Model development and validation for a tank in tank water thermal storage for domestic application

5noThe hot water tanks are the typical thermal storage systems in Solar Domestic Hot Water (SDHW) plants. In this paper a new model for ESP-r has been developed, in order to simulate a tank in tank heat storage. The tank in tank system is made up of two tanks in which the smaller, storing potable hot water, is contained in a larger buffer filled with heating-circuit water. The developed model is an enhanced version of a component already available in ESP-r. Experimental results are used to identify some parameters and to perform the validation of the developed code.openopenPadovan, Roberta; Manzan, Marco; Zandegiacomo De Zorzi, Ezio ; Gullì, Giuseppe; Frazzica, AndreaPadovan, Roberta; Manzan, Marco; ZANDEGIACOMO DE ZORZI, Ezio; Gullì, Giuseppe; Frazzica, Andre

β-hexachlorocyclohexane: a small molecule with a big impact on human cellular biochemistry

Organochlorine pesticides (OCPs) belong to a heterogeneous class of organic compounds blacklisted by the Stockholm Convention in 2009 due to their harmful impact on human health. Among OCPs, β-hexachlorocyclohexane (β-HCH) is one of the most widespread and, at the same time, poorly studied environmental contaminant. Due to its physicochemical properties, β-HCH is the most hazardous of all HCH isomers; therefore, clarifying the mechanisms underlying its molecular action could provide further elements to draw the biochemical profile of this OCP. For this purpose, LNCaP and HepG2 cell lines were used as models and were subjected to immunoblot, immunofluorescence, and RT-qPCR analysis to follow the expression and mRNA levels, together with the distribution, of key biomolecules involved in the intracellular responses to β-HCH. In parallel, variations in redox homeostasis and cellular bioenergetic profile were monitored to have a complete overview of β-HCH effects. Obtained results strongly support the hypothesis that β-HCH could be an endocrine disrupting chemical as well as an activator of AhR signaling, promoting the establishment of an oxidative stress condition and a cellular metabolic shift toward aerobic glycolysis. In this altered context, β-HCH can also induce DNA damage through H2AX phosphorylation, demonstrating its multifaceted mechanisms of action

Chemopreventive potential of caryophyllane sesquiterpenes: an overview of preliminary evidence

Chemoprevention is referred to as a strategy to inhibit, suppress, or reverse tumor development and progression in healthy people along with high-risk subjects and oncologic patients through using pharmacological or natural substances. Numerous phytochemicals have been widely described in the literature to possess chemopreventive properties, although their clinical usefulness remains to be defined. Among them, caryophyllane sesquiterpenes are natural compounds widely occurring in nature kingdoms, especially in plants, fungi, and marine environments. Several structures, characterized by a common caryophyllane skeleton with further rearrangements, have been identified, but those isolated from plant essential oils, including β-caryophyllene, β-caryophyllene oxide, α-humulene, and isocaryophyllene, have attracted the greatest pharmacological attention. Emerging evidence has outlined a complex polypharmacological profile of caryophyllane sesquiterpenes characterized by blocking, suppressing, chemosensitizing, and cytoprotective properties, which suggests a possible usefulness of these natural substances in cancer chemoprevention for both preventive and adjuvant purposes. In the present review, the scientific knowledge about the chemopreventive properties of caryophyllane sesquiterpenes and the mechanisms involved have been collected and discussed; moreover, possible structure-activity relationships have been highlighted. Although further high-quality studies are required, the promising preclinical findings and the safe pharmacological profile encourage further studies to define a clinical usefulness of caryophyllane sesquiterpenes in primary, secondary, or tertiary chemoprevention

Novel Insights into the Immunomodulatory Effects of Caryophyllane Sesquiterpenes: A Systematic Review of Preclinical Studies

Immunomodulation is a key factor in the homeostasis of organisms, both for physiological and inflammatory conditions. In this context, great attention has been devoted to immunomodulant agents, which can boost or modulate the immune system, thus favoring disease relief. The present systematic review is focused on the immunomodulatory properties of plant-based caryophyllane sesquiterpenes, which are unique natural compounds widely studied due to their multiple and pleiotropic bioactivities. Despite lacking clinical evidence, the selected studies highlighted the ability of these substances, especially β-caryophyllene and α-humulene, to modulate the immune system of both in vitro and in vivo models of disease, such as neurodegenerative and inflammatory-based diseases, cancer, and allergies; moreover, some mechanistic hypotheses have been made too. The present overview suggests a further interest in immunomodulation by caryophyllane sesquiterpenes as a possible novel strategy for immune-based diseases or as an adjuvant treatment and encourages further high-quality studies, using high-purity compounds, to better clarify the mechanisms accounting for these properties and to support a further pharmaceutical development

Novel Insights into the Immunomodulatory Effects of Caryophyllane Sesquiterpenes: A Systematic Review of Preclinical Studies

Immunomodulation is a key factor in the homeostasis of organisms, both for physiological and inflammatory conditions. In this context, great attention has been devoted to immunomodulant agents, which can boost or modulate the immune system, thus favoring disease relief. The present systematic review is focused on the immunomodulatory properties of plant-based caryophyllane sesquiterpenes, which are unique natural compounds widely studied due to their multiple and pleiotropic bioactivities. Despite lacking clinical evidence, the selected studies highlighted the ability of these substances, especially β-caryophyllene and α-humulene, to modulate the immune system of both in vitro and in vivo models of disease, such as neurodegenerative and inflammatory-based diseases, cancer, and allergies; moreover, some mechanistic hypotheses have been made too. The present overview suggests a further interest in immunomodulation by caryophyllane sesquiterpenes as a possible novel strategy for immune-based diseases or as an adjuvant treatment and encourages further high-quality studies, using high-purity compounds, to better clarify the mechanisms accounting for these properties and to support a further pharmaceutical development

Novel Insights into the Immunomodulatory Effects of Caryophyllane Sesquiterpenes: A Systematic Review of Preclinical Studies

Immunomodulation is a key factor in the homeostasis of organisms, both for physiological and inflammatory conditions. In this context, great attention has been devoted to immunomodulant agents, which can boost or modulate the immune system, thus favoring disease relief. The present systematic review is focused on the immunomodulatory properties of plant-based caryophyllane sesquiterpenes, which are unique natural compounds widely studied due to their multiple and pleiotropic bioactivities. Despite lacking clinical evidence, the selected studies highlighted the ability of these substances, especially β-caryophyllene and α-humulene, to modulate the immune system of both in vitro and in vivo models of disease, such as neurodegenerative and inflammatory-based diseases, cancer, and allergies; moreover, some mechanistic hypotheses have been made too. The present overview suggests a further interest in immunomodulation by caryophyllane sesquiterpenes as a possible novel strategy for immune-based diseases or as an adjuvant treatment and encourages further high-quality studies, using high-purity compounds, to better clarify the mechanisms accounting for these properties and to support a further pharmaceutical development

Caryophyllane sesquiterpenes reverse sorafenib-chemoresistance through Pgp and STAT3 pathways in liver cancer cells.

Introduction. Research of innovative and alternative therapeutic approaches is an important acquisition in the battle against hepatocellular carcinoma (HCC), a highly resistant tumour. In the last years, it has been highlighted the possibility to affect tumour growth with multi-target therapies, acting in synergy or on different targets but with additive effects. This approach could allow to increase the effectiveness of anticancer drug even at low-doses and to limit the systemic toxicity associated with standard chemotherapy. In this context, the aim of the present work was to investigate the ability of three structurally related natural compounds, namely ß- caryophyllene (CRY), ß-caryophyllene oxide (CRYO), and α-humulene (α-caryophyllene, HUM), to enhance the response of HCC cells to sorafenib (SOR) treatment by blocking its Pgp-mediated export or by inhibiting the sorafenib-mediated STAT3 (Ser727) phosphorylation, both mechanism being involved in sorafenib acquired resistance. Material and methods. Cytotoxicity of test compounds alone or in combination with sorafenib was evaluated by MTT assay in human hepatoma cells HepG2. The nature of interaction (synergistic, additive or antagonistic effect) was evaluated by reversal ratio value (RR) and combination index (CI). Moreover, the ability of CRY, CRYO and HUM to inhibit Pgp functional activity was measured by the efflux assay. Particularly, rhodamine 123 and verapamil were used as fluorescent probe and typical inhibitor of this pump, respectively. At last, the effect of both substances alone or in combination with sorafenib on Pgp and STAT3 (Ser 727) protein expression was evaluated by western blot analysis. Results. All compounds showed a low cytotoxicity in our cellular model (IC50 > 240 µM). The anticancer drug sorafenib was the most effective with an IC50 value of approximately 105 µM. In the combination experiments, all compounds were able to increase the sensitivity of HepG2 cell to sorafenib with a higher effect respect to the known Pgp inhibitor verapamil. In particular, CRY, CRYO, and HUM were able to increase the sorafenib cytotoxicity of about 6-, 26-, and 9-folds, while verapamil of about 2.5-fold. The CI highlighted a synergistic effect of sesquiterpenes towards sorafenib. In the efflux experiments, all substances showed to inhibit the Pgp functional activity in a similar way than the positive control verapamil. Particularly, the rhodamine 123 efflux was reduced of about 3-, 2.8-, 2.6-, 3.1-folds by verapamil, CRY, CRYO, and HUM, respectively. As regards Pgp protein expression, sorafenib determined a slight but statistically significant increase of its expression. The combination of the antitumor drug with verapamil and HUM further increased it. By contrast, both CRY and CRYO were able to reduce the Pgp expression to basal level, being CRYO the most effective. As regards STAT3 (Ser 727) phosphorilated expression, sorafenib was able to increase it of about 3-fold respect to the control and its combination with verapamil and HUM showed similar results. Conversely, both CRY and CRYO were able to reduce the STAT3 (Ser 727) phosphorilated expression of about 1.3- and 2- fold, respectively. Discussion and conclusions. Under our experimental conditions, in spite of a slight effect of HUM, CRY and CRYO showed to synergistically increase the sorafenib cytotoxicity by affecting Pgp pump at both functional and protein expression. Also, they reduced STAT3 (Ser727) phosphorylation, known to be involved in MDR1-transcription upregulation. Altogether these results highlight the possible role of CRY and CRYO as chemosensitizing agents in combination with sorafenib and support their potential usefulness to reverse the sorafenib-induced multidrug resistance by targeting Pgp and/or STAT3 pathways

beta-HEXACHLOROCYCLOHEXANE MAY INDUCE HORMONE RESISTANCE IN PROSTATE CANCER

Organochlorine pesticides (OCPs) are widely distributed in the environment and their toxicity is mostly associated with the molecular mechanisms of endocrine disruption and carcinogenesis. It is conceivable to hypothesize that OCPs may exert their toxic effects not only by interfering with the activity of endogenous hormones, but also through the activation of “non-genomic” pathways which cross-talk with other signalling cascades. The hormone resistance, referred as Castration-Resistant Prostate Cancer (CRPC), normally occurs after hormone therapy and leads to PCa transformation into a more aggressive and undifferentiated form. This event is a multifactorial process and seems to involve a crossover between the Androgen Receptor (AR) signalling and other regulatory pathways [Reichert, 2016] like those STAT3-mediated [Bishop et al, 2014]. Moreover, the CRPC development is also due to an altered glucose metabolism and a higher synthesis of one-carbon units. This new cellular condition interferes with energy metabolism by redirecting glycolysis to lactate production and triggering the Warburg effect [Yu et al, 2016]. Organochlorine pesticides (dioxins, lindane, hexachlobenzene) are among the most widespread pollutants and are also known to be endocrine disrupting chemicals, given to their capability to interfere with hormone-related activities. Among organochlorines, particular attention was addressed in investigating the molecular effects of the β- isomer of hexaclorocyclohexane (β-HCH) [Rubini et al., 2018], characterized by a high lipid solubility, environmental persistence and long biological half-lives in human tissues. The cellular impact of β-HCH was evaluated on LNCaP cells (human prostate cancer cells, androgen receptor positive) and obtained results showed that this organochlorine can act as endocrine disruptor on AR activation by interfering with STAT3 mediated regulatory pathways and triggering the synthesis of one- carbon units, leading to the Warburg effect

Sorafenib chemosensitization by caryophyllane sesquiterpenes in liver, biliary, and pancreatic cancer cells: the role of STAT3/ABC transporter axis

A combination of anticancer drugs and chemosensitizing agents has been approached as a promising strategy to potentiate chemotherapy and reduce toxicity in aggressive and chemoresistant cancers, like hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and pancreatic ductal adenocarcinoma (PDAC). In the present study, the ability of caryophyllane sesquiterpenes to potentiate sorafenib efficacy was studied in HCC, CCA, and PDAC cell models, focusing on the modulation of STAT3 signaling and ABC transporters; tolerability studies in normal cells were also performed. Results showed that the combination of sorafenib and caryophyllane sesquiterpenes synergized the anticancer drug, especially in pancreatic Bx-PC3 adenocarcinoma cells; a similar trend, although with lower efficacy, was found for the standard ABC transporter inhibitors. Synergistic effects were associated with a modulation of MDR1 (or Pgp) and MRP transporters, both at gene and protein level; moreover, activation of STAT3 cascade and cell migration appeared significantly affected, suggesting that the STAT3/ABC-transporters axis finely regulated efficacy and chemoresistance to sorafenib, thus appearing as a suitable target to overcome drawbacks of sorafenib-based chemotherapy in hepatobiliary-pancreatic cancers. Present findings strengthen the interest in caryophyllane sesquiterpenes as chemosensitizing and chemopreventive agents and contribute to clarifying drug resistance mechanisms in HCC, CCA, and PDAC cancers and to developing possible novel therapeutic strategies