Ignacio Encío

Heat-inactivated probiotics, also known as postbiotics, have emerged as an alternative to live probiotics, and have been shown to be good therapeutic tools for the management and treatment of metabolic dysfunctions such as obesity and type 2 diabetes (T2D). The present study aimed to assess the anti-obesogenic and anti-diabetic properties of heat-inactivated Pediococcus acidilactici pA1c^® (pA1c^®HI) in mice fed a high-fat diet (HFD). The animals were given an HFD or HFD enriched with either the probiotic alive pA1c^® or the postbiotic pA1c^®HI. Body weight (BW), serum biochemical markers, gene expression, and histological changes were determined following 15 weeks of supplementation. The postbiotic pA1c^®HI exerted a similar effect on glucose metabolism to that exerted by pA1c^® supplementation. Nevertheless, we observed that pA1c^®HI supplementation maintained BW, attenuated adipogenesis, and protected the mice from liver damage more efficiently than pA1c^®. Similarly, in adipose tissue, pA1c^®HI significantly downregulated markers of de novo lipogenesis (DNL) and fat storage. The observed results show that pA1c^®HI administration was even more effective in mitigating the HFD’s detrimental effects than pA1c^® supplementation, and therefore, the viability of this Pediococcus acidilactici CECT 9879 strain is not required for preserving its beneficial properties in the context of obesity and T2D.

Currently, cancer remains a global health problem. Despite the existence of several treatments, including chemotherapy, immunotherapy, and radiation therapy, the survival rate for most cancer patients, particularly those with metastasis, remains unsatisfactory. Thus, there is a continuous need to develop novel, effective therapies. In this work, 22 novel molecules containing selenium are reported, including seven Se-acylisoselenoureas synthesized from aliphatic carbodiimides as well as acylselenoureas with the same carbo- and heterocycles and aliphatic amines. After an initial screening at two doses (50 and 10 µM) in MDA-MB-231 (breast), HTB-54 (lung), DU-145 (prostate), and HCT-116 (colon) tumor cell lines, the ten most active compounds were identified. Additionally, these ten hits were also submitted to the DTP program of the NCI to study their cytotoxicity in a panel of 60 cancer cell lines. Compound 4 was identified as the most potent antiproliferative compound. The results obtained showed that compound 4 presented IC₅₀ values lower than 10 µM in the cancer cell lines, although it was not the most selective one. Furthermore, compound 4 was found to inhibit cell growth and cause cell death by inducing apoptosis partially via ROS production. Overall, our results suggest that compound 4 could be a potential chemotherapeutic drug for different types of cancer.

Small cell lung cancer (SCLC) stands out as the most aggressive form of lung cancer, characterized by an extremely high proliferation rate and a very poor prognosis, with a 5-year survival rate that falls below 7%. Approximately two-thirds of patients receive their diagnosis when the disease has already reached a metastatic or extensive stage, leaving chemotherapy as the remaining first-line treatment option. Other than the recent advances in immunotherapy, which have shown moderate results, SCLC patients cannot yet benefit from any approved targeted therapy, meaning that this cancer remains treated as a uniform entity, disregarding intra- or inter-tumoral heterogeneity. Continuous efforts and technological improvements have enabled the identification of new potential targets that could be used to implement novel therapeutic strategies. In this review, we provide an overview of the most recent approaches for SCLC treatment, providing an extensive compilation of the targeted therapies that are currently under clinical evaluation and inhibitor molecules with promising results in vitro and in vivo.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PC) that commonly emerges through a transdifferentiation process from prostate adenocarcinoma and evades conventional therapies. Extensive molecular research has revealed factors that drive lineage plasticity, uncovering novel therapeutic targets to be explored. A diverse array of targeting agents is currently under evaluation in pre-clinical and clinical studies with promising results in suppressing or reversing the neuroendocrine phenotype and inhibiting tumor growth and metastasis. This new knowledge has the potential to contribute to the development of novel therapeutic approaches that may enhance the clinical management and prognosis of this lethal disease. In the present review, we discuss molecular players involved in the neuroendocrine phenotype, and we explore therapeutic strategies that are currently under investigation for NEPC.

The introduction of selenium (Se) into organic scaffolds has been demonstrated to be a promising framework in the field of medicinal chemistry. A novel design of nonsteroidal anti-inflammatory drug (NSAID) derivatives based on a bioisosteric replacement via the incorporation of Se as diacyl diselenide is reported. The antioxidant activity was assessed using the DPPH radical scavenging assay. The new Se-NSAID derivatives bearing this unique combination showed antioxidant activity in a time- and dose-dependent manner, and also displayed different antiproliferative profiles in a panel of eight cancer cell lines as determined by the MTT assay. Ibuprofen derivative 5 was not only the most antioxidant agent, but also selectively induced toxicity in all the cancer cell lines tested (IC₅₀ < 10 µM) while sparing nonmalignant cells, and induced apoptosis partially without enhancing the caspase 3/7 activity. Furthermore, NSAID derivative 5 significantly suppressed tumor growth in a subcutaneous colon cancer xenograft mouse model (10 mg/kg, TGI = 72%, and T/C = 38%) without exhibiting any apparent toxicity. To our knowledge, this work constitutes the first report on in vitro and in vivo anticancer activity of an unprecedented Se-NSAID hybrid derivative and its rational use for developing precursors for bioisosteric selenocompounds with appealing therapeutic applications.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive subtype of prostate cancer (PC) that commonly emerges through a transdifferentiation process from prostate adenocarcinoma and evades conventional therapies. Extensive molecular research has revealed factors that drive lineage plasticity, uncovering novel therapeutic targets to be explored. A diverse array of targeting agents is currently under evaluation in pre-clinical and clinical studies with promising results in suppressing or reversing the neuroendocrine phenotype and inhibiting tumor growth and metastasis. This new knowledge has the potential to contribute to development of novel therapeutic approaches that may enhance clinical management and prognosis of this lethal disease.

Oxidative stress surrounding cancer cells provides them with certain growth and survival advantages necessary for disease progression. In this context, Se-containing molecules have gained attention due to their anticancer and antioxidant activity. In our previous work, we synthesized a library of 39 selenoesters containing functional groups commonly present in natural products (NP), which showed potent anticancer activity, but did not demonstrate high radical scavenger activity. Thus, 20 novel Se derivatives resembling NP have been synthesized presenting acylselenourea functionality in their structures. Radical scavenger activity was tested using DPPH assay and in vitro protective effects against ROS-induced cell death caused by H₂O₂. Additionally, antiproliferative activity was evaluated in prostate, colon, lung, and breast cancer cell lines, along with their ability to induce apoptosis. Compounds 1.I and 5.I showed potent cytotoxicity against the tested cancer cell lines, along with high selectivity indexes and induction of caspase-mediated apoptosis. These compounds exhibited potent and concentration-dependent radical scavenging activity achieving DPPH inhibition similar to ascorbic acid and trolox. To conclude, we have demonstrated that the introduction of Se in the form of acylselenourea into small molecules provides strong radical scavengers in vitro and antiproliferative activity, which may lead to the development of promising dual compounds.

Type 2 diabetes (T2D) is a complex metabolic disease, which involves maintained hyperglycemia, mainly due to the development of an insulin resistance process. Metformin administration is the most prescribed treatment for diabetic patients. In a previously published study, we demonstrated that Pediococcus acidilactici pA1c^® (pA1c) protects from insulin resistance and body weight gain in HFD-induced diabetic mice. The present work aimed to evaluate the possible beneficial impact of a 16-week administration of pA1c, metformin, or the combination of pA1c and metformin in a T2D HFD-induced mice model. We found that the simultaneous administration of both products attenuated hyperglycemia, increased high-intensity insulin-positive areas in the pancreas and HOMA-β, decreased HOMA-IR and also provided more beneficial effects than metformin treatment (regarding HOMA-IR, serum C-peptide level, liver steatosis or hepatic Fasn expression), and pA1c treatment (regarding body weight or hepatic G6pase expression). The three treatments had a significant impact on fecal microbiota and led to differential composition of commensal bacterial populations. In conclusion, our findings suggest that P. acidilactici pA1c^® administration improved metformin beneficial effects as a T2D treatment, and it would be a valuable therapeutic strategy to treat T2D.

Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimer’s disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 Se-derivatives were synthesized, purified, and spectroscopically characterized by NMR. Antioxidant ability was tested using the DPPH assay, while antiproliferative activity was screened in breast, lung, prostate, and colorectal cancer cell lines. In addition, as a first approach to evaluate their potential anti-Alzheimer activity, the in vitro acetylcholinesterase inhibition (AChEI) was tested. Regarding antioxidant properties, compound 13a showed concentration- and time-dependent radical scavenging activity. Additionally, compounds 14a and 17a showed high activity in the melanoma and ovarian cancer cell lines, with LD₅₀ values below 9.2 µM. Interestingly, in the AChEI test, compound 14a showed almost identical inhibitory activity to galantamine along with a 3-fold higher in vitro BBB permeation (Pe = 36.92 × 10⁻⁶ cm/s). Molecular dynamics simulations of the aspirin derivatives (14a and 14b) confirm the importance of the allylic group instead of the propargyl one. Altogether, it is concluded that some of these newly synthesized Se-derivatives, such as 14a, might become very promising candidates to treat both cancer and AD.

Currently, cancer, leishmaniasis and bacterial infections represent a serious public health burden worldwide. Six cinnamyl and benzodioxyl derivatives incorporating selenium (Se) as selenocyanate, diselenide, or selenide were designed and synthesized through a nucleophilic substitution and/or a reduction using hydrides. Ferrocene was also incorporated by a Friedel–Crafts acylation. All the compounds were screened in vitro for their antiproliferative, antileishmanial, and antibacterial properties. Their capacity to scavenge free radicals was also assessed as a first approach to test their antioxidant activity. Benzodioxyl derivatives 2a–b showed cytotoxicity against colon (HT-29) and lung (H1299) cancer cell lines, with IC₅₀ values below 12 µM, and were also fairly selective when tested in nonmalignant cells. Selenocyanate compounds 1–2a displayed potent antileishmanial activity in L. major and L. infantum, with IC₅₀ values below 5 µM. They also exhibited antibacterial activity in six bacterial strains, notably in S. epidermidis with MIC and MBC values of 12.5 µg/mL. Ferrocene-containing selenide 2c was also identified as a potent antileishmanial agent with radical scavenging activity. Remarkably, derivative 2a with a selenocyanate moiety was found to act as a multitarget compound with antiproliferative, leishmanicidal, and antibacterial activities. Thus, the current work showed that 2a could be an appealing scaffold to design potential therapeutic drugs for multiple pathologies.