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The diagnosis of obesity comprises subjects with totally different phenotypes and metabolic profiles. Systemic inflammation and oxidative stress derived from the white adipose tissue are suggested as the link between this disease and the development of insulin resistance and metabolic comorbidities. The presence of unicellular eukaryotic parasites colonizing the human gut ecosystem is a common circumstance, and yet their influence on the inflammatory and redox status of the obese host has not been assessed. Herein, a set of inflammatory and redox biomarkers were assessed together with a parasitological analysis of 97 severely obese subjects. Information was also collected on insulin resistance and on the antioxidant composition of the diet. The global prevalence of intestinal unicellular parasites was 49.5%, with Blastocystis sp. the most prevalent protozoan found (42.3%). Colonized subjects displayed a higher total antioxidant capacity and a trend towards higher extracellular superoxide dismutase activity, regardless of their insulin resistance status, along with lower reduced glutathione/oxidized glutathione (GSH/GSSG) ratios in plasma in the insulin-resistant subgroup. No changes in malondialdehyde levels, or in inflammatory cytokines in plasma, were found in regard to the colonization status. In conclusion, enteric eukaryotic unicellular parasites may play an important role in modulating the antioxidant defenses of an obese host, thus could have beneficial effects with respect to the development of systemic metabolic disorders.

Cancer-related opportunistic bacterial infections are one major barrier for successful clinical therapies, often correlated to the production of genotoxic factors and higher cancer incidence. Although dual anticancer and antimicrobial therapies are a growing therapeutic fashion, they still fall short when it comes to specific delivery and local action in in vivo systems. Nanoparticles are seen as potential therapeutic vectors, be it by means of their intrinsic antibacterial properties and effective delivery capacity, or by means of their repeatedly reported modulation and maneuverability. Herein we report on the production of a biocompatible, antimicrobial magneto-fluorescent nanosystem (NANO3) for the delivery of a dual doxorubicin-ofloxacin formulation against cancer-related bacterial infections. The drug delivery capacity, rendered by its mesoporous silica matrix, is confirmed by the high loading capacity and stimuli-driven release of both drugs, with preference for tumor-like acidic media. The pH-dependent emission of its surface fluorescent SiQDs, provides an insight into NANO3 surface behavior and pore availability, with the SiQDs working as pore gates. Hyperthermia induces heat generation to febrile temperatures, doubling drug release. NANO3-loaded systems demonstrate significant antimicrobial activity, specifically after the application of hyperthermia conditions. NANO3 structure and antimicrobial properties confirm their potential use in a future dual anticancer and antimicrobial therapeutical vector, due to their drug loading capacity and their surface availability for further modification with bioactive, targeting species.

Autophagy is a fundamental catabolic process of cellular survival. The role of autophagy in cancer is highly complex: in the early stages of neoplastic transformation, it can act as a tumor suppressor avoiding the accumulation of proteins, damaged organelles, and reactive oxygen species (ROS), while during the advanced stages of cancer, autophagy is exploited by cancer cells to survive under starvation. 6-(Methylsulfonyl) hexyl isothiocyanate (6-MITC) is the most interesting compound in the Wasabia Japonica rizhome. Recently, we proved its ability to induce cytotoxic, cytostatic, and cell differentiation effects on leukemic cell lines and its antimutagenic activity on TK6 cells. In the current study, to further define its chemopreventive profile, Jurkat and HL-60 cells were treated with 6-MITC for 24 h. The modulation of the autophagic process and the involvement of ROS levels as a possible trigger mechanisms were analyzed by flow cytometry. We found that 6-MITC induced autophagy in Jurkat and HL-60 cells at the highest concentration tested and increased ROS intracellular levels in a dose-dependent manner. Our results implement available data to support 6-MITC as an attractive potential chemopreventive agent.

We report herein the design of a strip-based rapid test utilizing bio-inspired hybrid nanomaterials for the in situ and at site detection of the drug scopolamine (SCP) using a smartphone for readout, allowing SCP identification in diluted saliva down to 40 nM in less than 15 min. For this purpose, we prepared a nanosensor based on mesoporous silica nanoparticles loaded with a fluorescent reporter (rhodamine B) and functionalized with bethanechol, a potent agonist of recombinant human muscarinic acetylcholine receptor M 2 (M 2 -AChR). M 2 -AChR interaction with the anchored bethanechol derivative leads to capping of the pores. The sensing mechanism relies on binding of SCP to M 2 -AChR resulting in pore opening and delivery of the entrapped rhodamine B reporter. Moreover, the material was incorporated into strips for lateral-flow assays coupled to smartphone readout, giving fast response time, good selectivity, and exceptional sensitivity. In an attempt to a mobile analytical test system for law enforcement services, we have also developed a dualplex lateral flow assay for SCP and 3,4-methylenedioxypyrovalerone (MDPV) also known as the so-called "cannibal drug".

Background: Gasdermin B (GSDMB) over-expression promotes poor prognosis and aggressive behavior in HER2 breast cancer by increasing resistance to therapy. Decoding the molecular mechanism of GSDMB-mediated drug resistance is crucial to identify novel effective targeted treatments for HER2/GSDMB aggressive tumors., Methods: Different in vitro approaches (immunoblot, qRT-PCR, flow cytometry, proteomic analysis, immunoprecipitation, and confocal/electron microscopy) were performed in HER2 breast and gastroesophageal carcinoma cell models. Results were then validated using in vivo preclinical animal models and analyzing human breast and gastric cancer samples., Results: GSDMB up-regulation renders HER2 cancer cells more resistant to anti-HER2 agents by promoting protective autophagy. Accordingly, the combination of lapatinib with the autophagy inhibitor chloroquine increases the therapeutic response of GSDMB-positive cancers in vitro and in zebrafish and mice tumor xenograft in vivo models. Mechanistically, GSDMB N-terminal domain interacts with the key components of the autophagy machinery LC3B and Rab7, facilitating the Rab7 activation during pro-survival autophagy in response to anti-HER2 therapies. Finally, we validated these results in clinical samples where GSDMB/Rab7/LC3B co-expression associates significantly with relapse in HER2 breast and gastric cancers., Conclusion: Our findings uncover for the first time a functional link between GSDMB over-expression and protective autophagy in response to HER2-targeted therapies. GSDMB behaves like an autophagy adaptor and plays a pivotal role in modulating autophagosome maturation through Rab7 activation. Finally, our results provide a new and accessible therapeutic approach for HER2/GSDMB + cancers with adverse clinical outcome., (© 2022. The Author(s).)

The investigation of the human gut microbiome during recent years has permitted us to understand its relevance for human health at a systemic level, making it possible to establish different functional axes (e.g., the gut-brain, gut-liver, and gut-lung axes), which support the organ-like status conferred to this microecological component of our body. The human gut microbiota is extremely variable but modifiable via diet, a fact that allows targeting of microbes through defined dietary strategies to uncover cost-effective therapies to minimize the burden of non-communicable diseases such as pandemic obesity and overweight and its metabolic comorbidities. Nevertheless, randomly controlled dietary interventions regularly exhibit low to moderate degrees of success in weight control, making their implementation difficult in clinical practice. Here, we review the predictive value of the baseline gut microbiota configurations to anticipate the success of dietary interventions aimed at weight loss, mostly based on caloric restriction regimes and oral fiber supplementation. This emergent research concept fits into precision medicine by considering different diet patterns and adopting the best one, based on the individual microbiota composition, to reach significant adiposity reduction and improve metabolic status. We review the results from this fresh perspective of investigation, taking into account studies released very recently. We also discuss some future outlooks in the field and potential pitfalls to overcome with the aim of gaining knowledge in the field and achieving breakthroughs in personalized nutrition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hernández-Calderón, Wiedemann and Benítez-Páez.)

The construction of a novel enzyme-controlled nanomachine with multiple release mechanisms for on-command delivery is described. This nanodevice was assembled by modifying mesoporous silica nanoparticles with 2-(benzo[ d ]thiazol-2-yl)phenyl 4-aminobenzoate moieties, and further capped with β-cyclodextrin-modified glucose oxidase neoglycoenzyme. The device released the encapsulated payload in the presence of H 2 O 2 and acidic media. The use of glucose as an input chemical signal also triggered cargo release through the enzymatic production of gluconic acid and hydrogen peroxide, and the subsequent disruption of the gating mechanism at the mesoporous surface. The nanodevice was successfully employed for the enzyme-controlled release of doxorubicin in HeLa cancer cells.

Many anticancer agents used in clinics induce premature senescence in healthy tissues generating accelerated aging processes and adverse side-effects in patients. Cardiotoxicity is a well-known limiting factor of anticancer treatment with doxorubicin (DOX), a very effective anthracycline widely used as antitumoral therapy in clinical practice, that leads to long-term morbidity and mortality. DOX exposure severely affects the population of cardiac cells in both mice and human hearts by inducing premature senescence, which may represent the molecular basis of DOX-induced cardiomyopathy. Here, we demonstrate that senescence induction in the heart contributes to impaired cardiac function in mice upon DOX treatment. Concomitant elimination of senescent cells with the senolytic Navitoclax in different formulations produces a significant decrease in senescence and cardiotoxicity markers together with the restoration of the cardiac function in mice followed by echocardiography. These results evidence the potential clinical use of senolytic therapies to alleviate cardiotoxicities induced in chemotherapy-treated patients., Competing Interests: Declaration of Interest The authors declare no conflicto of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cancer immunotherapy has emerged in the past decade as a promising strategy for treating many forms of cancer by stimulating the patient's immune system. Although immunotherapy has achieved some promising results in clinics, more efforts are required to improve the limitations of current treatments related to lack of effective and targeted cancer antigens delivery to immune cells, dose-limiting toxicity, and immune-mediated adverse effects, among others. In recent years, the use of nanomaterials has proven promising to enhance cancer immunotherapy efficacy and reduce side effects. Among nanomaterials, attention has been recently paid to mesoporous silica nanoparticles (MSNs) as a potential multiplatform for enhancing cancer immunotherapy by considering their unique properties, such as high porosity, and good biocompatibility, facile surface modification, and self-adjuvanticity. This review explores the role of MSN and other nano/micro-materials as an emerging tool to enhance cancer immunotherapy, and it comprehensively summarizes the different immunotherapeutic strategies addressed to date by using MSN., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The incorporation by ionic assembly of the hexanuclear molybdenum cluster (Bu 4 N) 2 [Mo 6 I 8 (CH 3 CO 2 ) 6 ] (1) in amino-decorated mesoporous silica nanoparticles MCM-41, has yielded the new molybdenum-based hybrid photosensitizer 1@MCM-41. The new photoactive material presents a high porosity, due to the intrinsic high specific surface area of MCM-41 nanoparticles (989 m 2  g -1 ) which is responsible for the good dispersion of the hexamolybdenum clusters on the nanoparticles surface, as observed by STEM analysis. The hybrid photosensitizer can generate efficiently singlet oxygen, which was demonstrated by using the benchmark photooxygenation reaction of 9,10-anthracenediyl-bis(methylene)dimalonic acid (ABDA) in water. The photodynamic therapy activity has been tested using LED light as an irradiation source (λ irr  ~ 400-700 nm; 15.6 mW/cm 2 ). The results show a good activity of the hybrid photosensitizer against human cervical cancer (HeLa) cells, reducing up to 70 % their viability after 20 min of irradiation, whereas low cytotoxicity is detected in the darkness. The main finding of this research is that the incorporation of molybdenum complexes at porous MCM-41 supports enhances their photoactivity and improves cellular uptake, compared to free clusters., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2022. Published by Elsevier B.V.)

Cage compounds offer unique binding pockets similar to enzyme-binding sites, which can be customized in terms of size, shape, and functional groups to point toward the cavity and many other parameters. Different synthetic strategies have been developed to create a toolkit of methods that allow preparing tailor-made organic cages for a number of distinct applications, such as gas separation, molecular recognition, molecular encapsulation, hosts for catalysis, etc. These examples show the versatility and high selectivity that can be achieved using cages, which is impossible by employing other molecular systems. This review explores the progress made in the field of fully organic molecular cages and containers by focusing on the properties of the cavity and their application to encapsulate guests.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder, of the so-called minority diseases, due to its low prevalence. It is caused by an abnormally long track of glutamines (polyQs) in mutant huntingtin (mHtt), which makes the protein toxic and prone to aggregation. Many pathways of clearance of badly-folded proteins are disrupted in neurons of patients with HD. In this work, we show that one Mn(II) quinone complex (4QMn), designed to work as an artificial superoxide dismutase, is able to activate both the ubiquitin-proteasome system and the autophagy pathway in vitro and in vivo models of HD. Activation of these pathways degrades mHtt and other protein-containing polyQs, which restores proteostasis in these models. Hence, we propose 4QMn as a potential drug to develop a therapy to treat HD.

The low toxicity and high adsorption capacities of clay minerals make them attractive for controlled delivery applications. However, the number of controlled-release studies in the literature using clay minerals is still scarce. In this work, three different clays from the smectite group (Kunipia F, montmorillonite; Sumecton SA, saponite; and Sumecton SWN, hectorite) were successfully loaded with rhodamine B dye and functionalized with oleic acid as a gatekeeper to produce organonanoclays for active and controlled payload-release. Moreover, hematin and cyanocobalamin have also been encapsulated in hectorite gated clay. These organonanoclays were able to confine the entrapped cargos in an aqueous environment, and effectively release them in the presence of surfactants (as bile salts). A controlled delivery of 49 ± 6 μg hematin/mg solid and 32.7 ± 1.5 μg cyanocobalamin/mg solid was reached. The cargo release profiles of all of the organonanoclays were adjusted to three different release-kinetic models, demonstrating the Korsmeyer-Peppas model with release dependence on (i) the organic-inorganic hybrid system, and (ii) the nature of loaded molecules and their interaction with the support. Furthermore, in vitro cell viability assays were carried out with Caco-2 cells, demonstrating that the organonanoclays are well tolerated by cells at particle concentrations of ca. 50 μg/mL.

Bladder cancer (BC) is the sixth leading cause of death by cancer. Depending on the invasiveness of tumors, patients with BC will undergo surgery and surveillance lifelong, owing the high rate of recurrence and progression. In this context, the development of strategies to support non-invasive BC diagnosis is focusing attention. Voltammetric electronic tongue (VET) has been demonstrated to be of use in the analysis of biofluids. Here, we present the implementation of a VET to study 207 urines to discriminate BC and non-BC for diagnosis and surveillance to detect recurrences. Special attention has been paid to the experimental setup to improve reproducibility in the measurements. PLSDA analysis together with variable selection provided a model with high sensitivity, specificity, and area under the ROC curve AUC (0.844, 0.882, and 0.917, respectively). These results pave the way for the development of non-invasive low-cost and easy-to-use strategies to support BC diagnosis and follow-up., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Aims: We aim to present data obtained from three patients belonging to three unrelated families with an infantile onset demyelinating neuropathy associated to somatic and neurodevelopmental delay and to describe the underlying genetic changes., Methods: We performed whole-exome sequencing on genomic DNA from the patients and their parents and reviewed the clinical, muscle and nerve data, the serial neurophysiological studies, brain and muscle MRIs, as well as the respiratory chain complex activity in the muscle of the three index patients. Computer modelling was used to characterise the new missense variant detected., Results: All three patients had a short stature, delayed motor milestone acquisition, intellectual disability and cerebellar abnormalities associated with a severe demyelinating neuropathy, with distinct morphological features. Despite the proliferation of giant mitochondria, the mitochondrial respiratory chain complex activity in skeletal muscle was normal, except in one patient in whom there was a mild decrease in complex I enzyme activity. All three patients carried the same two compound heterozygous variants of the TRMT5 (tRNA Methyltransferase 5) gene, one known pathogenic frameshift mutation [c.312_315del (p.Ile105Serfs*4)] and a second rare missense change [c.665 T > C (p.Ile222Thr)]. TRMT5 is a nuclear-encoded protein involved in the post-transcriptional maturation of mitochondrial tRNA. Computer modelling of the human TRMT5 protein structure suggests that the rare p.Ile222Thr mutation could affect the stability of tRNA binding., Conclusions: Our study expands the phenotype of mitochondrial disorders caused by TRTM5 mutations and defines a new form of recessive demyelinating peripheral neuropathy., (© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Proton-nuclear-magnetic-resonance-spectroscopy ( 1 H NMR) is the widely accepted reference method for monitoring honey adulteration; however, the need to find cheaper, faster, and more environmentally friendly methodologies makes the voltammetric-electronic-tongue (VET) a good alternative. The present study aims to demonstrate the ability of VET (in comparison with 1 H NMR) to predict the adulteration of honey with syrups. Samples of monofloral honeys (citrus, sunflower and heather, assessed by pollen analysis) simulating different levels of adulteration by adding syrups (barley, rice and corn) from 2.5 to 40% (w/w) were analyzed using both techniques. According to the indicators (slope, intercept, regression coefficient-R 2 , root mean square error of prediction-RMSEP) of the partial-least-squares (PLS) regression models, in general terms, the performance of these models obtained by both techniques was good, with an average error lower than 5% in both cases. These results support the use of VET as a screening technique to easily detect honey adulteration with syrups., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Neural progenitor cell (NPC) transplantation represents a promising treatment strategy for spinal cord injury (SCI); however, the underlying therapeutic mechanisms remain incompletely understood. We demonstrate that severe spinal contusion in adult rats causes transcriptional dysregulation, which persists from early subacute to chronic stages of SCI and affects nearly 20,000 genes in total tissue extracts. Functional analysis of this dysregulated transcriptome reveals the significant downregulation of cAMP signalling components immediately after SCI, involving genes such as EPAC2 (exchange protein directly activated by cAMP), PKA, BDNF, and CAMKK2. The ectopic transplantation of spinal cord-derived NPCs at acute or subacute stages of SCI induces a significant transcriptional impact in spinal tissue, as evidenced by the normalized expression of a large proportion of SCI-affected genes. The transcriptional modulation pattern driven by NPC transplantation includes the rescued expression of cAMP signalling genes, including EPAC2. We also explore how the sustained in vivo inhibition of EPAC2 downstream signalling via the intrathecal administration of ESI-05 for 1 week impacts therapeutic mechanisms involved in the NPC-mediated treatment of SCI. NPC transplantation in SCI rats in the presence and absence of ESI-05 administration prompts increased rostral cAMP levels; however, NPC and ESI-05 treated animals exhibit a significant reduction in EPAC2 mRNA levels compared to animals receiving only NPCs treatment. Compared with transplanted animals, NPCs + ESI-05 treatment increases the scar area (as shown by GFAP staining), polarizes microglia into an inflammatory phenotype, and increases the magnitude of the gap between NeuN + cells across the lesion. Overall, our results indicate that the NPC-associated therapeutic mechanisms in the context of SCI involve the cAMP pathway, which reduces inflammation and provides a more neuropermissive environment through an EPAC2-dependent mechanism., (© 2022. The Author(s).)

Background: The role of chest radiography in COVID-19 disease has changed since the beginning of the pandemic from a diagnostic tool when microbiological resources were scarce to a different one focused on detecting and monitoring COVID-19 lung involvement. Using chest radiographs, early detection of the disease is still helpful in resource-poor environments. However, the sensitivity of a chest radiograph for diagnosing COVID-19 is modest, even for expert radiologists. In this paper, the performance of a deep learning algorithm on the first clinical encounter is evaluated and compared with a group of radiologists with different years of experience., Methods: The algorithm uses an ensemble of four deep convolutional networks, Ensemble4Covid, trained to detect COVID-19 on frontal chest radiographs. The algorithm was tested using images from the first clinical encounter of positive and negative cases. Its performance was compared with five radiologists on a smaller test subset of patients. The algorithm's performance was also validated using the public dataset COVIDx., Results: Compared to the consensus of five radiologists, the Ensemble4Covid model achieved an AUC of 0.85, whereas the radiologists achieved an AUC of 0.71. Compared with other state-of-the-art models, the performance of a single model of our ensemble achieved nonsignificant differences in the public dataset COVIDx., Conclusion: The results show that the use of images from the first clinical encounter significantly drops the detection performance of COVID-19. The performance of our Ensemble4Covid under these challenging conditions is considerably higher compared to a consensus of five radiologists. Artificial intelligence can be used for the fast diagnosis of COVID-19., (© 2022. The Author(s).)

Brain damage is the major cause of permanent disability and it is particularly relevant in the elderly. While most studies focused on the immediate phase of neuronal loss upon injury, much less is known about the process of axonal regeneration after damage. The development of new refined preclinical models to investigate neuronal regeneration and the recovery of brain tissue upon injury is a major unmet challenge. Here, we present a novel experimental paradigm in mice that entails the (i) tracing of cortico-callosal connections, (ii) a mechanical lesion of the motor cortex, (iii) the stereological and histological analysis of the damaged tissue, and (iv) the functional characterization of motor deficits. By combining conventional microscopy with semi-automated 3D reconstruction, this approach allows the analysis of fine subcellular structures, such as axonal terminals, with the tridimensional overview of the connectivity and tissue integrity around the lesioned area. Since this 3D reconstruction is performed in serial sections, multiple labeling can be performed by combining diverse histological markers. We provide an example of how this methodology can be used to study cellular interactions. Namely, we show the correlation between active microglial cells and the perineuronal nets that envelop parvalbumin interneurons. In conclusion, this novel experimental paradigm will contribute to a better understanding of the molecular and cellular interactions underpinning the process of cortical regeneration upon brain damage.

In this article, we report one of the few examples of nanoparticles capable of simultaneously delivering CRISPR-Cas9 gene-editing machinery and releasing drugs for one-shot treatments. Considering the complexity of inflammation in diseases, the synergistic effect of nanoparticles for gene-editing/drug therapy is evaluated in an in vitro inflammatory model as proof of concept. Mesoporous silica nanoparticles (MSNs), able to deliver the CRISPR/Cas9 machinery to edit gasdermin D (GSDMD), a key protein involved in inflammatory cell death, and the anti-inflammatory drug VX-765 ( GSDMD45 CRISPR-VX-MSNs), were prepared. Nanoparticles allow high cargo loading and CRISPR-Cas9 plasmid protection and, thus, achieve the controlled codelivery of CRISPR-Cas9 and the drug in cells. Nanoparticles exhibit GSDMD gene editing by downregulating inflammatory cell death and achieving a combined effect on decreasing the inflammatory response by the codelivery of VX-765. Taken together, our results show the potential of MSNs as a versatile platform by allowing multiple combinations for gene editing and drug therapy to prepare advanced nanodevices to meet possible biomedical needs.

Brain Imaging Data Structure (BIDS) provides a valuable tool to organise brain imaging data into a clear and easy standard directory structure. Moreover, BIDS is widely supported by the scientific community and has been established as a powerful standard for medical imaging management. Nonetheless, the original BIDS is restricted to magnetic resonance imaging (MRI) of the brain, limiting its implantation to other techniques and anatomical regions. We developed Medical Imaging Data Structure (MIDS), conceived to extend BIDS methodology to other anatomical regions and multiple imaging systems in these areas. The MIDS standard was developed to store and manage medical images as an extension of BIDS. It allows the user to handily save studies of multiple anatomical regions and imaging techniques. Besides, MIDS improves the classification of multiple images within the structure, allowing the possibility to unify them in a single study to apply on them preprocessing or artificial intelligence algorithms. Finally, the results generated are saved in the derivatives folder.

There is evidence that demonstrates the effect of cannabinoid agonists inhibiting relevant aspects in lung cancer, such as proliferation or epithelial-to-mesenchymal transition (EMT). Most of these studies are based on evidence observed in in vitro models developed on cancer cell lines. These studies do not consider the complexity of the tumor microenvironment (TME). One of the main components of the TME is cancer-associated fibroblasts (CAFs), cells that are relevant in the control of proliferation and metastasis in lung cancer. In this work, we evaluated the direct effects of two cannabinoid agonists, tetrahydrocannabinol (THC) and cannabidiol (CBD), used alone or in combination, on CAFs and non-tumor normal fibroblasts (NFs) isolated from adenocarcinoma or from healthy lung tissue from the same patients. We observed that these compounds decrease cell density in vitro and inhibit the increase in the relative expression of type 1 collagen (COL1A1) and fibroblast-specific protein 1 (FSP1) induced by transforming growth factor beta (TGFβ). On the other hand, we studied whether THC and CBD could modulate the interactions between CAFs or NFs and cancer cells. We conditioned the culture medium with stromal cells treated or not with THC and/or CBD and cultured A549 cells with them. We found that culture media conditioned with CAFs or NFs increased cell density, induced morphological changes consistent with EMT, inhibited cadherin-1 (CDH1) gene expression, and induced an increase in the relative expression of cadherin-2 (CDH2) and vimentin (VIM) genes in A549 cells. These changes were inhibited or decreased by THC and CBD administered alone or in combination. In another series of experiments, we conditioned culture media with A549 cells treated or not with THC and/or CBD, in the presence or absence of TGFβ. We observed that culture media conditioned with A549 in the presence of TGFβ induced an increase in the expression of COL1A1 and VIM, both in CAFs and in non-tumor NFs. Both THC and CBD ameliorated these effects. In summary, the results presented here reinforce the usefulness of cannabinoid agonists for the treatment of some relevant aspects of lung cancer pathology, and demonstrate in a novel way their possible effects on CAFs as a result of their relationship with cancer cells. Likewise, the results reinforce the usefulness of the combined use of THC and CBD, which has important advantages in relation to the possibility of using lower doses, thus minimizing the psychoactive effects of THC.

Computational techniques for analyzing biological images offer a great potential to enhance our knowledge of the biological processes underlying disorders of the nervous system. Friedreich's Ataxia (FRDA) is a rare progressive neurodegenerative inherited disorder caused by the low expression of frataxin, which is a small mitochondrial protein. In FRDA cells, the lack of frataxin promotes primarily mitochondrial dysfunction, an alteration of calcium (Ca 2+ ) homeostasis and the destabilization of the actin cytoskeleton in the neurites and growth cones of sensory neurons. In this paper, a computational multilinear algebra approach was used to analyze the dynamics of the growth cone and its function in control and FRDA neurons. Computational approach, which includes principal component analysis and a multilinear algebra method, is used to quantify the dynamics of the growth cone (GC) morphology of sensory neurons from the dorsal root ganglia (DRG) of the YG8sR humanized murine model for FRDA. It was confirmed that the dynamics and patterns of turning were aberrant in the FRDA growth cones. In addition, our data suggest that other cellular processes dependent on functional GCs such as axonal regeneration might also be affected. Semiautomated computational approaches are presented to quantify differences in GC behaviors in neurodegenerative disease. In summary, the deficiency of frataxin has an adverse effect on the formation and, most importantly, the growth cones' function in adult DRG neurons. As a result, frataxin deficient DRG neurons might lose the intrinsic capability to grow and regenerate axons properly due to the dysfunctional GCs they build., Competing Interests: EI was employed by company The Mathworks B.V. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Muñoz-Lasso, Mollá, Sáenz-Gamboa, Insuasty, de la Iglesia-Vaya, Pook, Pallardó, Palau and Gonzalez-Cabo.)

The detection of reactive oxygen species (ROS) and the analysis of oxidative stress are frequent applications of functional flow cytometry. Identifying and quantifying the ROS species generated during oxidative stress are crucial steps for the investigation of molecular mechanisms underlying stress responses. Currently, there is a wide availability of fluorogenic substrates for such purposes, but limitations in their specificity and sensitivity may affect the accuracy of the analysis. The aim of our work was to validate a new experimental model based in different strains of Escherichia coli B deficient in key genes for antioxidant defense, namely oxyR , sodA and s odB . We applied this model to systematically assess issues of specificity in fluorescent probes and the involvement of different ROS in a bacterial model of oxidative stress, as the probes can react with a variety of oxidants and free radical species. Our results confirm the higher sensitivity and specificity of the fluorescent probe mitochondrial peroxy yellow 1 (MitoPY1) for the detection of H 2 O 2 , and its very low capacity for organic hydroperoxides, thus extending MitoPY1's specificity for H 2 O 2 in mammalian cells to a bacterial model. On the contrary, the fluorescent probe 2',7'-dichlorodihydrofluorescein diacetate (H 2 DCF-DA) is more sensitive to organic peroxides than to H 2 O 2 , confirming the lack of selectivity of H 2 DCF-DA to H 2 O 2 . Treatment with organic peroxides and H 2 O 2 suggests a superoxide-independent oxidation of the fluorescent probe Hydroethidine (HE). We found a positive correlation between the lipophilicity of the peroxides and their toxicity to E. coli , suggesting greater quantitative importance of the peroxidative effects on the bacterial membrane and/or greater efficiency of the protection systems against the intracellular effects of H 2 O 2 than against the membrane oxidative stress induced by organic peroxides. Altogether, our results may aid in preventing or minimizing experimental errors and providing recommendations for the proper design of cytometric studies of oxidative stress, in accordance with current recommendations and guidelines.

The objective of this study is to describe the alterations occurring during the neurodegenerative process in skin fibroblast cultures from C9orf72 patients. We characterized the oxidative stress, autophagy flux, small ubiquitin-related protein SUMO2/3 levels as well as the mitochondrial function in skin fibroblast cultures from C9orf72 patients. All metabolic and bioenergetic findings were further correlated with gene expression data obtained from RNA sequencing analysis. Fibroblasts from C9orf72 patients showed a 30% reduced expression of C9orf72, ~3-fold increased levels of oxidative stress and impaired mitochondrial function obtained by measuring the enzymatic activities of mitochondrial respiratory chain complexes, specifically of complex III activity. Furthermore, the results also reveal that C9orf72 patients showed an accumulation of p62 protein levels, suggesting the alteration of the autophagy process, and significantly higher protein levels of SUMO2/3 ( p = 0.03). Our results provide new data reinforcing that C9orf72 cells suffer from elevated oxidative damage to biomolecules and organelles and from increased protein loads, leading to insufficient autophagy and an increase in SUMOylation processes.

Huntington disease (HD) is a neurodegenerative disorder produced by an expansion of CAG repeats in the HTT gene. Patients of HD show involuntary movements, cognitive decline and psychiatric impairment. People carrying abnormally long expansions of CAGs (more than 35 CAG repeats) produce mutant huntingtin (mHtt), which encodes tracks of polyglutamines (polyQs). These polyQs make the protein prone to aggregate and cause it to acquire a toxic gain of function. Principally affecting the frontal cortex and the striatum, mHtt disrupts many cellular functions. In addition, this protein is expressed ubiquitously, and some reports show that many other cell types are affected by the toxicity of mHtt. Several studies reported that metformin, a widely-used anti-diabetic drug, is neuroprotective in models of HD. Here, we provide a review of the benefits of this substance to treat HD. Metformin is a pleiotropic drug, modulating different targets such as AMPK, insulin signalling and many others. These molecules regulate autophagy, chaperone expression, and more, which in turn reduce mHtt toxicity. Moreover, metformin alters gut microbiome and its metabolic processes. The study of potential targets, interactions between the drug, host and microbiome, or genomic and pharmacogenomic approaches may allow us to design personalised medicine to treat HD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

We have established an easy synthetic protocol for selectively developing all-orthogonal BODIPY trimers with unprecedented geometries on the basis of selecting methyl oxidation versus electrophilic formylation of key dimeric precursors. Photophysical characterization together with biological assays unraveled the most suitable BODIPY-BODIPY geometrical arrangements within the trimer, forcing them to serve as molecular platforms for the development of new, advanced heavy-atom-free photosensitizers for photodynamic therapy and phototheragnosis.

Automatic and reliable quantitative tools for MR brain image analysis are a very valuable resource for both clinical and research environments. In the past few years, this field has experienced many advances with successful techniques based on label fusion and more recently deep learning. However, few of them have been specifically designed to provide a dense anatomical labeling at the multiscale level and to deal with brain anatomical alterations such as white matter lesions (WML). In this work, we present a fully automatic pipeline (vol2Brain) for whole brain segmentation and analysis, which densely labels ( N > 100) the brain while being robust to the presence of WML. This new pipeline is an evolution of our previous volBrain pipeline that extends significantly the number of regions that can be analyzed. Our proposed method is based on a fast and multiscale multi-atlas label fusion technology with systematic error correction able to provide accurate volumetric information in a few minutes. We have deployed our new pipeline within our platform volBrain (www.volbrain.upv.es), which has been already demonstrated to be an efficient and effective way to share our technology with the users worldwide., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Manjón, Romero, Vivo-Hernando, Rubio, Aparici, de la Iglesia-Vaya and Coupé.)

Neurodegenerative disorders, caused by prone-to-aggregation proteins, such as Alzheimer disease or Huntington disease, share other traits such as disrupted homeostasis of essential metal ions, like copper. In this context, in an attempt to identify Cu 2+ chelating agents, we study several organic compounds (ethylenediaminetetraacetic acid, phenylenediamine, metformin, salicylate, and trehalose) and organic extracts obtained from Bacopa monnieri L., which has been used in Ayurvedic therapies and presented a broad spectrum of biological properties. For this purpose, UV-visible spectroscopy analysis and electrochemical measurements were performed. Further, biological assays were performed in Caenorhabditis elegans models of polyQ toxicity, in an attempt to obtain better insights on neurodegenerative disorders., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated with biobanks for the collection of real-world data and biological samples of gynaecological cancer patients. This collaborative project aims to promote research by providing broad access to high-quality clinical data and biospecimens for future research according to the needs of investigators and to increase diagnostic and therapeutic opportunities for gynaecological cancer patients in Spain. The VCR will include the participation of more than 60 Spanish hospitals entering relevant clinical information in harmonised electronic case report forms (eCRFs) in four different cohorts: ovarian, endometrial, cervical, and rare gynaecological cancers (gestational trophoblastic disease). Initial data for the cases included till December 2021 are presented. The model described herein establishes a real-world win-win collaboration between multicentre structures, promoted and supported by GEICO, that will contribute to the success of translational research in gynaecological cancer.

Contact inhibition of locomotion (CIL) is a process that regulates cell motility upon collision with other cells. Improper regulation of CIL has been implicated in cancer cell dissemination. Here, we identify the cell adhesion molecule JAM-A as a central regulator of CIL in tumor cells. JAM-A is part of a multimolecular signaling complex in which tetraspanins CD9 and CD81 link JAM-A to αvβ5 integrin. JAM-A binds Csk and inhibits the activity of αvβ5 integrin-associated Src. Loss of JAM-A results in increased activities of downstream effectors of Src, including Erk1/2, Abi1, and paxillin, as well as increased activity of Rac1 at cell-cell contact sites. As a consequence, JAM-A-depleted cells show increased motility, have a higher cell-matrix turnover, and fail to halt migration when colliding with other cells. We also find that proper regulation of CIL depends on αvβ5 integrin engagement. Our findings identify a molecular mechanism that regulates CIL in tumor cells and have implications on tumor cell dissemination., (© 2022 Kummer et al.)

Oxidative stress plays a major role in the pathogenesis of retinitis pigmentosa (RP). The main goal of this study was to evaluate the effect of 2-year nutritional intervention with antioxidant nutraceuticals on the visual function of RP patients. Secondly, we assessed how nutritional intervention affected ocular and systemic redox status. We carried out a randomized, double-blind, placebo-controlled study. Thirty-one patients with RP participated in the study. RP patients randomly received either a mixture of nutraceuticals (NUT) containing folic acid, vitamin B6, vitamin A, zinc, copper, selenium, lutein, and zeaxanthin or placebo daily for 2 years. At baseline and after 2-year of the nutritional supplementation, visual function, dietetic-nutritional evaluations, serum concentration of nutraceuticals, plasma and aqueous humor concentration of several markers of redox status and inflammation were assessed. Retinal function and structure were assessed by multifocal electroretinogram (mfERG), spectral domain-optical coherence tomography (SD-OCT) and automated visual field (VF) tests. Nutritional status was estimated with validated questionnaires. Total antioxidant capacity, extracellular superoxide dismutase (SOD3), catalase (CAT), and glutathione peroxidase (GPx) activities, protein carbonyl adducts (CAR) content, thiobarbituric acid reactive substances (TBARS) formation (as indicator of lipid peroxidation), metabolites of the nitric oxide (NOX) and cytokine (interleukin 6 and tumor necrosis factor alpha) concentrations were assessed by biochemical and immunological techniques in aqueous humor or/and blood. Bayesian approach was performed to determine the probability of an effect. Region of practical equivalence (ROPE) was used. At baseline, Bayesian analysis revealed a high probability of an altered ocular redox status and to a lesser extent systemic redox status in RP patients compared to controls. Twenty-five patients (10 in the treated arm and 15 in the placebo arm) completed the nutritional intervention. After 2 years of supplementation, patients who received NUT presented better retinal responses (mfERG responses) compared to patients who received placebo. Besides, patients who received NUT showed better ocular antioxidant response (SOD3 activity) and lower oxidative damage (CAR) than those who received placebo. This study suggested that long-term NUT supplementation could slow down visual impairment and ameliorate ocular oxidative stress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Olivares-González, Salom, González-García, Hervás, Mejía-Chiqui, Melero, Velasco, Muresan, Campillo, Vila-Clérigues, López-Briz, Merino-Torres, Millán, Soriano Del Castillo and Rodrigo.)

Microbiome research is advancing rapidly, and every new study should definitively be based on updated methods, trends and milestones in this field to avoid the wrong interpretation of results. Most human microbiota surveys rely on data captured from snapshots-single data points from subjects-and have permitted uncovering the recognized interindividual variability and major covariates of such microbial communities. Currently, changes in individualized microbiota profiles are under the spotlight to serve as robust predictors of clinical outcomes (e.g. weight loss via dietary interventions) and disease anticipation. Therefore, novel methods are needed to provide robust evaluation of longitudinal series of microbiota data with the aim of assessing intrapersonally short-term to long-term microbiota changes likely linked to health and disease states. Consequently, we developed microbiota STability ASsessment via Iterative cluStering (μSTASIS)-a multifunction R package to evaluate individual-centered microbiota stability. μSTASIS targets the recognized interindividual variability inherent to microbiota data to stress the tight relationships observed among and characteristic of longitudinal samples derived from a single individual via iteratively growing-partitioned clustering. The algorithms and functions implemented in this framework deal properly with the sparse and compositional nature of microbiota data. Moreover, the resulting metric is intuitive and independent of beta diversity distance methods and correlation coefficients, thus estimating stability for each microbiota sample rather than giving nonconsensus magnitudes that are difficult to interpret within and between datasets. Our method is freely available under GPL-3 licensing. We demonstrate its utility by assessing gut microbiota stability from three independent studies published previously with multiple longitudinal series of multivariate data and respective metadata., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The engineering of chemical communication at the micro/nanoscale is a key emergent topic in micro/nanotechnology, synthetic biology, and related areas. However, the field is still in its infancy; previous advances, although scarce, have mainly focused on communication between abiotic micro/nanosystems or between microvesicles and living cells. Here, we have implemented a nanoprogrammed cross-kingdom communication involving two different microorganisms and tailor-made nanodevices acting as "nanotranslators". Information flows from the sender cells (bacteria) to the nanodevice and from the nanodevice to receiver cells (yeasts) in a hierarchical way, allowing communication between two microorganisms that otherwise would not interact.

In the recent years, research in oncologyhas focused on liquid biopsies, which rely on thedetection of cancer-derived components, includingcirculating tumor cells (CTCs), circulating tumor DNA(ctDNA), circulating free RNA (cfRNA), and extracellularvesicles (EVs), in the biofluids of patients, providinggenomic, epigenetic and transcriptomic, informationabout tumors and metastatic sites. In this reviewwe collect current evidence regarding the potentialof liquid biopsies for the diagnosis and follow-up ofuro-oncology patients, as well as the advantages andlimitations of these approaches. Although promising,the way in which this methodology must be incorporatedinto the clinical routine needs to be still definedboth at the pre-analytical and analytical level beforetheir clinical utility is demonstrated.

Introduction and Objectives: Active surveillance (AS) is currently a therapeuticstrategy recommended by all Clinical Guidelines forthe initial management of very low-risk, low-risk, andsome intermediate-risk prostate cancer (PCa). However,a high percentage of cases will present the need for active treatment and a quarter of them will presentunfavorable anatomopathological characteristics., Methods: review of the biomarkers' literature oncircumscribed to the inclusion and follow-up of patientsin AS., Results: PSA and its variants remain the most widelyused and most cost-effective biomarker in AS. Inparticular, the use of PSA density based on the prostatevolume detected by mpMRI has gained much weight.Different multipanel biomarkers in blood and urineare commercially available to predict progressionto PCa ≥3 + 4 (GG2), but they have not clearly beenprospectively tested in AS cohorts. Tissue biomarkersanalyze gene panels that offer predictive informationindependent of classical clinicopathological variablesand may play a role in controversial indications for AS.Lastly, risk calculators are cost-effective and validatedfor their care use in AS and are probably underused., Conclusions: Although there is no specific biomarkerfor the optimization of AS, its rational use togetherwith mpMRI may in the future optimize the inclusionof patients in AS and follow-up differentiatedby risk groups.

The field of nanomedicine has significantly influenced research areas such as drug delivery, diagnostics, theranostics, and regenerative medicine; however, the further development of this field will face significant challenges at the regulatory level if related guidance remains unclear and unconsolidated. This review describes those features and pathways crucial to the clinical translation of nanomedicine and highlights considerations for early-stage product development. These include identifying those critical quality attributes of the drug product essential for activity and safety, appropriate analytical methods (physical, chemical, biological) for characterization, important process parameters, and adequate pre-clinical models. Additional concerns include the evaluation of batch-to-batch consistency and considerations regarding scaling up that will ensure a successful reproducible manufacturing process. Furthermore, we advise close collaboration with regulatory agencies from the early stages of development to assure an aligned position to accelerate the development of future nanomedicines., (© 2021. The Author(s).)

(1) Background: Sepsis is a life-threatening condition caused by an abnormal host response to infection that produces altered physiological responses causing tissue damage and can result in organ dysfunction and, in some cases, death. Although sepsis is characterized by a malfunction of the immune system leading to an altered immune response and immunosuppression, the high complexity of the pathophysiology of sepsis requires further investigation to characterize the immune response in sepsis and septic shock. (2) Methods: This study analyzes the immune-related responses occurring during the early stages of sepsis by comparing the amounts of cytokines, immune modulators and other endothelial mediators of a control group and three types of severe patients: critically ill non-septic patients, septic and septic shock patients. (3) Results: We showed that in the early stages of sepsis the innate immune system attempts to counteract infection, probably via neutrophils. Conversely, the adaptive immune system is not yet fully activated, either in septic or in septic shock patients. In addition, immunosuppressive responses and pro-coagulation signals are active in patients with septic shock. (4) Conclusions: The highest levels of IL-6 and pyroptosis-related cytokines (IL-18 and IL-1α) were found in septic shock patients, which correlated with D-dimer. Moreover, endothelial function may be affected as shown by the overexpression of adhesion molecules such as s-ICAM1 and E-Selectin during septic shock.

MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) is an OXPHOS disease mostly caused by the m.3243A>G mutation in the mitochondrial tRNA Leu(UUR) gene. Recently, we have shown that the mutation significantly changes the expression pattern of several mitochondrial tRNA-derived small RNAs (mt tsRNAs or mt tRFs) in a cybrid model of MELAS and in fibroblasts from MELAS patients versus control cells. Among them are those derived from mt tRNA LeuUUR containing or not the m.3243A>G mutation (mt 5'-tRF LeuUUR-m.3243A>G and mt 5'-tRF LeuUUR), whose expression levels are, respectively, increased and decreased in both MELAS cybrids and fibroblasts. Here, we asked whether mt 5'-tRF LeuUUR and mt 5'-tRF LeuUUR-m.3243A>G are biologically relevant and whether these mt tRFs are detected in diverse patient samples. Treatment with a mimic oligonucleotide of mt tRNA LeuUUR fragment (mt 5'-tRF LeuUUR) showed a therapeutic potential since it partially restored mitochondrial respiration in MELAS cybrids. Moreover, these mt tRFs could be detected in biofluids like urine and blood. We also investigated the participation of miRNA pathway components Dicer and Ago2 in the mt tRFs biogenesis process. We found that Dicer and Ago2 localize in the mitochondria of MELAS cybrids and that immunoprecipitation of these proteins in cytoplasm and mitochondria fractions revealed an increased mt tRF/mt tRNA ratio in MELAS condition compared to WT. These preliminary results suggest an involvement of Dicer and Ago2 in the mechanism of mt tRF biogenesis and action., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Meseguer and Rubio.)

Background: Postoperative cognitive dysfunction affects the quality of recovery, particularly affecting the elderly, and poses a burden on the health system. We hypothesize that the use of sugammadex (SG) could optimize the quality of postoperative cognitive function and overall recovery through a neuroprotective effect., Methods: A pilot observational study on patients undergoing cardiac surgery with enhanced recovery after cardiac surgery (ERACS) approach, was designed to compare SG-treated ( n = 14) vs. neostigmine (NG)-treated ( n = 7) patients. The Postoperative Quality Recovery Scale (PQRS) was used at different times to evaluate cognitive function and overall recovery of the patients. An online survey among anesthesiologists on SG use was also performed. Additionally, an animal model study was designed to explore the effects of SG on the hippocampus., Results: Sugammadex (SG) was associated with favorable postoperative recovery in cognitive domains particularly 30 days after surgery in patients undergoing aortic valve replacement by cardiopulmonary bypass and the ERACS approach; however, it failed to demonstrate a short-term decrease in length of intensive care unit (ICU) and hospital stay. The survey information indicated a positive appreciation of SG recovery properties. SG reverts postoperative memory deficit and induces the expression of anti-inflammatory microglial markers., Conclusion: The results show a postoperative cognitive improvement by SG treatment in patients undergoing aortic valve replacement procedure by the ERACS approach. Additionally, experimental data from an animal model of mild surgery confirm the cognitive effect of SG and suggest a potential effect over glia cells as an underlying mechanism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Muedra, Rodilla, Llansola, Agustí, Pla, Canto and Hernández-Rabaza.)

Mesoporous silica nanoparticles loaded with rhodamine B and capped with curcumin are used for the selective and sensitive fluorogenic detection of human serum albumin (HSA). The sensing mesoporous silica nanoparticles are loaded with rhodamine B, decorated with aminopropyl moieties and capped with curcumin. The nanoparticles selectively release the rhodamine B cargo in the presence of HSA. A limit of detection for HSA of 0.1 mg/mL in PBS (pH 7.4)-acetonitrile 95:5 v / v was found, and the sensing nanoparticles were used to detect HSA in spiked synthetic urine samples.

Introduction: Breast cancer has the highest mortality rate among cancers in women. Patients suffering from certain breast cancers, such as triple-negative breast cancer (TNBC), lack effective treatments. This represents a clinical concern due to the associated poor prognosis and high mortality. As an approach to succeed over conventional therapy limitations, we present herein the design and evaluation of a novel nanodevice based on enzyme-functionalized gold nanoparticles to efficiently perform enzyme prodrug therapy (EPT) in breast cancer cells., Results: In particular, the enzyme horseradish peroxidase (HRP) - which oxidizes the prodrug indole-3-acetic acid (IAA) to release toxic oxidative species - is incorporated on gold nanoconjugates (HRP-AuNCs), obtaining an efficient nanoplatform for EPT. The nanodevice is biocompatible and effectively internalized by breast cancer cell lines. Remarkably, co-treatment with HRP-AuNCs and IAA (HRP-AuNCs/IAA) reduces the viability of breast cancer cells below 5%. Interestingly, 3D tumor models (multicellular tumor spheroid-like cultures) co-treated with HRP-AuNCs/IAA exhibit a 74% reduction of cell viability, whereas the free formulated components (HRP, IAA) have no effect., Conclusion: Altogether, our results demonstrate that the designed HRP-AuNCs nanoformulation shows a remarkable therapeutic performance. These findings might help to bypass the clinical limitations of current tumor enzyme therapies and advance towards the use of nanoformulations for EPT in breast cancer., Competing Interests: The authors report no conflicts of interest in this work, (© 2022 Vivo-Llorca et al.)

Aggregation of mutant huntingtin, because of an expanded polyglutamine track, underlies the cause of neurodegeneration in Huntington disease (HD). However, it remains unclear how some alterations at the cellular level lead to specific structural changes in HD brains. In this context, the neuroprotective effect of the activation of AMP-activated protein kinase (AMPK) appears to be a determinant factor in several neurodegenerative diseases, including HD. In the present work, we describe a series of indole-derived compounds able to activate AMPK at the cellular level. By using animal models of HD (both worms and mice), we demonstrate the in vivo efficacy of one of these compounds (IND1316), confirming that it can reduce the neuropathological symptoms of this disease. Taken together, in vivo results and in silico studies of druggability, allow us to suggest that IND1316 could be considered as a promising new lead compound for the treatment of HD and other central nervous system diseases in which the activation of AMPK results in neuroprotection.

Calcium (Ca 2+ ) is a versatile secondary messenger involved in the regulation of a plethora of different signaling pathways for cell maintenance. Specifically, intracellular Ca 2+ homeostasis is mainly regulated by the endoplasmic reticulum and the mitochondria, whose Ca 2+ exchange is mediated by appositions, termed endoplasmic reticulum-mitochondria-associated membranes (MAMs), formed by proteins resident in both compartments. These tethers are essential to manage the mitochondrial Ca 2+ influx that regulates the mitochondrial function of bioenergetics, mitochondrial dynamics, cell death, and oxidative stress. However, alterations of these pathways lead to the development of multiple human diseases, including neurological disorders, such as amyotrophic lateral sclerosis, Friedreich's ataxia, and Charcot-Marie-Tooth. A common hallmark in these disorders is mitochondrial dysfunction, associated with abnormal mitochondrial Ca 2+ handling that contributes to neurodegeneration. In this work, we highlight the importance of Ca 2+ signaling in mitochondria and how the mechanism of communication in MAMs is pivotal for mitochondrial maintenance and cell homeostasis. Lately, we outstand potential targets located in MAMs by addressing different therapeutic strategies focused on restoring mitochondrial Ca 2+ uptake as an emergent approach for neurological diseases.

Bispecific antibodies (bsAbs) are considered as an important class of biopharmaceutical drugs, with about 160 products in clinical trials. From an analytical point of view, the correct chain-association is one of the most critical challenge to monitor during bsAbs development and production. In the present study, a full analytical workflow has been developed based on the use of various chromatographic modes: size exclusion chromatography (SEC), ion exchange chromatography (IEX), reversed phase liquid chromatography (RPLC), and hydrophilic interaction chromatography (HILIC), all combined with high resolution mass spectrometry (MS). This analytical strategy was applied to Hemlibra® (emicizumab), which is certainly the most successful commercial bsAb to date. Using this strategy, it was possible to monitor the presence of mispaired bsAb species and detect and identify additional post-translational modifications (PTMs)., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Fecal microbiota transplantation (FMT) is currently used for treating Clostridium difficile infection and explored for other clinical applications in experimental trials. However, the effectiveness of this therapy could vary, and partly depend on the donor's bacterial species engraftment, whose evaluation is challenging because there are no cost-effective strategies for accurately tracking the microbe transference. In this regard, the precise identification of bacterial species inhabiting the human gut is essential to define their role in human health unambiguously. We used Nanopore-based device to sequence bacterial rrn operons (16S-ITS-23S) and to reveal species-level abundance changes in the human gut microbiota of a FMT trial. By assessing the donor and recipient microbiota before and after FMT, we further evaluated whether this molecular approach reveals strain-level genetic variation to demonstrate microbe transfer and engraftment. Strict control over sequencing data quality and major microbiota covariates was critical for accurately estimating the changes in gut microbial species abundance in the recipients after FMT. We detected strain-level variation via single-nucleotide variants (SNVs) at rrn regions in a species-specific manner. We showed that it was possible to explore successfully the donor-bacterial strain (e.g., Parabacteroides merdae) engraftment in recipients of the FMT by assessing the nucleotide frequencies at rrn-associated SNVs. Our findings indicate that the engraftment of donors' microbiota is to some extent correlated with the improvement of metabolic health in recipients and that parameters such as the baseline gut microbiota configuration, sex, and age of donors should be considered to ensure the success of FMT in humans. The study was prospectively registered at the Dutch Trial registry - NTR4488 (https://www.trialregister.nl/trial/4488).

Neonatal sepsis constitutes a highly relevant public health challenge and is the most common cause of infant morbidity and mortality worldwide. Recent studies have demonstrated that during infection epigenetic changes may occur leading to reprogramming of gene expression. Post-transcriptional regulation by short non-coding RNAs (e.g., microRNAs) have recently acquired special relevance because of their role in the regulation of the pathophysiology of sepsis and their potential clinical use as biomarkers. ~22-nucleotide of microRNAs are not only involved in regulating multiple relevant cellular and molecular functions, such as immune cell function and inflammatory response, but have also been proposed as good candidates as biomarkers in sepsis. Nevertheless, establishing clinical practice guidelines based on microRNA patterns as biomarkers for diagnosis and prognosis in neonatal sepsis has yet to be achieved. Given their differential expression across tissues in neonates, the release of specific microRNAs to blood and their expression pattern can differ compared to sepsis in adult patients. Further in-depth research is necessary to fully understand the biological relevance of microRNAs and assess their potential use in clinical settings. This review provides a general overview of microRNAs, their structure, function and biogenesis before exploring their potential clinical interest as diagnostic and prognostic biomarkers of neonatal sepsis. An important part of the review is focused on immune and inflammatory aspects of selected microRNAs that may become biomarkers for clinical use and therapeutic intervention., (Copyright © 2021. Published by Elsevier Masson SAS.)