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Summary: Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, characterized by rapid growth and invasion and poor prognosis. Due to its rarity and aggressive nature, ATC is a difficult condition to treat, thus knowledge of the mechanisms underlying its progression represents important research challenges. Benzyl isothiocyanate (BITC) is a natural compound that has shown promising anticancer properties. The aim of this study was to evaluate the antitumor effect of BITC in ATC, highlighting signaling pathways involved in BITC mechanism of action. This work included in vitro and in vivo studies. Results obtained indicate that BITC, both in vitro and in vivo, has the potential to slow the progression of ATC through interactions with autophagy, reduction in epithelial-mesenchymal transition (EMT) and attenuation of inflammation. In conclusion, this study identifies BITC as a compound worth further investigation for the development of new treatment strategies for this aggressive form of thyroid cancer.

Anaplastic thyroid carcinoma (ATC) is a rare thyroid neoplasm characterized by aggressiveness and a high mortality rate. Troxerutin (Trox) is a bioflavonoid widely found in various fruits and vegetables with numerous protective effects, including anticancer activities. To evaluate the anti-oxidant and anti-inflammatory effect of Trox, in vitro and in vivo studies were conducted in a model of ATC. Human ATC 8305C cell lines were treated with increasing concentrations of Trox (10 μg/mL, 30 μg/mL, 100 μg/mL, 300 μg/mL), and our results revealed that Trox treatment was able to reduce the viability of ATC cells and migratory capacity, reducing the expression of anti-apoptotic factors, such as B-cell lymphoma (bcl-2), and increasing the expression of pro-apoptotic factors, such as Caspase-3 and BID, activating oxidative stress mediators, such as manganese superoxide dismutase (MnSOD), heme oxygenase-1 (HO-1), glutathione (GSH) and reactive oxygen species modulator 1 (ROMO-1). Furthermore, Trox modulates NF-κB pathway markers, such as NIK and TRAF-6. Further confirmation was obtained through in vivo studies, in which Trox treatment, at doses of 12.5, 25 and 50 mg/kg, reduced morphological alteration, decreasing mast cell accumulation. Therefore, the use of Trox could be considered a promising strategy to counteract the progression of ATC.

Abstract Background Pulmonary fibrosis is a progressive disease characterized by lung remodeling due to excessive deposition of extracellular matrix. Although the etiology remains unknown, aberrant angiogenesis and inflammation play an important role in the development of this pathology. In this context, recent scientific research has identified new molecules involved in angiogenesis and inflammation, such as the prolyl oligopeptidase (PREP), a proteolytic enzyme belonging to the serine protease family, linked to the pathology of many lung diseases such as pulmonary fibrosis. Therefore, the aim of this study was to investigate the effect of a selective inhibitor of PREP, known as KYP-2047, in an in vitro and in an in vivo model of pulmonary fibrosis. Methods The in vitro model was performed using human alveolar A549 cells. Cells were exposed to lipopolysaccharide (LPS) 10 μg/ml and then, cells were treated with KYP-2047 at the concentrations of 1 μM, 10 μM and 50 μM. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide colorimetric assay, while inflammatory protein expression was assessed by western blots analysis. The in vivo model was induced in mice by intra-tracheal administration of bleomycin (1 mg/kg) and then treated intraperitoneally with KYP-2047 at doses of 1, 2.5 and 5 mg/kg once daily for 12 days and then mice were sacrificed, and lung tissues were collected for analyses. Results The in vitro results demonstrated that KYP-2047 preserved cell viability, reduced inflammatory process by decreasing IL-18 and TNF-α, and modulated lipid peroxidation as well as nitrosative stress. The in vivo pulmonary fibrosis has demonstrated that KYP-2047 was able to restore histological alterations reducing lung injury. Our data demonstrated that KYP-2047 significantly reduced angiogenesis process and the fibrotic damage modulating the expression of fibrotic markers. Furthermore, KYP-2047 treatment modulated the IκBα/NF-κB pathway and reduced the expression of related pro-inflammatory enzymes and cytokines. Moreover, KYP-2047 was able to modulate the JAK2/STAT3 pathway, highly involved in pulmonary fibrosis. Conclusion In conclusion, this study demonstrated the involvement of PREP in the pathogenesis of pulmonary fibrosis and that its inhibition by KYP-2047 has a protective role in lung injury induced by BLM, suggesting PREP as a potential target therapy for pulmonary fibrosis. These results speculate the potential protective mechanism of KYP-2047 through the modulation of JAK2/STAT3 and NF-κB pathways. Graphical abstract

Abstract Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal neurons, which causes disabling motor disorders. Scientific findings support the role of epigenetics mechanism in the development and progression of many neurodegenerative diseases, including PD. In this field, some studies highlighted an upregulation of Enhancer of zeste homolog 2 (EZH2) in the brains of PD patients, indicating the possible pathogenic role of this methyltransferase in PD. The aim of this study was to evaluate the neuroprotective effects of GSK-343, an EZH2 inhibitor, in an in vivo model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic degeneration. Specifically, nigrostriatal degeneration was induced by MPTP intraperitoneal injection. GSK-343 was administered intraperitoneally daily at doses of 1 mg/kg, 5 mg/kg and 10 mg/kg, mice were killed 7 days after MPTP injection. Our results demonstrated that GSK-343 treatment significantly improved behavioral deficits and reduced the alteration of PD hallmarks. Furthermore, GSK-343 administration significantly attenuated the neuroinflammatory state through the modulation of canonical and non-canonical NF-κB/IκBα pathway as well as the cytokines expression and glia activation, also reducing the apoptosis process. In conclusion, the obtained results provide further evidence that epigenetic mechanisms play a pathogenic role in PD demonstrating that the inhibition of EZH2, mediated by GSK-343, could be considered a valuable pharmacological strategy for PD.

Abstract Bacterial vaginosis (BV) is a common vaginal dysbiosis characterized by a malodorous discharge and irritation. The imbalance of the vaginal microbiota plays a key role in the development of BV. It has been demonstrated that Gardnerella vaginalis (GV), a facultative anaerobic bacillus, is involved in BV. Due to the rising number of antimicrobial-resistant species, recurrence of BV is becoming more frequent in women; thus, alternative treatments to antibiotics are needed. Natural substances have recently shown a great efficacy for the treatment of vaginal dysbiosis. Thus, this study aimed to investigate the beneficial effect of a product containing pea protein (PP), grape seed extract (GS) and lactic acid (LA) in an in vivo model of Gardnerella vaginalis-induced vaginosis by intravaginal administration of GV suspension (1 × 106 CFU/20 µL saline). Our results demonstrated that the product containing PP, GS and LA significantly reduced GV proliferation. More specifically, it significantly preserved tissue architecture and reduced neutrophil infiltration, inflammatory markers and sialidase activity when used both as a pre- or a post-treatment. Moreover, the product displayed strong bioadhesive properties. Therefore, our data suggested that the product containing PP, GS and LA could be used as alternative preventive or curative treatment for the management of BV.

Abstract Background Parkinson’s disease (PD) is the second most frequent neurodegenerative disease. PD etiopathogenesis is multifactorial and not yet fully known, however, the scientific world advised the establishment of neuroinflammation among the possible risk factors. In this field, basic fibroblast growth factor/fibroblast growth factor receptor-1 (bFGF/FGFR1) could be a promising way to treat CNS-mediated inflammation; unfortunately, the use of bFGF as therapeutic agent is limited by its side effects. The novel synthetic compound SUN11602 exhibited neuroprotective activities like bFGF. With this perspective, this study aimed to evaluate the effect of SUN11602 administration in a murine model of MPTP-induced dopaminergic degeneration. Methods Specifically, nigrostriatal degeneration was induced by intraperitoneal injection of MPTP (80 mg/kg). SUN11602 (1 mg/kg, 2.5 mg/kg, and 5 mg/kg) was administered daily by oral gavage starting from 24 h after the first administration of MPTP. Mice were killed 7 days after MPTP induction. Results The results obtained showed that SUN11602 administration significantly reduced the alteration of PD hallmarks, attenuating the neuroinflammatory state via modulation of glial activation, NF-κB pathway, and cytokine overexpression. Furthermore, we demonstrated that SUN11602 treatment rebalanced Ca2+ overload in neurons by regulating Ca2+-binding proteins while inhibiting the apoptotic cascade. Conclusion Therefore, in the light of these findings, SUN11602 could be considered a valuable pharmacological strategy for PD.

Atopic dermatitis (AD) is the most common chronically relapsing inflammatory skin disease, predominantly common in children; it is characterized by an eczematous pattern generally referable to skin dryness and itchy papules that become excoriated and lichenified in the more advanced stages of the disease. Although the pathophysiology of AD is not completely understood, numerous studies have demonstrated the complex interaction between genetic, immunological, and environmental factors, which acts to disrupt skin barrier function. Free radicals play a key role by directly damaging skin structure, inducing inflammation and weakening of the skin barrier. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) is a membrane-permeable radical scavenger, known to be a stable nitroxide, which exhibits excellent antioxidant effects in several human disorders, such as osteoarthritis and inflammatory bowel diseases. Considering the few existing studies on dermatological pathologies, this study aimed to evaluate tempol, in a cream formulation, in a murine model of AD. Dermatitis was induced in mice via dorsal skin application of 0.5% Oxazolone, three times a week for two weeks. After induction, mice were treated with tempol-based cream for another two weeks at three different doses of 0.5%, 1% and 2%. Our results demonstrated the ability of tempol, at the highest percentages, to counteract AD by reducing the histological damage, decreasing mast cell infiltration, and improving the skin barrier properties, by restoring the tight junction (TJs) and filaggrin. Moreover, tempol, at 1% and 2%, was able to modulate inflammation by reducing the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) pathway, as well as tumor necrosis factor (TNF)-α and interleukin (IL)-1β expression. Topical treatment also attenuated oxidative stress by modulating nuclear factor erythroid 2-related factor 2 (Nrf2), manganese superoxide dismutase (MnSOD), and heme oxygenase I (HO-1) expression levels. The obtained results demonstrate the numerous advantages provided by the topical administration of a tempol-based cream formulation, in reducing inflammation and oxidative stress through modulation of the NF-κB/Nrf2 signaling pathways. Therefore, tempol could represent an alternative anti-atopic approach to treating AD, thereby improving skin barrier function.

Oxygen is a central molecule for numerous metabolic and cytophysiological processes, and, indeed, its imbalance can lead to numerous pathological consequences. In the human body, the brain is an aerobic organ and for this reason, it is very sensitive to oxygen equilibrium. The consequences of oxygen imbalance are especially devastating when occurring in this organ. Indeed, oxygen imbalance can lead to hypoxia, hyperoxia, protein misfolding, mitochondria dysfunction, alterations in heme metabolism and neuroinflammation. Consequently, these dysfunctions can cause numerous neurological alterations, both in the pediatric life and in the adult ages. These disorders share numerous common pathways, most of which are consequent to redox imbalance. In this review, we will focus on the dysfunctions present in neurodegenerative disorders (specifically Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis) and pediatric neurological disorders (X-adrenoleukodystrophies, spinal muscular atrophy, mucopolysaccharidoses and Pelizaeus–Merzbacher Disease), highlighting their underlining dysfunction in redox and identifying potential therapeutic strategies.

Abstract Background Oxidative stress and inflammatory pathways are involved in migraine and endogenous antioxidant defense system has a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of the most pharmacologically effective molecules among the fumaric acid esters (FAEs), dimethyl fumarate, nuclear factor E2-related factor 2/antioxidant response element (Nrf-2/ARE) pathway-mediated, in regulating the hypersensitivity in a mouse model of nitroglycerine (NTG)-induced migraine. Methods Mice were orally administered with DMF at the doses of 10, 30, and 100 mg/kg, 5 min after NTG intraperitoneal injections. We performed histological and molecular analysis on the whole brain and behavioral tests after 4 h by NTG-migraine induction. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) subunit p65, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (IκBα), inducible nitrite oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Nrf-2, manganese superoxide dismutase (Mn-SOD), and heme-oxygenase-1 (HO-1) were detected by Western blot. Tail flick, hot plate, orofacial formalin, and photophobia tests were used to evaluate migraine-like pain and migraine-related light sensitivity. Moreover, we evaluate Nrf-2-dependent mechanism by the in vitro stimulation of cells extracted by trigeminal ganglia with diethylenetriamine/nitric oxide (DETA/NO), a nitric oxide (NO) donor. The cells were pre-treated with DMF and an antagonist of Nrf-2, trigonelline (TR) 2 h before DETA/NO stimulation. Results DMF treatment notably reduced histological damage as showed by cresyl violet staining; also, regulating both NF-κB and Nrf-2 pathway, DMF treatment decreased the severity of inflammation and increased the protective antioxidant action. Moreover, the headache was significantly reduced. The protective effect of DMF treatment, via Nrf-2, was confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline. Cytotoxicity, iNOS, and MnSOD expression were evaluated. Conclusion These results provided the evidence that DMF, by Nrf-2 modulation, has a protective effect on central sensitization induced by NTG, suggesting a new insight into the potential application of DMF as novel candidates in drug development for migraine.

Cancer is the leading cause of death worldwide; thus, it is necessary to find successful strategies. Several growth factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF, FGF2), and transforming growth factor beta (TGF-β), are involved in the main processes that fuel tumor growth, i.e., cell proliferation, angiogenesis, and metastasis, by activating important signaling pathways, including PLC-γ/PI3/Ca2+ signaling, leading to PKC activation. Here, we focused on bFGF, which, when secreted by tumor cells, mediates several signal transductions and plays an influential role in tumor cells and in the development of chemoresistance. The biological mechanism of bFGF is shown by its interaction with its four receptor subtypes: fibroblast growth factor receptor (FGFR) 1, FGFR2, FGFR3, and FGFR4. The bFGF–FGFR interaction stimulates tumor cell proliferation and invasion, resulting in an upregulation of pro-inflammatory and anti-apoptotic tumor cell proteins. Considering the involvement of the bFGF/FGFR axis in oncogenesis, preclinical and clinical studies have been conducted to develop new therapeutic strategies, alone and/or in combination, aimed at intervening on the bFGF/FGFR axis. Therefore, this review aimed to comprehensively examine the biological mechanisms underlying bFGF in the tumor microenvironment, the different anticancer therapies currently available that target the FGFRs, and the prognostic value of bFGF.

Moderate traumatic brain injury (mTBI) has been associated with emotional dysregulation such as loss of consciousness, post-traumatic amnesia and major depressive disorder. The gene Leucine-rich repeat kinase 2 (LRRK2) is involved in protein synthesis and degradation, apoptosis, inflammation and oxidative stress, processes that trigger mTBI. The aim of this study was to investigate the role of LRRK2 in reducing depression-related symptoms after mTBI and to determine whether inhibition of LRRK2 mediated by PF-06447475 could have antidepressant effects. Moderate traumatic brain injury was induced by controlled cortical impact (CCI) and mice were treated with PF-06447475 at doses of 1, 2.5 and 5 mg/kg once daily for 14 days. We performed histological, immunohistochemical and molecular analyses of brain tissue 24 days after mTBI. Furthermore, the tissue changes found in the hippocampus and amygdala confirmed the depression-like behavior. PF-treatment with 06447475 significantly reduced the histological damage and behavioral disturbances. Thus, this study has shown that mTBI induction promotes the development of depression-like behavioral changes. LRRK2 inhibition showed an antidepressant effect and restored the changes in the copper/glutamate/N-methyl-D-aspartic acid receptor (Cu/NMDAR) system.

Background: Vulvovaginal candidiasis (VVC) is considered the second most common vaginal infection. Up to 8% of women in various populations experience more than three or four episodes within one year, which is regarded as recurrent vulvovaginal candidiasis (RVVC). Current therapies involve antifungal drugs that provide static effects but do not prevent recurrences due to increased antimicrobial resistance; thus, alternative therapies to antifungals are needed to prevent RVVC. Methods: A murine model of Candida albicans-induced RVVC was performed to evaluate the efficacy of a topical product containing pea protein (PP), grape seed extract (GS), and lactic acid (LA) to treat recurrent infections. Mice were inoculated with three separate vulvovaginal infections of 5 × 104 cells/mL C. albicans, and histological evaluation, a myeloperoxidase (MPO) assay. and an ELISA kit for Prostaglandin E2 (PGE2) on vaginal tissues were performed. Results: The data obtained highlighted that the combination of PP, GS, and LA significantly preserved vaginal tissue architecture and prevented vaginal inflammation, proving its efficacy for the management of RVVC. Moreover, the combination of PP, GS, and LA notably increased azole efficacy by adding a new mechanism of action when administered concomitantly. Conclusion: Taken together, results demonstrated that the treatment with a combination of PP, GS, and LA is able to reduce the adhesion of C. albicans.

The management of post-operative (PO) pain has generally been shown to be inadequate; therefore, acquiring a novel understanding of PO pain mechanisms would increase the therapeutic options available. There is accumulating evidence to implicate N-methyl-d-aspartate (NMDA) receptors in the induction and maintenance of central sensitization during pain states by reinforcing glutamate sensory transmission. It is known that DMF protects from oxidative glutamate toxicity. Therefore, NMDA receptor antagonists have been implicated in peri-operative pain management. Recent advances demonstrated that dimethyl fumarate (DMF), a non-opioid and orally bioavailable drug, is able to resolve neuroinflammation through mechanisms that drive nociceptive hypersensitivity. Therefore, in this study, we evaluated the role of DMF on pain and neuroinflammation in a mouse model of PO pain. An incision of the hind paw was performed, and DMF at two different doses (30 and 100 mg/kg) was administered by oral gavage for five consecutive days. Mechanical allodynia, thermal hyperalgesia and locomotor dysfunction were evaluated daily for five days after surgery. Mice were sacrificed at day 7 following PO pain induction, and hind paw and lumbar spinal cord samples were collected for histological and molecular studies. DMF administration significantly reduced hyperalgesia and allodynia, alleviating motor disfunction. Treatment with DMF significantly reduced histological damage, counteracted mast cell activation and reduced the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) inflammatory pathway, in addition to downregulating tumor necrosis factor-α (TNF-α), Interleukin-1β (Il-1β) and Il-4 expression. Interestingly, DMF treatment lowered the activation of NMDA receptor subtypes (NR2B and NR1) and the NMDA-receptor-interacting PDZ proteins, including PSD93 and PSD95. Furthermore, DMF interfered with calcium ion release, modulating nociception. Thus, DMF administration modulated PO pain, managing NMDA signaling pathways. The results suggest that DMF positively modulated persistent nociception related to PO pain, through predominantly NMDA-receptor-operated calcium channels.

Glioblastoma (GB), also known as grade IV astrocytoma, represents the most aggressive form of brain tumor, characterized by extraordinary heterogeneity and high invasiveness and mortality. Thus, a great deal of interest is currently being directed to investigate a new therapeutic strategy and in recent years, the research has focused its attention on the evaluation of the anticancer effects of some drugs already in use for other diseases. This is the case of peroxisome proliferator-activated receptors (PPARs) ligands, which over the years have been revealed to possess anticancer properties. PPARs belong to the nuclear receptor superfamily and are divided into three main subtypes: PPAR-α, PPAR-β/δ, and PPAR-γ. These receptors, once activated by specific natural or synthetic ligands, translocate to the nucleus and dimerize with the retinoid X receptors (RXR), starting the signal transduction of numerous genes involved in many physiological processes. PPARs receptors are activated by specific ligands and participate principally in the preservation of homeostasis and in lipid and glucose metabolism. In fact, synthetic PPAR-α agonists, such as fibrates, are drugs currently in use for the clinical treatment of hypertriglyceridemia, while PPAR-γ agonists, including thiazolidinediones (TZDs), are known as insulin-sensitizing drugs. In this review, we will analyze the role of PPARs receptors in the progression of tumorigenesis and the action of PPARs agonists in promoting, or not, the induction of cell death in GB cells, highlighting the conflicting opinions present in the literature.

Background: There is a growing realization that the gut–brain axis signaling is critical for maintaining the health and homeostasis of the Central Nervous System (CNS) and the intestinal environment. The role of Short-Chain Fatty Acids (SCFAs), such as Sodium Propionate (SP) and Sodium Butyrate (SB), has been reported to counteract inflammation activation in the central and Enteric Nervous System (ENS). Methods: In this study, we evaluated the role of the SCFAs in regulating the pathophysiology of migraine and correlated dysregulations in the gut environment in a mouse model of Nitroglycerine (NTG)-induced migraine. Results: We showed that, following behavioral tests evaluating pain and photophobia, the SP and SB treatments attenuated pain attacks provoked by NTG. Moreover, treatments with both SCFAs reduced histological damage in the trigeminal nerve nucleus and decreased the expression of proinflammatory mediators. Ileum evaluation following NTG injection reported that SCFA treatments importantly restored intestinal mucosa alterations, as well as the release of neurotransmitters in the ENS. Conclusions: Taken together, these results provide evidence that SCFAs exert powerful effects, preventing inflammation through the gut–brain axis, suggesting a new insight into the potential application of SCFAs as novel supportive therapies for migraine and correlated intestinal alterations.

Background: Intestinal ischemia/reperfusion injury (IRI) remains a clinical event that contributes to high morbidity and mortality rates. Intestinal epithelium is exposed to histological and vascular changes following tissue ischemia. Prolyl endopeptidase (PREP), involved in inflammatory responses, could be targeted for recovery from the permanent consequences following intestinal ischemia. Our aim was to investigate the role of PREP inhibitor KYP-2047 in tissue damage, angiogenesis, and endothelial barrier permeability after intestinal IRI in mice. Methods: KYP-2047 treatments were performed 5 min prior to intestinal damage. Intestinal IRI was induced in mice by clamping the superior mesenteric artery and the celiac trunk for 30 min, followed by 1 h of reperfusion. Results: PREP inhibition by KYP-2047 treatment reduced intestinal IR-induced histological damage and neutrophil accumulation, limiting inflammation through decrease of NF-ĸB nuclear translocation and fibrotic processes. KYP-2047 treatment restored barrier permeability and structural alteration following intestinal IRI, attenuating neovascular processes compromised by ischemia/reperfusion. Additionally, loss of epithelial cells during intestinal ischemia occurring by apoptosis was limited by KYP-2047 treatment, which showed strong effects counteracting apoptosis and DNA damage. Conclusions: These findings provide the first evidence that PREP inhibition through KYP-2047 inhibitor use could be a validate strategy for resolving alterations of intestinal epithelium the pathophysiology of intestinal disease.

Cisplatin is one of the chemotherapeutic drugs used for the management of oral carcinoma, in which combined therapies are estimated to exert superior therapeutic efficacy compared with monotherapy. It is known that poly(ADP-ribosyl)ation is implicated in a multiplicity of cellular activities, such as DNA repair and cell death. Based on these, PARP inhibitors are used for the treatment of cancers; however, the capacity of PARP inhibitors associated to anti-cancer drugs have not been completely assessed in oral carcinoma. Here, we evaluated the effects of PARPi veliparib (ABT888) in combination with cisplatin on the survival of three human oral cancer cell lines HSC-2, Ca9-22 and CAL27 and we observed the effects of ABT888 alone or in combination with cisplatin on apoptosis and DNA damage repair mechanism. The results obtained showed that ABT888 induces a cytotoxicity effect on cell viability increasing the apoptotic pathway as well as DNA strand break; moreover, our results displayed the effects with cisplatin in a dose-dependent manner. Therefore, our results indicate PARP inhibitors as adjuvants for therapeutic strategy of oral cancer.

Since cancer is a multifactorial disease with a high mortality rate, the study of new therapeutic strategies is one of the main objectives in modern research. Numerous chemotherapeutic agents, although widely used, have the disadvantage of being not very soluble in water or selective towards cancerous cells, with consequent side effects. Therefore, in recent years, a greater interest has emerged in innovative drug delivery systems (DDSs) such as calixarene, a third-generation supramolecular compound. Calixarene and its water-soluble derivatives show good biocompatibility and have low cytotoxicity. Thanks to their chemical–physical characteristics, calixarenes can be easily functionalized, and by itself can encapsulate host molecules forming nanostructures capable of releasing drugs in a controlled way. The encapsulation of anticancer drugs in a calixarene derivate improves their bioavailability and efficacy. Thus, the use of calixarenes as carriers of anticancer drugs could reduce their side effects and increase their affinity towards the target. This review summarizes the numerous research advances regarding the development of calixarene nanoparticles capable of encapsulating various anticancer drugs.

Microglia, a type of differentiated tissue macrophage, are considered to be the most plastic cell population of the central nervous system (CNS). Microglia substantially contribute to the growth and invasion of tumor mass in brain tumors including glioblastoma (GB). In response to pathological conditions, resting microglia undergo a stereotypic activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation. Considering their immune effector function, it is not surprising to see microglia accumulation in almost every CNS disease process, including malignant brain tumors. Large numbers of glioma associated microglia and macrophages (GAMs) can accumulate within the tumor where they appear to have an important role in prognosis. GAMs constitute the largest portion of tumor infiltrating cells, contributing up to 30% of the entire glioma mass and upon interaction with neoplastic cells. GAMs acquire a unique phenotype of activation, including both M1 and M2 specific markers. It has been demonstrated that microglia possess a dual role: on one hand, microglia may represent a CNS anti-tumor response, which is inactivated by local secretion of immunosuppressive factors by glioma cells. On the other hand, taking into account that microglia are capable of secreting a variety of immunomodulatory cytokines, it is possible that they are attracted by gliomas to promote tumor growth. A better understanding of microglia-glioma interaction will be helpful in designing novel immune-based therapies against these fatal tumors. Concluding, as microglia significantly may contribute to glioma biology, favoring tumor growth and invasiveness, these cells represent a valuable alternative/additional target for the development of more effective treatments for gliomas.

Hydrogen sulfide (H2S), a mammalian gasotransmitter, is involved in the regulation of a variety of fundamental processes including intracellular signaling, cellular bioenergetics, cell proliferation, and cell differentiation. Cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST) are currently considered the three principal mammalian H2S-generating enzymes. However, recently, a fourth H2S-producing enzyme, selenium-binding-protein 1 (SELENBP1), has also been identified. The cellular regulatory role(s) of SELENBP1 are incompletely understood. The current study investigated whether SELENBP1 plays a role in the regulation of adipocyte differentiation in vitro. 3T3-L1 preadipocytes with or without SELENBP1 knock-down were subjected to differentiation-inducing conditions, and H2S production, cellular lipid accumulation, cell proliferation, and mitochondrial activity were quantified. Adipocyte differentiation was associated with an upregulation of H2S biosynthesis. SELENBP1 silencing decreased cellular H2S levels, suppressed the expression of the three “classical” H2S-producing enzymes (CBS, CSE, and 3-MST) and significantly suppressed adipocyte differentiation. Treatment of SELENBP1 knock-down cells with the H2S donor GYY4137 partially restored lipid accumulation, increased cellular H2S levels, and exerted a bell-shaped effect on cellular bioenergetics (enhancement at 1 and 3 mM, and inhibition at 6 mM). We conclude that SELENBP1 in adipocytes (1) contributes to H2S biosynthesis and (2) acts as an endogenous stimulator of adipocyte differentiation.

(1) Background: Chronic venous insufficiency (CVI) is a common disorder related to functional and morphological abnormalities of the venous system. Inflammatory processes and angiogenesis alterations greatly concur to the onset of varicose vein. KYP-2047 is a selective inhibitor of prolyl oligopeptidase (POP), a serine protease involved in the release of pro-angiogenic molecules. The aim of the present study is to evaluate the capacity of KYP-2047 to influence the angiogenic and inflammatory mechanisms involved in the pathophysiology of CVI. (2) Methods: An in vivo model of CVI-induced by saphene vein ligation (SVL) and a tissue block culture study were performed. Mice were subjected to SVL followed by KYP-2047 treatment (intraperitoneal, 10 mg/kg) for 7 days. Histological analysis, Masson’s trichrome, Van Gieson staining, and mast cells evaluation were performed. Release of cytokines, nitric oxide synthase production, TGF-beta, VEGF, α-smooth muscle actin, PREP, Endoglin, and IL-8 quantification were investigated. (3) Results: KYP-2047 treatment ameliorated the histological abnormalities of the venous wall, reduced the collagen increase and modulated elastin content, lowered cytokines levels and prevented mast degranulation. Moreover, a decreased expression of TGF-beta, eNOS, VEGF, α-smooth muscle actin, IL-8, and PREP was observed in in vivo study; also a reduction in VEGF and Endoglin expression was confirmed in tissue block culture study. (4) Conclusions: For the first time, this research, highlighting the importance of POP as new target for vascular disorders, revealed the therapeutic potential of KYP-2047 as a helpful treatment for the management of CVI.

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a multifactorial chronic gastrointestinal disorder characterized by inflammation and immune response. In this context, NLRP3 over-activation is associated with a breakdown of enteric-immune balance related to IBS-D. The aim of this study was to evaluate the effect of the inflammasome inhibitor, BAY 11-7082, in a rat model of IBS-D. Syndrome was induced by intracolonic instillation of 1 mL 4% acetic acid at 8 cm proximal to the anus for 30 s and sacrificed 2 weeks after IBS-D induction. BAY 11-7082 (10 and 30 mg/kg) was administered daily by oral gavage. The results obtained showed that the treatment with BAY 11-7082 (30 mg/kg) significantly reduced tissue injury characterized by edema, neutrophil infiltration, and loss of colon structure. We demonstrated that BAY 11-7082 treatment inhibited NLRP3 inflammasome activation and NF-kB translocation, reducing inflammatory mediators. Moreover, treatment with BAY 11-7082 restored tight junction alteration following IBS-D induction and reduced the restraint stress. Taken together, our data demonstrate that IBS-D induced NLRP3 inflammasome pathway activation, accompanied by the production of proinflammatory response. The modulation of the inflammosome pathway with BAY 11-7082 inhibitor significantly reduced pathological signs of IBS-D, therefore, can be considered a valuable strategy to reduce the development of IBS-D.

Periodontitis is a dental disease that produces the progressive destruction of the bone surrounding the tooth. Especially, lipopolysaccharide (LPS) is involved in the deterioration of the alveolar bone, inducing the release of pro-inflammatory mediators, which cause periodontal tissue inflammation. Luteolin (Lut), a molecule of natural origin present in a large variety of fruits and vegetables, possess beneficial properties for human health. On this basis, we investigated the anti-inflammatory properties of Lut in a model of periodontitis induced by LPS in rats. Animal model predicted a single intragingival injection of LPS (10 μg/μL) derived from Salmonella typhimurium. Lut administration, was performed daily at different doses (10, 30, and 100 mg/kg, orally), starting from 1 h after the injection of LPS. After 14 days, the animals were sacrificed, and their gums were processed for biochemical analysis and histological examinations. Results showed that Lut (30 and 100 mg/kg) was equally able to reduce alveolar bone loss, tissue damage, and neutrophilic infiltration. Moreover, Lut treatment reduced the concentration of collagen fibers, mast cells degranulation, and NF-κB activation, as well as the presence of pro-inflammatory enzymes and cytokines. Therefore, Lut implementation could represent valid support in the pharmacological strategy for periodontitis, thus improving the well-being of the oral cavity.

Marine species represent a great source of biologically active substances; Actinia equina (AE), an Anthozoa Cnidaria belonging to the Actinidiae family, have been proposed as original food and have already been included in several cooking recipes in local Mediterranean shores, and endowed with excellent nutraceutical potential. The aim of this study was to investigate some unexplored features of AE, through analytical screening and an in-vitro and in-vivo model. An in-vitro study, made on RAW 264.7 stimulated with H2O2, showed that the pre-treatment with AE exerted an antioxidant action, reducing lipid peroxidation and up-regulating antioxidant enzymes. On the other hand, the in-vivo study over murine model demonstrated that the administration of AE extracts is able to reduce the carrageenan (CAR)-induced paw edema. Furthermore, the histological damage due to the neutrophil infiltration is prevented, and this highlights precious anti-inflammatory features of the interesting food-stuff. Moreover, it was assessed that AE extract modulated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and The nuclear factor erythroid 2–related factor 2 (Nrf-2) pathways. In conclusion, our data demonstrated that thanks to the antioxidant and anti-inflammatory properties, AE extract could be used as a new food supplement for inflammatory pathology prevention.