, and exhibit good stability, remaining suspended in various media for up to 20 days. The formulation has a stable pH of 6 and demonstrated no bacterial growth, indicating sterility and suitability for clinical use. In vitro, both 0.15% (w/v) and 0.30% (w/v) nano-NCL significantly reduced Demodex survival, with mortality rates ranging from 70.6% to 92.3% within 2 h. Safety evaluations showed minimal corneal staining and inflammation. Notably, 0.15% nano-NCL displayed efficacy comparable to that of 20% tea tree oil (TTO) and Okra, which are established anti-Demodex treatments. Conclusions: Nano-NCL, particularly at 0.15%, rapidly eliminates mites while maintaining excellent ocular tolerability, making it a promising treatment for Demodex-related ocular surface diseases. Full article

Background/objectives: Schistosomiasis is a parasitic disease that represents a serious public health problem. An alternative for the control of snails, intermediate hosts of schistosomiasis, is the use of molluskicides. Niclosamide, recommended by the WHO, has limitations, such as environmental toxicity, which has driven the search for safer and biodegradable alternatives, especially of plant origin. In this context, this study investigated the biological activity of Cymbopogon winterianus essential oil on embryos, juveniles, and adults of Biomphalaria glabrata and cercariae of Schistosoma mansoni. Methods: Essential oils (EOs) were extracted from fresh leaves via the Clevenger system and characterized via gas chromatography (GC/MS and GC/FID), revealing geraniol (25.0%), citronellal (29.2%), citronellol (10.5%) and elemol (9.6%) as the main components. Results: The results revealed lethal concentrations 90 (LC₉₀) for young and adult snails of 60.72 mg/L, 74.21 mg/L and 115.35 mg/L, respectively. In the histological analysis, no changes were observed in the tissues of the mollusks exposed to the lethal concentration 25 (LC₂₅). However, the lethal concentrations 50 (LC₅₀) and 75 (LC₇₅) caused crystalline concretions in proximity to the renal saccular portion. At a concentration of 60 mg/L, the oil resulted in 100% lethality in embryos and cercaricidal activity greater than 90% in 3 h. Acute toxicity tests in mice via the intraperitoneal or oral route did not reveal toxic effects, with hematological and biochemical parameters within the reference values. Furthermore, the oil did not inhibit acetylcholinesterase (AChE), indicating low toxicity to fish, and caused a slight reduction in human butyrylcholinesterase (hBChE) activity without affecting human AChE, which suggests low toxicity to mammalian tissues. In terms of environmental impact, the oil was not toxic to algae until the 75th day, with mortality observed thereafter. Conclusions: These results indicate that essential oils have great potential as biodegradable and safe alternatives for controlling mollusks and interrupting the schistosomiasis cycle. Full article

Background/Objectives: This study investigates the preparation of coamorphous systems composed entirely of active pharmaceutical ingredients (APIs), namely praziquantel, niclosamide, and mebendazole. The objective was to formulate and characterize binary and ternary coamorphous systems to evaluate their structural, thermal, and stability properties. Methods: Ten different mixtures (binary and ternary) were designed through a mixture design approach and prepared using a sustainable, one-step neat grinding process in a lab-scale vibrational mill. The systems were prepared reproducibly within 4 h across the entire experimental domain. Structural characterization was performed using PXRD and FTIR to confirm the absence of crystalline domains and the presence of molecular interactions. The glass transition temperature (T_g) was theoretically calculated using the Gordon–Taylor equation for three-component systems and determined experimentally via DSC. Stability studies were conducted on seven systems under different storage conditions (−30 °C, 5 °C, 25 °C, and 40 °C) for six months. Results: PXRD analysis confirmed the formation of coamorphous systems with no crystalline phases. DSC revealed a single T_g for most systems, indicating homogeneity. Stability studies demonstrated that five out of seven systems adhered to the “T_g—50 °C” stability rule, remaining physically stable over six months. Recrystallization studies indicated diverse pathways: some systems reverted to their original crystalline phases, while others formed new entities such as cocrystals. Conclusions: This study highlights the feasibility of coamorphous systems composed of multiple APIs using a simple, solvent-free grinding approach. The findings underscore the importance of molecular interactions in determining stability and recrystallization behavior, offering insights for designing robust coamorphous formulations. Full article