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The maintenance of redox homeostasis is associated with a healthy status while the disruption of this mechanism leads to the development of various pathological conditions. Bioactive molecules such as carbohydrates accessible to the microbiota (MACs), polyphenols, and polyunsaturated fatty acids (PUFAs) are food components best characterized for their beneficial effect on human health. In particular, increasing evidence suggests that their antioxidant ability is involved in the prevention of several human diseases. Some experimental data indicate that the activation of the nuclear factor 2-related erythroid 2 (Nrf2) pathway—the key mechanism in the maintenance of redox homeostasis—is involved in the beneficial effects exerted by the intake of PUFAs and polyphenols. However, it is known that the latter must be metabolized before becoming active and that the intestinal microbiota play a key role in the biotransformation of some ingested food components. In addition, recent studies, indicating the efficacy of the MACs, polyphenols, and PUFAs in increasing the microbial population with the ability to yield biologically active metabolites (e.g., polyphenol metabolites, short-chain fatty acids (SCFAs)), support the hypothesis that these factors are responsible for the antioxidant action on the physiology of the host. The underlying mechanisms through which MACs, polyphenols, and PUFAs might influence the redox status have not been fully elucidated, but based on the efficacy of SCFAs as Nrf2 activators, their contribution to the antioxidant efficacy of dietary bioactives cannot be excluded. In this review, we aimed to summarize the main mechanisms through which MACs, polyphenols, and PUFAs can modulate the host’s redox homeostasis through their ability to directly or indirectly activate the Nrf2 pathway. We discuss their probiotic effects and the role played by the alteration of the metabolism/composition of the gut microbiota in the generation of potential Nrf2-ligands (e.g., SCFAs) in the host’s redox homeostasis.

The serious side effects caused by chemotherapeutics and the development of cancer chemoresistance represent the most significant limitations in the treatment of cancer. Some alternative approaches have been developed in recent years, which are based on natural compounds, and have allowed important advances in cancer therapeutics. During the last 50 years, sponges have been considered a promising source of natural products from the marine environment, representing ~30% of all marine natural products. Among sponges, the Mediterranean species

Background The gut-brain axis is considered a neuroendocrine system, which connects the brain and gastrointestinal tract and plays an important role in stress response. The homeostasis of gut-brain axis is important for health conditions and its alterations are associated to neurological disorders and neurodegenerative diseases. Method We selected recent papers analysing the association among alterations in the homeostasis of the gut-brain axis and neurological disorders. In addition, we described how bioactive natural molecules - such as polyphenols - by influencing gut microbiota composition may help rescue neural signalling pathways impaired in neurodegenerative diseases. Results Recent studies show that gut microbiota is a dynamic ecosystem that can be altered by external factors such as diet composition, antibiotics or xenobiotics. Gut bacterial community plays a key role in maintaining normal brain functions. Metagenomic analyses have elucidated that the relationship between gut and brain, either in normal or in pathological conditions, reflects the existence of a "microbiota-gut-brain" axis. Gut microbiota composition can be influenced by dietary ingestion of probiotics or natural bioactive molecules such as prebiotics and polyphenols. Their derivatives coming from microbiota metabolism can affect both the gut bacterial composition and brain biochemistry. Conclusion This review highlights the role of gut microbiota in regulating regulates brain biochemistry and the role of microbiota metabolites on neuropathologies. Dietary ingestion of probiotics, prebiotics and polyphenols affect gut microbiota composition underlining the key role played by specific metabolites not only in the gut microbiota composition but also in the brain health maintenance.

Multiple myeloma (MM) is an incurable malignancy of mature plasma cells. Despite major advances in the therapeutic armamentarium of MM, only 50% of patients survive more than 5 years after diagnosis, with significantly lower rates (21%) for high-risk patients. Chimeric Antigen Receptor (CAR) T-cell therapy targeting BCMA (B-cell maturation antigen) shows high response rates in relapsed/refractory patients. However, most patients have disease remission that lasts less than 18 months, prompting the search for additional and synergistic therapeutic approaches. We unbiasedly mapped the cell surface proteome of MM by integrating Mass-Spectrometry (MS) and RNA-seq analyses from 7 MM cell lines and 904 primary MM patient samples bearing high-risk cytogenetics. To identify cell surface proteins, we ran a pool of 4,761 proteins and 16,000+ transcripts through five repositories. An integrated scoring database was developed by scoring each ID based on the number of databases (0-5) it was identified in, with 0 if the molecule was not found in any and 5 if the protein was found in all five. We identified 402 proteins with a surface score of 3 or higher in MM cell lines and patient samples by transcriptomics and proteomics. We prioritized the 326 candidates that were more highly expressed in patients. Based on functional enrichment analyses, we found the proteins formed three main networks with immune mechanisms representing the largest cluster (227 out of 326 cell surface proteins) followed by transporters and adhesion proteins.Based on a pipeline we previously established (1), we further selected 97 candidates minimally expressed in normal tissues. This list included current therapeutic targets such as BCMA, SLAMF7, ITGB7 and LY9. Validation in primary patient samples by western blot and flow-cytometric analyses, enabled the identification of 10 top candidates (CCR1, CD320, FCRL3, IL12RB1, ITGA4, LAX1, LILRB4, LRRC8D, SEMA4A, SLAMF6) that resulted most frequently and highly expressed. We found that LAX1, LILRB4 and SEMA4A significantly impact myeloma patient overall survival based on Kaplan-Meier analysis in the MM Research Foundation (MMRF) cohort (2). CCR1, IL12RB1, LILRB4 and SEMA4A were upregulated by the treatment with Bortezomib or Venetoclax that conversely, decreased BCMA expression in MM U266 cells. By stratifying the patient population, we found that the SEMA4A and LAX1 were up-regulated in patients with t(4;14) compared to patients with no cytogenetic abnormality; LILRB4 in patients with t(14;16) and CCR1 patients with t(14;16) and t(14;20). By calculating co-expression levels CCR1-LILRB4 and CCR1-FCRL3 resulted co-expressed in 100% of patients. For safety purposes (3), we excluded candidates with high (>55%) protein abundance in highly-purified normal hematopoietic stem cells and activated T-cells, narrowing down the list to 6 top candidates (CCR1, FCRL3, IL12RB1, LILRB4, LRRC8D, SEMA4A). To define the function of this group of promising cell surface targets, we used a CRISPR/Cas9 inducible system in KMS11 MM cells. We found that knock-out of CCR1, LRRC8D and SEMA4A individually reduces the MM cell growth by ~60%, 50% and 50% respectively, and almost completely abrogates MM cell migration through porous chambers by >80%. By co-culturing irradiated KO and control MM cells with healthy donor T-cells we also found that lack of CCR1 increased T-cell proliferation by 50% compared to controls and enhanced killing of MM cells, suggesting that CCR1 may suppress T-cell mediated immune responses in addition to play a role in MM cell survival and migration. This study suggests the contribution of an altered MM surfaceome to disease development and may lead to potential novel immunotherapeutic approaches for high-risk MM. References 1. Perna F et al., Cancer Cell 2017 3. Dong C et al., in press Oncogene 2021 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Curcumin, a nontoxic, naturally occurring polyphenol, has been recently proposed for the management of neurodegenerative and neurological diseases. However, a discrepancy exists between the well-documented pharmacological activities that curcumin seems to possess in vivo and its poor aqueous solubility, bioavailability, and pharmacokinetic profiles that should limit any therapeutic effect. Thus, it is possible that curcumin could exert direct regulative effects primarily in the gastrointestinal tract, where high concentrations of curcumin are present after oral administration. Indeed, a new working hypothesis that could explain the neuroprotective role of curcumin despite its limited availability is that curcumin acts indirectly on the central nervous system by influencing the “microbiota−gut−brain axis”, a complex bidirectional system in which the microbiome and its composition represent a factor which preserves and determines brain “health”. Interestingly, curcumin and its metabolites might provide benefit by restoring dysbiosis of gut microbiome. Conversely, curcumin is subject to bacterial enzymatic modifications, forming pharmacologically more active metabolites than curcumin. These mutual interactions allow to keep proper individual physiologic functions and play a key role in neuroprotection.

Background: pulmonary rehabilitation (PR) improves health status and exercise tolerance, but not respiratory function in patients with chronic obstructive pulmonary disease (COPD). Our objective was to identify predictors of improvement in the 6-min walked distance (6 � WD) in elderly COPD patients after PR. Methods:this was a prospective observational study performed in an ambulatory rehabilitation setting. We enrolled 74 patients aged 65–83 years (mean: 74.2, SD: 4.4) with stable COPD in GOLD stage 3–4. About half (45.6%) of them had a basal O2 saturation of 90% or less. After a baseline multi-dimensional assessment, patients underwent a 20-session rehabilitation cycle including training of the upper and lower extremities, and respiratory exercises, along with education sessions. The difference between final and basal 6 � WD was expressed as a per cent of the basal value (6 � WD gain). Patients were divided into two groups according to whether the 6 � WD gain was above or under the 75th percentile, corresponding to 33% gain. Results: patients whose 6 � WD improved more had lower baseline forced expiratory volume in the first second (FEV1)/forced vital capacity (FVC) (46.0 versus 52.2%, P = 0.03) and baseline 6 � WD, both as an absolute value (329.5 versus 408.9 m, P = 0.01) and as a per cent of the predicted (71.1 versus 93.5%, P = 0.002). After correction for potential confounders, baseline 6 � WD was the only variable associated with the outcome (OR for 5% increments: 0.79; 95% CI 0.65-0.95). Conclusions: among elderly patients with COPD, a comprehensive rehabilitation programme can significantly improve the 6 � WD even in the presence of chronic hypoxemia. The most physically impaired patients achieve the greatest benefit from rehabilitation, but we could not develop a model accurately predicting the response to rehabilitation.

Brunelli S, Averna T, Porcacchia P, Paolucci S, Di Meo F, Traballesi M. Functional status and factors influencing the rehabilitation outcome of people affected by above-knee amputation and hemiparesis. Objectives To evaluate the functional status of people with transfemoral amputation and hemiparesis and to identify the factors that influence rehabilitation outcome after inpatient treatment. Design Retrospective study. Setting Rehabilitation hospital. Participants Forty-five patients (30 men, 15 women; mean age, 69±9y) with intact mental status affected by unilateral transfemoral amputation for vascular disease and mild or moderate hemiparesis. Interventions Not applicable. Main Outcome Measures Barthel Index, Barthel Index effectiveness, and Locomotor Capabilities Index (LCI) scores were measured. The following factors were studied: side and cause of amputation, side and severity of hemiparesis, sequence and laterality of dual impairment, time interval between impairments, and hospital length of stay. Results At discharge, mean Barthel Index and LCI scores ±1 standard deviation were 79±12 and 15±5.6, respectively; Barthel Index effectiveness was 55±23.8. Only 2 patients ambulated without walking aids. Barthel Index effectiveness was better in patients with mild hemiparesis than in patients with more severe impairment. Ipsilateral localization of dual impairment increased the probability of higher LCI scores. Conclusions Selected patients with dual impairment can recover the ability to walk. Severity of hemiparesis and laterality were the 2 clinical factors that had the greatest influence on functional measures.