In December 2019, a novel coronavirus, COVID-19, was discovered to be the causal agent of a severe respiratory infection named SARS-CoV-2, and it has since been recognized worldwide as a pandemic. There are still numerous doubts concerning its pathogenesis and particularly the underlying causes of the various clinical courses, ranging from severe manifestations to asymptomatic forms, including acute respiratory distress syndrome. The major factor responsible for acute respiratory distress syndrome is the so-called “cytokine storm,” which is an aberrant response from the host immune system that induces an exaggerated release of proinflammatory cytokines/chemokines. In this review, we will discuss the role of cytokine storm in COVID-19 and potential treatments with which counteract this aberrant response, which may be valuable in the clinical translation.

Exploring and developing multifunctional intelligent biomaterials is crucial to improve next-generation therapies in tissue engineering and regenerative medicine. Recent findings show how distinct characteristics of in situ microenvironment can be mimicked by using different biomaterials. In vivo tissue architecture is characterized by the interconnection between cells and specific components of the extracellular matrix (ECM). Last evidence shows the importance of the structure and composition of the ECM in the development of cellular and molecular techniques, to achieve the best biodegradable and bioactive biomaterial compatible to human physiology. Such biomaterials provide specialized bioactive signals to regulate the surrounding biological habitat, through the progression of wound healing and biomaterial integration. The connection between stem cells and biomaterials stimulate the occurrence of specific modifications in terms of cell properties and fate, influencing then processes such as self-renewal, cell adhesion and differentiation. Recent studies in the field of tissue engineering and regenerative medicine have shown to deal with a broad area of applications, offering the most efficient and suitable strategies to neural repair and regeneration, drawing attention towards the potential use of biomaterials as 3D tools for in vitro neurodevelopment of tissue models, both in physiological and pathological conditions. In this direction, there are several tools supporting cell regeneration, which associate cytokines and other soluble factors delivery through the scaffold, and different approaches considering the features of the biomaterials, for an increased functionalization of the scaffold and for a better promotion of neural proliferation and cells-ECM interplay. In fact, 3D scaffolds need to ensure a progressive and regular delivery of cytokines, growth factors, or biomolecules, and moreover they should serve as a guide and support for injured tissues. It is also possible to create scaffolds with different layers, each one possessing different physical and biochemical aspects, able to provide at the same time organization, support and maintenance of the specific cell phenotype and diversified ECM morphogenesis. Our review summarizes the most recent advancements in functional materials, which are crucial to achieve the best performance and at the same time, to overcome the current limitations in tissue engineering and nervous tissue regeneration.

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The progressive consumption growth of non-steroidal anti-inflammatory drugs (NSAIDs) has progressively raised the attention toward the gastrointestinal, renal, and cardiovascular toxicity. Increased risk of cardiovascular diseases was strictly associated with the usage of COX-2 selective NSAIDs. Other studies allowed to clarify that the cardiovascular risk is not limited to COX-2 selective but also extended to non-selective NSAIDs, such as Diclofenac and Ketoprofen. To date, although a less favorable cardiovascular risk profile for Diclofenac as compared to Ketoprofen is reported, the mechanisms through which NSAIDs cause adverse cardiovascular events are not entirely understood. The present study aimed to evaluate the effects of Ketoprofen in comparison with Diclofenac in immortalized human cardiomyocytes. The results obtained highlight the dose-dependent cardiotoxicity of Diclofenac compared to Ketoprofen. Despite both drugs induce the increase in ROS production, decrease of mitochondrial membrane potential, and proteasome activity modulation, only Diclofenac exposure shows a marked alteration of these intracellular parameters, leading to cell death. Noteworthy, Diclofenac decreases the proteasome 26S DC and this scenario may be dependent on the intracellular overload of oxidized proteins. The data support the hypothesis that immortalized human cardiomyocytes exposed to Ketoprofen are subjected to tolerable stress events, conversely Diclofenac exposition triggers cell death.

Neurodegenerative disease etiology is still unclear, but different contributing factors, such as lifestyle and genetic factors are involved. Altered components of the gut could play a key role in the gut-brain axis, which is a bidirectional system between the central nervous system and the enteric nervous system. Variations in the composition of the gut microbiota and its function between healthy people and patients have been reported for a variety of human disorders comprising metabolic, autoimmune, cancer, and, notably, neurodegenerative disorders. Diet can alter the microbiota composition, affecting the gut-brain axis function. Different nutraceutical interventions have been devoted to normalizing gut microbiome dysbiosis and to improving biological outcomes in neurological conditions, including the use of probiotics. Preclinical and clinical investigations discussed in this review strengthen the correlation between intestinal microbiota and brain and the concept that modifying the microbiome composition may improve brain neurochemistry, modulating different pathways. This review will discuss the potential use of probiotics for Parkinson’s disease prevention or treatment or as adjuvant therapy, confirming that gut microbiota modulation influences different pro-survival pathways. Future investigations in Parkinson’s disease should consider the role of the gut-brain axis and additional comprehension of the underlying mechanisms is extremely necessary.

Chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSRs) are among the most frequent and impairing side effects of the antineoplastic agent paclitaxel. Here, we demonstrated that paclitaxel can bind and activate complement component 5a receptor 1 (C5aR1) and that this binding is crucial in the etiology of paclitaxel-induced CIPN and anaphylaxis. Starting from our previous data demonstrating the role of interleukin (IL)-8 in paclitaxel-induced neuronal toxicity, we searched for proteins that activate IL-8 expression and, by using the Exscalate platform for molecular docking simulations, we predicted the high affinity of C5aR1 with paclitaxel. By in vitro studies, we confirmed the specific and competitive nature of the C5aR1-paclitaxel binding and found that it triggers intracellularly the NFkB/P38 pathway and c-Fos. In F11 neuronal cells and rat dorsal root ganglia, C5aR1 inhibition protected from paclitaxel-induced neuropathological effects, while in paclitaxel-treated mice, the absence (knock-out mice) or the inhibition of C5aR1 significantly ameliorated CIPN symptoms—in terms of cold and mechanical allodynia—and reduced the chronic pathological state in the paw. Finally, we found that C5aR1 inhibition can counteract paclitaxel-induced anaphylactic cytokine release in macrophages in vitro, as well as the onset of HSRs in mice. Altogether these data identified C5aR1 as a key mediator and a new potential pharmacological target for the prevention and treatment of CIPN and HSRs induced by paclitaxel.

Background: preclinical, clinical, and epidemiological evidence support the notion that Alzheimer's disease (AD) is a multifactorial condition in which, along with β-amyloid (Aβ) and tau-related pathology, the synergistic activity of genetic, environmental, vascular, metabolic, and inflammatory factors promote the onset and progression of the disease. Epidemiological evidence indicate that glucose intolerance, deficits in insulin secretion or type 2 diabetes mellitus (T2DM) participate in increasing the risk of developing cognitive impairment or dementia. A pivotal role in the process is played by insulin as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a GLP-1R agonist, characterized by an extended half-life, employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models of brain aging and neurodegeneration.Methods: in this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. To that aim, we investigated the effects of 3-month exenatide treatment in 3xTg-AD mice challenged for six months with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, levels of Aβ and tau pathology as well as changes in cognitive performances. Findings and interpretation:results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD.

Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder disease of unknown etiology characterized by urinary frequency and episodic and chronic pain. Analgesic treatments for IC/BPS are limited, especially for patients with non-Hunner (non-ulcerative) type IC who usually have poor overall outcomes. Here, we demonstrate that oral treatment with DF2755A, a potent and selective inhibitor of chemokine receptors CXCR1/2, can prevent and reverse peripheral neuropathy associated to non-Hunner IC/BPS by directly inhibiting chemokine-induced excitation of sensory neurons. We tested DF2755A antinociceptive effects in a cyclophosphamide (CYP)-induced non-ulcerative IC rat model characterized by severe peripheral neuropathy in the absence of bladder inflammatory infiltrate, urothelial hyperplasia, and hemorrhage. Treatment with DF2755A prevented the onset of peripheral neuropathy and reversed its development in CYP-induced IC rats, showing a strong and long-lasting anti-hyperalgesic effect. Ex vivo and in vitro studies showed that DF2755A treatment strongly inhibited the expression of CXCR2 agonists, CXCL1/KC, and CXCL5 and of transient receptor potential vanilloid 1 (TRPV1) compared to vehicle, suggesting that its effects can be due to the inhibition of the nociceptive signaling passing through the CXCL1/CXCR1-2 axis and TRPV1. In conclusion, our results highlight the key pathophysiological role played by the CXCL1/CXCR1-2 axis and TRPV1 in the onset and development of peripheral neuropathy in non-Hunner IC and propose DF2755A as a potential therapeutic approach for the treatment of not only inflammatory painful conditions but also neuropathic ones and in particular non-Hunner IC/BPS.