Globally, colorectal cancer (CRC) is amongst the top prevalent cancer incidences, being the second most common amongst women and third most common amongst men as revealed by ‘GLOBOCAN 2022’ statistics. The projected morbidity for CRC is more than 3 million by the year 2040 according to the ‘WHO Cancer Tomorrow’’ predictions. Surgery, chemotherapy, and radiation therapy continue to be the primary treatment options, each accompanied by their limitations. There is a growing need for identification of alternate therapies for treatment of the same to overcome the shortfalls of these treatment options. Phytoconstituents offer diverse pharmacophoric scaffolds with unique chemical features. In this work, successive extracts of aerial plant parts of a Vernonia species (family Asteraceae) have been screened in vitro on colorectal adenocarcinoma cell lines Colo205 and HT-29 by MTT assay and compared with 5-Flurouracil as reference standard. The plant is known to possess triterpenoids, quaternary alkaloids, phenolics, and sesquiterpene lactones. In silico docking studies have been carried out on the plausible phytoconstituents of the active extracts against vital protein targets involved in the progression of CRCs such as cyclin dependent kinases and enzymes of apoptotic pathways such as caspases etc. These studies will help in probing the mechanistic details of the anticancer activity of the plant and will provide a platform for development of novel multi-targeted small molecules.

The aim of this study was to evaluate the antidiabetic properties of hydro alcoholic extract and supernatant fraction of the roots of Anogeissus leiocarpus, a plant used by traditional healers to treat Diabetes mellitus. Diabetes mellitus was induced by a single intraperitoneal administration of Streptozocin to Sprague Dawley rats under a fructose-enriched fat diet. Diabetic rats were treated with 500 mg/kg of total extract and 100 mg/kg of supernatant. The antidiabetic activity was assessed by measuring blood glucose level, lipid profile, insulin and biochemical parameters together with the antioxidant potential.

The administration of total extract and supernatant exhibited significant decrease (p < 0.01) of the blood glucose level in the diabetic rats after 7 days of treatment compared to the diabetic rats. A significant reduction of cholesterol level (19.7%) and triglycerides level (56.7%) was observed in the treated diabetic rats. The levels of insulin did not differ across all the groups. However, compared to diabetic rats, HOMA-IR (Homeostasis Model Assessment for Insulin-resistance) and HOMA-β (Homeostasis Model Assessment for β cell function) showed a statistical decrease in insulin resistance and an increase in pancreatic β cell function in the treated diabetic rats. Moreover, total extract and supernatant significantly increased GSH level and decreased lipid peroxidation. In comparison, the supernatant fraction exerted stronger antidiabetic and antioxidant effects than the total extract.

Hence, the roots of A. leiocarpus are a potent antidiabetic agent that can be developed as an alternative medicine for diabetes and its complications.

Triple negative breast cancer (TNBC), a poor survival cancer has high resistance to therapy, with low drug efficacy. Adenosine is present in high concentrations in tumor microenvironment. Recently, adenosine was found to sensitize ovarian cisplatin-resistant cancer. This work aims at addressing if adenosine can sensitize TNBC resistance to platinum drugs. Concomitant/preincubation of adenosine with cisplatin or carboplatin induced cell proliferation in TNBC cisplatin-sensitive (MDA) and -resistant (MDA/R) cells (using Lionheart-FX microscope). Phosphorylation of ERK or NF-κB pathways and cAMP production were evaluated (AlphaScreen assays). Data analyzed with One-way ANOVA t-test. Results: concomitant or preincubation of adenosine (300, 600, 700 µM) with cisplatin reduced resistance in MDA/R, with proliferation levels approaching those observed in MDA. In MDA, endogenous and exogenous adenosine have no effect over ERK phosphorylation; in MDA/R, exogenous adenosine lowers ERK phosphorylation. NF-κB phosphorylation was induced by A₃R and A_2BR tonic activation in MDA and MDA/R, respectively, increasing survival - exogenous adenosine inactivates this via. Tonically cAMP production was altered in MDA and MDA/R, revealing inhibitory and stimulatory effects in cAMP production by A₁R and A_2BR, respectively, in MDA/R. By contrast, exogenous adenosine revealed that adenosine receptors in MDA contribute differently while in MDA/R all receptor subtypes have a similar contribution to cAMP production. Thus, adenosine contributes to overcome platinum-derived resistance in TNBC, involving the inactivation of NF-κB pathway and decrease of ERK phosphorylation (partially mediated by A₃R). Fund FCT (UIDB/QUI/50006/2020).

The number of multidrug resistant (MDR) cancer cases across the globe is continuing to rise, such that the search for novel anti-cancer therapeutics is paramount. However, in MDR cancers, such as the overexpression of membrane transport proteins like P-glycoprotein (P-gp) or the modulation of Protein Kinases C (PKC) isoforms, continues to be a major impediment to effective therapy. Known for their medicinal properties, species from Plectranthus have reported cytotoxicity against various cancer cell lines, due to diterpenes, such as 7α-acetoxy-6β-hydroxyroyleanone (Roy) and 6,7-dehydroroyleanone (DeRoy). Based on molecular docking simulations, 10 semi-synthetic derivates of Roy that displayed strong P-gp interactions in silico were prepared. The antitumoral activity was evaluated in resistant human cancer cell lines NCI-H460/R and DLD1-TxR, showing three derivatives having the most prominent selectivity towards cancer cells, compared to normal lung fibroblasts MRC5. Moreover, they showed a reduction in P-gp activity in Rho123 accumulation and indicated P-gp inhibition in the DOX accumulation assay using the same resistant cell lines. Overall, it was demonstrated that three abietane diterpenoid derivatives induced P-gp inhibition in MDR cancer cell lines. As for the PKC activity, further analogues were tested as PKC (α, βI, δ, ε and ζ) modulators; one benzoylated derivative showed the ability to selectively activate PKC-δ, while the natural compound DeRoy displayed improved PKC activity, compared with the positive control, in all tested isoforms. Further investigations are ongoing to prepare analogues of other biological active diterpenoids to obtain potential hits as P-gp and PKC modulators.

The development of multidrug resistance (MDR) is one of the major challenges in the successful treatment of cancer. MDR is often associated with the P-glycoprotein efflux pump. Natural products are a source of promising lead compounds to overcome MDR and, among them, diterpenoids from Plectranthus spp. are known as P-gp modulators. Bioguided fractionation of P. mutabilis acetone extract led to the isolation of one new nor-abietane diterpene, mutabilol (1), and three coleon compounds (coleon-U-quinone (2), 8α,9α-epoxycoleon-U-quinone (3), and coleon U (4)). Moreover, an additional acetoxy derivative of an abietane diterpenoid was tentatively identified using HPLC-MS/MS. The compounds were quantified using HPLC-DAD and coleon U was found to be the major compound in the extract. Using computational studies, a biosynthetic relationship between compounds 2 - 4 revealed that both compounds 2 and 3 were formed directly from compound 4. Compounds 2 - 4 were found to be selective towards the cancer cell lines and their anticancer effect was not compromised by the P-gp activity in resistant NCI-H460/R cells. Importantly 2, 3, and 4 were able to inhibit P-gp activity in NCI-H460/R cells at longer exposure (72 h) and revert doxorubicin (DOX) resistance in combined treatment. None of the compounds influenced the P-gp expression in NCI-H460/R cells, while the extract significantly increased it. Our study identified abietane diterpenoids from P. mutabilis that can evade MDR in cancer cells and inhibit the P-gp activity in prolonged treatment.

Pollution is regarded as a relevant driver of both Human and Environmental Health. Plastic contaminants have been a target of extensive risk assessment research, mainly because of their persistence and fragmentation to nano sizes in the environment, potentiating its uptake to biota, including humans. Polyhydroxybutyrate (PHB) is a bio-based and biodegradable polyester, praised in the medical field due to its biocompatibility and non-toxicity to humans. Notwithstanding, little is known regarding its toxicity when used as nanoparticles (PHB-NPs). In addition to its individual exposure threat, NPs may serve as vectors for chemicals, promoting its incorporation by Humans (e.g. inhalation of NPs loaded with other chemicals) and other biota. Caffeine is the world's most widely consumed psychoactive drug and a relevant representative of pharmaceutically active pollutants. On mammals, caffeine can induce teratogenic and embryotoxic effects. This work aimed to assess the lethal and sublethal toxicity of these two xenobiotics, in single and mixed exposures, by using in vivo (embryos and tadpoles of Xenopus laevis) and in vitro (two cell lines of X. laevis) biological models. Caffeine was toxic to both life stages of X. laevis. Embryos were more sensitive than tadpoles with LC₅₀ of 196 and 226 mg/L, and EC_{50, malformations} of 124 and 241 mg/L, respectively. PHB-NPs showed no effect when exposed alone and in mixture. Cytotoxicity assays revealed LC_50s of 864 (XTC-2), 587 (A6) and 131 (XTC-2) mg/L after caffeine and PHB-NPs exposure, respectively. In co-exposure, the concentration of PHB-NPs was positively correlated with the toxic effect of the mixture.

N-methyl-D-aspartate receptors (NMDAR) are heterotetrameric, ionotropic glutamate receptors, typically consisting of two GluN1 and two GluN2 subunits and play a crucial role in neuroplasticity, memory and learning. Seven different subunits lead to a variety of possible subunit combinations in NMDARs. Thus, subunit selective modulation is required for the characterization of properties and (patho)physiological relevance of NMDARs containing different subunits. TCN-201 was the first reported negative allosteric modulator with pronounced selectivity towards GluN2A containing NMDARs. The compound binds at the level of the ligand binding domains (LBD) of the receptor, more precisely at the interface of a local heterodimer of GluN1 and GluN2A LBDs. Three fluorescently labeled ligands based on the scaffold of TCN-201 were developed and autodisplay used as a tool to display the GluN1 and GluN2A LBDs on the surface of E. coli. Surface display was confirmed by proteinase K accessibility assay for GluN1 and GluN2A LBDs individually. Additionally, co-display of both LBDs within one cell sample was established. Ligand binding to surface displayed LBDs was investigated by flow cytometry. Fluorescently labeled ligands were shown to bind to LBD co-displaying cells in a concentration dependant manner. Comparing detection efficiencies suggested that fluorescein-labeled compound 3 was the most suitable tracer molecule. For compound 3 it was additionally shown that practically no off-target binding was detected for non-displaying cells and cells displaying an unrelated dimeric protein. This approach paves the road for developing a competitive binding assay with non-fluorescent ligands to identify novel GluN2A selective high-affinity binders.

Prostate cancer is the third most diagnosed cancer worldwide, and the second cause of cancer deaths in men. The currently available treatments are not always effective and may be associated with unwanted side effects. The process of developing new drugs is expensive and can take several years. Thus, drug repurposing emerges as an interesting alternative since it uses clinically studied and available drugs for a new clinical use. The present study aimed to explore the effects of a β-blocker (carvedilol), a selective serotonin reuptake inhibitor (sertraline) and an antimetabolite drug (5-fluorouracil), alone or in binary mixtures, on the cancer cell line (22Rv1) as well as on the normal prostate cell line (PNT-2) cell viability. Overall, the tested conditions demonstrated the ability of the drugs to induce toxic effects and allowed the estimation of median lethal concentrations. The cell line 22Rv1, compared to the normal cell line, was more sensitive to sertraline and 5-fluorouracil but more resistant to carvedilol. Data from combined exposures conditions demonstrated the potential value of these substances

Cholinesterase inhibitors (ChEis) play an important role enhancing cholinergic synaptic activity and, consequently, have therapeutic applications in the treatment of neurodegenerative diseases like Alzheimer's disease (AD). The inhibition of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) avoids the degradation of the neurotransmitter acetylcholine and constitutes a pharmacotherapeutic strategy that has shown important efficacy reducing AD symptoms.

Based on previous results obtained by our group and with the purpose of obtaining diverse and more effective compounds, a series of new azobenzene derivatives were designed and synthesized. Additionally, considering the powerful AChE inhibition displayed by this type of compounds, in this work, it was decided to expand the research by testing BChE inhibitory activity. Nine azobenzene derivatives, with different spacer lengths (4-8 carbons) and terminal tertiary amines, were synthesized by microwave-assisted synthesis and tested for biological activity in vitro. The synthesis was carried out using a microwave oven (in two steps) with a reaction time of around 20 min and moderate to good yields. Also cytotoxic properties of the compounds in SH-SY5Y human neuroblastoma cells will be tested.

The inhibitory activity of BChE was determined using Ellman's method. All the compounds synthesized were active against BChE, being the most effective the one with a six carbon atom spacer and ethylbenzylamine moiety (IC₅₀: 6.621 µM ± 0.001). From these results we could establish that the optimum length for the spacer was six carbons and that diamines were less active than monoamines.

Malaria is a disease that affect many people in the world. In Mexico, malaria still a disease with active zones especially in the states of Chiapas and southern Chihuahua where several communities are affected year after year. According to previous studies, a moderate antimalarial effect has been attributed of some Cecropia species in countries like Brazil, Panama and Colombia. To date in México, it doesn't exist studies have been evaluations of the possible antimalarial activity of Cecropia Obtisifolia Bertol.

The objective of the present was to identify the main metabolites present in acetonic extract of C. Obtusifolia and evaluate their possible antimalarial activity in silico analysis.

An acetonic extraction of C. Obtusifolia leaves was carried out and by means of Thin Layer Chromatography (TLC) and HPLC the main compounds were identified. The identified compounds were evaluated with specific molecular docking studies using four different malaria targets with PDB codes 1CET, 1PZ4, 2BL9 and 4ZL4 using AutodockVina and visualized using LigPlot and PyMOL.

From the acetone extract the compounds were found ursolic acid, α-amyrin, chrysin and isoorientin by of TLC and HPLC. The docking studies showed that the ligands docked well with the targets, resulting in the next strongest binding energies between ligands and targets (kcal/mol): isoorientin-1CET (- 9.1), chrysine-1PZ4 (9.6 kcal/mol), isoorientin-2BL9 (-8.8) and chrysine-4ZL4 (-9.6). These binding affinities were stronger than the control ligands. Analysis of the results suggests that isoorientin and chrysine could act as an anti-malaria agent.