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We have studied the effect of propolis and its main active ingredient caffeic acid phenetyl ester (CAPE) on formation of aberrant crypt foci (ACF) and tumors in the rat colon in vivo. CAPE (50 mg/kg i.p.) reduced the formation of ACF and tumor induced by azoxymethane, while propolis ethanolic extract was without effect. These results suggest a potential anti-carcinogenesis of CAPE but not propolis.

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1 The aim of this study was to evaluate whether ca€eic acid phenethyl ester (CAPE), an active component of propolis, was able to reduce neointimal formation in a model of endothelial injury of rat carotid artery (balloon angioplasty). Furthermore, we investigated the relationship between neointima formation and nuclear factor-kB (NF-kB) activation and we correlated NF-kB activation to the expression of inducible isoform of cyclo-oxygenase (COX-2) in injured carotids. 2 In control group a signi®cant proliferation of neointima was observed 14 days after balloon angioplasty, which was correlated to an increase of NF-kB/DNA binding activity as well as p50/p65 nuclear levels compared to those observed in the carotids from sham-operated rats. Furthermore, NF-kB activation was correlated to increased COX-2, but not b-actin, protein expression. 3 Treatment of rats for 14 days with CAPE (3, 10, 30 mg kg71) caused a significantcant inhibition of all the parameters assayed, except beta-actin protein expression. 4 These results indicate that treatment with CAPE may lead to a reduction of neointima formation by inhibiting NF-kB activation and suggest that this agent may have therapeutic relevance for the prevention of human restenosis.

Salvinorin A, the active component of the hallucinogenic herb Salvia divinorum, inhibits intestinal motility through activation of kappa-opioid receptors (KORs). However, this compound may have target(s) other than the KORs in the inflamed gut. Because intestinal inflammation upregulates cannabinoid receptors and endogenous cannabinoids, in the present study we investigated the possible involvement of the endogenous cannabinoid system in salvinorin A-induced delay in motility in the inflamed gut.Motility in vivo was measured by evaluating the distribution of a fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; direct or indirect activity at cannabinoid receptors was evaluated by means of binding, enzymic and cellular uptake assays.Salvinorin A as well as the KOR agonist U-50488 reduced motility in croton oil treated mice. The inhibitory effect of both salvinorin A and U-50488 was counteracted by the KOR antagonist nor-binaltorphimine and by the cannabinoid CB(1) receptor antagonist rimonabant. Rimonabant, however, did not counteract the inhibitory effect of salvinorin A on motility in control mice. Binding experiments showed very weak affinity of salvinorin A for cannabinoid CB(1) and CB(2) and no inhibitory effect on 2-arachidonoylglycerol and anandamide hydrolysis and cellular uptake.The inhibitory effect of salvinorin A on motility reveals a functional interaction between cannabinoid CB(1) receptors and KORs in the inflamed--but not in the normal--gut in vivo.

Endocannabinoids (via cannabinoid CB(1) receptor activation) are physiological regulators of intestinal motility and food intake. However, their role in the regulation of gastric emptying is largely unexplored. The purpose of the present study was to investigate the involvement of the endocannabinoid system in the regulation of gastric emptying in mice fed either a standard diet (STD) or a high-fat diet (HFD) for 14 weeks. EXPERIMENTAL APPROACH: Gastric emptying was evaluated by measuring the amount of phenol red recovered in the stomach after oral challenge; CB(1) expression was analysed by quantitative reverse transcription-PCR; endocannabinoid (anandamide and 2-arachidonoyl glycerol) levels were measured by liquid chromatography-mass spectrometry. KEY RESULTS: Gastric emptying was reduced by anandamide, an effect counteracted by the CB(1) receptor antagonist rimonabant, but not by the CB(2) receptor antagonist SR144528 or by the transient receptor potential vanilloid type 1 (TRPV1) antagonist 5'-iodoresiniferatoxin. The fatty acid amide hydrolase (FAAH) inhibitor N-arachidonoyl-5-hydroxytryptamine (but not the anandamide uptake inhibitor OMDM-2) reduced gastric emptying in a way partly reduced by rimonabant. Compared to STD mice, HFD mice exhibited significantly higher body weight and fasting glucose levels, delayed gastric emptying and lower anandamide and CB(1) mRNA levels. N-arachidonoylserotonin (but not rimonabant) affected gastric emptying more efficaciously in HFD than STD mice. CONCLUSIONS AND IMPLICATIONS: Gastric emptying is physiologically regulated by the endocannabinoid system, which is downregulated following a HFD leading to overweight.

The ARS Component B gene (EMBL ID: HSARS81S, AC: X99977) encodes a 9 kD non-glycosylated polypeptide (also known as SLURP-1, SwissProt/TrEMBL: P55000), a soluble member of the human Ly6/uPAR superfamily. ARS Component B gene mutations have been implicated in Mal de Meleda. In this study we show by immunohistochemistry that SLURP-1 (secreted Ly-6/uPAR related protein, the protein product of the ARS Component B gene) is localized to human skin, exocervix, gums, stomach and esophagus. In the epidermis, keratinocytes underlying the stratum corneum are highly positive for SLURP1 immunostaining and cultured keratinocytes secrete the expected 9 kD protein. Circulating SLURP1 is detected in human plasma and urine. In the mouse, expression is evident in skin, eye, whole lung, trachea, esophagus and stomach. Human ARS Component B mRNA expression is regulated by retinoic acid, epidermal growth factor and interferon-gamma. The tissue localization and the association with Mal de Meleda suggest that ARS Component B and its protein product SLURP1 are implicated in maintaining the physiological and structural integrity of the keratinocyte layers of the skin.

1. The aim of this study was to evaluate whether caffeic acid phenethyl ester (CAPE), an active component of propolis, was able to reduce neointimal formation in a model of endothelial injury of rat carotid artery (balloon angioplasty). Furthermore, we investigated the relationship between neointima formation and nuclear factor-kappaB (NF-kappaB) activation and we correlated NF-kappaB activation to the expression of inducible isoform of cyclo-oxygenase (COX-2) in injured carotids. 2. In control group a significant proliferation of neointima was observed 14 days after balloon angioplasty, which was correlated to an increase of NF-kappaB/DNA binding activity as well as p50/p65 nuclear levels compared to those observed in the carotids from sham-operated rats. Furthermore, NF-kappaB activation was correlated to increased COX-2, but not beta-actin, protein expression. 3. Treatment of rats for 14 days with CAPE (3, 10, 30 mg x kg(-1)) caused a significant inhibition of all the parameters assayed, except beta-actin protein expression. 4. These results indicate that treatment with CAPE may lead to a reduction of neointima formation by inhibiting NF-kappaB activation and suggest that this agent may have therapeutic relevance for the prevention of human restenosis.

Literature about Industrial Districts has largely emphasized the importance of both economic and social factors in determining the competitiveness of these particular firms' clusters. For thirty years, the Industrial District productive and organizational model represented an alternative to the integrated model of fordist enterprise. Nowadays, the district model suffers from competitive gaps, largely due to the increase of competitive pressure of globalization. This work aims to analyze, through an agent-based simulation model, the influence of informal socio-cognitive coordination mechanisms on district's performances, in relation to different competitive scenarios. The agent-based simulation approach is particularly fit for this purpose as it is able to represent the Industrial District's complexity. Furthermore, it permits to develop dynamic analysis of district's performances according to different types of environment evolution. The results of this work question the widespread opinion that cooperative districts can answer to environmental changes more effectively that non-cooperative ones. In fact, the results of simulations show that, in the presence of turbulent scenarios, the best performer districts are those in which cooperation and competition, trust and opportunism balance out.

Clonidine, an alpha 2 agonist, is known to prolong the action of local anesthetics, and to provide a satisfactory analgesia; hypotension and bradycardia have been observed after its intrathecal administration. The aim of our study was to determine whether intrathecal administration of clonidine can reduce the dose of local anesthetic, and the effects of clonidine on the cardiovascular system, and on arousal level.In a prospective, randomized study we evaluated 56 patients scheduled for minor surgical procedure (spermatic vein ligature) under unilateral spinal anesthesia with hyperbaric bupivacaine 1%. One half of patients received clonidine (105 micrograms) in addition to bupivacaine. Mean arterial pressure, heart rate were recorded baseline until 1 hour after surgery. Cardiac output, stroke volume, ejection fraction, systemic vascular resistance and left cardiac work were measured, by thoracic electric bioimpedance method, baseline until 1 hour after surgery. Sensory block, motor block and sedation level were measured at the beginning of anesthesia and for 6 hours after the end of surgery.In the clonidine treated group we did not observe variations of cardiovascular parameters; in the same group we did observe sensory block and motor block significantly prolonged, a higher sedation level and a significant postoperative analgesia.In summary, the addition of clonidine to hyperbaric bupivacaine seems to be particularly useful in unilateral spinal anesthesia, exerting minimal influence on haemodynamic parameters, and guaranting a satisfactory postoperative analgesia.

1 We have evaluated the effect of cannabinoid drugs, administered intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.) on upper gastrointestinal transit in control and in croton oil-treated mice. 2 The cannabinoid agonists, WIN 55,212-2 (2-239 nmol mouse(-1)) and cannabinol (24-4027 nmol mouse(-1)), decreased while the CB1 antagonist SR141716A (2-539 nmol mouse(-1)) increased transit in control mice. WIN 55,212-2, cannabinol and SR141716A had lower ED50 values when administered i.c.v., than when administered i.p. The CB2 antagonist SR144528 (52 nmol mouse(-1), i.p.) was without effect. 3 During croton oil (0.01 ml mouse(-1), p.o.)-induced diarrhoea, the ED50 values of i.p.-injected WIN 55,212-2 and cannabinol (but not SR141716A) were significantly decreased (compared to control mice). However, the ED50 values of WIN 55,212-2 were similar after i.p. or i.c.v. administration. 4 The inhibitory effects of WIN 55.212-2 and cannabinol were counteracted by SR141716A (16 nmol mouse(-1), i.p.) but not by SR144528 (52 nmol mouse(-1) i.p.) both in control and croton-oil treated mice. 5 Ganglionic blockade with hexamethonium (69 nmol mouse(-1), i.p.) did not modify the inhibitory effect of i.p.-injected cannabinoid agonists either in control or in croton-oil treated mice. 6 The lower ED50 values of cannabinoid drugs after i.c.v. administration suggest a central (CB1) of action. However, a peripheral site of action is suggested by the lack of effect of 6 site hexamethonium. In addition, croton oil-induced diarrhoea enhances the effect of cannabinoid agonists by a peripheral mechanism.

Current evidence suggests that aberrant crypt foci (ACF) can be used to evaluate agents for their potential colon carcinogenic activity. The aim of the present study was to determine whether senna pod extract (SE) itself induces ACF and tumors in the rat colon or increases the development of ACF and tumors induced by azoxymethane (AOM). A daily administration of SE 10 mg/kg by mouth for 13-28 weeks produced a weak laxative effect but did not itself cause the appearance of ACF or tumors. The numbers of ACF and tumors induced by AOM were, however, increased by a dose of SE (100 mg/kg) able to induce chronic diarrhea over three months. These results suggest that SE does not cause the appearance of ACF or tumors in the rat colon nor does it have a promoting effect when given to rats at a dose that produces laxation (10 mg/kg), whereas a diarrhogenic dose (100 mg/kg) increases the appearance of tumors induced by AOM.

Objective to assess the inter-rater reliability (IRR) of the revised Cochrane risk-of-bias tool for randomised trials (RoB2). Methods Four raters independently applied RoB2 on critical and important outcomes of individually randomized parallel-group trials (RCTs) included in the Cochrane Review “Cannabis and cannabinoids for people with multiple sclerosis.” We calculated Fleiss’ Kappa for multiple raters and time to complete the tool; we performed a calibration exercise on five studies, then we developed an implementation document (ID) specific for the condition, and the intervention addressed by the review with instructions on how to answer the signalling questions of RoB2 tool. We measured IRR before and after the ID adoption Results Eighty results related to seven outcomes from 16 RCTs were assessed. During calibration exercise we reached no agreement for overall judgment (IRR -0.15); IRR for individual domains ranged from no agreement to fair. Mean time to apply the tool was 168.5 minutes per study. Time to complete the calibration exercise and develop the ID was about 40 hours. After the ID adoption ID, overall agreement increased to slightly (IRR 0.11) for the first five studies and moderate (IRR 0.42) for the remaining 11. IRR for individual domains ranged from no agreement to almost perfect. Mean time to apply the tool decreased to 41 minutes. Conclusion RoB2 tool is comprehensive but complex even for high experienced raters. The development of an ID specific for the review may improve reliability substantially.

Background and Purpose: Transient receptor potential melastatin type-8 (TRPM8) is a cold-sensitive cation channel protein belonging to the TRP superfamily of ion channels. Here, we reveal the molecular mechanism of TRPM8 and its clinical relevance in colorectal cancer (CRC). Experimental Approach: TRPM8 expression and its correlation with the survival rate of CRC patients was analysed. To identify the key pathways and genes related to TRPM8 high expression, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted in CRC patients. TRPM8 functional role was assessed by using Trpm8−/− mice in models of sporadic and colitis-associated colon cancer. TRPM8 pharmacological targeting by WS12 was evaluated in murine models of CRC. Key Results: TRPM8 is overexpressed in colon primary tumours and in CD326+ tumour cell fraction. TRPM8 high expression was related to lower survival rate of CRC patients, Wnt–Frizzled signalling hyperactivation and adenomatous polyposis coli down-regulation. In sporadic and colitis-associated models of colon cancer, either absence or pharmacological desensitization of TRPM8 reduced tumour development via inhibition of the oncogenic Wnt/β-catenin signalling. TRPM8 pharmacological blockade reduced tumour growth in CRC xenograft mice by reducing the transcription of Wnt signalling regulators and the activation of β-catenin and its target oncogenes such as C-Myc and Cyclin D1. Conclusion and Implications: Human data provide valuable insights to propose TRPM8 as a prognostic marker with a negative predictive value for CRC patient survival. Animal experiments demonstrate TRPM8 involvement in colon cancer pathophysiology and its potential as a drug target for CRC.

ObjectiveTo summarise the available clinical evidence on the efficacy and safety of osteopathic manipulative treatment (OMT) for different conditions.DesignOverview of systematic reviews (SRs) and meta-analyses (MAs). PROSPERO CRD42020170983.Data sourcesAn electronic search was performed using seven databases: PubMed, EMBASE, CINAHL, Scopus, JBI, Prospero and Cochrane Library, from their inception until November 2021.Eligibility criteria for selecting studiesSRs and MAs of randomised controlled trials evaluating the efficacy and safety of OMT for any condition were included.Data extraction and synthesisThe data were independently extracted by two authors. The AMSTAR-2 tool was used to assess the methodological quality of the SRs and MAs. The overview was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.ResultsThe literature search revealed nine SRs or MAs conducted between 2013 and 2020 with 55 primary trials involving 3740 participants. The SRs reported a wide range of conditions including acute and chronic non-specific low back pain (NSLBP, four SRs), chronic non-specific neck pain (CNSNP, one SR), chronic non-cancer pain (CNCP, one SR), paediatric (one SR), neurological (primary headache, one SR) and irritable bowel syndrome (IBS, one SR). Although with a different effect size and quality of evidence, MAs reported that OMT is more effective than comparators in reducing pain and improving functional status in acute/chronic NSLBP, CNSNP and CNCP. Due to small sample size, presence of conflicting results and high heterogeneity, questionable evidence existed on OMT efficacy for paediatric conditions, primary headache and IBS.No adverse events were reported in most SRs. According to AMSTAR-2, the methodological quality of the included SRs was rated low or critically low.ConclusionBased on the currently available SRs and MAs, promising evidence suggests the possible effectiveness of OMT for musculoskeletal disorders. Limited and inconclusive evidence occurs for paediatric conditions, primary headache and IBS. Further well-conducted SRs and MAs are needed to confirm and extend the efficacy and safety of OMT.

Fish oil (FO) and phytocannabinoids have received considerable attention for their intestinal anti-inflammatory effects. We investigated whether the combination of FO with cannabigerol (CBG) and cannabidiol (CBD) or a combination of all three treatments results in a more pronounced intestinal antiinflammatory action compared to the effects achieved separately. Colitis was induced in mice by 2,4-dinitrobenzenesulfonic acid (DNBS). CBD and CBG levels were detected and quantified by liquid chromatography coupled with time of flight mass spectrometry and ion trap mass spectrometry (LC-MS-IT-TOF). Endocannabinoids and related mediators were assessed by LC-MS. DNBS increased colon weight/colon length ratio, myeloperoxidase activity, interleukin-1β, and intestinal permeability. CBG, but not CBD, given by oral gavage, ameliorated DNBS-induced colonic inflammation. FO pretreatment (at the inactive dose) increased the antiinflammatory action of CBG and rendered oral CBD effective while reducing endocannabinoid levels. Furthermore, the combination of FO, CBD, and a per se inactive dose of CBG resulted in intestinal anti-inflammatory effects. Finally, FO did not alter phytocannabinoid levels in the serum and in the colon. By highlighting the apparent additivity between phytocannabinoids and FO, our preclinical data support a novel strategy of combining these substances for the potential development of a treatment of inflammatory bowel disease.

A case of visceral Leishmaniasis in a renal transplant recipient is reported because of its peculiar clinical presentation: the presence of most clinical signs of the disease, such as high-grade fever, marked leucopenia, and splenomegaly, but persistent negativity of serology and of bone marrow smear. Forty days after the first bone marrow biopsy, the diagnosis was made possible by a second biopsy, and the treatment was started with antimonial compounds, which led to complete remission of symptoms. A relapse was observed 1 month after discontinuation of therapy, successfully treated with a new cycle of the same drug and allopurinol. The diagnosis of Leishmaniasis must always be considered in immunosuppressed transplant recipients with fever and leucopenia of unknown origin, even when serology and bone marrow smear are negative.

Background and purpose N-acylethanolamine acid amidase (NAAA) is a lysosomal enzyme accountable for the breakdown of N-acylethanolamides (NAEs) and its pharmacological inhibition determines beneficial effects in inflammatory conditions. The knowledge of NAAA in cancer is fragmentary with an unclarified mechanism whereas its contribution to colorectal cancer (CRC) is unknown to date. Experimental approach CRC xenograft and azoxymethane models assessed the in vivo pharmacological effect of NAAA inhibition; tumor secretome was evaluated by an oncogenic array; CRC cell lines were used for in vitro studies; cell cycle was analyzed by cytofluorimetry; NAAA was knocked down with siRNA; human biopsies were obtained from surgically resected CRC patients; gene expression was revealed by RT-PCR; NAEs were measured by LC-MS. Key results The NAAA inhibitor AM9053 reduced CRC xenograft tumor growth and counteracted tumor development in the azoxymethane model. NAAA inhibition impacted the composition of the tumor secretome that negatively affected the expression of epidermal growth factor family members. In CRC cells, AM9053 reduced proliferation with a mechanism mediated by PPAR-α and TRPV1 and induced cell cycle arrest in the S phase with cyclin A2/CDK2 downregulation. NAAA knock-down mirrored the effects of NAAA pharmacological inhibition. NAAA expression was downregulated in human CRC tissues, with a consequential augmentation of NAEs levels and dysregulation of some of their targets. Conclusions and implications Our results provide unprecedented data on the functional importance of NAAA in CRC progression and its mechanism. We propose this enzyme as a valid drug target for the treatment of CRC growth and development.

Background: Posttraumatic stress disorder (PTSD) is a psychiatric condition that manifests through a broad range of symptoms and shares several phenotypes with anxiety and depression. Refractory PTSD affects 10 – 30% of the patients and highlights the need for alternative pharmacotherapy. The suggested involvement of the endocannabinoid system (ECS) with the emotional processes has enlightened the use of Cannabis sp. Then, this study aimed to evaluate the therapeutic effects of a broad-spectrum Cannabis oil on anxiety- and depressive-like behaviors triggered by stressors from combined nature. In addition, this study investigated the effect of the oil on central cannabinoid receptor 1 and serum levels of cytokines, chemokines, and growth factors. Methods: Mice were randomized into five groups (vehicle; Cannabis oil; fluoxetine; single oral dose) and submitted to acute restraint and chronic unpredictable stress. Then, they were behaviorally assessed in the elevated plus-maze test (EPMT), forced swimming test (FST), splash test (ST), and open field test (OFT). The tetrad cannabinoid assay evaluated the central effect of the oil. Serum biomarkers levels were measured by a multiplex bead-based assay. Results: Cannabis oil (0.1 mg/kg, p.o.) significantly reduced the anxiety-like behavior in EPMT in the acute restraint stress model (p < 0.05) as compared to vehicle. Moreover, compared to the vehicle, Cannabis oil significantly reverted the despair and anhedonic-like behaviors in FST (p < 0.05) and ST (p < 0.05), respectively, in chronically stressed mice. Yet, compared to vehicle, therapy with Cannabis oil did not induce cannabinoid-tetrad (p < 0.0001); downregulated granulocyte-macrophage colony-stimulating factor (GM-CSF; p < 0.01) and advanced glycation end-products (RAGE; p < 0.0001); and upregulated vascular endothelial growth factor (VEGF; p < 0.01) serum levels. Conclusion: Altogether, our data suggest the potential of the broad-spectrum Cannabis oil to improve symptoms related to anxiety and depression caused by traumatic events.

Nonprenylated rotenoids isolated from Boerhaavia diffusa are identified as new class of breast cancer resistance protein inhibitors (ABCG2). The recent determination of high-resolution structure of ABCG2 (with chemotherapeutics mitoxantrone or Ko143) enables the investigation of molecular interaction capacities of boeravinones. In this research pharmacokinetic/pharmacodynamic relationship of 17 boeravinones considering their molecular properties, ADMET profile and binding energies for ABCG2 was studied for the first time. All 17 compounds met the requirements of empirical rules for drug-likeness. Based on the obtained results lipophilicity was determined as the key property of boeravinones for the intestinal absorption, total clearance and acute and chronic toxicity in rats while polarity was the limiting factor for blood brain barrier permeation. Both lipophilicity and the fraction of sp3 hybridized carbon atoms influenced the binding affinity of boeravinones to ABCG2 proteins (6XVI and 6FFC) expressed as ChemPLP and GOLD Score. The performed in silico analysis implies that boeravinones could be used as potent safe leads to human ABCG2.

δ-Valerobetaine (δVB) is a constitutive milk metabolite with antioxidant and anti-inflammatory activities. Here, we tested the antineoplastic properties of milk δVB on human colorectal cancer cells. CCD 841 CoN (non-tumorigenic), HT-29 (p53 mutant adenocarcinoma) and LoVo (APC/RAS mutant adenocarcinoma) cells were exposed to 3 kDa milk extract, δVB (2 mM) or milk+δVB up to 72 h. Results showed a time- and dose-dependent capability of δVB to inhibit cancer cell viability, with higher potency in LoVo cells. Treatment with milk+δVB arrested cell cycle in G2/M and SubG1 phases by upregulating p21, cyclin A, cyclin B1 and p53 protein expressions. Noteworthy, δVB also increased necrosis (P P P SIRT6 silencing by small interfering RNA blocked autophagy and apoptosis activated by milk+δVB, unveiling the role of this sirtuin in the ROS-mediated apoptotic LoVo cell death.

The paper presents the design of a lateral stability controller for ground vehicles based on front steering and four wheels independent braking. The control objective is to track yaw rate and lateral velocity reference signals while avoiding front and rear wheel traction force saturation. Control design is based on an approximate piecewise-affine nonlinear dynamical model of the vehicle. Vehicle longitudinal velocity and drivers steering input are modelled as measured disturbances taking values in a compact set. A time-optimal control strategy which ensures convergence into a maximal robust control invari- ant (RCI) set is proposed. This paper presents the uncertain model, the RCI computation, and the control algorithm. Experimental tests at high-speed on ice with aggressive driver manoeuvres show the effectiveness of the proposed scheme.