Estrogen receptors in colorectal cancer: Facts, novelties and perspectives

Colorectal cancer (CRC) is the second cause of cancer-related death in both sexes worldwide. As pre-menopausal women are less likely to develop CRC compared to age-matched men, a protective role for estrogens has been hypothesized. Indeed, two isoforms of nuclear estrogen receptors (ER) have been described: ERα and ERβ. While the binding of 17beta-estradiol to ERα activates anti-apoptotic pathways, the interaction with ERβ activates caspase-3, inducing apoptosis. In this regard, several pieces of evidence show that ERβ tends to be under-regulated in advanced adenomas and CRC, with an opposite trend for ERα. Furthermore, ERβ stimulation slows adenomatous polyp growth and modulates relevant CRC pathways. Based on such considerations, dietary modulation of ER is promising, particularly in subjects with genetic predisposition for CRC. Nevertheless, the main limitation is the lack of clinical trials on a large population scale

Cyclooxygenase-2-Derived Prostacyclin Protective Role on Endotoxin-Induced Mouse Cardiomyocyte Mortality

Cardiovascular dysfunction characterizes septic shock, inducing multiple organ failure and a high mortality rate. In the heart, it has been shown an up-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions with subsequent overproduction of nitric oxide (NO) and eicosanoids. This study is focused on the links between these products of inflammation and cell loss of mouse cardiomyocytes during treatment by the Salmonella typhimurium lipopolysaccharide (LPS) in presence or in absence of NOS or COX inhibitors. LPS induced RelA/NF-κB p65 activation, iNOS and COX-2 up-regulations, resulting in NO and prostacyclin releases. These effects were reversed by the NO-synthase inhibitor and increased by the specific COX-2 inhibitor. Immunostainings with FITC-conjugated anti-Annexin-V and propidium iodide and caspase 3/7 activity assay showed that cardiomyocyte necrosis was inhibited by L-NA during LPS treatment challenge, while apoptosis was induced in presence of both LPS and NS-398. No effect on LPS cellular injury was observed using the specific cyclooxygenase-1 (COX-1) inhibitor, SC-560. These findings strongly support the hypothesis of a link between iNOS-dependent NO overproduction and LPS-induced cell loss with a selective protective role allotted to COX-2 and deriving prostacyclins

Silymarin, boswellic acid and curcumin enriched dietetic formulation reduces the growth of inherited intestinal polyps in an animal model

BACKGROUND Some substances of plant origin have been reported to exert an effect in reducing intestinal neoplasm development, especially in animal models. Adenomatous polyposis coli multiple intestinal neoplasia-ApcMin/+ is the most studied murine model of genetic intestinal carcinogenesis. AIM To assess whether an enriched nutritional formulation (silymarin, boswellic acid and curcumin) with proven "in vitro" and "in vivo" anti-carcinogenetic properties may prevent inherited intestinal cancer in animal model. METHODS Forty adenomatous polyposis coli multiple intestinal neoplasia-ApcMin/+ mice were used for the study of cancer prevention. They were divided into two groups: 20 assumed standard and 20 enriched diet. At the 110th d animals were sacrificed. In each group, four subgroups received intraperitoneal bromodeoxyuridine injection at different times (24, 48, 72 and 96 h before the sacrifice) in order to assess epithelial turnover. Moreover, we evaluated the following parameters: Intestinal polypoid lesion number and size on autoptic tissue, dysplasia and neoplasia areas by histological examination of the whole small intestine, inflammation by histology and cytokine mRNA expression by real-Time polymerase chain reaction, bromodeoxyuridine and TUNEL immunofluorescence for epithelial turnover and apoptosis, respectively. Additionally, we performed western blotting analysis for the expression of estrogen alpha and beta receptors, cyclin D1 and cleaved caspase 3 in normal and polypoid tissues. RESULTS Compared to standard, enriched diet reduced the total number (203 vs 416) and the mean ± SD/animal (12.6 ± 5.0 vs 26.0 ± 8.8; P< 0.001) of polypoid lesions. In enriched diet group a reduction in polyp size was observed (P< 0.001). Histological inflammation and pro-inflammatory cytokine expression were similar in both groups. Areas of low-grade dysplasia (P< 0.001) and intestinal carcinoma (IC; P< 0.001) were significantly decreased in enriched diet group. IC was observed in 100% in standard and 85% in enriched formulation assuming animals. Enriched diet showed a faster epithelial migration and an increased apoptosis in normal mucosa and low-grade dysplasia areas (P< 0.001). At western blotting, estrogen receptor beta protein was well expressed in normal mucosa of enriched and standard groups, with a more marked trend associated to the first one. Estrogen receptor alpha was similarly expressed in normal and polypoid mucosa of standard and enriched diet group. Cleaved caspase 3 showed in normal mucosa a stronger signal in enriched than in standard diet. Cyclin D1 was more expressed in standard than enriched diet group of both normal and polypoid tissue. CONCLUSION Our results are suggestive of a chemo-preventive synergic effect of the components (silymarin, boswellic acid and curcumin) of an enriched formulation in inherited IC. This effect may be mediated by the reduction of epithelial proliferation, the increase of apoptosis and the acceleration of villous cell renewal due to dietary formulation intake

Chemoprevention of inflammation-related colorectal cancer by silymarin-, acetyl-11-keto-beta-boswellic acid-, curcumin- and maltodextrin-enriched dietetic formulation in animal model

On the basis of preliminary in vitro experience, we assessed whether an enriched nutritional formulation with estrogen receptor (ER)-beta agonist and anti-inflammatory properties may prevent inflammation-associated colorectal cancer (CRC) in an animal model. Study sample enclosed 110 C57BL/6J male mice. Forty underwent dietary supplement safety assessment (20 standard diet and 20 enriched formulation). Seventy were treated with azoxymethane (AOM)/dextran sulfate sodium and divided into two groups: 35 received standard diet and 35 enriched formulation (curcumin, boswellic acids, silymarin and maltodextrins). Miniature colonoscopy demonstrated colitis and solid lesion development in five mice/group 100 days after first AOM injection. Mice were killed after 10 days. In each group, four subgroups received intraperitoneal bromodeoxyuridine (BrdU) injection at 24th/48th/72nd/96th hour before killing. Anti-inflammatory effect and chemoprevention were evaluated by lesion number/size, histological inflammation/dysplasia/neoplasia assessment, pro-inflammatory cytokine messenger RNA (mRNA), ER-beta/ER-alpha/BrdU immunohistochemistry and TUNEL immunofluorescence. Standard formulation assumption was associated with colon shortening compared with enriched one (P = 0.04), which reduced solid lesion number and size (P < 0.001 for both), histological inflammation score (P = 0.04), pro-inflammatory cytokine mRNA expression (P < 0.001), number of low-grade dysplasia (LGD; P = 0.03) and high-grade dysplasia (P < 0.001) areas. CRC was observed in 69.6% in standard and 23.5% in enriched formulation assuming animals (P < 0.001). Enriched formulation induced lower ER-alpha expression in CRC (P < 0.001) and higher ER-beta expression in LGD (P < 0.001) being associated to higher epithelial turnover (BrdU; P<0.001) in normal mucosa and increased apoptosis in LGD and CRC (P < 0.001 for both). Our results are promising for a successful anti-inflammatory and chemopreventive effect of enriched formulation in CRC arising from inflamed tissue

Applications of Human Tissue-Engineered Blood Vessel Models to Study the Effects of Shed Membrane Microparticles from T-Lymphocytes on Vascular Function

Microparticles (MPs) are membrane vesicles harboring cell surface proteins and containing cytoplasmic components of the original cell. High levels of circulating MPs have been detected in pathological states associated with vascular dysfunction. We took advantage of the self-assembly method of tissue engineering to produce in vitro three vascular constructs from human vascular smooth muscle cells and fibroblasts to investigate the role of the adventitia in the modulation of vascular tone by MPs, comparing the contractile response of each of these constructs to histamine. The first two were composed of an adventitia (tissue-engineered vascular adventitia (TEVA)) or a media (tissue-engineered vascular media (TEVM)) solely, and the third one contained a media and an adventitia (tissue-engineered vascular media and adventitia (TEVMA)). In the three constructs, the results show that histamine induces contraction insensitive to blockade of inducible nitric oxide (NO) synthase (iNOS) and cyclooxygenase-2 (COX-2) and not affected by MP treatment. MPs decreased NO production and nuclear factor (NF)-κB expression but did not affect superoxide anion (O2−) release in TEVA. MPs enhanced NF-κB expression but did not affect iNOS and COX-2 expression or NO or O2− release in TEVM. In TEVMA, MPs did not enhance NF-κB expression, but COX-2 expression was higher, and O2− release was lower. Thus, MPs affected NO, O2−, NF-κB, and COX-2 in a subtle fashion to maintain the contractile response to histamine. The use of tissue-engineered vascular constructs results in a better understanding of the effect of MPs on human adventitia and media

Helicobacter pylori primary and secondary genotypic resistance to clarithromycin and levofloxacin detection in stools: A 4-year scenario in Southern Italy

Antibiotic resistance has become an emerging problem for treating Helicobacter pylori (H. pylori) infection. Clarithromycin and levofloxacin are two key antibiotics used for its eradication. Therefore, we reviewed our experience with genotypic resistance analysis in stools to both clarithromycin and levofloxacin in the last four years to evaluate time trends, both in naive and failure patients. Patients collected a fecal sample using the THD fecal test device. Real-time polymerase chain reaction was performed to detect point mutations conferring resistance to clarithromycin (A2142C, A2142G, and A2143G in 23S rRNA) and levofloxacin (substitutions at amino acid position 87 and 91 of gyrA). One hundred and thirty-five naive patients were recruited between 2017-2020. Clarithromycin resistance was detected in 37 (27.4%). The time trend did not show any significant variation from 2017 to 2020 (p = 0.33). Primary levofloxacin resistance was found in 26 subjects (19.2%), and we observed a dramatic increase in rates from 2017 (10%) to 2018 (3.3%), 2019 (20%), and 2020 (37.8%). Ninety-one patients with at least one eradication failure were recruited. Secondary resistance to clarithromycin and levofloxacin was found in 59 (64.8%) and 45 patients (59.3%), respectively. In conclusion, our geographic area has a high risk of resistance to clarithromycin. There is also a progressive spreading of levofloxacin-resistant strains

Italian good practice recommendations on management of persons with Long-COVID

A significant number of people, following acute SARS-CoV-2 infection, report persistent symptoms or new symptoms that are sustained over time, often affecting different body systems. This condition, commonly referred to as Long-COVID, requires a complex clinical management. In Italy new health facilities specifically dedicated to the diagnosis and care of Long-COVID were implemented. However, the activity of these clinical centers is highly heterogeneous, with wide variation in the type of services provided, specialistic expertise and, ultimately, in the clinical care provided. Recommendations for a uniform management of Long-COVID were therefore needed. Professionals from different disciplines (including general practitioners, specialists in respiratory diseases, infectious diseases, internal medicine, geriatrics, cardiology, neurology, pediatrics, and odontostomatology) were invited to participate, together with a patient representative, in a multidisciplinary Panel appointed to draft Good Practices on clinical management of Long-COVID. The Panel, after extensive literature review, issued recommendations on 3 thematic areas: access to Long-COVID services, clinical evaluation, and organization of the services. The Panel highlighted the importance of providing integrated multidisciplinary care in the management of patients after SARS-CoV-2 infection, and agreed that a multidisciplinary service, one-stop clinic approach could avoid multiple referrals and reduce the number of appointments. In areas where multidisciplinary services are not available, services may be provided through integrated and coordinated primary, community, rehabilitation and mental health services. Management should be adapted according to the patient's needs and should promptly address possible life-threatening complications. The present recommendations could provide guidance and support in standardizing the care provided to Long-COVID patients

Glucose transport in brain and retina: implications in the management and complications of diabetes

Neural tissue is entirely dependent on glucose for normal metabolic activity. Since glucose stores in the brain and retina are negligible compared to glucose demand, metabolism in these tissues is dependent upon adequate glucose delivery from the systemic circulation. In the brain, the critical interface for glucose transport is at the brain capillary endothelial cells which comprise the blood–brain barrier (BBB). In the retina, transport occurs across the retinal capillary endothelial cells of the inner blood–retinal barrier (BRB) and the retinal pigment epithelium of the outer BRB. Because glucose transport across these barriers is mediated exclusively by the sodium-independent glucose transporter GLUT1, changes in endothelial glucose transport and GLUT1 abundance in the barriers of the brain and retina may have profound consequences on glucose delivery to these tissues and major implications in the development of two major diabetic complications, namely insulin-induced hypoglycemia and diabetic retinopathy. This review discusses the regulation of brain and retinal glucose transport and glucose transporter expression and considers the role of changes in glucose transporter expression in the development of two of the most devastating complications of long-standing diabetes mellitus and its management. Copyright © 1999 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35242/1/43_ftp.pd

The Burden of Type 1 and Type 2 Diabetes Among Adolescents and Young Adults in 24 Western European Countries, 1990–2019:Results From the Global Burden of Disease Study 2019

Objectives: As little is known about the burden of type 1 (T1DM) and type 2 diabetes (T2DM) in adolescents in Western Europe (WE), we aimed to explore their epidemiology among 10–24 year-olds. Methods: Estimates were retrieved from the Global Burden of Diseases Study (GBD) 2019. We reported counts, rates per 100,000 population, and percentage changes from 1990 to 2019 for prevalence, incidence and years lived with disability (YLDs) of T1DM and T2DM, and the burden of T2DM in YLDs attributable to high body mass index (HBMI), for 24 WE countries. Results: In 2019, prevalence and disability estimates were higher for T1DM than T2DM among 10–24 years old adolescents in WE. However, T2DM showed a greater increase in prevalence and disability than T1DM in the 30 years observation period in all WE countries. Prevalence increased with age, while only minor differences were observed between sexes. Conclusion: Our findings highlight the substantial burden posed by DM in WE among adolescents. Health system responses are needed for transition services, data collection systems, education, and obesity prevention.</p

The Burden of Type 1 and Type 2 Diabetes Among Adolescents and Young Adults in 24 Western European Countries, 1990–2019:Results From the Global Burden of Disease Study 2019

Objectives: As little is known about the burden of type 1 (T1DM) and type 2 diabetes (T2DM) in adolescents in Western Europe (WE), we aimed to explore their epidemiology among 10–24 year-olds. Methods: Estimates were retrieved from the Global Burden of Diseases Study (GBD) 2019. We reported counts, rates per 100,000 population, and percentage changes from 1990 to 2019 for prevalence, incidence and years lived with disability (YLDs) of T1DM and T2DM, and the burden of T2DM in YLDs attributable to high body mass index (HBMI), for 24 WE countries. Results: In 2019, prevalence and disability estimates were higher for T1DM than T2DM among 10–24 years old adolescents in WE. However, T2DM showed a greater increase in prevalence and disability than T1DM in the 30 years observation period in all WE countries. Prevalence increased with age, while only minor differences were observed between sexes. Conclusion: Our findings highlight the substantial burden posed by DM in WE among adolescents. Health system responses are needed for transition services, data collection systems, education, and obesity prevention.</p