Pyrones isolated from Annona acutiflora exhibit promising cytotoxic effects on cancer cell lines.

This work discusses the ongoing challenge of cancer, focusing on therapy issues such as chemotherapy resistance and adverse drug effects. It emphasizes the need for new anticancer agents with improved efficacy and fewer side effects, exploring natural products from plant sources. The Annonaceae family, specifically the Annona genus, is highlighted for its medicinal properties, including anti-inflammatory and anticancer effects. The study focuses on the isolation and elucidation of the substances present in Annona acutiflora leaves. The methodology involves chromatographic and spectroscopy techniques. The isolated compounds, (6S)-5'-oxohepten-1'E,3'E-dienyl)-5,6-dihydro-2H-pyran-2-one (1), (6R)-5'-oxohepten-1'Z,3'E-dienyl)-5,6-dihydro-2H-pyran-2-one (2) and (6R)-5'-oxohepten-1'Z,3'E-dienyl)-5,6-dihydro-2H-pyran-2-one (3) were investigated for cytotoxicity assays on cancer cell lines and normal cells. Results show promising cytotoxic activity, particularly with compound 3, demonstrating potential activity against oral cancer (43.18µM), hepatocarcinoma (17.24µM), melanoma (5.39µM), and colon cancer (59.03µM). The compound outperforms carboplatin in selectivity against oral cancer (S.I. 2.15) and melanoma (S.I. 17.22). The study concludes by suggesting the potential of these α-pyrones as effective and less toxic alternatives for cancer therapy.

Drug Resistance and Novel Targets for Cancer Therapy: An Overview of Recent Findings.

The complex nature of cancer cells poses a challenge to the scientific community [...].

Anticancer Activity and Molecular Targets of Piper cernuum Substances in Oral Squamous Cell Carcinoma Models.

Oral squamous cell carcinoma (OSCC) is a worldwide public health problem, with high morbidity and mortality rates. The development of new drugs to treat OSCC is paramount. Piper plant species have shown many biological activities. In the present study, we show that dichloromethane partition of Piper cernuum (PCLd) is nontoxic in chronic treatment in mice, reduces the amount of atypia in tongues of chemically induced OSCC, and significantly increases animal survival. To identify the main active compounds, chromatographic purification of PCLd was performed, where fractions 09.07 and 14.05 were the most active and selective. These fractions promoted cell death by apoptosis characterized by phosphatidyl serine exposition, DNA fragmentation, and activation of effector caspase-3/7 and were nonhemolytic. LC-DAD-MS/MS analysis did not propose matching spectra for the 09.07 fraction, suggesting compounds not yet known. However, aporphine alkaloids were annotated in fraction 14.05, which are being described for the first time in P. cernuum and corroborate the observed cytotoxic activity. Putative molecular targets were determined for these alkaloids, in silico, where the androgen receptor (AR), CHK1, CK2, DYRK1A, EHMT2, LXRß, and VEGFR2 were the most relevant. The results obtained from P. cernuum fractions point to promising compounds as new preclinical anticancer candidates.

A Novel MDM2-Binding Chalcone Induces Apoptosis of Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) represents ~90% of all oral cancers, being the eighth most common cancer in men. The overall 5-year survival rate is only 39% for metastatic cancers, and currently used chemotherapeutics can cause important side effects. Thus, there is an urgency in developing new and effective anti-cancer agents. As both chalcones and 1,2,3-triazoles are valuable pharmacophores/privileged structures in the search for anticancer compounds, in this work, new 1,2,3-triazole-chalcone hybrids were synthesized and evaluated against oral squamous cell carcinoma. By using different in silico, in vitro, and in vivo approaches, we demonstrated that compound 1f has great cytotoxicity and selectivity against OSCC (higher than carboplatin and doxorubicin) and other cancer cells in addition to showing minimal toxicity in mice. Furthermore, we demonstrate that induced cell death occurs by apoptosis and cell cycle arrest at the G2/M phase. Moreover, we found that 1f has a potential affinity for MDM2 protein, similar to the known ligand nutlin-3, and presents a better selectivity, pharmacological profile, and potential to be orally absorbed and is not a substrate of Pg-P when compared to nutlin-3. Therefore, we conclude that 1f is a good lead for a new chemotherapeutic drug against OSCC and possibly other types of cancers.

Ethyl acetate fractions of Myrciaria floribunda, Ocotea pulchella, and Ocotea notata exhibit promising in vitro activity against Sporothrix brasiliensis isolates with low susceptibility to itraconazole.

Sporothrix brasiliensis with low susceptibility isolates were described from the Brazilian zoonotic sporotrichosis hyperendemics. The aim of this work was to evaluate distinct fractions of Ocotea pulchella, Ocotea notata, Myrciaria floribunda, and Hypericum brasiliense plant extracts against itraconazole-sensitive and low susceptibility S. brasiliensis isolates. Crude extracts were tested against clinical isolates and the ATCC MYA4823 to determine the minimum inhibitory concentrations (MICs) and fungicidal or fungistatic activities (MFC). A high MICs and MFCs amplitude (1 - > 128 µg/mL) were obtained for seven extracts. The highest antimicrobial activities against sensitive S. brasiliensis were displayed by the ethyl acetate extracts of O. notata (MIC = 2-128 µg/mL) and M. floribunda (MIC = 1-8 µg/mL). A fungicidal effect was observed for all fraction extracts. Ocotea spp. and M. floribunda ethyl acetate extracts provide promising profiles against itraconazole-sensitive or low susceptibility S. brasiliensis. Future studies will determine if these extracts can contribute as alternative therapies to this neglected zoonosis.

New substances of Equisetum hyemale L. extracts and their in vivo antitumoral effect against oral squamous cell carcinoma.

ETHNOBOTANICAL RELEVANCE: Equisetum hyemale is used in traditional medicine as an anti-inflammatory, antioxidant, diuretic and anticancer agent. Recent studies have observed antiproliferative activity of this species in some tumor cell lines. AIM OF THE STUDY: The aim of this study was to evaluate the antiproliferative activity of the ethanol extract of E. hyemale and its partitions in oral squamous carcinoma cell lines, the death pathways induced by the most active partition, the acute toxicity and therapeutic activity, and the identification of the main compounds. MATERIALS AND METHODS: The ethanol crude extract was prepared from the stems of E. hyemale and partitions were obtained from this extract with n-hexane, dichloromethane and ethyl acetate. Cytotoxicity assays were performed using MTT on human oral tumor lines SCC-9, SCC4 and SCC-25, and normal primary fibroblasts. The main pathways of programmed cell death were analyzed. Acute toxicity in mice was performed using the most active partition, ethyl acetate. Antitumor activity was accessed in xenotransplants grafts of SCC-9 cells in Balb/nude mice. Phytochemical analysis was performed using UHPLC-MS/MS and dereplication was done using Global Natural Product Social Molecular Networking (GNPS) analysis. RESULTS: Ethanol extract, n-hexane and ethyl acetate partitions showed dose-dependent activity and selectivity towards oral tumor cells, with the ethyl acetate being the most bioactive. This medium polarity partition was shown to induce tumor cell death through apoptosis due to the presence of activated caspase 3/7, DNA fragmentation, chromatin condensation and phosphatidylserine exposure. The ethyl acetate partition also produced low toxicity in mice, provoking mild hepatic changes, but without causing necrosis and significantly reduced tumors volume and weight in xenotransplants of SCC-9 cells. Phytochemical analysis allowed identification of kaempferol glycosides and cinnamic acid derivatives previously described for E. hyemale. In addition it was possible to identify 6 new non-glycolyzed flavonoids 5-Hydroxy-3',4',7,8-tetramethoxyflavone (14), 5,4'-Dihydroxy-7,8,3'-trimethoxyflavone (15), 5,7-Dihydroxy-3',4'-dimethoxyflavone (16), 3',4,5,7-Tretramethoxyflavone (17), 5-Hydroxy-3'4',7-trimethoxyflavone (18), and 5,4'-Dihydroxy-3'-7'-dimethoxyflavone (19); besides 5 compounds already determined to be cytotoxic in other species, Isoferulic acid (1), Ferulic acid (2), Atractylenolide III (6), Dihydroxy-3',4'-dimethoxyflavone (16), and 5-Hydroxy-3'4 ',7-trimethoxyflavone (18). CONCLUSION: The results indicate that the E. hyemale extract and partitions inhibited 3 different cell lines of OSCC in a highly selective nontoxic way by inducing apoptosis of the cells. We identified 6 new non-glycosylated flavonoids and 5 other substances in this species.

Pro-Apoptotic Antitumoral Effect of Novel Acridine-Core Naphthoquinone Compounds against Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a global public health problem with high incidence and mortality. The chemotherapeutic agents used in the clinic, alone or in combination, usually lead to important side effects. Thus, the discovery and development of new antineoplastic drugs are essential to improve disease prognosis and reduce toxicity. In the present study, acridine-core naphthoquinone compounds were synthesized and evaluated for their antitumor activity in OSCC cells. The mechanism of action, pharmacokinetics, and toxicity parameters of the most promising compound was further analyzed using in silico, in vitro, and in vivo methods. Among the derivatives, compound 4e was highly cytotoxic (29.99 µM) and selective (SI 2.9) at levels comparable and generally superior to chemotherapeutic controls. Besides, compound 4e proved to be non-hemolytic, stable, and well tolerated in animals at all doses tested. Mechanistically, compound 4e promoted cell death by apoptosis in the OSCC cell, and molecular docking studies suggested this compound possibly targets enzymes important for tumor progression, such as RSK2, PKM2, and topoisomerase IIα. Importantly, compound 4e presented a pharmacological profile within desirable parameters for drug development, showing promise for future preclinical trials.

Apoptotic effect of ß-pinene on oral squamous cell carcinoma as one of the major compounds from essential oil of medicinal plant Piper rivinoides Kunth.

Oral squamous cell carcinoma (OSCC) is the most common type of head and neck malignancy. Research on essential oils (EOs) has shown important cytotoxic and anti-tumor properties, among others. Piperaceae species are rich in EOs and here we highlight Piper rivinoides Kunth. We investigated the crude EOs from P. rivinoides, their pure major constituents and an enriched fraction with the main EO compounds (EF) as cytotoxic and selective OSCC agents. EOs presented as main compounds (-)-α-pinene, (-)-ß-pinene and limonene. EOs showed an IC50 lower than all isolated compounds, except for (-)-ß-pinene in OSCC cells. The (-)-ß-pinene induced cell death with apoptotic characteristics. Commercial standards showed greater selectivity than EOs, and (-)-ß-pinene was the most selective among them. EF showed higher selectivity compared to crude EOs and carboplatin, turning it into a good candidate as an anticancer fraction. These results are important for the possible development of new treatments for OSCC.

Effects of infrared light laser therapy on in vivo and in vitro periodontitis models.

BACKGROUND: This study evaluated the effects of infrared light laser therapy (ILLT) on ligature-induced periodontitis in rats using micro-computed tomography (micro-CT), histology, fibroblast migration, and viability analysis. METHODS: Forty-eight rats were randomly distributed into three groups: control (no periodontitis), PDC (periodontitis without laser therapy), and PD+L (periodontitis with laser therapy). Periodontitis was induced by ligature placement for 4 weeks. The 12-week-old rats (baseline) were subjected to laser treatment and euthanized 30 days after. After treatment, the mandibular first molars were prepared for micro-CT scanning, and histological sections were assessed as to the cementoenamel junction, alveolar bone crest, and polymorphonuclear (PMN) cell infiltration. In vitro assays were carried out to examine NIH/3T3 fibroblast viability after laser therapy. RESULTS: Migration and cell viability assays revealed that the ILLT maintained fibroblast cell viability with 4 J/cm2 , reaching 100% healing. The control group (at baseline and 30 days) presented a statistically significant difference from the PDC group at 30 days in terms of distance from the cementoenamel junction to the alveolar bone crest (CEJ-ABC). The PD+L group showed a statistically substantial difference from the PDC group at 30 days in terms of trabecular thickness (Tb.Th), degree of anisotropy (DA), and closed porosity percentage (Po%). CONCLUSION: ILLT seemed to preserve the bone structure in the in vivo periodontitis induction model at 30 days and did not reduce cell viability or increase fibroblast migration in vitro. The ILLT provides positive effects on mandibular bone microstructure.

Cytotoxic effect of pure compounds from Piper rivinoides Kunth against oral squamous cell carcinoma.

The oral squamous cell carcinoma (OSCC) is the eighth more common cancer in men. The development of new and more efficient drugs is needed. Plants of the genus Piper are popularly used in the treatment of many diseases. This study evaluated the antitumor effect of extract, fraction and isolated compounds from leaves of P. rivinoides in oral cancer. The isolated compounds (conocarpan, eupomatenoid-5 and eupomatenoid-6) were effective in inducing cell death in OSCC cell lines (SCC4, SCC9 and SCC25) compared to the standard chemotherapeutic agent carboplatin, and this effect was time-dependent. Conocarpan was more selective and stable than eupomatenoid-5 and eupomatenoid-6, resembling the stability of carboplatin. There was a significant presence of pyknotic nuclei and active caspase-3 expression under conocarpan treatment, suggesting cell death through apoptosis. In conclusion, conocarpan was the most effective compound against OSCC cells and might be considered for future cancer studies.

Possíveis mecanismos de ação dos microRNAs na doença periodontal / Possible mechanisms of action of microRNAs in periodontal disease

Objetivo: o propósito deste estudo foi revisar os possíveis mecanismos de ação dos microRNAs na doença periodontal. Material e Métodos: o estudo foi baseado em artigos científicos encontrados na base de dados PubMed. Resultados: a recente descoberta de microRNAs (miRNAs) revolucionou a maneira como a regulação gênica é analisada. Estudos demonstram que os miRNAs podem atuar na resposta inata, em vários estágios, entre eles na sinalização de receptores Toll-like. Os miRNAs também estão relacionados à regulação de elementos centrais da resposta imune adaptativa, como apresentação de antígenos. No entanto, muito ainda precisa ser estudado para identificar a atividade de miRNAs na regulação gênica. A doença periodontal é uma doença bucal causada por patógenos bacterianos, com resposta inflamatória e imune agressiva, que afeta os tecidos ao redor dos dentes, podendo levar à sua perda. Conclusão: concluiu-se que os recentes achados do papel dos microRNAs na resposta inflamatória, incluindo tanto a imunidade inata como a adaptativa, ocorrem na doença periodontal

Objective: the purpose of this study was to review the role of possible mechanisms of action of microRNAs in periodontal disease. Material and Methods: the study was based on PubMed scientific papers. Results: the recent discovery of microRNAs (miRNAs) has revolutionized the way that gene regulation is analyzed. Studies demonstrate that they can act on the innate response, in several stages, among them the signaling of Toll-like receptors. The miRNAs are also related to the regulation of central elements of the adaptive immune response, such as antigen presentation. However, much still needs to be studied to identify miRNAs activity in gene regulation. Periodontal disease is an oral disease caused by bacterial pathogens, with an aggressive immune and inflammatory response, which affects the tissues around the teeth, which may lead to their loss. Conclusion: it was concluded that the recent findings of the role of microRNAs in the inflammatory response, including both innate and adaptative immunity, that occurs in periodontal disease

PTEN Overexpression Cooperates With Lithium to Reduce the Malignancy and to Increase Cell Death by Apoptosis via PI3K/Akt Suppression in Colorectal Cancer Cells.

Lithium is a well-established non-competitive inhibitor of glycogen synthase kinase-3ß (GSK-3ß), a kinase that is involved in several cellular processes related to cancer progression. GSK-3ß is regulated upstream by PI3K/Akt, which is negatively modulated by PTEN. The role that lithium plays in cancer is controversial because lithium can activate or inhibit survival signaling pathways depending on the cell type. In this study, we analyzed the mechanisms by which lithium can modulate events related to colorectal cancer (CRC) progression and evaluated the role that survival signaling pathways such as PI3K/Akt and PTEN play in this context. We show that the administration of lithium decreased the proliferative potential of CRC cells in a GSK-3ß-independent manner but induced the accumulation of cells in G2/M phase. Furthermore, high doses of lithium increased apoptosis, which was accompanied by decreased proteins levels of Akt and PTEN. Then, cells that were induced to overexpress PTEN were treated with lithium; we observed that low doses of lithium strongly increased apoptosis. Additionally, PTEN overexpression reduced proliferation, but this effect was minor compared with that in cells treated with lithium alone. Furthermore, we demonstrated that PTEN overexpression and lithium treatment separately reduced cell migration, colony formation, and invasion, and these effects were enhanced when lithium treatment and PTEN overexpression were combined. In conclusion, our findings indicate that PTEN overexpression and lithium treatment cooperate to reduce the malignancy of CRC cells and highlight lithium and PTEN as potential candidates for studies to identify new therapeutic approaches for CRC treatment.

Osteopontin-c splicing isoform contributes to ovarian cancer progression.

Ovarian carcinoma is one of the most aggressive gynecological diseases and generally diagnosed at advanced stages. Osteopontin (OPN) is one of the proteins overexpressed in ovarian cancer and is involved in tumorigenesis and metastasis. Alternative splicing of OPN leads to 3 isoforms, OPNa, OPNb, and OPNc. However, the expression pattern and the roles of each of these isoforms have not been previously characterized in ovarian cancer. Herein, we have evaluated the expression profiling of OPN isoforms in ovarian tumor and nontumor samples and their putative roles in ovarian cancer biology using in vitro and in vivo functional assays. OPNa and OPNb were expressed both in tumor and nontumor ovarian samples, whereas OPNc was specifically expressed in ovarian tumor samples. The isoform OPNc significantly activated OvCar-3 cell proliferation, migration, invasion, anchorage-independent growth and tumor formation in vivo. Additionally, we have also shown that some of the OPNc-dependent protumorigenic roles are mediated by PI3K/Akt signaling pathway. OPNc stimulated immortalized ovarian epithelial IOSE cell proliferation, indicating a role for this isoform in ovarian cancer tumorigenesis. Functional assays using OPNc conditioned medium and an anti-OPNc antibody have shown that most cellular effects observed herein were promoted by the secreted OPNc. According to our data, OPNc-specific expression in ovarian tumor samples and its role on favoring different aspects of ovarian cancer progression suggest that secreted OPNc contributes to the physiopathology of ovarian cancer progression and tumorigenesis. Altogether, the data open possibilities of new therapeutic approaches for ovarian cancer that selectively down regulate OPNc, altering its properties favoring ovarian tumor progression.

Melatonin protects CD4+ T cells from activation-induced cell death by blocking NFAT-mediated CD95 ligand upregulation.

Over the past 20 y, the hormone melatonin was found to be produced in extrapineal sites, including cells of the immune system. Despite the increasing data regarding the biological effects of melatonin on the regulation of the immune system, the effect of this molecule on T cell survival remains largely unknown. Activation-induced cell death plays a critical role in the maintenance of the homeostasis of the immune system by eliminating self-reactive or chronically stimulated T cells. Because activated T cells not only synthesize melatonin but also respond to it, we investigated whether melatonin could modulate activation-induced cell death. We found that melatonin protects human and murine CD4(+) T cells from apoptosis by inhibiting CD95 ligand mRNA and protein upregulation in response to TCR/CD3 stimulation. This inhibition is a result of the interference with calmodulin/calcineurin activation of NFAT that prevents the translocation of NFAT to the nucleus. Accordingly, melatonin has no effect on T cells transfected with a constitutively active form of NFAT capable of migrating to the nucleus and transactivating target genes in the absence of calcineurin activity. Our results revealed a novel biochemical pathway that regulates the expression of CD95 ligand and potentially other downstream targets of NFAT activation.