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Bovine alphaherpesvirus 1 (BoAHV-1), the pathogen causing Infectious Bovine Rhinotracheitis (IBR) and predisposing to polymicrobial infections in cattle, provokes farm economic losses and trading restrictions in the world. However, nontoxic antiviral agents for BoAHV-1 infection are still unavailable, but plant extracts, such as flavonoid derivatives possess activity against BoAHV-1. Taurisolo®, a nutraceutical produced by Aglianico grape pomace, has recently shown promising antiviral activity. Herein, the potential activity of Taurisolo® during BoAHV-1 infection in Madin Darby bovine kidney (MDBK) cells was tested. Taurisolo® enhanced cell viability and reduced morphological death signs in BoAHV-1-infected cells. Moreover, Taurisolo® influenced the expression of bICP0, the key regulatory protein of BoAHV-1, and it strongly diminished virus yield. These effects were associated with an up-regulation of aryl hydrocarbon receptor (AhR), a transcription factor involved in microbial metabolism and immune response.In conclusion, our findings indicate that Taurisolo® may represent a potential antiviral agent against BoAHV-1 infection. Noteworthy, AhR could be involved in the observed effects and become a new target in antiviral therapy.

Based on the multifaceted molecular machinery that tightly controls iron cellular homeostasis, this review delves into its paradoxical, potentially dangerous role in biological systems, with a special focus on double-edged sword correlations with cancer. Indeed, though iron is a vital micronutrient and a required cofactor participating in several essential cell functions, its tendency to cause oxidative stress can be related both to cancer risk and to the activation of cancer cell death pathways. In this scenario, ferroptosis refers to an iron-dependent form of regulated cell death (RCD) powered by an overload of lethal peroxides sharing distinctive oxidized phospholipid profiles. As a unique cell death pathway, ferroptosis is both morphologically and mechanistically different from other types of programmed cell death involving executioner family proteins. The accumulation of cytotoxic lipid peroxides encompasses a cellular antagonism between ferroptosis execution and defense systems, with iron-dependent death occurring when ferroptosis-promoting activities significantly exceed the cellular antioxidant defenses. The most recent molecular breakthroughs in the execution of ferroptosis have aroused great consideration in tumor biology, as targeting ferroptosis can provide new tools for exploring therapeutic strategies for tumor suppression. Mutations and death/survival pathway alterations, as well as distinctive metabolic regulations of cancer cells, including the propensity to generate ROS, are seen as features that can render cancer cells unprotected to ferroptosis, thereby exposing vulnerabilities which deserve further attention to be regarded as targetable for cancers with limited therapeutic options.

Based on compelling preclinical evidence concerning the progress of our novel ruthenium-based metallotherapeutics, we are focusing research efforts on challenging indications for the treatment of invasive neoplasms such as the triple-negative breast cancer (TNBC). This malignancy mainly afflicts younger women, who are black, or who have a BRCA1 mutation. Because of faster growing and spreading, TNBC differs from other invasive breast cancers having fewer treatment options and worse prognosis, where existing therapies are mostly ineffective, resulting in a large unmet biomedical need. In this context, we benefited from an experimental model of TNBC both in vitro and in vivo to explore the effects of a biocompatible cationic liposomal nanoformulation, named HoThyRu/DOTAP, able to effectively deliver the antiproliferative ruthenium(III) complex AziRu, thus resulting in a prospective candidate drug. As part of the multitargeting mechanisms featuring metal-based therapeutics other than platinum-containing agents, we herein validate the potential of HoThyRu/DOTAP liposomes to act as a multimodal anticancer agent through inhibition of TNBC cell growth and proliferation, as well as migration and invasion. The here-obtained preclinical findings suggest a potential targeting of the complex pathways network controlling invasive and migratory cancer phenotypes. Overall, in the field of alternative chemotherapy to platinum-based drugs, these outcomes suggest prospective brand-new settings for the nanostructured AziRu complex to get promising goals for the treatment of metastatic TNBC.

Countless expectations converge in the multidisciplinary endeavour for the search and development of effective and safe drugs in fighting cancer. Although they still embody a minority of the pharmacological agents currently in clinical use, metal-based complexes have great yet unexplored potential, which probably hides forthcoming anticancer drugs. Following the historical success of cisplatin and congeners, but also taking advantage of conventional chemotherapy limitations that emerged with applications in the clinic, the design and development of non-platinum metal-based chemotherapeutics, either as drugs or prodrugs, represents a rapidly evolving field wherein candidate compounds can be fine-tuned to access interactions with druggable biological targets. Moving in this direction, over the last few decades platinum family metals, e.g., ruthenium and palladium, have been largely proposed. Indeed, transition metals and molecular platforms where they originate are endowed with unique chemical and biological features based on, but not limited to, redox activity and coordination geometries, as well as ligand selection (including their inherent reactivity and bioactivity). Herein, current applications and progress in metal-based chemoth are reviewed. Converging on the recent literature, new attractive chemotherapeutics based on transition metals other than platinum—and their bioactivity and mechanisms of action—are examined and discussed. A special focus is committed to anticancer agents based on ruthenium, palladium, rhodium, and iridium, but also to gold derivatives, for which more experimental data are nowadays available. Next to platinum-based agents, ruthenium-based candidate drugs were the first to reach the stage of clinical evaluation in humans, opening new scenarios for the development of alternative chemotherapeutic options to treat cancer.

Antimicrobial peptides (AMPs) are an ancient group of defense molecules distributed in nature being found in mammals, birds, amphibians, insects, plants, and microorganisms. They display antimicrobial as well as immunomodulatory properties. The aim of this study was to investigate, for the first time, the anti-inflammatory activities of two synthetic temporin-L analogues (here named peptide 1 and 2) by an in vivo model of inflammation caused by intraperitoneal sub-lethal dose of zymosan. Our results show that peptide 1 and 2 exert anti-inflammatory activity in vivo in response to zymosan-induce peritonitis. Simultaneous administration of 10 mg/kg of both temporins, with a sub-lethal dose of zymosan (500 mg/kg), significantly rescued mice from the classical hallmarks of inflammation, including leukocyte infiltration and synthesis of inflammatory mediators including IL-6, TNF-α and MCP-1. More importantly, flow cytometry analysis highlighted a selective modulation of infiltrating inflammatory monocytes (defined as B220−/GR1hi-F480hi/CD115+) after peptide 2 treatment. Our results and presented models offer the possibility to test, in a preclinical setting, the potential of temporin analogues as anti-inflammatory agents.

Selectivity and efficacy towards target cancer cells, as well as biocompatibility, are current challenges of advanced chemotherapy powering the discovery of unconventional metal-based drugs and the search for novel therapeutic approaches. Among second-generation metal-based chemotherapeutics, ruthenium complexes have demonstrated promising anticancer activity coupled to minimal toxicity profiles and peculiar biochemical features. In this context, our research group has recently focused on a bioactive Ru(III) complex—named AziRu—incorporated into a suite of ad hoc designed nucleolipid nanosystems to ensure its chemical stability and delivery. Indeed, we proved that the structure and properties of decorated nucleolipids can have a major impact on the anticancer activity of the ruthenium core. Moving in this direction, here we describe a preclinical study performed by a mouse xenograft model of human breast cancer to establish safety and efficacy in vivo of a cationic Ru(III)-based nucleolipid formulation, named HoThyRu/DOTAP, endowed with superior antiproliferative activity. The results show a remarkable reduction in tumour with no evidence of animal suffering. Blood diagnostics, as well as biochemical analysis in both acute and chronic treated animal groups, demonstrate a good tolerability profile at the therapeutic regimen, with 100% of mice survival and no indication of toxicity. In addition, ruthenium plasma concentration analysis and tissue bioaccumulation were determined via appropriate sampling and ICP-MS analysis. Overall, this study supports both the efficacy of our Ru-containing nanosystem versus a human breast cancer model and its safety in vivo through well-tolerated animal biological responses, envisaging a possible forthcoming use in clinical trials.

The role of the cerebellum in Alzheimer’s disease (AD) has been neglected for a long time. Recent studies carried out using transgenic mouse models have demonstrated that amyloid-β (Aβ) is deposited in the cerebellum and affects synaptic transmission and plasticity, sometimes before plaque formation. A wide variability of motor phenotype has been observed in the different murine models of AD, without a consistent correlation with the extent of cerebellar histopathological changes or with cognitive deficits. The loss of noradrenergic drive may contribute to the impairment of cerebellar synaptic function and motor learning observed in these mice. Furthermore, cerebellar neurons, particularly granule cells, have been used as in vitro model of Aβ-induced neuronal damage. An unexpected conclusion is that the cerebellum, for a long time thought to be somehow protected from AD pathology, is actually considered as a region vulnerable to Aβ toxic damage, even at the early stage of the disease, with consequences on motor performance.

In this review we have showcased the preclinical development of original amphiphilic nanomaterials designed for ruthenium-based anticancer treatments, to be placed within the current metallodrugs approach leading over the past decade to advanced multitarget agents endowed with limited toxicity and resistance. This strategy could allow for new options for breast cancer (BC) interventions, including the triple-negative subtype (TNBC) with poor therapeutic alternatives. BC is currently the second most widespread cancer and the primary cause of cancer death in women. Hence, the availability of novel chemotherapeutic weapons is a basic requirement to fight BC subtypes. Anticancer drugs based on ruthenium are among the most explored and advanced next-generation metallotherapeutics, with NAMI-A and KP1019 as two iconic ruthenium complexes having undergone clinical trials. In addition, many nanomaterial Ru complexes have been recently conceived and developed into anticancer drugs demonstrating attractive properties. In this field, we focused on the evaluation of a Ru(III) complex—named AziRu—incorporated into a suite of both zwitterionic and cationic nucleolipid nanosystems, which proved to be very effective for the in vivo targeting of breast cancer cells (BBC). Mechanisms of action have been widely explored in the context of preclinical evaluations in vitro, highlighting a multitarget action on cell death pathways which are typically deregulated in neoplasms onset and progression. Moreover, being AziRu inspired by the well-known NAMI-A complex, information on non-nanostructured Ru-based anticancer agents have been included in a precise manner.

Chemical analysis of the Mediterranean ascidian Polyandrocarpa zorritensis (Van Name 1931) resulted in the isolation of a series of molecules including two monoindole alkaloids, 3-indolylglyoxylic acid (3) and its methyl ester (4), 4-hydroxy-3-methoxyphenylglyoxylic acid methyl ester (1) and a new alkaloid we named zorrimidazolone (2). The structure of the novel compound 2 has been elucidated by spectroscopic analysis and bioactivity of all compounds has been investigated. Zorrimidazolone (2) showed a modest cytotoxic activity against C6 rat glioma cell line.

Mammalian cells require iron to satisfy metabolic needs or to accomplish specialized functions, and DNA viruses, like bovine herpesvirus 1 (BHV-1), require an iron-replete host to efficiently replicate, so that iron bioavailability is an important component of viral virulence. Cellular iron metabolism is coordinately controlled by the Iron Regulatory Proteins (IRP1 and IRP2), whose activity is affected by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a current and persistent environmental contaminant. Considering that TCDD enhances BHV-1 replication, herein we analyzed the effects of TCDD on iron metabolism during BHV-1 infection in MDBK cells, and presented evidences of a divergent modulation of IRP1 and IRP2 RNA-binding capacity. Moreover, an up-regulation of transferrin receptor 1 (TfR1) and a concomitant down-regulation of ferritin were observed. This scenario led to an expansion of the labile iron pool (LIP) and induces a significant enhance of viral titer, as confirmed by increased levels of BHV-1 infected cell protein 0 (bICP0), the major transcriptional regulatory protein of BHV-1. Taken together, our data suggest that TCDD increases the free intracellular iron availability thereby promoting the onset of BHV-1 infection and rendering bovine cells more vulnerable to the virus.

This paper is dedicated to the memory of our wonderful colleague Professor Alfredo Colonna, who passed away the same day of its acceptance. Fatty liver accumulation, inflammatory process and insulin resistance appear to be crucial in non-alcoholic fatty liver disease (NAFLD), nevertheless emerging findings pointed an important role also for iron overload. Here, we investigate the molecular mechanisms of hepatic iron metabolism in the onset of steatosis to understand whether its impairment could be an early event of liver inflammatory injury. Rats were fed with control diet or high fat diet (HFD) for 5 or 8 weeks, after which liver morphology, serum lipid profile, transaminases levels and hepatic iron content (HIC), were evaluated. In liver of HFD fed animals an increased time-dependent activity of iron regulatory protein 1 (IRP1) was evidenced, associated with the increase in transferrin receptor-1 (TfR1) expression and ferritin down-regulation. Moreover, ferroportin (FPN-1), the main protein involved in iron export, was down-regulated accordingly with hepcidin increase. These findings were indicative of an increased iron content into hepatocytes, which leads to an increase of harmful free-iron also related to the reduction of hepatic ferritin content. The progressive inflammatory damage was evidenced by the increase of hepatic TNF-α, IL-6 and leptin, in parallel to increased iron content and oxidative stress. The major finding that emerged of this study is the impairment of iron homeostasis in the ongoing and sustaining of liver steatosis, suggesting a strong link between iron metabolism unbalance, inflammatory damage and progression of disease.

Vitis vinifera sensitivity to tropospheric ozone (O3) has been evidenced in several studies. In this work, physiological and metabolic effects of O3 on two wine cultivars of V. vinifera (i.e. Maturano and San Giuseppe) have been studied. Moreover, chlorogenic acid (CGA) production, in consideration of its importance in the biosynthetic pathway of polyphenols and as antioxidant, has been investigated. Maturano cultivar resulted more sensitive to O3, as evidenced by the gas exchange reduction at the early stage of treatment, and by the increase in Ci/Ca and the decoupling of net photosynthesis and the stomatal conductance at the end of the treatment. Unexpectedly, O3 did not activate stilbene production. Ozone induced an early CGA decrease, significantly more consistent in cv. Maturano, and an increase after 8 days, more consistent in cv. S. Giuseppe. These results suggest that CGA could be considered a biochemical marker of O3-induced stress in V. vinifera. [ABSTRACT FROM AUTHOR]

Simple Summary: In this manuscript, we review the progress in knowledge made over the last decade, which, thanks to the commitment of many academics and researchers, has clarified many aspects relating to ferroptosis and its connections with cancer. Ferroptosis is currently regarded as a distinct type of regulated cell death (RCD), characterized by iron-dependent oxidative stress and the accumulation of lethal oxidized lipids. With a focus on the recent literature, the connection between iron homeostasis, oxidative stress and lipid metabolism is highlighted, which overall regulates ferroptotic cellular death. Moreover, special attention is devoted to the possible activation of this RCD pathway as a mechanism of tumor suppression. Its in-depth understanding from a regulatory and molecular perspective could provide important information for the development of new candidate drugs for the treatment of tumors resistant to conventional therapies. Based on the multifaceted molecular machinery that tightly controls iron cellular homeostasis, this review delves into its paradoxical, potentially dangerous role in biological systems, with a special focus on double-edged sword correlations with cancer. Indeed, though iron is a vital micronutrient and a required cofactor participating in several essential cell functions, its tendency to cause oxidative stress can be related both to cancer risk and to the activation of cancer cell death pathways. In this scenario, ferroptosis refers to an iron-dependent form of regulated cell death (RCD) powered by an overload of lethal peroxides sharing distinctive oxidized phospholipid profiles. As a unique cell death pathway, ferroptosis is both morphologically and mechanistically different from other types of programmed cell death involving executioner family proteins. The accumulation of cytotoxic lipid peroxides encompasses a cellular antagonism between ferroptosis execution and defense systems, with iron-dependent death occurring when ferroptosis-promoting activities significantly exceed the cellular antioxidant defenses. The most recent molecular breakthroughs in the execution of ferroptosis have aroused great consideration in tumor biology, as targeting ferroptosis can provide new tools for exploring therapeutic strategies for tumor suppression. Mutations and death/survival pathway alterations, as well as distinctive metabolic regulations of cancer cells, including the propensity to generate ROS, are seen as features that can render cancer cells unprotected to ferroptosis, thereby exposing vulnerabilities which deserve further attention to be regarded as targetable for cancers with limited therapeutic options. [ABSTRACT FROM AUTHOR]

Camptotheca acuminata Decne., a significant natural source of the anticancer drug camptothecin (CPT), synthesizes CPT through the monoterpene indole alkaloid (MIA) pathway. In this study, we used single-cell RNA sequencing (scRNA-seq) to generate datasets encompassing over 60,000 cells from C. acuminata shoot apexes and leaves. After cell clustering and annotation, we identified five major cell types in shoot apexes and four in leaves. Analysis of MIA pathway gene expression revealed that most of them exhibited heightened expression in proliferating cells (PCs) and vascular cells (VCs). In contrast to MIA biosynthesis in Catharanthus roseus, CPT biosynthesis in C. acuminata did not exhibit multicellular compartmentalization. Some putative genes encoding enzymes and transcription factors (TFs) related to the biosynthesis of CPT and its derivatives were identified through co-expression analysis. These include 19 cytochrome P450 genes, 8 O-methyltransferase (OMT) genes, and 62 TFs. Additionally, these pathway genes exhibited dynamic expression patterns during VC and EC development. Furthermore, by integrating gene and transposable element (TE) expression data, we constructed novel single-cell transcriptome atlases for C. acuminata. This approach significantly facilitated the identification of rare cell types, including peripheral zone cells (PZs). Some TE families displayed cell type specific, tissue specific, or developmental stage-specific expression patterns, suggesting crucial roles for these TEs in cell differentiation and development. Overall, this study not only provides novel insights into CPT biosynthesis and spatial-temporal TE expression characteristics in C. acuminata, but also serves as a valuable resource for further comprehensive investigations into the development and physiology of this species., (© 2024 Scandinavian Plant Physiology Society.)

Based on compelling preclinical evidence concerning the progress of our novel ruthenium-based metallotherapeutics, we are focusing research efforts on challenging indications for the treatment of invasive neoplasms such as the triple-negative breast cancer (TNBC). This malignancy mainly afflicts younger women, who are black, or who have a BRCA1 mutation. Because of faster growing and spreading, TNBC differs from other invasive breast cancers having fewer treatment options and worse prognosis, where existing therapies are mostly ineffective, resulting in a large unmet biomedical need. In this context, we benefited from an experimental model of TNBC both in vitro and in vivo to explore the effects of a biocompatible cationic liposomal nanoformulation, named HoThyRu/DOTAP, able to effectively deliver the antiproliferative ruthenium(III) complex AziRu, thus resulting in a prospective candidate drug. As part of the multitargeting mechanisms featuring metal-based therapeutics other than platinum-containing agents, we herein validate the potential of HoThyRu/DOTAP liposomes to act as a multimodal anticancer agent through inhibition of TNBC cell growth and proliferation, as well as migration and invasion. The here-obtained preclinical findings suggest a potential targeting of the complex pathways network controlling invasive and migratory cancer phenotypes. Overall, in the field of alternative chemotherapy to platinum-based drugs, these outcomes suggest prospective brand-new settings for the nanostructured AziRu complex to get promising goals for the treatment of metastatic TNBC. [ABSTRACT FROM AUTHOR]

To investigate how plants cope with multi-stress conditions, we analyzed the biochemical and molecular changes of Vitis vinifera leaves subjected to single or sequential double stresses (infection by Botrytis cinerea (Bc) and ozone (O3, 100 ppb for 3 h) treatment). In Bc+/O3− leaves, the hydrogen peroxide (H2O2) induction (observed at 12 and 24 h from the end of treatment (FET)) triggered a production of ethylene (Et; +35% compared with Bc−/O3− leaves), which was preceded by an increase of salicylic acid (SA; +45%). This result confirms a crosstalk between SA- and Et-related signaling pathways in lesion spread. The ozone induced an early synthesis of Et followed by jasmonic acid (JA) and SA production (about 2-fold higher), where Et and SA signaling triggered reactive oxygen species production by establishing a feedback loop, and JA attenuated this cycle by reducing Et biosynthesis. In Bc+ + O3+ leaves, Et peaked at 6 and 12 h FET, before SA confirmed a crosstalk between Et- and SA-related signaling pathways in lesion propagation. In O3+ + Bc+ leaves, the H2O2 induction triggered an accumulation of JA and Et, demonstrating a synergistic action in the regulation of defence reactions. The divergence in these profiles suggests a rather complex network of events in the transcriptional regulation of genes involved in the systemic acquired resistance. [ABSTRACT FROM AUTHOR]

The application of ozonated water in the vineyard is an increasingly popular tool for disease management, but the quality of grapes and resulting wines is likely to be affected. Endotherapy, or trunk injection, is a particularly useful method to apply phytosanitary products since many fungal pathogens colonize the grapevine woody tissues. Thus, the present study aimed to evaluate the effect on wine quality of the ozonated water applied to Bobal grapevines, one of the most cultivated red varieties in Spain, through endotherapy (E) or its combination with spraying (E + S). Endotherapy was carried out four times before harvest for both E and E + S treatments, and spraying was performed 2 days before and after each endotherapy application. Grapes were harvested, vinified, and the quality of the finished wines was evaluated through several enological parameters and the phenolic and volatile composition. Both treatments resulted in less alcoholic and more acidic wines. The E treatment, although it reduced the content of phenolic acids, stilbenes and flavanols, significantly increased anthocyanins, whereas E + S decreased the overall amount of phenolics, which had different implications for wine colour. In terms of aroma, both treatments, but E to a greater extent, reduced the content of glycosylated precursors and differentially affected free volatiles, both varietal and fermentative. Thus, the dose of ozonated water, frequency and/or method of application are determining factors in the effect of these treatments on wine quality and must be carefully considered by winegrowers to establish the optimum treatment conditions so as not to impair the quality of wines. [ABSTRACT FROM AUTHOR]

Countless expectations converge in the multidisciplinary endeavour for the search and development of effective and safe drugs in fighting cancer. Although they still embody a minority of the pharmacological agents currently in clinical use, metal-based complexes have great yet unexplored potential, which probably hides forthcoming anticancer drugs. Following the historical success of cisplatin and congeners, but also taking advantage of conventional chemotherapy limitations that emerged with applications in the clinic, the design and development of non-platinum metal-based chemotherapeutics, either as drugs or prodrugs, represents a rapidly evolving field wherein candidate compounds can be fine-tuned to access interactions with druggable biological targets. Moving in this direction, over the last few decades platinum family metals, e.g., ruthenium and palladium, have been largely proposed. Indeed, transition metals and molecular platforms where they originate are endowed with unique chemical and biological features based on, but not limited to, redox activity and coordination geometries, as well as ligand selection (including their inherent reactivity and bioactivity). Herein, current applications and progress in metal-based chemoth are reviewed. Converging on the recent literature, new attractive chemotherapeutics based on transition metals other than platinum—and their bioactivity and mechanisms of action—are examined and discussed. A special focus is committed to anticancer agents based on ruthenium, palladium, rhodium, and iridium, but also to gold derivatives, for which more experimental data are nowadays available. Next to platinum-based agents, ruthenium-based candidate drugs were the first to reach the stage of clinical evaluation in humans, opening new scenarios for the development of alternative chemotherapeutic options to treat cancer. [ABSTRACT FROM AUTHOR]

Ozone (O3) stress severely affects the normal growth of grape (Vitis vinifera L.) leaves. Melatonin (MT) plays a significant role in plant response to various abiotic stresses, but its role in O3 stress and related mechanisms are poorly understood. In order to understand the mechanism of MT in alleviate O3 stress in grape leaves, we perform a transcriptome analyses of grapes leaves under O3 stress with or without MT treatment. Transcriptome analysis showed that the processes of ethylene biosynthesis and signaling were clearly changed in "Cabernet Sauvignon" grapes under O3 and MT treatment. O3 stress induced the expression of genes related to ethylene biosynthesis and signal transduction, while MT treatment significantly inhibited the ethylene response mediated by O3 stress. Further experiments showed that both MT and aminoethoxyvinylglycine (AVG, an inhibitor of ethylene biosynthesis) enhanced the photosynthetic and antioxidant capacities of grape leaves under O3 stress, while ethephon inhibited those capacities. The combined treatment effect of MT and ethylene inhibitor was similar to that of MT alone. Exogenous MT reduced ethylene production in grape leaves under O3 stress, while ethephon and ethylene inhibitors had little effect on the MT content of grape leaves after O3 stress. However, overexpression of VvACO2 (1-aminocyclopropane-1-carboxylate oxidase2) in grape leaves endogenously induced ethylene accumulation and aggravated O3 stress. Overexpression of the MT synthesis gene VvASMT1 (acetylserotonin methyltransferase1) in tobacco (Nicotiana tabacum L.) alleviated O3 stress and reduced ethylene biosynthesis after O3 stress. In summary, MT can alleviate O3 stress in grape leaves by inhibiting ethylene biosynthesis. [ABSTRACT FROM AUTHOR]

Introduction: Melanocytes are engaged in synthesis, transport, and release of pigments at the epidermal-melanin units in response to the finely regulated melanogenic pathway. A multifaceted combination of both intrinsic and extrinsic factors – from endocrine and paracrine dynamics to exogenous stimuli such as sunlight and xenobiotics – modulates expression and activity of proteins involved in pigmentation, including the rate-limiting enzyme tyrosinase. As well as playing critical physiological functions comprising skin photoprotection, melanins define hair and skin pigmentation which in turn have impacted considerably to human social communication since time immemorial. Additionally, numerous skin diseases based on pigmentation alterations can have serious public influence. While several melanogenesis inhibitors are already available, the number of melanin activators and tyrosinase stimulators as drug-like agents is still limited. Methods: To explore the biological effects of an Annurca Apple-based nutraceutical preparation (AMS) on melanin production, experiments in cellular models of human skin were performed. Both primary cultures and co-cultures of epidermal melanocytes (HEMa) and follicular keratinocytes (HHFK) were used. Results: We show that AMS, by now branded for its cutaneous beneficial effects, induces in total biocompatibility a significant promelanogenic effect in human primary melanocytes. In line, we found melanin cytosolic accumulation consistent with tyrosinase up-regulation. Conclusion: Disposal of skin pigmenting agents would be attractive for the treatment of hypopigmentation disorders, to postpone skin photoaging or simply for fashion, so that discovery and development of melanogenesis stimulators, especially from natural sources, is nowadays a dynamic area of research. [ABSTRACT FROM AUTHOR]

Bacterial canker of Actinidia, caused by the bacterium Pseudomonas syringae pv. actinidiae (Psa), is the most serious disease of these plants worldwide. Leaves of three species of Actinidia, namely A. chinensis var. chinensis, A. chinensis var. deliciosa and A. arguta, having different degrees of tolerance to Psa, were analyzed by Nuclear Magnetic Resonance spectroscopy. Aqueous extracts of leaves were studied and several metabolites, classified as organic acids, amino acids, carbohydrates, phenols and other metabolites, were identified by 1D and 2D NMR experiments and quantified. The metabolic profiles of these species were compared through univariate statistical analysis ANOVA and multivariate PCA. Levels of metabolites with known antibacterial activity, such as caffeic and chlorogenic acids, were observed to be higher in the A. arguta samples. Moreover, these metabolites have different Pearson correlation patterns among the three Actinidia species, suggesting a difference at the phenylpropanoid biosynthetic pathway. [ABSTRACT FROM AUTHOR]

While protein synthesis in neurons is largely attributed to cell body and dendrites, the capability of synaptic regions to synthesize new proteins independently of the cell body has been widely demonstrated as an advantageous mechanism subserving synaptic plasticity. Thus, the contribution that local protein synthesis at synapses makes to physiology and pathology of brain plasticity may be more prevalent than initially thought. In this study, we tested if local protein synthesis at synapses is deregulated in the brains of TgCRND8 mice, an animal model for Alzheimer's disease (AD) overexpressing mutant human amyloid precursor protein (APP). To this end, we used synaptosomes as a model system to study the functionality of the synaptic regions in mouse brains. Our results showed that, while TgCRND8 mice exhibit early signs of brain inflammation and deficits in learning, the electrophoretic profile of newly synthesized proteins in their synaptosomes was subtly different from that of the control mice. Interestingly, APP itself was, in part, locally synthesized in the synaptosomes, underscoring the potential importance of local translation at synapses. More importantly, after the contextual fear conditioning, de novo synthesis of some individual proteins was significantly enhanced in the synaptosomes of control animals, but the TgCRND8 mice failed to display such synaptic modulation by training. Taken together, our results demonstrate that synaptic synthesis of proteins is impaired in the brain of a mouse model for AD, and raise the possibility that this deregulation may contribute to the early progression of the pathology. [ABSTRACT FROM AUTHOR]

The role of the cerebellum in Alzheimer's disease (AD) has been neglected for a long time. Recent studies carried out using transgenic mouse models have demonstrated that amyloid-β (Aβ) is deposited in the cerebellum and affects synaptic transmission and plasticity, sometimes before plaque formation. A wide variability of motor phenotype has been observed in the different murine models of AD, without a consistent correlation with the extent of cerebellar histopathological changes or with cognitive deficits. The loss of noradrenergic drive may contribute to the impairment of cerebellar synaptic function and motor learning observed in these mice. Furthermore, cerebellar neurons, particularly granule cells, have been used as in vitro model of Aβ-induced neuronal damage. An unexpected conclusion is that the cerebellum, for a long time thought to be somehow protected from AD pathology, is actually considered as a region vulnerable to Aβ toxic damage, even at the early stage of the disease, with consequences on motor performance. [ABSTRACT FROM AUTHOR]