Preclinical development of anticancer Ru-based nanoaggregates in breast cancer models

Cancer, a growing health problem around the world, affects millions of people every year, so that innovative anticancer drugs with specific molecular mechanisms of action are essential in chemotherapeutic treatment to kill specific cancer types, and to overcome toxic side effects as well as chemoresistance. Impaired apoptosis and autophagy seem to play a central role in cancer development and constantly limit the efficacy of conventional cytotoxic therapies. Indeed, current research efforts are focused on a deeper understanding of the cellular response and/or resistance to anticancer treatments, including the role of cell death pathways activation by metallochemotherapeutics such as novel ruthenium-based drugs, proposed as safe and effective potential drugs. Moreover, in the last few years nanostructures have gained considerable interest for the safe delivery of therapeutic agents. In these fields, we have recently developed a novel approach for the in vivo delivery of novel Ru(III) complexes, preparing stable nucleolipidic-based formulations endowed with considerable antiproliferative activity. In particular, aiming at improving the suitability of Ru(III) complexes in biological environment - specifically of AziRu, a pyridine NAMI-A analog - as well as their advantages for biomedical applications, we have designed innovative nanoaggregates by means of high-functionalized nucleolipidic Ru(III) complexes, ad hoc mixed with zwitterionic or cationic lipids to provide stable and biocompatible liposome formulations for cancer therapy. Hence, in line with this project and by in vitro bioscreens in the frame of preclinical studies, we have focused on the ability of nucleolipidic ruthenium-containing liposomes to inhibit cancer proliferation in selected human breast cancer models in vitro, possibly by predisposing cells to programmed cell death. In the case, breast cancer is the second most common cancer worldwide after lung cancer, the fifth most common cause of cancer death, and the leading cause of cancer death in women. The global weight of breast cancer exceeds all other cancers and the incidence rates of breast cancer are increasing. Luckily, the total survival rates of most cancers have been prolonged due to the energies of both clinicians and scientists. Behind an in-depth microstructural characterization, we have herein demonstrated that the most efficient ruthenium-containing cationic nanoaggregates we have hitherto developed are able to elicit both extrinsic and intrinsic apoptosis, as well as autophagy. Using especially designed fluorescent formulations and confocal microscopy approaches for targeted studies of intracellular localization, in addition to subcellular fractionation and inductively coupled plasma-mass spectrometry (ICP-MS) to assess cellular accumulation, we have detected, unlike the naked AziRu, a wide both cytosolic and nuclear distribution of the active Ru(III) complex. This would allow the ruthenium to interact with both mitochondrial and nuclear molecular targets, accounting for its ability to inhibit breast cancer cell proliferation by the activation of multiple cell death pathways, possibly via mitochondrial perturbations involving Bcl-2 family members, and Ru(III) ions incorporation into double-stranded DNA. To limit chemoresistance and counteract uncontrolled proliferation, multiple cell death pathways activation is a promising strategy for targeted therapy development, especially in aggressive cancer diseases such as triple-negative breast cancer with limited treatment options. The heterogeneity of breast cancers makes them both a fascinating and difficult solid tumour to diagnose and treat. Triple-negative breast cancers in particular are difficult to define lacking Her2 expression, estrogen and progesterone receptor, and do not respond to hormonal therapies or Her2-targeted therapies; hence, new systemic therapies are desperately needed. The oncology community needs for a new dawn of innovative and creative means to overcome these challenges so we can witness further breakthroughs. Moreover, allowing for the importance of the tumour microenvironment as well as of the stromal components playing both critical role in the tumourigenic process, the function of cancer-associated immune cell system and their cellular secrets were also investigated, in order to achieve a deeper understanding of the typical molecular pathways involved in the cross-talk between tumour components and stromal cells; this would allow to properly act on tumour microenvironment in order to further improve the efficacy of chemotherapy. In this case, the EPO/ESA treatment – commonly used in therapy for anaemia – can induce tumour progression and growth, because of its impact on the anti-cancer immune response. So overall these outcomes discharge original knowledge in the field of anticancer therapy and on ruthenium-based candidate drugs, thus providing new insights for future optimized cancer treatment protocols

Bioactivity and Development of Small Non-Platinum Metal-Based Chemotherapeutics

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

Health-related quality of life and psychological features in post-stroke patients with chronic pain: a cross-sectional study in the neuro-rehabilitation context of care

Abstract: This study aims at exploring disability, health-related quality of life (HrQoL), psycholog- ical distress, and psychological features in post-stroke patients with chronic pain. An observational cross-sectional study involving 50 post-stroke patients (25 with chronic pain and 25 without pain) was conducted. The primary outcome was the self-reported level of disability and HrQoL which were both assessed through the Stroke Impact Scale 3.0. Both psychological distress and specific psychological features (i.e., self-efficacy, coping strategies, psychological flexibility, perceived social support) were examined. Post-stroke patients with chronic pain reported statistically significant higher levels of disability and worse HrQoL, higher psychological distress and inflexibility, as well as a lower level of self-efficacy and problem-oriented coping strategies than patients without pain (p < 0.001). Finally, correlation analysis in the group of stroke survivors with pain showed that higher levels of disability were significantly related to higher psychological distress. This study con- firms the negative influence of chronic pain on disability and HrQoL in post-stroke patients and presents preliminary insights on the association between chronic pain, disability, HrQoL, psycho- social distress, and the patient\u2019s approach in dealing with personal difficulties and emotions. These findings carry further implications for multidisciplinary management of post-stroke patients with chronic pain

e-Health interventions targeting pain-related psychological variables in fibromyalgia: a systematic review

There is growing evidence to support the potential benefit of e-Health interventions targeting psychosocial outcomes and/or pain-related psychological variables for chronic pain conditions, including fibromyalgia syndrome (FMS). This systematic review aims at providing an in-depth description of the available e-Health psychological and/or multicomponent interventions for patients with FMS. Searches were made in PubMed, Cochrane, Web of Science, and PsycINFO up to 15 May 2023, finally including twenty-six articles. The quality of the included articles was medium–high (average quality assessment score of 77.1%). 50% of studies were randomized controlled trials (RCTs) (n = 13), and the majority of them focused exclusively on adult patients with FMS (n = 23) who were predominantly female. Four categories of e-Health modalities were identified: web-based (n = 19), mobile application (m-Health) (n = 3), virtual reality (VR) (n = 2), and video consulting (n = 2). Interventions were mainly based on the cognitive behavioral therapy (CBT) approach (n = 14) and mostly involved contact with a healthcare professional through different digital tools. Overall, a growing number of psychological and multicomponent interventions have been created and delivered using digital tools in the context of FMS, showing their potentiality for improving psychosocial outcomes and pain-related psychological variables. However, some digital tools resulted as underrepresented, and the literature on this topic appears highly heterogeneous precluding robust conclusions

Cysteine Prevents the Reduction in Keratin Synthesis Induced by Iron Deficiency in Human Keratinocytes

L-cysteine is currently recognized as a conditionally essential sulphur amino acid. Besides contributing to many biological pathways, cysteine is a key component of the keratin protein by its ability to form disulfide bridges that confer strength and rigidity to the protein. In addition to cysteine, iron represents another critical factor in regulating keratins expression in epidermal tissues, as well as in hair follicle growth and maturation. By focusing on human keratinocytes, the aim of this study was to evaluate the effect of cysteine supplementation as nutraceutical on keratin biosynthesis, as well as to get an insight on the interplay of cysteine availability and cellular iron status in regulating keratins expression in vitro. Herein we demonstrate that cysteine promotes a significant up-regulation of keratins expression as a result of de novo protein synthesis, while the lack of iron impairs keratin expression. Interestingly, cysteine supplementation counteracts the adverse effect of iron deficiency on cellular keratin expression. This effect was likely mediated by the up-regulation of transferrin receptor and ferritin, the main cellular proteins involved in iron homeostasis, at last affecting the labile iron pool. In this manner, cysteine may also enhance the metabolic iron availability for DNA synthesis without creating a detrimental condition of iron overload. To the best of our knowledge, this is one of the first study in an in vitro keratinocyte model providing evidence that cysteine and iron cooperate for keratins expression, indicative of their central role in maintaining healthy epithelia. This article is protected by copyright. All rights reserved

Breast cancer chemotherapeutic options: a general overview on the preclinical validation of a multi-target ruthenium(III) complex lodged in nucleolipid nanosystems

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 nextgeneration 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

Promelanogenic Effects by an Annurca Apple-Based Natural Formulation in Human Primary Melanocytes

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

A prospective observational cohort study on pharmacological habitus, headache-related disability and psychological profile in patients with chronic migraine undergoing onabotulinumtoxina prophylactic treatment

Chronic Migraine (CM) is a disabling neurologic condition with a severe impact on functioning and quality of life. Successful therapeutic management of patients with CM is complex, and differences in therapeutic response could be attributable to genetically determined factors, sensitivity to pharmacological treatment, psychosocial and relational factors affecting the patient's compliance and approach on the therapeutic treatment. The aim of this prospective observational study was to explore self-efficacy, coping strategies, psychological distress and headache-related disability in a cohort of 40 patients with CM (mean age: 46.73; standard deviation 13.75) treated with OnabotulinumtoxinA and the relationship between these clinical and psychological aspects and acute medication consumption during OnabotulinumtoxinA prophylactic treatment. Patients presented an overall significant reduction in the Headache Index (HI) (p < 0.001), HI with severe intensity (p = 0.009), and total analgesic consumption (p = 0.003) after the prophylactic treatment. These results are in line with the literature. Despite this, higher nonsteroidal anti-inflammatory drugs consumption was associated with higher psychological distress, higher HI with severe and moderate intensity, and worse quality of life. Conversely, triptans consumption was correlated with HI of mild intensity, and problem-focused coping strategies. To conclude, the psychological profile, and in particular, the psychological distress and specific coping strategies might influence the self-management of acute medication

A Prospective Observational Cohort Study on Pharmacological Habitus, Headache-Related Disability and Psychological Profile in Patients with Chronic Migraine Undergoing OnabotulinumtoxinA Prophylactic Treatment

Chronic Migraine (CM) is a disabling neurologic condition with a severe impact on functioning and quality of life. Successful therapeutic management of patients with CM is complex, and differences in therapeutic response could be attributable to genetically determined factors, sensitivity to pharmacological treatment, psychosocial and relational factors affecting the patient’s compliance and approach on the therapeutic treatment. The aim of this prospective observational study was to explore self-efficacy, coping strategies, psychological distress and headache-related disability in a cohort of 40 patients with CM (mean age: 46.73; standard deviation 13.75) treated with OnabotulinumtoxinA and the relationship between these clinical and psychological aspects and acute medication consumption during OnabotulinumtoxinA prophylactic treatment. Patients presented an overall significant reduction in the Headache Index (HI) (p < 0.001), HI with severe intensity (p = 0.009), and total analgesic consumption (p = 0.003) after the prophylactic treatment. These results are in line with the literature. Despite this, higher nonsteroidal anti-inflammatory drugs consumption was associated with higher psychological distress, higher HI with severe and moderate intensity, and worse quality of life. Conversely, triptans consumption was correlated with HI of mild intensity, and problem-focused coping strategies. To conclude, the psychological profile, and in particular, the psychological distress and specific coping strategies might influence the self-management of acute medication