The cardiotoxicity of anticancer drugs is the second leading cause of death in cancer patients. Among other adverse effects, left ventricular ejection fraction decrease or heart failure emerge after anticancer treatments comprising old or new targeted therapies. In the last few years, our group has been trying to unveil the cardiac adverse outcome pathways of classic chemotherapeutic agents, mainly focusing on two topoisomerase inhibitors, mitoxantrone and doxorubicin.

Mitoxantrone and doxorubicin both cause cumulative dose cardiotoxicity and were tested in in vitro and in pre-clinical models. Results obtained in mice and rats, following a clinical relevant dosing scheme, were mimicked in vitro and demonstrated that those drugs change cellular redox homeostasis and promote inflammation, although in different biomarkers. Moreover, autophagy and energetic pathways were affected, the first mainly after mitoxantrone treatments and the latter when doxorubicin was used. Thus, distinct cardiac fingerprints for these two drugs exist.

In conclusion, although their clinical cardiac effects are similar in humans, mitoxantrone and doxorubicin have different initiating cardiotoxic events. These were revealed taking into account the use of proper experimental models, clinical relevant concentrations and Omics methods. These data are of the essence to promote drug specific cardioprotective measures in the future, for patients treated with these drugs.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and/or a dysfunctional β-cells. In the Philippines, 3.7 million people were reported to have the disease in 2017 and at least 100 deaths are caused by diabetes-related complications daily. The goal of T2DM management is to maintain blood glucose at normal physiologic levels. While drugs like oral hypoglycemic agents and insulin are available, the use of herbal medicine by T2DM patients to treat the disease is prevalent. One of the most common herbal medicines used to alleviate the symptoms of T2DM is ashitaba (Angelica keiskei). In the Philippines, ashitaba is commonly marketed as a tea and over 50 ashitaba-containing preparations are registered under the Philippine FDA. Since T2DM is a chronic disorder, consumption of such herbal preparation can lead to possible drug-herb interaction that may alter the pharmacokinetics and pharmacodynamics of drugs used in the management of T2DM. Hence, insights on the biomolecular mechanisms of ashitaba against T2DM is essential to determine possible drug-herb interactions if any, or to rationalize its therapeutic use. Through network pharmacology and molecular docking, reported ashitaba compounds are found to target TNF-α, STAT3, p53, AKT1, HAT p300, PPAR-γ and COX-2 in T2DM. Because of these biomolecular mechanisms, consumption of ashitaba compounds can possibly synergize or antagonize the effects of drugs used in the management of T2DM if taken concomitantly.

Covid-19 is an inflammatory and infectious disease caused by SARS-CoV-2 virus with a complex pathophysiology. While Covid-19 vaccines and boosters are available, treatment of the disease is primarily supportive and symptomatic. Several research have suggested the potential of herbal medicines as an adjunctive treatment for the disease. A popular herbal medicine approved in the Philippines for the treatment of acute respiratory disease is Vitex negundo L. In fact, the Department of Science and Technology of the Philippines has funded a clinical trial to establish its potential as an adjunctive treatment for Covid-19. Here, we utilized network pharmacology and molecular docking in determining pivotal targets of Vitex negundo compounds against Covid-19. The results showed that significant targets of Vitex negundo compounds in Covid-19 are CSB, SERPINE1 and PLG which code for cathepsin B, plasminogen activator inhibitor-1, and plasminogen, respectively. Molecular docking revealed that α-terpinyl acetate and geranyl acetate have good binding affinity in cathepsin B; 6,7,4-trimethoxyflavanone, 5,6,7,8,3',4',5'-heptamethoxyflavone, artemetin, demethylnobiletin, gardenin A, geranyl acetate in plasminogen; and 7,8,4-trimethoxyflavanone in plasminogen activator inhibitor-1. While the results are promising, these are bound to the limitations of computational methods and further experimentation are needed to completely establish the molecular mechanisms of Vitex negundo against Covid-19.

The bacterial susceptibility and the translocation of fluoroquinolones (FQs) are influenced by pH, since it determines the proportion of microspecies of the drug. Norfloxacin (NOR) and Oxalic Acid (AO) are antibacterial compounds. In this work, we evaluated the antibacterial activity of the NOR-AO combination on the Escherichia coli ATCC 25922 strain using the checkerboard method. Besides, we analyzed the pH effect on the NOR-AO combination. We determined the extent of NOR ionization equilibrium and calculated the apparent log P to establish the lipophilicity of NOR at the different pHs assayed. The minimum inhibitory concentration (MIC) obtained for AO and NOR was 1250 µg/mL and 0.25 µg/mL, respectively. The interaction of NOR-AO was indifferent in the concentrations worked (CIF 1.12). However, an atypical behavior was observed in E.coli growth. We observed that at pH values ​​<5.8 and log D < -0.3, the cationic species of NOR predominates, decreasing its activity. As pH increases, the predominant species is zwitterionic with increased lipophilicity and restoration of NOR activity. Therefore, the acid conditions given by the presence of AO decrease the concentration of the neutral species of NOR and therefore the amount of drug capable of diffusing directly through the membrane. There is controversy in the literature regarding the mechanism of FQs translocation through the bacterial membrane, however, our results show that the pH of the medium is a determining factor that directly impacts the antibacterial activity. To deepen this study, we will continue testing new concentrations and combinations with other organic acids.

Compare the efficacy of monoclonal antibody drugs against the calcitonin gene-related peptide pathway in migraine and to establish whether they can be considered equivalent therapeutic alternatives in this pathology

Retrospective observational study. 21 patients with chronic migraine on treatment with Fremanezumab 225mg/30 days and 24 patients on treatment with Erenumab 70mg/30 days for at least 6 months. Data were collected at baseline and six months on the following. Scales: Headache Impact Test (HIT), Migraine Disability Assessment Scale (MIDAS), pain intensity numerical scale: 0 (no pain) and 10 (unbearable pain). Days of migraine per month.

Results:

Mean HIT at baseline and 6 months for Fremanezumab and Erenumab was 68.6 (62-76);54(36-70) and 66 (42-78); 53 (9-72) respectively. In both it decreased by more than 6 points (efficacy criteria).

Mean MIDAS at baseline and 6 months for Fremanezumab and Erenumab was 70 (25-127); 25 (0-135) and 73.3 (19-150); 23 (0-68) respectively. In both cases it decreased more than 30% (efficacy criteria).

Mean pain intensity at baseline, and 6 months for Fremanezumab and Erenumab was 8.8 (6-10); 6(5-8) and 8.6 (7-10); 6 (10-0) respectively.

Migraine days at the mean month at baseline and 6 months for Fremanezumab and Erenumab were16.6 (10-30); 5.3 (0-11) days and 17 (3-30); 5.8(2-15) days. In both cases reduction > 50%.

Conclusion:

The initial values of the scales are very similar. The initial situation of the patient is not a trigger for the use of one or the other.

Clinically there is no difference between the two drugs.

The tumor suppressor p53 is responsible for the genome integrity of the cells, controlling cell cycle arrest and apoptosis in response to stress signals. However, in virtually all human cancers p53 is inactivated either by negative regulation or direct mutation. Thus, there is a high interest to reactivate its tumor suppressor functions. So far, there are no mut-p53 reactivators approved for clinical use and most mut-p53 reactivators fail due to toxic side effects and/or pharmacodynamics properties. So, the development of new and more selective small molecules with less toxic side effects is extremely important.

In the last years, our research group has developed mut- and wt- p53 small molecule activators based on the tryptophanol-derived oxazoloisoindolinone scaffold with promising in vitro and in vivo activity. These compounds are obtained by enantioselective cyclocondensation of (R)- or (S)- tryptophanol with different oxo-acids in toluene under reflux using a Dean-Stark apparatus. Hit compound was optimized, leading to the discovery of (R)- and (S)- tryptophanol-derived oxazoloisoindolinones . Specifically, one compound showed 6-fold higher antiproliferative activity, as well as increased selectivity for HCT116 p53^+/+ over HCT116 p53^-/- compared with the hit compound and is selective towards cancer cells over normal cells .

In this poster communication we will present our recent results on the hit-to-lead optimization process, synthesis and also, the development of a differential scanning fluorimetry assay.

The nutritional composition of cowpea (Vigna unguiculata (L.) Walp.) has been related to the prevention of diverse metabolic and cardiovascular diseases. Previous works have shown that cowpea immature pods exhibited higher phenolic composition and antioxidant activity as compared to immature and dry seeds. This work aims to develop a cowpea immature pod ready-to-eat purée for elderly to promote the maintenance of their muscle mass and synthesis of neurotransmitters implicated in depression disorder and sleep quality. In a preliminary approach, this study intends to assess the phenolic content, antioxidant capacity, nutritional composition, and essential and non-essential amino acids of the cowpea at two different growth stages: immature pods and green seeds. Immature pods showed a significantly higher content of total phenols (11.73 ± 0.43 mg AG/g dry weight), ortho-diphenols (13.18 ± 1.26 mg GA/g dw) and flavonoids (6.04 ± 0.51 mg CAT/g dw) as compared to the green seeds. The higher antioxidant capacity was also displayed by the pods (ABTS•⁺: 0.05 ± 0.00 mmol Trolox/g dw, DPPH•: 0.04 ± 0.00 mmol Trolox/g dw, FRAP: 0.04 ± 0.00 mol Trolox/g dw) in contrast with the green seeds. Immature pods demonstrated the lowest crude fat content (1.74 ± 0.03%) and the highest content of crude protein (27.48 ± 1.05%) and of insoluble dietary fibre (35.63 ± 0.53%). To our knowledge, we present the first study concerning the nutritional composition of cowpea immature pod, suggesting that it have remarkable potential to be included in the development of a new functional food product for the elderly.

Increasing antimicrobial resistance poses a critical problem to public health. Many strategies are engaged to combat this problem; one of them is the synthesis of hybrid drugs consisting of diverse bioactive parts merged into one molecule [1]. The risk that bacteria will mutate and evolve defense mechanisms is lower since the various pharmacophoric parts act against different molecular targets.

We developed a new class of fluoroquinolone-quaternary ammonium conjugates to obtain inhibitors of bacterial topoisomerases with membrane destabilization activity [2]. Docking studies revealed that compounds can interact with topoisomerases in the fluoroquinolone-binding mode. Hybrids were screened against Gram-positive and negative bacteria, including pathogens from the ESKAPE group and antibiotic-resistant strains, in planktonic and biofilm forms. The most effective were moderately lipophilic (CHI 10-20) cyclopropyl-substituted molecules [3]. Moreover, novel compounds exhibit negligible cytotoxicity.

The Project was financed by the Polish National Agency for Academic Exchange as a part of the Bekker Scholarship Programme.

[1] Fedorowicz, J.; Sączewski, J. Modifications of quinolones and fluoroquinolones: hybrid compounds and dual-action molecules. Monatsh Chem 2018, 149,1199–1245. https://doi.org/10.1007/s00706-018-2215-x

[2] Fedorowicz, J.; Sączewski, J.; Konopacka, A.; Waleron, K.; Lejnowski, D.; Ciura, K.; Tomašič, T.; Skok, Ž.; Savijoki, K.; Morawska, M.; Gilbert-Girard, S.; Fallarero, A. Synthesis and biological evaluation of hybrid quinolone-based quaternary ammonium antibacterial agents, Eur. J. Med. Chem. 2019, 179, 576-590, https://doi.org/10.1016/j.ejmech.2019.06.071

[3] Ciura, K.; Fedorowicz, J.; Kapica, H.; Adamkowska, A.; Sawicki, W.; Sączewski, J. Affinity of Fluoroquinolone–Safirinium Dye Hybrids to Phospholipids Estimated by IAM-HPLC. Processes 2020, 8, 1148. https://doi.org/10.3390/pr8091148

Increasing resistance of fungi, especially Candida spp., successively has reduced the already short list of effective antifungal drugs used in clinical therapy. Thus there is an urgent need for new, non-toxic antifungals with novel mode of action. A very interesting and attractive group of compounds seems to be complexes of Co(III) with diamine chelate ligands due to their therapeutic uses as antiviral, antibacterial, antifungal, antiparasitic, or antitumor agents. Two Co(III) complexes with diamine chelate ligands ([CoCl₂(dap)₂]Cl (1) and [CoCl₂(en)₂]Cl (2)) (where dap = 1,3-diaminopropane, en = ethylenediamine) were synthesized and characterized by elemental analysis, an ATR technique, and a scan method and sequentially tested against a wide range of Candida spp. strains. Analysed complexes exhibited strong antifungal activity against tested yeasts and were more effective than commercial antifungal drug, ketoconazole. However, antifungal activity of ketoconazole increased in combination with the tested complexes, what has been proven by checkerboard assay (the synergistic antimicrobial activity). The effects of Co(III) complexes on yeast cell morphology were also studied by transmission electron microscopy and showed changes in yeast cell morphology, indicating significant disruptions in the molecular machinery of cells. The complexes of Co(III) turned out also to be non-toxic in the concentrations tested for the antimicrobial activity, the cytotoxic effects of the tested compounds on red blood cells and the human keratinocyte (HaCaT) cell line were evaluated. This study provides new data on potential antifungal drugs, especially against Candida species.

2-Styrylchromones (2-SC) are heterocyclic compounds, with a structure of at least 17 carbons and a styryl group attached to a benzoannelated γ-pyrone ring. While the anti-inflammatory potential of 2-SC has become a subject of interest, their effects in inflammatory pathways are still unexplored. Therefore, to better understand 2-SC’s mechanisms of anti-inflammatory action, this study investigated the influence of 10 hydroxylated and methoxylated 2-SC on the inhibitory activity of cyclooxygenase (COX-2), through an in vitro non-cellular assay and an ex vivo assay in human whole blood, based on fluorometric detection of prostaglandin (PG) G₂ and colorimetric detection of PGE₂, respectively.

A 2-SC hydroxylated at C-7 and C-8 on A-ring and C-3’ and C-4’ on B-ring was the most active in the direct inhibition of COX-2 activity, whereas a 2-SC methoxylated at C-4’ on B-ring was the most active in the ex vivo inhibition of PGE₂ production. The obtained results suggest that the presence of OH groups, especially at C-8 on A-ring, favor the direct inhibition of COX-2. Conversely, for inhibition of PGE₂ production in a more complex matrix, human blood, it is the presence of an OCH₃ at C-4’ on B-ring that seems to be important.