EXCLI Journal

The neuroscience of body memory

2023-01-30T08:26:42+01:00

The body is a very special object, as it corresponds to the physical component of the self and it is the medium through which we interact with the world. Our body awareness includes the mental representation of the body that happens to be our own, and traditionally has been defined in terms of body schema and body image. Starting from the distinction between these two types of representations, the present paper tries to reconcile the literature around body representations under the common framework of body memory. The body memory develops ontogenetically from birth and across all the life span and is directly linked to the development of the self. Therefore, our sense of self and identity is fundamentally based on multisensory knowledge accumulated in body memory, so that the sensations collected by our body, stored as implicit memory, can unfold in the future, under suitable circumstances. Indeed, these sets of bodily information had been proposed as possible key factors underpinning several mental health illnesses. Following this perspective, the Embodied Medicine approach put forward the use of advanced technologies to alter the dysfunctional body memory to enhance people’s well-being. In the last sections, recent experimental pieces of evidence will be illustrated that targeted specifically bodily information for increasing health and wellbeing, by means of two strategies: interoceptive feedback and bodily illusions.

Bortezomib advanced mechanisms of action in multiple myeloma, solid and liquid tumors along with its novel therapeutic applications

2022-12-20T09:54:32+01:00

Bortezomib (BTZ) is a first-in-class reversible and selective proteasome inhibitor. It inhibits the ubiquitin proteasome pathway that leads to the degradation of many intracellular proteins. Initially, BTZ was FDA approved for the treatment of refractory or relapsed multiple myeloma (MM) in 2003. Later, its usage was approved for patients with previously untreated MM. In 2006, BTZ was approved for the treatment of relapsed or refractory Mantle Cell Lymphoma (MCL) and, in 2014, for previously untreated MCL. BTZ has been extensively studied either alone or in combination with other drugs for the treatment of different liquid tumors especially in MM. However, limited data evaluated the efficacy and safety of using BTZ in patients with solid tumors. In this review, we will discuss the advanced and novel mechanisms of action of BTZ documented in MM, solid tumors and liquid tumors. Moreover, we will shed the light on the newly discovered pharmacological effects of BTZ in other prevalent diseases.

Can melatonin reduce the severity of post-COVID-19 syndrome?

2023-01-30T08:16:20+01:00

This short review aimed at (i) providing an update on the health benefits associated with melatonin supplementation, while (ii) considering future potential research directions concerning melatonin supplementation use relative to Coronavirus disease of 2019 (COVID-19). A narrative review of the literature was undertaken to ascertain the effect of exogenous melatonin administration on humans. Night-time melatonin administration has a positive impact on human physiology and mental health. Indeed, melatonin (i) modulates the circadian components of the sleep-wake cycle; (ii) improves sleep efficiency and mood status; (iii) improves insulin sensitivity; and (iv) reduces inflammatory markers and oxidative stress. Melatonin has also remarkable neuroprotective and cardioprotective effects and may therefore prevent deterioration caused by COVID-19. We suggest that melatonin could be used as a potential therapy in the post-COVID-19 syndrome, and therefore call for action the research community to investigate on the potential use of exogenous melatonin to enhance the quality of life in patients with post-COVID-19 syndrome.

Casposons – silent heroes of the CRISPR-Cas systems evolutionary history

2022-11-07T10:40:39+01:00

Many archaeal and bacterial organisms possess an adaptive immunity system known as CRISPR-Cas. Its role is to recognize and degrade foreign DNA showing high similarity to repeats within the CRISPR array. In recent years computational techniques have been used to identify cas1 genes that are not associated with CRISPR systems, named cas1-solo. Often, cas1-solo genes are present in a conserved neighborhood of PolB-like polymerase genes, which is a characteristic feature of self-synthesizing, eukaryotic transposons of the Polinton class. Nearly all cas1-polB genomic islands are flanked by terminal inverted repeats and direct repeats which correspond to target site duplications. Considering the patchy taxonomic distribution of the identified islands in archaeal and bacterial genomes, they were characterized as a new superfamily of mobile genetic elements and called casposons. Here, we review recent experiments on casposons' mobility and discuss their discovery, classification, and evolutionary relationship with the CRISPR-Cas systems.

Sodium-glucose cotransporter 2 inhibitors and mitochondrial functions

2022-10-27T13:00:38+02:00

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are a class of newly introduced antidiabetic drugs with potent hypoglycemic effects. Recent evidence suggests that these drugs have extraglycemic impacts and are therefore able to provide additional benefits beyond glucose lowering. Mitochondrial dysfunction is a central facet of many disorders that negatively impacts many tissues and organs, especially in the setting of diabetes. Therefore, it would be hugely beneficial if an antidiabetic drug could also provide mitochondrial benefits to improve cellular function and reduce the risk of diabetic complications. In this review, we have surveyed the literature for possible mitochondrial benefits of SGLT2is and we discuss the possible mechanisms involved.

The versatility of 18β-glycyrrhetinic acid in attenuating pulmonary inflammatory disorders

2023-01-30T08:07:21+01:00

The vaccination status of COVID-19 hospitalized patients during the Omicron BQ.1.1 wave in Northeast Brazil suggests the need for a fifth booster dose in the elderly, with a time since the last dose of more than 6 months

2023-01-31T07:53:27+01:00

Comment on the manuscript entitled "Clinical presentation vs endoscopy for an early diagnosis of eosinophilic esophagitis: a case report" by Di Stefano et al.

2022-12-15T10:04:12+01:00

Elucidating the antiviral potential of polysaccharides

2022-12-08T10:38:09+01:00

A temporal cluster of acute promyelocytic leukemia

2022-12-08T12:41:43+01:00

The bovine dialyzable leukocyte extract, immunepotent CRP, synergically enhances cyclophosphamide-induced breast cancer cell death, through a caspase-independent mechanism

2022-12-13T08:56:52+01:00

Breast cancer (BC) is one of the leading causes of cancer death worldwide. Cyclophosphamide (CTX) remains a mainstay in cancer therapy despite harmful adverse effects and cell death-resistances. To face this, combinational therapy of chemotherapies and immunotherapies has been proposed. IMMUNEPOTENT CRP (ICRP) is an immunotherapy that has cytotoxic effects in several cancer cells without affecting peripheral blood mononuclear cells (PBMC) and CD3+ cells. The aim of this study was to evaluate cytotoxicity, the type of cytotoxic effect, and several features involved in cell death induced by the combination of CTX with ICRP (ICRP+CTX) in breast cancer cells as well as their effect on healthy cells. For this purpose, human and murine breast cancer cells, MCF-7, MDA-MB-231 and 4T1, or PBMC were treated for 24 hours with ICRP, CTX or ICRP+CTX in different combination ratios for the assessment of cell death. Flow cytometry and microscopy were used to determine biochemical and morphological characteristics of cell death. Assays showed that ICRP in combination with CTX induce potentiated cell death manifested with morphological changes, loss of mitochondrial membrane potential, reactive oxygen species (ROS) production, and caspase activation. In addition, it was determined that ICRP+CTX-cell death is caspase-independent in all the breast cancer cells assessed. On the other hand, ICRP did not affect CTX-cytotoxicity in PBMC. For all the above, we can propose that the combination of ICRP with CTX an effective combination therapy, promoting their use even in tumoral cells with defects on proteins implicated in the apoptotic pathway.

Anti-tumor effects of low-dose metronomic vinorelbine in combination with alpelisib in breast cancer cells

2023-01-11T13:13:52+01:00

In metastatic breast cancer (MBC), PIK3CA mutations, activating the phosphatidylinositol 3-kinase (PI3K) signaling pathway seem to be associated with chemotherapy resistance and poor outcome. Inhibition of the PI3K signaling pathway may lead to sensitization and prevention of the development of resistance to cytotoxic drugs. The present study aimed to investigate the anti-tumor activity of low-dose vinorelbine (VRL) combined with alpelisib, an α-selective PI3K inhibitor and degrader, in breast cancer (BC) cells. Human BC cell lines MCF-7, T-47D [both hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated], MDA-MB-231 and BT-549 (both triple-negative, wild-type PIK3CA) were exposed to a combination of low-dose VRL and alpelisib for 3 and 7 days. Cell viability was detected by the Alamar blue assay, and cell proliferation was determined by the BrdU incorporation. The effect of the substances on the p110α protein expression that is encoded by PIK3CA gene was investigated by Western blot. Low-dose VRL plus alpelisib showed synergistic anti-tumor effects and significantly inhibited cell viability and proliferation of MCF-7 and T-47D cells. Even lower alpelisib concentrations (10 ng/ml and 100 ng/ml) combined with low-dose metronomic VRL led to a significant reduction of cell viability of PIK3CA-mutated cells, and the anti-tumor activity was comparable with the effects at 1000 ng/ml alpelisib. Cell viability and proliferation of MDA-MB-231 and BT-549 cells were inhibited by VRL but not by alpelisib alone. This indicates that alpelisib did not significantly affect the cell growth of triple-negative, PIK3CA wild-type BC cells. The p110α expression was downregulated or not affected in PIK3CA-mutated cell lines, and not significantly upregulated in PIK3CA wild-type cell lines. In conclusion, combination of low-dose metronomic VRL and alpelisib showed synergistic anti-tumor effects and significantly inhibited the growth of HR-positive, HER2-negative, PIK3CA-mutated BC cells, providing a rationale for further efforts to evaluate this combination in vivo.

PARP1pred: a web server for screening the bioactivity of inhibitors against DNA repair enzyme PARP-1

2022-11-14T10:58:24+01:00

Cancer is the leading cause of death worldwide, resulting in the mortality of more than 10 million people in 2020, according to Global Cancer Statistics 2020. A potential cancer therapy involves targeting the DNA repair process by inhibiting PARP-1. In this study, classification models were constructed using a non-redundant set of 2018 PARP-1 inhibitors. Briefly, compounds were described by 12 fingerprint types and built using the random forest algorithm concomitant with various sampling approaches. Results indicated that PubChem with an oversampling approach yielded the best performance, with a Matthews correlation coefficient > 0.7 while also affording interpretable molecular features. Moreover, feature importance, as determined from the Gini index, revealed that the aromatic/cyclic/heterocyclic moiety, nitrogen-containing fingerprints, and the ether/aldehyde/alcohol moiety were important for PARP-1 inhibition. Finally, our predictive model was deployed as a web application called PARP1pred and is publicly available at https://parp1pred.streamlitapp.com, allowing users to predict the biological activity of query compounds using their SMILES notation as the input. It is anticipated that the model described herein will aid in the discovery of effective PARP-1 inhibitors.

Antineoplastic multi-drug chemotherapy to sensitize tumors triggers multi-drug resistance and inhibits efficiency of maintenance treatment in glioblastoma cells

2022-12-06T11:48:40+01:00

Combinations of the well-known antineoplastic agents 5-fluorouracil (5-Fu), cisplatin, and paclitaxel are employed to increase radiotherapy/immunotherapy efficacy against persistent and resistant tumors. However, data remains needed on the hormetic, chronic, and long-term side effects of these aggressive combination chemotherapies. Here we investigated cellular and molecular responses associated with these combined agents, and their potential to induce multi-drug resistance against the temozolomide (TMZ) and etoposide (EP) used in glioblastoma maintenance treatment. We analyzed resistance and survival signals in U87 MG cells using molecular probes, fluorescent staining, qRT-PCR, and immunoblot. Repeated treatment with combined 5-Fu, cisplatin, and paclitaxel induced cross-resistance against TMZ and EP. Resistant cells exhibited elevated gene/protein expression of MRP1/ABCC1, ABCC2, BRCP/ABCG2, and GST. Moreover, they managed oxidative stress, cell cycle, apoptosis, and autophagy signaling to ensure survival. In these groups TMZ and etoposide efficiency dramatically reduced. Our result suggests that combined high-dose treatments of classical antineoplastic agents to sensitize tumors may trigger multi-drug resistance and inhibit maintenance treatment. When deciding on antineoplastic combination therapy for persistent/resistant glioblastoma, we recommend analyzing the long-term hormetic and chronic effects on cross-resistance and multi-drug resistance in primary cell cultures from patients.

Optimization of extracellular matrix for primary human hepatocyte cultures using mixed collagen-matrigel matrices

2022-11-17T12:47:09+01:00

Loss of differentiation of primary human hepatocytes (PHHs) ex vivo is a known problem of in vitro liver models. Culture optimizations using collagen type I and Matrigel reduce the dedifferentiation process but are not able to prevent it. While neither of these extracellular matrices (ECMs) on their own correspond to the authentic hepatic ECM, a combination of them could more closely resemble the in vivo situation. Our study aimed to systematically analyze the influence of mixed matrices composed of collagen type I and Matrigel on the maintenance and reestablishment of hepatic functions. Therefore, PHHs were cultured on mixed collagen-Matrigel matrices in monolayer and sandwich cultures and viability, metabolic capacity, differentiation markers, cellular arrangement and the cells’ ability to repolarize and form functional bile canaliculi were assessed by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), functional assays and immunofluorescence microscopy. Our results show that mixed matrices were superior to pure matrices in maintaining metabolic capacity and hepatic differentiation. In contrast, Matrigel supplementation can impair the development of a proper hepatocytic polarization. Our systematic study helps to compose an optimized ECM to maintain and reestablish hepatic differentiation on cellular and multicellular levels in human liver models.

Effects of acute and chronic disease on cell junctions in mouse liver

2022-11-14T11:40:46+01:00

Cell junctions, including anchoring, occluding and communicating junctions, play an indispensable role in tissue architecture and homeostasis. Consequently, malfunctioning of cell junctions is linked with a wide range of disorders, including in liver. The present study was set up to investigate the effects of acute and chronic disease induced by chemical compounds on hepatic cell junctions in mice. Mice were either overdosed with paracetamol or repeatedly administered carbon tetrachloride followed by sampling at 24 hours or 8 weeks, respectively. mRNA and protein expression levels of adherens, gap and tight junction components were measured in liver using reverse transcription quantitative real-time polymerase chain reaction analysis and immunoblot techniques, respectively. It was found that protein levels of the adherens junction building blocks β-catenin and γ-catenin, the gap junction components Cx26 and Cx32, and the tight junction constituent zonula occludens 2 were decreased, while mRNA levels of the adherens junction building block E-cadherin, and the tight junction constituent zonula occludens 2 and claudin 1 were upregulated following paracetamol overdosing. Repeated administration of carbon tetrachloride increased protein levels of E-cadherin, β-catenin, Cx26, Cx32, Cx43 and claudin 1. The latter was reflected at the mRNA level. In conclusion, acute and chronic liver disease have different effects on cell junctions in liver.