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Background: Breast cancer remains the leading cause of cancer-related deaths among women despite advances in early detection. Neoadjuvant chemotherapy (NACT) is now standard for early-stage BC, with vitamin D (VD) emerging as a potential prognostic biomarker considering its positive pleiotropic effects. This review and meta-analysis assess the impact of baseline VD levels on outcomes in BC patients undergoing NACT. Methods: Inclusion criteria required patients to be over 18 years of age, have a pathologically confirmed BC diagnosis, and have their VD levels assessed prior to chemotherapy. Studies were included if they reported odds ratios (ORs) for response and/or hazard ratios (HRs) for PFS with 95% confidence intervals (CIs). A comprehensive literature search of PubMed/MEDLINE and Scopus/ELSEVIER (2014-2024) was conducted, and data were analyzed using fixed- and random-effects models, with Forest plots illustrating the results. Study quality and potential biases were assessed using the MINORS, NOS, and RoB2 scales, and statistical heterogeneity was evaluated with I 2 statistics and funnel plots. Results: Six studies were included in the analysis. All studies addressed stages II and III, with three also including stage I. The meta-analysis covered data from 722 patients regarding NACT response and 1033 patients for PFS. The results revealed a 22% reduction in the likelihood of non-response to NACT associated with adequate VD levels (low/deficient VD vs. high/sufficient VD; OR: 0.78; 95% CI: 0.30-1.25; p = 0.001) and a 35% reduction in progression risk with sufficient baseline VD levels (low/deficient VD vs. high/sufficient VD; HR: 0.65; 95% CI: 0.33-0.97; p < 0.001). Conclusions: These findings highlight the significance of maintaining adequate vitamin D levels in BC treatment and encourage further studies to unravel the role of VD on cancer biology.

The gut microbiota is a very important factor in the state of health of an individual, its alteration implies a situation of "dysbiosis," which can be connected to functional gastrointestinal disorders and pathological conditions, such as Inflammatory Bowel Disease (IBD), Irritable Bowel Syndrome (IBS), Ulcerative Colitis (UC) and Crohn's Disease (CD), and Colorectal Cancer (CRC). In this work, we studied the effect of a food supplement called ENTERO-AD containing a mix of probiotics ( Lactobacillus acidophilus LA1, L. reuteri LR92, Bifidobacterium breve Bbr8), Matricaria Chamomilla , and B group vitamins (B1, B2, B6) on intestinal inflammation. The in vitro model used for the study is the Caco-2 cell, a culture derived from human intestinal adenocarcinoma; the inflammatory condition was achieved with treatment with Lipopolysaccharide (LPS) and the association between Tumor necrosis factor α/Interferon γ (TNF-α/IFN-γ) [1,2]. The effect of ENTERO-AD was evaluated by cell viability, measures of Transepithelial Electrical Resistance (TEER), paracellular permeability, and immunofluorescence. Results of the study have shown that ENTERO-AD has a favorable effect on Caco-2 cells in inflammatory conditions. It improves the integrity of Occludin and Zonula Occludens-1 (ZO-1) proteins, leading to an improvement in terms of TEER values and a reduction of paracellular permeability. This evidence underlines the protective effect of ENTERO-AD and its components in intestinal inflammation., (Copyright ©2024, Yale Journal of Biology and Medicine.)

Since the beginning of the COVID-19 pandemic, it has been evident that women and young people were less susceptible to severe infections compared to males. In a previous study, we observed a reduced prevalence of SARS-CoV-2 infections in hormonal-driven breast cancer patients undergoing SERM (selective estrogen receptor modulator) therapy with respect to other treatments inhibiting estrogen synthesis. In addition to being used in anticancer therapy, SERMs are also prescribed for postmenopausal osteoporosis prevention and treatment. Therefore, in this study, a retrospective analysis of the clinical outcomes of SARS-CoV-2 infections in a population of women over 50 years who were treated for the management of menopausal symptoms was performed. SARS-CoV-2 infections, hospitalizations, and death rates were evaluated in women residing in the Italian north-eastern Veneto Region who were undergoing treatment with Estrogen Modulators (EMs); Estrogen or Progestin, and their combination (EPs); Bisphosphonates (BIs); or cholecalciferol (vitamin D3) ± calcium supplementation (CC). The final cohort study included 124,393 women, of whom 6412 were found to be SARS-CoV-2 infected (CoV2+ve). The results indicated that only women treated with vitamin D3 alone or in combination with calcium showed a significant reduction in their SARS-CoV-2 infection risk by 26% (OR 0.74; 95%CI 0.60-0.91). On the other hand, an increased risk of hospitalization (OR 2.69; 95%CI 1.77-4.07) was shown for the same treatments. The results highlighted in this work contribute to shedding some light on the widely debated role of vitamin D in the prevention of SARS-CoV-2 infections and the disease's treatment.

Accumulating senescent cells within tissues contribute to the progression of aging and age-related diseases. Botanical extracts, rich in phytoconstituents, present a useful resource for discovering therapies that could target senescence and thus improve healthspan. Here, we show that daily oral administration of a standardized extract of Salvia haenkei (Haenkenium (HK)) extended lifespan and healthspan of naturally aged mice. HK treatment inhibited age-induced inflammation, fibrosis and senescence markers across several tissues, as well as increased muscle strength and fur thickness compared with age-matched controls. We also found that HK treatment reduced acutely induced senescence by the chemotherapeutic agent doxorubicin, using p16 LUC reporter mice. We profiled the constituent components of HK by mass spectrometry, and identified luteolin-the most concentrated flavonoid in HK-as a senomorphic compound. Mechanistically, by performing surface plasmon resonance and in situ proximity ligation assay, we found that luteolin disrupted the p16-CDK6 interaction. This work demonstrates that administration of HK promotes longevity in mice, possibly by modulating cellular senescence and by disrupting the p16-CDK6 interaction., (© 2024. The Author(s).)

Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in "immunologically cold" tumors., Competing Interests: Declaration of interests A.A. is a co-founder of and owns stock in OncoSense, and A.A., M.C., and A.R. are inventors of the patent WO2019142095A1 (Title: new alk inhibitor senolytic drugs)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Imaging disdrometers are widely used in field campaigns to provide information on the shape of hydrometeors, together with the diameter and the fall velocity, which can be used to derive information on the shape-size relations of hydrometeors. However, due to their higher price compared to laser disdrometers, their use is limited to scientific research purposes. The 3D stereo (3DS) is a commercial imaging disdrometer recently made available by Thies Clima and on which there are currently no scientific studies in the literature. The most innovative feature of the 3DS is its ability in capturing images of the particles passing through the measurement volume, crucial to provide an accurate classification of hydrometeors based on information about their shape, especially in the case of solid precipitation. In this paper. the performance of the new device is analyzed by comparing 3DS with the Laser Precipitation Monitor (LPM) from the same manufacturer, which is a known laser disdrometer used in many research works. The data used in this paper were obtained from measurements of the two instruments carried out at the Casale Calore site in L'Aquila during the CORE-LAQ (Combined Observations of Radar Experiments in L'Aquila) campaign. The objective of the comparison analysis is to analyze the differences between the two disdrometers in terms of hydrometeor classification, number and falling speed of particles, precipitation intensity, and total cumulative precipitation on an event basis. As regards the classification of precipitation, the two instruments are in excellent agreement in identifying rain and snow; greater differences are observed in the case of particles in mixed phase (rain and snow) or frozen phase (hail). Due to the different measurement area of the two disdrometers, the 3DS generally detects more particles than the LPM. The performance differences also depend on the size of the hydrometeors and are more significant in the case of small particles, i.e., D < 1 mm. In the case of rain events, the two instruments are in agreement with respect to the terminal velocity in still air predicted by the Gunn and Kinzer model for drops with a diameter of less than 3 mm, while, for larger particles, terminal velocity is underestimated by both the disdrometers. The agreement between the two instruments in terms of total cumulative precipitation per event is very good. Regarding the 3DS ability to capture images of hydrometeors, the raw data provide, each minute, from one to four images of single particles and information on their size and type. Their number and coarse resolution make them suitable to support only qualitative analysis of the shape of precipitating particles.

This conference addresses the topic of integrative, multidisciplinary approaches to cancer settings according to evidence-based medicine. The multidisciplinary approach of the researchers involved characterizes this new and complex scenario. The Integrative Medicine Research Group (IMRG) has always been committed to the activities and dissemination of CAM in cancer patients, focusing on the safety and efficacy of these approaches. Thus, one of the main goals of IMRG is to demonstrate that CAM can support cancer patients during treatment and improve their quality of life and survival. In addition, IMRG's multidisciplinary network is ever vigilant in assessing the risks of interactions between cancer drugs and nutraceuticals. We hope that the integrative medicine approach can be transferred to the level of all chronic diseases, including oncology.

Clouds cover substantial parts of the Earth's surface and they are one of the most essential components of the global climate system impacting the Earth's radiation balance as well as the water cycle redistributing water around the globe as precipitation. Therefore, continuous observation of clouds is of primary interest in climate and hydrological studies. This work documents the first efforts in Italy in remote sensing clouds and precipitation using a combination of K- and W-band (24 and 94 GHz, respectively) radar profilers. Such a dual-frequency radar configuration has not been widely used yet, but it could catch on in the near future given its lower initial cost and ease of deployment for commercially available systems at 24 GHz, with respect to more established configurations. A field campaign running at the Casale Calore observatory at the University of L'Aquila, Italy, nestled in the Apennine mountain range is described. The campaign features are preceded by a review of the literature and the underpinning theoretical background that might help newcomers, especially in the Italian community, to approach cloud and precipitation remote sensing. This activity takes place in interesting time for radar sensing clouds and precipitation, stimulated both by the launch of the ESA/JAXA EarthCARE satellite missions scheduled in 2024, which will have on-board, among other instruments, a W-band Doppler cloud radar and the proposal of new missions using cloud radars currently undergoing their feasibility studies (e.g., WIVERN and AOS in Europe and Canada, and U.S., respectively).

Background: Vitamin D (VD) has been implicated in several diseases, including colorectal cancer (CRC). This study aimed to determine whether there is an association between VD levels and time-to-outcome in stage III CRC patients through a systematic review and meta-analysis., Methods: The study adhered to the PRISMA 2020 statement. Articles were searched in PubMed/MEDLINE and Scopus/ELSEVIER. Four articles were selected, with the primary objective of providing a pooled estimate of the risk of death specifically in stage III CRC patients based on pre-operative VD levels. Study heterogeneity and publication bias were analyzed using Tau 2 statistics and funnel plots., Results: The selected studies showed significant heterogeneity regarding time-to-outcome, technical assessments, and serum VD concentration measures. The pooled analysis of 2628 and 2024 patients revealed a 38% and 13% increase in the risk of death (HR: 1.38, 95% CI: 0.71-2.71) and recurrence (HR: 1.13; 95% CI: 0.84-1.53), respectively, for random-effects models among patients with lower levels of VD., Conclusions: Our findings suggest that a low concentration of VD has a significant negative impact on time-to-outcome in stage III CRC.

Background: Irritable bowel syndrome (IBS) and Inflammatory bowel disease (IBD) are pathological conditions that severely hamper the quality of life of patients. Especially in pediatric and adolescent patients, the use of Complementary and alternative medicine is an appealing approach as an adjuvant for the management of symptoms, limiting the detrimental effect of the conventional therapy. In this work, we tested the effect of Enterokind Junior (EntJ), a mix of two probiotic strains Lactobacillus reuteri DSM 25175 and Lactobacillus acidophilus DSM 24936, Matricaria Chamomilla, and vitamins, in in vitro model of intestinal inflammation. Caco-2 cells were subjected to LPS treatment or THP-1 cells stimulated with LPS treatment, as paradigms of inflammatory conditions., Methods: The effect of the probiotic formulation was evaluated by measuring Caco-2 monolayer's Transepithelial Electrical resistance (TEER) and paracellular permeability alterations, tight junction proteins expression and localization by confocal microscopy, and release of pro-inflammatory cytokines (TNF-α and IL-8) by ELISA assay., Results: Results demonstrated that upon impairment of intestinal parameters induced by inflammatory stimuli, the combination of probiotic was able to prevent TEER decrease and paracellular permeability alterations and to maintain the tight junction expression and localization. Moreover, the release of proinflammatory cytokines induced by inflammation was reduced by EntJ treatment., Conclusions: This work, in line with previous observations, supports a protective role of Lactobacillus reuteri DSM 25175, Lactobacillus acidophilus DSM 24936 and the other components in the maintenance of a healthy gut, holding up the use of this combination as an adjuvant for irritable bowel syndrome-related symptoms management.

The introduction of highly active antiretroviral therapy (ART) has deeply modified the outcome of HIV patients by improving their overall survival and ameliorating their quality of life (QoL). The prolongation of these patients' survival has led to an increased risk of highly diffused non-infectious diseases, e.g., cardiovascular diseases, endocrine disease, neurological diseases, and cancer. The management of antiretroviral therapy and anticancer agents (AC) can be challenging, due to the possible drug-drug interactions (DDI) between AC and ART. For this reason, a multidisciplinary approach is always preferred as demonstrated by the GICAT (Italian Cooperation Group on AIDS and Tumors). This review aims to analyze the current scientific data regarding the possible effects of ART on the management of HIV-positive cancer patients and to evaluate the possible DDIs that must be taken into consideration when co-administrating ART and AC. A collaboration between all the involved professional figures, particularly infectious disease specialists and oncologists, represents the key to the correct managing of these patients in order to guarantee the best oncological outcome possible.

Tumor cells promote the recruitment of immunosuppressive neutrophils, a subset of myeloid cells driving immune suppression, tumor proliferation, and treatment resistance. Physiologically, neutrophils are known to have a short half-life. Here, we report the identification of a subset of neutrophils that have upregulated expression of cellular senescence markers and persist in the tumor microenvironment. Senescent-like neutrophils express the triggering receptor expressed on myeloid cells 2 (TREM2) and are more immunosuppressive and tumor-promoting than canonical immunosuppressive neutrophils. Genetic and pharmacological elimination of senescent-like neutrophils decreases tumor progression in different mouse models of prostate cancer. Mechanistically, we have found that apolipoprotein E (APOE) secreted by prostate tumor cells binds TREM2 on neutrophils, promoting their senescence. APOE and TREM2 expression increases in prostate cancers and correlates with poor prognosis. Collectively, these results reveal an alternative mechanism of tumor immune evasion and support the development of immune senolytics targeting senescent-like neutrophils for cancer therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Osteosarcoma is considered the most common bone tumor affecting children and young adults. The standard of care is chemotherapy; however, the onset of drug resistance still jeopardizes osteosarcoma patients, thus making it necessary to conduct a thorough investigation of the possible mechanisms behind this phenomenon. In the last decades, metabolic rewiring of cancer cells has been proposed as a cause of chemotherapy resistance. Our aim was to compare the mitochondrial phenotype of sensitive osteosarcoma cells (HOS and MG-63) versus their clones when continuously exposed to doxorubicin (resistant cells) and identify alterations exploitable for pharmacological approaches to overcome chemotherapy resistance. Compared with sensitive cells, doxorubicin-resistant clones showed sustained viability with less oxygen-dependent metabolisms, and significantly reduced mitochondrial membrane potential, mitochondrial mass, and ROS production. In addition, we found reduced expression of TFAM gene generally associated with mitochondrial biogenesis. Finally, combined treatment of resistant osteosarcoma cells with doxorubicin and quercetin, a known inducer of mitochondrial biogenesis, re-sensitizes the doxorubicin effect in resistant cells. Despite further investigations being needed, these results pave the way for the use of mitochondrial inducers as a promising strategy to re-sensitize doxorubicin cytotoxicity in patients who do not respond to therapy or reduce doxorubicin side effects.

Platinum agents, which include cisplatin, oxaliplatin and carboplatin, are chemotherapeutic drugs that represent the first-line treatment for different types of solid tumors, such as ovarian, head and neck, testicular, and bladder cancers. Their beneficial effect is limited by the onset of drug resistance and severe toxicities, involving mainly ototoxicity, neurotoxicity and nephrotoxicity. Recent studies highlight the supplementation of herbal products, vitamins and minerals with antioxidant properties to prevent and protect from side effects. In particular, the introduction of nutraceuticals associated with chemotherapy has improved the patients' quality of life. However, if from one side, complementary and alternative medicine ameliorates chemotherapeutics-induced toxicities, from the other side, it is important to take into consideration the possible interference with drug metabolism. This review aims to consider the current literature focusing on clinical trials that report an association between nutraceutical supplementation and platinum- based chemotherapy to prevent toxicities, highlighting both beneficial and side effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 as its primary infection mechanism. Interactions between S and endogenous proteins occur after infection but are not well understood. We profiled binding of S against >9000 human proteins and found an interaction between S and human estrogen receptor α (ERα). Using bioinformatics, supercomputing, and experimental assays, we identified a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 subunit. In cultured cells, S DNA transfection increased ERα cytoplasmic accumulation, and S treatment induced ER-dependent biological effects. Non-invasive imaging in SARS-CoV-2-infected hamsters localized lung pathology with increased ERα lung levels. Postmortem lung experiments from infected hamsters and humans confirmed an increase in cytoplasmic ERα and its colocalization with S in alveolar macrophages. These findings describe the discovery of a S-ERα interaction, imply a role for S as an NRC, and advance knowledge of SARS-CoV-2 biology and coronavirus disease 2019 pathology.

The purpose of this conference was to explain the relationship between the integrative and complementary medicine and cancer disease through evidence-based medicine. The topics covered are numerous and are characterized by the multidisciplinary approach of the researchers involved in this complex scenario. The Integrative Medicine Research Group (IMRG) studies the complementary and integrative approach in cancer patients with the aim to highlight the risk of drug and nutraceutical interactions and, at the same time, improve the quality of life in this particular set of patients. Our auspicious is to have an integrative medicine approach to all chronic diseases, oncological included.

CAM is used by about 40% of cancer patients in Western Countries, with peaks of 80% for breast cancer patients. Cancer patients use CAM to boost immune function, to control cancer symptoms and treatment-related side effects, and to improve health-related quality of life (HR-QoL) and survival. Unfortunately, self-prescription of natural remedies in cancer patients can lead to unexpected toxicities and can reduce the effectiveness of cancer therapy. Although CAM usually refers to all the "natural or organic" products/methods that are generally considered less toxic, there are concerns about drug interactions, especially in patients participating in clinical trials with experimental agents. Despite the claims of the promising and potential benefits made by prescribers, many CAMs lack clear scientific evidence of their safety and efficacy. Given the widespread use of CAM-both clearly declared and overt-in this review, we focused on the most important known data on the risk of interactions between biologics and oncology drugs with the goal of opening up CAM in accordance with the meaning of integrative medicine., Competing Interests: The Authors declare no conflict of interest.

Background: Inflammatory bowel disease (IBD) is an inflammatory condition of the gastrointestinal tract, characterized by chronic and relapsing immune system activation, often diagnosed in adolescence, with a rising incidence in pediatric populations. IBD results from altered interactions between gut microbes and the intestinal immune system which induce an aberrant immune response, thus anti-inflammatory or immunosuppressive therapies are generally used. Recent interest has been given to the identification of integrative and complementary approaches that could be able to restore and preserve the intestinal barrier function., Methods: In this work, we tested the effect of a fixed combination of probiotics and herbal extract (Colikind Gocce ® [CKG], Schwabe Pharma, Egna-Neumarkt, Bolzano, Italy) in an in-vitro model of intestinal inflammation. Caco-2 cells stimulated with LPS-conditioned monocytes culture medium was used as a paradigm of intestinal inflammation. The possible effect of CKG in maintaining the homeostasis of the intestinal epithelial barrier was investigated by measurement of the trans-epithelial electrical resistance, the paracellular permeability, and the release of inflammatory cytokines (TNF-α, IL-8, and IL-10)., Results: Results obtained in this work demonstrated that CKG is able to prevent the impairment of intestinal barrier function induced by inflammation, ameliorating the transepithelial electrical resistance and the paracellular permeability of the Caco-2 monolayer; moreover, CKG is able to counteract the increased release of TNF-a and IL-8 induced by inflammatory stimulus, thus reducing the intestinal inflammation., Conclusions: This work underlines the protective effect of CKG on intestinal barrier, reducing the damages induced by inflammatory stimulus. This suggests CKG as an interesting product in the management of intestinal inflammatory conditions.

Background: Myoclonus, Epilepsy and Ragged-Red-Fibers (MERRF) is a mitochondrial encephalomyopathy due to heteroplasmic mutations in mitochondrial DNA (mtDNA) most frequently affecting the tRNA Lys gene at position m.8344A > G. Defective tRNA Lys severely impairs mitochondrial protein synthesis and respiratory chain when a high percentage of mutant heteroplasmy crosses the threshold for full-blown clinical phenotype. Therapy is currently limited to symptomatic management of myoclonic epilepsy, and supportive measures to counteract muscle weakness with co-factors/supplements., Methods: We tested two therapeutic strategies to rescue mitochondrial function in cybrids and fibroblasts carrying different loads of the m.8344A > G mutation. The first strategy was aimed at inducing mitochondrial biogenesis directly, over-expressing the master regulator PGC-1α, or indirectly, through the treatment with nicotinic acid, a NAD + precursor. The second was aimed at stimulating the removal of damaged mitochondria through prolonged rapamycin treatment., Results: The first approach slightly increased mitochondrial protein expression and respiration in the wild type and intermediate-mutation load cells, but was ineffective in high-mutation load cell lines. This suggests that induction of mitochondrial biogenesis may not be sufficient to rescue mitochondrial dysfunction in MERRF cells with high-mutation load. The second approach, when administered chronically (4 weeks), induced a slight increase of mitochondrial respiration in fibroblasts with high-mutation load, and a significant improvement in fibroblasts with intermediate-mutation load, rescuing completely the bioenergetics defect. This effect was mediated by increased mitochondrial biogenesis, possibly related to the rapamycin-induced inhibition of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and the consequent activation of the Transcription Factor EB (TFEB)., Conclusions: Overall, our results point to rapamycin-based therapy as a promising therapeutic option for MERRF., (© 2022. The Author(s).)

Objectives: According to the National Cancer Institute, the integrative medicine (IM) approach to medical care combines standard medicine with complementary and alternative medicine practices that have proved safe and effective. Methods: We describe the clinical cases of four patients with malignant pleural mesothelioma (MPM), diffuse malignant peritoneal mesothelioma (DMPM), intrahepatic cholangiocarcinoma, and breast cancer (BC) who received supportive treatment (ST) according to an IM approach after the failure of standard cancer treatments or the appearance of serious adverse events caused by antiblastic chemotherapy. The critical role of complementary drugs in reducing the side effects of cancer treatments and normalizing the white cell count is especially apparent in the case of the patient with metastatic BC, who experienced prolonged neutropenia. Results: The IM approach was well-tolerated and had no adverse side effects. It improved the quality of life (QoL) of all patients and in two cases extended overall survival. Conclusion: The extended clinical and instrumental response to IM of the patients with malignant mesothelioma and the improved health-related QoL and good tolerance of the ST demonstrated in all cases support the value of this approach in patients whose cancer therapies have failed but who show a good performance status. Our data require confirmation in a well-designed prospective clinical trial., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MC declared a shared affiliation, with no collaboration, with two of the authors, NM and VQ to the handling editor at the time of the review., (Copyright © 2022 Berretta, Morra, Taibi, Monari, Maurea, Ippolito, Tirelli, Fiorica, Montella, Facchini, Quagliariello and Montopoli.)

Background: Vitamin D exerts multiple beneficial effects in humans, including neuronal, immune, and bone homeostasis and the regulation of cardiovascular functions. Recent studies correlate vitamin D with cancer cell growth and survival, but meta-analyses on this topic are often not consistent., Methods: A systematic search of the PubMed database and the Clinical Trial Register was performed to identify all potentially relevant English-language scientific papers containing original research articles on the effects of vitamin D on human health., Results: In this review, we analyzed the antioxidant and anti-inflammatory effects of vitamin D against acute and chronic diseases, focusing particularly on cancer, immune-related diseases, cardiomyophaties (including heart failure, cardiac arrhythmias, and atherosclerosis) and infectious diseases., Conclusions: Vitamin D significantly reduces the pro-oxidant systemic and tissue biomarkers involved in the development, progression, and recurrence of chronic cardiometabolic disease and cancer. The overall picture of this review provides the basis for new randomized controlled trials of oral vitamin D supplementation in patients with cancer and infectious, neurodegenerative, and cardiovascular diseases aimed at reducing risk factors for disease recurrence and improving quality of life.

The new coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic, which so far has caused over 6 million deaths in 2 years, despite new vaccines and antiviral medications. Drug repurposing, an approach for the potential application of existing pharmaceutical products to new therapeutic indications, could be an effective strategy to obtain quick answers to medical emergencies. Following a virtual screening campaign on the most relevant viral proteins, we identified the drug raloxifene, a known Selective Estrogen Receptor Modulator (SERM), as a new potential agent to treat mild-to-moderate COVID-19 patients. In this paper we report a comprehensive pharmacological characterization of raloxifene in relevant in vitro models of COVID-19, specifically in Vero E6 and Calu-3 cell lines infected with SARS-CoV-2. A large panel of the most common SARS-CoV-2 variants isolated in Europe, United Kingdom, Brazil, South Africa and India was tested to demonstrate the drug's ability in contrasting the viral cytopathic effect (CPE). Literature data support a beneficial effect by raloxifene against the viral infection due to its ability to interact with viral proteins and activate protective estrogen receptor-mediated mechanisms in the host cells. Mechanistic studies here reported confirm the significant affinity of raloxifene for the Spike protein, as predicted by in silico studies, and show that the drug treatment does not directly affect Spike/ACE2 interaction or viral internalization in infected cell lines. Interestingly, raloxifene can counteract Spike-mediated ADAM17 activation in human pulmonary cells, thus providing new insights on its mechanism of action. A clinical study in mild to moderate COVID-19 patients (NCT05172050) has been recently completed. Our contribution to evaluate raloxifene results on SARS-CoV-2 variants, and the interpretation of the mechanisms of action will be key elements to better understand the trial results, and to design new clinical studies aiming to evaluate the potential development of raloxifene in this indication., (© 2022. The Author(s).)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 (ACE2) at the cell surface, which constitutes the primary mechanism driving SARS-CoV-2 infection. Molecular interactions between the transduced S and endogenous proteins likely occur post-infection, but such interactions are not well understood. We used an unbiased primary screen to profile the binding of full-length S against >9,000 human proteins and found significant S-host protein interactions, including one between S and human estrogen receptor alpha (ERα). After confirming this interaction in a secondary assay, we used bioinformatics, supercomputing, and experimental assays to identify a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 subunit and an S-ERα binding mode. In cultured cells, S DNA transfection increased ERα cytoplasmic accumulation, and S treatment induced ER-dependent biological effects and ACE2 expression. Noninvasive multimodal PET/CT imaging in SARS-CoV-2-infected hamsters using [ 18 F]fluoroestradiol (FES) localized lung pathology with increased ERα lung levels. Postmortem experiments in lung tissues from SARS-CoV-2-infected hamsters and humans confirmed an increase in cytoplasmic ERα expression and its colocalization with S protein in alveolar macrophages. These findings describe the discovery and characterization of a novel S-ERα interaction, imply a role for S as an NRC, and are poised to advance knowledge of SARS-CoV-2 biology, COVID-19 pathology, and mechanisms of sex differences in the pathology of infectious disease.

Cannabis sativa L. is increasingly emerging for its protective role in modulating neuroinflammation, a complex process orchestrated among others by microglia, the resident immune cells of the central nervous system. Phytocannabinoids, especially cannabidiol (CBD), terpenes, and other constituents trigger several upstream and downstream microglial intracellular pathways. Here, we investigated the molecular mechanisms of a CBD- and terpenes-enriched C. sativa extract (CSE) in an in vitro model of neuroinflammation. We evaluated the effect of CSE on the inflammatory response induced by exposure to lipopolysaccharide (LPS) in BV-2 microglial cells, compared with CBD and β-caryophyllene (CAR), CB2 receptors (CB2r) inverse and full agonist, respectively. The LPS-induced upregulation of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α was significantly attenuated by CSE and only partially by CBD, whereas CAR was ineffective. In BV-2 cells, these anti-inflammatory effects exerted by CSE phytocomplex were only partially dependent on CB2r modulation and they were mediated by the regulation of enzymes responsible for the endocannabinoids metabolism, by the inhibition of reactive oxygen species release and the modulation of JNK/p38 cascade with consequent NF-κB p65 nuclear translocation suppression. Our data suggest that C. sativa phytocomplex and its multitarget mechanism could represent a novel therapeutic strategy for neuroinflammatory-related diseases., (© 2022 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.)

Cisplatin (CDDP) is commonly used to treat a multitude of tumors including sarcomas, ovarian and cervical cancers. Despite recent investigations allowed to improve chemotherapy effectiveness, the molecular mechanisms underlying the development of CDDP resistance remain a major goal in cancer research. Here, we show that mitochondrial morphology and autophagy are altered in different CDDP resistant cancer cell lines. In CDDP resistant osteosarcoma and ovarian carcinoma, mitochondria are fragmented and closely juxtaposed to the endoplasmic reticulum; rates of mitophagy are also increased. Specifically, levels of the mitophagy receptor BNIP3 are higher both in resistant cells and in ovarian cancer patient samples resistant to platinum-based treatments. Genetic BNIP3 silencing or pharmacological inhibition of autophagosome formation re-sensitizes these cells to CDDP. Our study identifies inhibition of BNIP3-driven mitophagy as a potential therapeutic strategy to counteract CDDP resistance in ovarian carcinoma and osteosarcoma., (© 2022. The Author(s).)

The aim of this conference was to explain the role of integrative and complementary medicine in breast cancer patients. The topics covered are numerous and their peculiarities are the multidisciplinary characteristics of the researchers involved. The Integrative Medicine Research Group (IMRG) believes in the complementary and integrative approach in cancer patients to improve the quality of life in this particular setting.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed and self-prescribed drugs to treat inflammation and pain associated with several conditions. Although their efficacy and overall safety have been recognized when used according to medical prescriptions and for a short period time, their acute impact on enteric physiology has rarely been studied. NSAIDs are known to cause gastrointestinal side effects due to their intrinsic mechanism of action, which involves prostaglandins synthesis, leading to impaired mucopolysaccharide layer production. Despite this well-known and investigated side effect, the short- and long-term influences of acute administration of these drugs on the biochemical environment of enteric cells are not well understood. This study investigates the rate of adenosine triphosphate (ATP) loss and permeability alterations occurring in a model of human enteric cells, as a consequence of acute administration of NSAIDs as major perpetrators of enteric toxicity. For the first time, we investigate the ability of a novel ATP-containing formulation to prevent ATP hydrolysis in the stomach and ensure its delivery at the proximal duodenal site.

Human immunodeficiency virus (HIV) affects more than 37 million people globally, and in 2020, more than 680,000 people died from HIV-related causes. Recently, these numbers have decrease substantially and continue to reduce thanks to the use of antiretroviral therapy (ART), thus making HIV a chronic disease state for those dependent on lifelong use of ART. However, patients with HIV have an increased risk of developing some type of cancer compared to patients without HIV. Therefore, treatment of patients who are diagnosed with both HIV and cancer represents a complicated scenario because of the risk associated with drug-drug interaction (DDIs) and related toxicity. Selection of an alternative chemotherapy or ART or temporarily discontinuation of ART constitute a strategy to manage the risk of DDIs. Temporarily withholding ART is the less desirable clinical plan but risks and benefits must be considered in each scenario. In this review we focus on the hepatotoxicity associated with a simultaneous treatment with ART and chemotherapeutic drugs and mechanisms behind. Moreover, we also discuss the effect on the liver caused by the association of immunotherapeutic drugs, which have recently been used in clinical trials and also in HIV patients.

Objective: Our study aimed to confirm the expression of the endocannabinoid system in the human epithelial ovarian tumors, assessing the immunohistochemical expression of Cannabinoid Receptor Type 1 and Fatty Acid Amide Hydrolase in benign, borderline and malignant tumors., Materials and Methods: Cannabinoid Receptor Type 1 and Fatty Acid Amide Hydrolase immunohistochemical expression was determined in 118 epithelial ovarian tumors sequentially treated during the last decade in our department: 36 benign, 34 borderline and 48 malignant neoplasms. Cannabinoid Receptor type 1 and Fatty Acid Amide Hydrolase expression resulted predominantly weak-moderate in the benign and borderline forms., Results: concerning malignant tumors, Cannabinoid Receptor Type 1 expression resulted predominantly moderate-strong in Type I tumors and negative-weak in Type II tumors. Fatty Acid Amide Hydrolase expression resulted, instead, independent by the tumor types. Furthermore, there was no significant difference in the Cannabinoid Receptor Type 1 and Fatty Acid Amide Hydrolase expression relatively to the tumoral stages., Conclusions: The present study confirmed a variable expression of the endocannabinoid system in human ovarian tumors. Cannabinoid Receptor Type 1 expression was significantly different in malignant epithelial ovarian tumors according to dualistic model of ovarian carcinogenesis. Thus, in the most aggressive types II ovarian tumors, Cannabinoid Receptor Type 1 expression resulted predominantly negative or weak.

Renal cell carcinoma (RCC) represents the main renal tumors and are highly metastatic. Sunitinib, a recently-approved, multi-targeted Tyrosine Kinases Inhibitor (TKi), prolongs survival in patients with metastatic renal cell carcinoma and gastrointestinal stromal tumors, however a dose related cardiotoxicity was well described. Polydatin (3,4',5-trihydroxystilbene-3-β-d-glucoside) is a monocrystalline compound isolated from Polygonum cuspidatum with consolidated anti-oxidant and anti-inflammatory properties, however no studies investigated on its putative cardioprotective and chemosensitizing properties during incubation with sunitinib. We investigated on the effects of polydatin on the oxidative stress, NLRP3 inflammasome and Myd88 expression, highlighting on the production of cytokines and chemokines (IL-1β, IL-6, IL-8, CXCL-12 and TGF-β) during treatment with sunitinib. Exposure of cardiomyocytes and cardiomyoblasts (AC-16 and H9C2 cell lines) and human renal adenocarcinoma cells (769-P and A498) to polydatin combined to plasma-relevant concentrations of sunitinib reduces significantly iROS, MDA and LTB4 compared to only sunitinib-treated cells (P<0.001). In renal cancer cells and cardiomyocytes polydatin reduces expression of pro-inflammatory cytokines and chemokines involved in myocardial damages and chemoresistance and down-regulates the signaling pathway of NLRP3 inflammasome, MyD88 and NF-κB. Data of the present study, although in vitro , indicate that polydatin, besides reducing oxidative stress, reduces key chemokines involved in cancer cell survival, chemoresistance and cardiac damages of sunitinib through downregulation of NLRP3-MyD88 pathway, applying as a potential nutraceutical agent in preclinical studies of preventive cardio-oncology., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Quagliariello, Berretta, Buccolo, Iovine, Paccone, Cavalcanti, Taibi, Montopoli, Botti and Maurea.)

Hereditary spastic paraplegia (HSP) is a group of inherited neurodegenerative conditions that share a characteristic feature of degeneration of the longest axons within the corticospinal tract, which leads to progressive spasticity and weakness of the lower limbs. Mutations of over 70 genes produce defects in various biological pathways: axonal transport, lipid metabolism, endoplasmic reticulum (ER) shaping, mitochondrial function, and endosomal trafficking. HSPs suffer from an adequate therapeutic plan. Currently the treatments foreseen for patients affected by this pathology are physiotherapy, to maintain the outgoing tone, and muscle relaxant therapies for spasticity. Very few clinical studies have been conducted, and it's urgent to implement preclinical animal studies devoted to pharmacological test and screening, to expand the rose of compounds potentially attractive for clinical trials. Small animal models, such as Drosophila melanogaster and zebrafish, have been generated, analyzed, and used as preclinical model for screening of compounds and their effects. In this work, we briefly described the role of HSP-linked proteins in the organization of ER endomembrane system and in the regulation of ER homeostasis and stress as a common pathological mechanism for these HSP forms. We then focused our attention on the pharmacodynamic and pharmacokinetic features of some recently identified molecules with antioxidant property, such as salubrinal, guanabenz, N-acetyl cysteine, methylene blue, rapamycin, and naringenin, and on their potential use in future clinical studies. Expanding the models and the pharmacological screening for HSP disease is necessary to give an opportunity to patients and clinicians to test new molecules., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gumeni, Vantaggiato, Montopoli and Orso.)

The relevance and incidence of intestinal bowel diseases (IBD) have been increasing over the last 50 years and the current therapies are characterized by severe side effects, making essential the development of new strategies that combine efficacy and safety in the management of human IBD. Herbal products are highly considered in research aimed at discovering new approaches for IBD therapy and, among others, Cannabis sativa L. has been traditionally used for centuries as an analgesic and anti-inflammatory remedy also in different gastrointestinal disorders. This study aims to investigate the effects of different C. sativa isolated compounds in an in vitro model of intestinal epithelium. The ability of treatments to modulate markers of intestinal dysfunctions was tested on Caco-2 intestinal cell monolayers. Our results, obtained by evaluation of ROS production, TEER and paracellular permeability measurements and tight junctions evaluation show Cannabidiol as the most promising compound against intestinal inflammatory condition. Cannabidiol is able to inhibit ROS production and restore epithelial permeability during inflammatory and oxidative stress conditions, suggesting its possible application as adjuvant in IBD management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cocetta, Governa, Borgonetti, Tinazzi, Peron, Catanzaro, Berretta, Biagi, Manetti, Dall’Acqua and Montopoli.)

Cupping therapy (CT) represents a cornerstone of traditional Chinese and Persian medicine, but it has its roots in the history of therapy. Although its exact mechanisms of action have been not fully understood, it is widely used as an alternative or complementary treatment of a broad spectrum of diseases, mainly musculoskeletal pain and muscular tension. Some practitioners use CT to cure dermatoses, but the most common adverse events occur at the skin level. We describe a case and briefly review the related literature.

Integrative Medicine Research Group (IMRG) presents a new conference scene about the "Ageing and osteoarticular system for healthy ageing" within a multidisciplinary approach of Integrative Medicine.

Resistance to chemotherapy still remains a major challenge in the clinic, impairing the quality of life and survival rate of patients. The identification of unconventional chemosensitizing agents is therefore an interesting aspect of cancer research. Resveratrol has emerged in the last decades as a fascinating molecule, able to modulate several cancer-related molecular mechanisms, suggesting a possible application as an adjuvant in cancer management. This review goes deep into the existing literature concerning the possible chemosensitizing effect of resveratrol associated with the most conventional chemotherapeutic drugs. Despite the promising effects observed in different cancer types in in vitro studies, the clinical translation still presents strong limitations due to the low bioavailability of resveratrol. Recently, efforts have been moved in the field of drug delivery to identifying possible strategies/formulations useful for a more effective administration. Despite the necessity of a huge implementation in this research area, resveratrol appears as a promising molecule able to sensitize resistant tumors to drugs, suggesting its potential use in therapy-refractory cancer patients.

Skin is the essential barrier of the human body which performs multiple functions. Endogenous factors, in concert with external assaults, continuously affect skin integrity, leading to distinct structural changes that influence not only the skin appearance but also its various physiological functions. Alterations of the barrier functions lead to an increased risk of developing disease and side reactions, thus the importance of maintaining the integrity of the epidermal barrier and slowing down the skin aging process is evident. Salvia haenkei (SH) has been recently identified as a potential anti-senescence agent; its extract is able to decrease the level of senescent cells by affecting the IL1α release and reducing reactive oxygen species (ROS) generation. In this study, SH extract was tested on human keratinocyte cell line (HaCaT) exposed to stress factors related to premature aging of cells such as free radicals and ultraviolet B radiation. We confirmed that SH acts as scavenger of ROS and found its ability to restore the skin barrier integrity by reinforcing the cytoskeleton structure, sealing the tight junctions and increasing the migration rate of cells. Given these results, this work becomes relevant, identifying Salvia haenkei as a compound useful for anti-aging skin treatment in clinical performance.

Benign prostatic hyperplasia (BPH) is an age-related chronic disorder, characterized by the hyperproliferation of prostatic epithelial and stromal cells, which drives prostate enlargement. Since BPH aetiology and progression have been associated with the persistence of an inflammatory stimulus, induced both by Nuclear Factor-kappa B (NF-κB) activation and reactive oxygen species (ROS) production, the inhibition of these pathways could result in a good tool for its clinical treatment. This study aimed to evaluate the antioxidant and anti-inflammatory activity of a combined formulation of Serenoa repens and Urtica dioica (SR/UD) in an in vitro human model of BPH. The results confirmed both the antioxidant and the anti-inflammatory effects of SR/UD. In fact, SR/UD simultaneously reduced ROS production, NF-κB translocation inside the nucleus, and, consequently, interleukin 6 (IL-6) and interleukin 8 (IL-8) production. Furthermore, the effect of SR/UD was also tested in a human androgen-independent prostate cell model, PC3. SR/UD did not show any significant antioxidant and anti-inflammatory effect, but was able to reduce NF-κB translocation. Taken together, these results suggested a promising role of SR/UD in BPH and BPH-linked disorder prevention.

Severe disease commonly manifests as a systemic inflammatory process. Inflammation is associated withthe enhanced production of reactive oxygen and nitrogen species and with a marked reduction in the plasma concentrations of protective antioxidant molecules. This imbalance gives rise to oxidative stress, which is greater in patients with more severe conditions such as sepsis, cancer, cardiovascular disease, acute respiratory distress syndrome, and burns. In these patients, oxidative stress can trigger cell, tissue, and organ damage, thus increasing morbidity and mortality. Ascorbic acid (ASC) is a key nutrient thatserves as an antioxidant and a cofactor for numerous enzymatic reactions. However, humans, unlike most mammals, are unable to synthesize it. Consequently, ASC must be obtained through dietary sources, especially fresh fruit and vegetables. The value of administering exogenous micronutrients, to reestablish antioxidant concentrations in patients with severe disease, has been recognized for decades. Despite the suggestion that ASC supplementation may reduce oxidative stress and prevent several chronic conditions, few large, randomized clinical trials have tested it in patients with severe illness. This article reviews the recent literature on the pharmacological profile of ASC and the role of its supplementation in critically ill patients.

Recently, there has been a great effort to develop tests based on non-invasive urinary biomarkers (NMIBCs). These tests are based on the fact that NMIBCs are heterogeneous at the molecular level and can be divided into different molecular groups useful to predict prognosis and response to treatment. The assessment of epigenetic alterations, such as DNA methylation, represents a promising cancer biomarker. DNA methylation is an epigenetic modification that affects gene expression without modifying the DNA sequence. Several studies have highlighted the presence of methylated loci in the context of bladder cancer, indicating its potential application as a diagnostic and prognostic biomarker. One of the novel assays based on a DNA methylation profile, the Bladder EpiCheck, analyzes DNA from spontaneous urine, detecting disease-specific DNA methylation patterns in bladder cancer patients. This test, due to its non-invasive nature and highly promising performance could, in future, become an invaluable tool in the follow-up of bladder cancer patients. Potential new applications could include diagnosis and surveillance of upper-tract disease, for the replacement of invasive testing and ureteroscopy.