Search Results (49)

Overexpression of protein phosphatase 5 (PP5) is linked to tumor cell growth, making it a candidate for small-molecule drug therapy. Since the PP2A domain has been selectively inhibited using functionalized scaffolds that maximize contacts, a similar approach is proposed to work for PP5. As cantharidin’s demethylated cousin, norcantharidin, is a potent but unselective phosphatase inhibitor that can be prepared in just two synthetic steps, the bicyclic scaffold holds promise as an attractive target upon functionalization. Our hypothesis targets PP5 selectivity through derivatives of norcantharidin with functionalized attachments for optimal active-site binding. The methodology offers a promising platform for developing PP5-selective anticancer therapeutics. The approach reported herein exploits anhydride reactivity to yield a carboxylic acid derivative as our next-generation inhibitor of PP5. The methodology offers groundwork for future optimization of norcantharidin-based drug candidates with improved tumor selectivity, potency, and synthetic feasibility. Full article

Colorectal cancer is one of the most common malignant tumors worldwide, significantly impacting human health. Cantharidin (CTD), an active compound derived from the Spanish fly, exhibits antitumor properties. Its derivative, norcantharidin (NCTD), is synthesized by removing methyl groups from positions 1 and 2 of cantharidin. NCTD has demonstrated lower toxicity while maintaining similar antitumor effects compared to CTD. However, the mechanism by which NCTD exerts its effects against colorectal cancer remains unclear. Here, we conducted a comprehensive analysis of the effects of NCTD on colorectal cancer both in vitro and in vivo. Whole-transcriptome sequencing and bioinformatics tools were employed to identify potential key targets of NCTD in the treatment of colorectal cancer. Additionally, we designed folate-receptor-targeting NCTD liposomes (FA-NCTD) and assessed their anticancer efficacy in vivo. NCTD effectively inhibited cell viability, clonal formation, and migration in HCT116 and HT-29 cell lines. NCTD also induced apoptosis, influenced the cell cycle, altered mitochondrial membrane potential, and increased reactive oxygen species levels. The whole-transcriptome sequencing and bioinformatics analysis identified TRAF5 as a key target for NCTD’s action against colorectal cancer. Furthermore, NCTD was found to regulate the TRAF5/NF-κB signaling pathway in both HCT116 and HT-29 cells. The FA-NCTD liposomes demonstrated effective tumor targeting and significantly inhibited tumor growth in vivo. This result showed that NCTD effectively suppresses the malignant proliferation of colon cancer cells by modulating the TRAF5/NF-κB signaling pathway and inducing programmed apoptosis, thereby offering a novel strategy for colorectal cancer treatment. The prepared FA-NCTD liposomes provide a promising approach for achieving the precise targeting and controlled release of NCTD. Full article

Melanoma, a lethal type of cancer originating from melanocytes, is the leading cause of death among skin cancers. While surgical excision of the lesions is the primary treatment for melanoma, not all cases are candidates for surgical procedures. New treatments and complementary options are necessary, given the increasing diagnosis rate. In the present study, a norcantharidin-containing nanoemulsion was developed and evaluated in vivo using a syngeneic graft murine model. Norcantharidin is the demethylated analog of cantharidin, known for its anticancer properties. Our model contemplates surgical excision surgery simulating the standard treatment and the role of the nanoemulsion as a potential adjuvant therapy. We observed a significant decrease in the growth rate of the melanoma lesion in the treated groups compared to the control group, both at the 20th and 30th days of treatment. Moreover, we evaluated the drug bioavailability in serum samples, and the results showed that norcantharidin was detectable in a range of 0.1 to 0.18 mg/mL in the treated groups. Furthermore, histopathological analysis was performed on the amputated tumors, where significant differences were found regarding size, mitosis rate, lymphocytic infiltration, and multispectral quantitative image analysis compared to the control group. If more clinical studies are conducted, the norcantharidin-containing nanoemulsion could be a potential alternative or adjuvant therapy. Topical nanosystems can become or complement standard therapies, which is needed as melanoma affects not only in terms of mortality but also the patient’s morbidity and life quality. Full article

Osteoarthritis (OA), particularly in the knee and hip, poses a significant global health challenge due to limited therapeutic options. To elucidate the molecular mechanisms of OA and identify potential biomarkers and therapeutic targets, we utilized genome-wide association studies (GWAS) and cis-miRNA expression quantitative trait loci (cis-miR-eQTL) datasets to identify miRNAs associated with OA, revealing 16 that were linked to knee OA and 21 to hip OA. Among these, hsa-miR-1303 was significantly upregulated in both knee and hip OA (IVW: p = $6.8164\times {10}^{-36}$ and $4.7919\times {10}^{-2}$ respectively, OR > 1) and identified as a key factor in disease progression. Hsa-miR-1303 potentially regulates 30 genes involved in critical signaling pathways, such as the neurotrophin signaling pathway, and interacts with competing endogenous RNAs (ceRNAs) like circ_0041843 and LINC01338, thereby influencing key regulatory proteins such as SUMO2 and PARP1. Pharmacologically, hsa-miR-1303 targets nine druggable genes, including NRAS, H2AZ1, and RPS3, which have implications for drugs like cantharidin and diindolylmethane, potentially critical for developing novel OA treatments. Conversely, hsa-miR-125a-5p and hsa-miR-125b-5p, which are downregulated in both knee and hip OA, are associated with pathways such as HIF-1 and JAK-STAT, which modulate apoptotic signaling and transcriptional regulation. These miRNAs also interact with ceRNAs such as circ_0000254 and SPACA6P-AS, impacting proteins like STAT3, MCL1, and TRAF6. A drug interaction analysis identified 47 potential treatments, including Resveratrol and Acetaminophen, suggesting new therapeutic possibilities for OA management. This study not only highlights the role of miRNAs like hsa-miR-1303 and hsa-miR-125 in OA but also opens avenues for miRNA-based therapeutic development. Full article

Background/Objectives: Essential oils (EOs) have been exploited by humans for centuries, but many sources remain poorly investigated, mainly due to the low yields associated with conventional extraction. Recently, new techniques have been developed, like solvent-free microwave extraction (SFME), able to enhance efficiency and sustainability. The use of Papaver rhoeas L. in traditional medicine has led researchers to investigate non-volatile fractions, but there are little data available on EOs. Methods: In the present work, we prepared EOs from the petals and leaves of P. rhoeas by SFME. GC/MS analysis of EOs revealed the presence of 106 compounds belonging to 13 different classes. Isomers of the different alkenes were identified thanks to an alkylthiolation reaction. Results: The results highlighted a predominance of saturated and unsaturated hydrocarbons, alcohols, and esters that might suggest a specific relationship with pollinators. Each population has been compared using PCA, heatmap, and barplot tools, highlighting differences in terms of composition by both comparing leaves and flowers and hill and lowland samples. Furthermore, cantharidin, a metabolite usually produced by insects, was detected in the flowers, possible present for attractiveness purposes. Conclusions: These results could contribute to ensuring a better understanding of the pollination process and of the biological activities of EOs from P. rhoeas. Full article

Background: Plantar warts, caused by human papillomavirus (HPV), are a common condition that can be painful and resistant to treatment. There are various therapeutic options for managing them, but it is not always clear which are the most effective and tolerated by patients. Among the most commonly used treatments are a zinc and nitric complex (nitrizinc complex), cantharidin, and bleomycin, each with different mechanisms of action and profiles in terms of pain and patient satisfaction. Objectives: We aimed to evaluate and compare the clinical efficacy, post-treatment pain, and patient satisfaction among three common treatments (zinc and nitric complex, cantharidin, and bleomycin) in subjects with plantar warts, as well as identify the most effective and best-tolerated treatment. Materials and Methods: This is a retrospective case series study analyzing 60 records of subjects aged 18 to 40 years diagnosed with plantar warts without systemic diseases or allergies and without any prior treatment. Complete records from 2020 to 2023 were selected. Subjects were divided into three groups according to the treatment received (zinc and nitric complex, cantharidin, bleomycin), and demographic variables, post-treatment pain (measured using the visual analog scale), the number of sessions required, and satisfaction after discharge (evaluated with the Likert scale) were analyzed. Results: Of the 60 subjects included, the group treated with bleomycin experienced higher levels of pain after the first session (mean of 7.1 points on the VAS) compared to the cantharidin group (2.7 points) and the zinc and nitric complex group (1.1 points). However, the bleomycin group required fewer sessions for complete healing (an average of 1.8 sessions), while the nitric acid group needed more (3.4 sessions), with cantharidin falling in between (2.5 sessions). Regarding post-discharge satisfaction, all groups showed comparable scores (between 7.9 and 8.5 points), although cantharidin demonstrated slightly higher satisfaction. A statistical analysis showed significant differences in the number of sessions and post-treatment pain between treatments (p < 0.05) but not in final satisfaction. Conclusions: Although bleomycin treatment is more painful, it is the most effective in terms of reducing the number of sessions required for complete healing. Cantharidin offers a good balance between efficacy and patient satisfaction, while a zinc and nitric complex, although less painful, requires more sessions for complete treatment. Each treatment has specific advantages, suggesting that therapeutic choices should be personalized according to the patient’s needs and preferences. Full article

Cyclic acid anhydride is a not very widespread structure in nature, but with a determining role in natural products possessing this functionality in their skeleton. To the best of our knowledge, no revision of terpenes containing cyclic anhydrides has been previously reported. The result was that more than 100 terpenic cyclic anhydrides and related compounds were found to be in need of being reported. This review has been systematically organized by terpene skeletons, from the smallest to largest, describing their sources and bioactivities. In addition, different biosynthetic pathways for their final oxidations, namely, routes A, B and C, leading to the formation of these heterocyclic natural products, have been proposed. We have also included the most plausible precursors of these natural products, which mostly happened to be present in the same natural source. Some molecules derived from terpene cyclic anhydrides, such as their natural imide derivatives, have also been described due to their significant biological activity. In this sense, special attention has been paid to cantharidin because of its historical relevance and its broad bioactivity. A plausible biosynthesis of cantharidin has been proposed for the first time. Finally, cyclic anhydride structures that were firstly assigned as anhydrides and later corrected have been also described. Full article

Currently, there is a dearth of in-depth analysis and research on the impact of canthaxanthin on the production performance, egg quality, physical characteristics, and offspring health of laying hens. Furthermore, the metabolic mechanism of cantharidin in the body remains unclear. Therefore, to solve the above issues in detail, our study was conducted with a control group (C group), a low-dose canthaxanthin group (L group), and a high-dose canthaxanthin group (H group), each fed for a period of 40 days. Production performance was monitored during the experiment, in which L and H groups showed a significant increase in ADFI. Eggs were collected for quality analysis, revealing no significant differences in qualities except for yolk color (YC). The YC of the C group almost did not change, ranging from 6.08 to 6.20; however, the trend in YC change in other groups showed an initial intense increase, followed by a decrease, and eventually reached dynamic equilibrium. By detecting the content of canthaxanthin in the yolk, the YC change trend was found to be correlated with canthaxanthin levels in the yolk. The content of unsaturated fatty acid increased slightly in L and H groups. Following the incubation period, the physical characteristics and blood biochemical indices of chicks were evaluated. It was observed that the shank color of chicks in the L and H groups was significantly higher than that in the C group at birth. However, by the 35th day, there were no significant differences in shank color among the three groups. Further investigation into the metabolic mechanism involving canthaxanthin revealed that the substance underwent incomplete metabolism upon entering the body, resulting in its accumulation as well as metabolic by-product accumulation in the yolk. In summary, this study highlighted the importance of understanding canthaxanthin’s role in production performance, egg quality, and offspring health, providing valuable insights for breeders to optimize feeding strategies. Full article

The high recurrence rate of cervical cancer is a leading cause of cancer deaths in women. 5-Fluorouracil (5-FU) is an antitumor drug used to treat many types of cancer, but its diminishing effectiveness and side effects limit its use. Norcantharidin (NCTD), a demethylated derivative of cantharidin, exhibits various biological activities. Here, we investigated whether NCTD could potentiate 5-FU to induce cervical cancer cell death. To assess the cell viability and synergistic effects of the drugs, cell counting kit-8 and colony formation assays were performed using HR-HPV-positive cervical cancer cell lines. Annexin V-FITC/PI staining and TUNEL assays were performed to confirm the induction of apoptosis. The synergistic effect of NCTD on the antitumor activity of 5-FU was analyzed using network pharmacology, molecular docking, and molecular dynamics simulations. Apoptosis-related proteins were examined using immunoblotting. The combination of NCTD and 5-FU was synergistic in cervical cancer cell lines. Network pharmacological analysis identified 10 common targets of NCTD and 5-FU for cervical cancer treatment. Molecular docking showed the strong binding affinity of both compounds with CA12, CASP9, and PTGS1. Molecular dynamics simulations showed that the complex system of both drugs with caspase-9 could be in a stable state. NCTD enhanced 5-FU-mediated cytotoxicity by activating apoptosis-related proteins. NCTD acts synergistically with 5-FU to inhibit cervical cancer cell proliferation. NCTD enhances 5-FU-induced apoptosis in cervical cancer cell lines via the caspase-dependent pathway. Full article

Norcantharidin (NCTD), a cantharidin derivative, induces ROS generation and is widely used to treat CRC. In this study, we clarified the role and mechanism of action of norcantharidin in increasing CRC sensitivity to radiotherapy. We treated the CRC cell lines LoVo and DLD-1 with NCTD (10 or 50 μmol/L), ionizing radiation (IR, 6 Gy), and a combination of the two and found that NCTD significantly inhibited the proliferation of CRC cells and enhanced their sensitivity to radiotherapy. NCTD induced ROS generation by decreasing the mitochondrial membrane potential, increasing mitochondrial membrane permeability, and promoting cytochrome C release from mitochondria into the cytoplasm. IR combined with NCTD induced ROS production, which activated the mitochondrial fission protein DRP1, leading to increased mitochondrial fission and CRC sensitivity to radiotherapy. NCTD also reduced CRC cell resistance to radiotherapy by blocking the cell cycle at the G2/M phase and decreasing p-CHK2, cyclin B1, and p-CDC2 expression. NCTD and IR also inhibited radiation resistance by causing DNA damage. Our findings provide evidence for the potential therapeutic use of NCTD and IR against CRC. Moreover, this study elucidates whether NCTD can overcome CRC radiation tolerance and provides insights into the underlying mechanisms. Full article

The diamondback moth is a detrimental insect pest of brassicaceous crops which was among the first crop insects to be reported as DDT resistant. It has since proven to be significantly resistant to nearly every synthetic insecticide used in the field in many crucifer-producing regions. Due to insecticide control failures in some parts of the world, economically viable crucifer production is now all but impossible. As a result, there has been an increasing effort to identify new compounds with strong pesticidal activity. Cantharidin is one such compound that has been shown to be highly effective against a variety of insect pests. However, its chemical synthesis and potential toxicity to non-target organisms have been a major source of concern. Herein, using rational design approaches, a new series of cantharidin-based verbenone derivatives were synthesized and evaluated for their insecticidal activities against the diamondback moth. Among different compounds screened, compounds 6a, 6h, 6i, and 6q emerged as the most potent compounds exhibiting 100% mortality at a concentration of 100 mg/L after four days. These compounds demonstrated a good anti-feeding effect against the diamondback moth on cabbage leaves. Subsequently, a 3D QSAR study was carried out to identify the key structural features of the synthesized compounds and their correlation with insecticidal activity. Full article

Tree peonies (Paeonia Section Moutan)—including nine wild species, which belong to subsections Vaginatae and Delavayanae—are economically important plants with ornamental, nutritional, and medicinal applications. In this study, for the first time, we determined the bioactive components and antioxidant activities and antibacterial activities of the newly grown leaves of nine wild tree peony species (WTPS). A total of 276 bioactive components were identified through non-targeted metabolomics; more than 80% of the 276 metabolites identified are terpenoids and flavonoids. A total of 42 differential metabolites were quantitatively determined. The main differential metabolites were Paeoniflorin, Luteoloside, Hyperin, Apigenin-7-glucoside, Rhoifolin, and Cantharidin. Such a high terpenoid and flavonoid content of the leaf extracts renders them as species with strong antibacterial capacities, and most of the bacteria tested showed greater sensitivity derived from the members of subsection Vaginatae than those of subsection Delavayanae. All WTPS have significant antioxidant activity; this activity is attributed to high levels of the total phenolic content (TPC) and total flavonoid content (TFC), of which, among the nine WTPS, P. lutea has the strongest antioxidant capacity. Our results provided a theoretical basis for the in-deep application of tree peony leaves for food, medical, and pharmaceutical industries. Full article

Cantharidin, a toxic monoterpene secreted by blister beetles, has long been used in traditional Chinese and modern medicine for its unique properties. However, despite its widespread use, its effects on fish have not been studied. The aim of this study was to evaluate the potential therapeutic applications of cantharidin in fish by examining its antioxidant, hemagglutinating, hemolytic, and cytotoxic activities at different concentrations (0, 0.625, 1.25, 2.5, 5, and 10 μg mL⁻¹) in three different cell lines. In addition, the study explored the bactericidal and bacteriostatic properties of cantharidin against various fish pathogenic bacteria. The results revealed that there were no significant differences in antioxidant, hemagglutinating, or hemolytic activities between the different concentrations of cantharidin tested. However, the study found that cantharidin exhibited dose- and time-dependent cytotoxicity in seabream (Sparus aurata) erythrocytes and in SAF-1, PLHC-1, and Hela cell lines, resulting in morphological changes indicative of apoptosis. Interestingly, the highest dose of cantharidin tested demonstrated potent bactericidal activity against four marine fish opportunistic bacteria, including Vibrio harveyi, V. anguillarum, Photobacterium damselae, and Tenacibaculum maritimum, but no statistically significant changes in bacteriostatic activity were observed against any of the bacteria tested. Overall, these results provide valuable information on the potential therapeutic applications of cantharidin in fish aquaculture. Further research is needed to fully understand the mechanisms of action and to explore possible preventive uses of cantharidin in fish. Full article

Labdane-related diterpenoids, momilactones A and B were isolated and identified in rice husks in 1973 and later found in rice leaves, straws, roots, root exudate, other several Poaceae species and the moss species Calohypnum plumiforme. The functions of momilactones in rice are well documented. Momilactones in rice plants suppressed the growth of fungal pathogens, indicating the defense function against pathogen attacks. Rice plants also inhibited the growth of adjacent competitive plants through the root secretion of momilactones into their rhizosphere due to the potent growth-inhibitory activity of momilactones, indicating a function in allelopathy. Momilactone-deficient mutants of rice lost their tolerance to pathogens and allelopathic activity, which verifies the involvement of momilactones in both functions. Momilactones also showed pharmacological functions such as anti-leukemia and anti-diabetic activities. Momilactones are synthesized from geranylgeranyl diphosphate through cyclization steps, and the biosynthetic gene cluster is located on chromosome 4 of the rice genome. Pathogen attacks, biotic elicitors such as chitosan and cantharidin, and abiotic elicitors such as UV irradiation and CuCl₂ elevated momilactone production through jasmonic acid-dependent and independent signaling pathways. Rice allelopathy was also elevated by jasmonic acid, UV irradiation and nutrient deficiency due to nutrient competition with neighboring plants with the increased production and secretion of momilactones. Rice allelopathic activity and the secretion of momilactones into the rice rhizosphere were also induced by either nearby Echinochloa crus-galli plants or their root exudates. Certain compounds from Echinochloa crus-galli may stimulate the production and secretion of momilactones. This article focuses on the functions, biosynthesis and induction of momilactones and their occurrence in plant species. Full article

Despite advances in understanding the molecular mechanisms underlying prostate cancer progression, the development of effective therapeutic approaches remains a major challenge. In this context, the protein phosphatase 1 (PP1) and its complexes have been recognized as potential drug targets. Herein, we designed and synthetized a peptide sequence based on the PP1-binding motif of CAV1, which was coupled with penetratin to improve cellular uptake. To evaluate the effect of the synthetized peptide, named CAVPENET, prostate cancer cells (PC-3 and LnCaP) were incubated with CAVPENET for 48 h, and several parameters were analyzed. We found that CAVPENET significantly decreased the LnCaP and PC-3 cells viability and invasive ability. A significant decrease in the phosphorylation of AKT at Ser⁴⁷³ was also observed after 48 h of incubation with CAVPENET. Moreover, a slight recovery of AKT phosphorylation levels after the simultaneous incubation of CAVPENET (10 µM) with tautomycin (10 nM)—a highly specific PP1 inhibitor—suggested the role of PP1 in the CAVPENET-induced alterations in AKT phosphorylation. Moreover, incubation with CAVPENET (10 µM) + cantharidin (0.5 µM), a potent and selective PP2A inhibitor, almost completely recovered the phosphorylation levels of AKT, suggesting the role of PP2A in the effect of CAVPENET. Altogether, these results highlight the potential of the synthesized peptide to negatively impact the PCa cells’ proliferation and invasive ability by interfering with the interaction of CAV1 with PP1 and/or PP2A. Further analyses are now required to confirm the disruption of the interactions and to better elucidate the mechanisms of cell death. Full article