Role of matrix metalloproteinase-2 in newborn mouse lungs under hypoxic conditions

Hypoxia impairs normal neonatal pulmonary artery remodeling and alveolar development. Matrix metalloproteinase-2 (MMP-2), which regulates collagen breakdown, is important during development. Our objective was to test the hypothesis that hypoxia attenuates the normal postnatal increase in MMP-2 and evaluate alveolar development and pulmonary arterial remodeling in Mmp2 mice. C57BL/6 wild-type (WT), Mmp2, Mmp2, and MMP-inhibited (with doxycycline) mice were exposed to hypoxia (12% O2) or air from birth to 2 wk of age. Pulmonary arterial remodeling, alveolar development, and vascular collagen and elastin were evaluated. MMP-2 was estimated by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry, and zymography. We observed that 1) in WT mice, hypoxia led to thicker-walled pulmonary arteries and impaired alveolarization, accompanied by decreased MMP-2 and increased tissue inhibitor of metalloproteinases-2 (TIMP-2); 2) Mmp2 mice in air had thicker-walled arteries, impaired alveolarization, and increased perivascular collagen and elastin compared with WT; 3) hypoxia further inhibited alveolarization but did not alter arterial thickening in Mmp2 mice. Mmp2 and MMP-inhibited mice also had thicker-walled arteries than WT in air, but alveolarization was not different. We conclude that hypoxia reduces the postnatal MMP-2 increase in the lung, which may contribute to abnormal pulmonary arterial remodeling and impaired alveolarization.     

Synthesis,anticancer activity,and molecular modeling of etodolac‐thioether derivatives as potent methionine aminopeptidase (type II) inhibitors

A series of (R,S)‐1‐{[5‐(substituted)sulfanyl‐4‐substituted‐4H‐1,2,4‐triazole‐3‐yl]methyl}‐1,8‐diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐b]indoles ( 5a–v ) were designed and synthesized using a five‐step synthetic protocol that involves substituted benzyl chlorides and (R,S)‐5‐[(1,8‐diethyl‐1,3,4,9‐tetrahydropyrano[3,4‐b]indole‐1‐yl)methyl]‐4‐substituted‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones in the final step. The synthesized derivatives were evaluated for cytotoxicity and anticancer activity in vitro using the MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) colorimetric method against VERO, HEPG2 (human hepatocellular liver carcinoma), SKOV3 (ovarian carcinoma), MCF7 (human breast adenocarcinoma), PC3 and DU145 (prostate carcinoma) cells at 10^?5 M (10 μM) for 24 h. Compounds 5d and 5h showed the best biological potency against the SKOV3 cancer cell line (IC₅₀ = 7.22 and 5.10 μM, respectively) and did not display cytotoxicity toward VERO cells compared to etodolac. Compounds 5k , 5s , and 5v showed the most potent biological activity against the PC3 cancer cell line (IC₅₀ = 8.18, 3.10, and 4.00 μM, respectively) and did not display cytotoxicity. Moreover, these compounds were evaluated for caspase‐3, ‐9, and ‐8 protein expression and activation in the apoptosis pathway for 6, 12, and 24 h, which play a key role in the treatment of cancer. In this study, we also investigated the apoptotic mechanism and molecular modeling of compounds 5k and 5v on the methionine aminopeptidase (type II) enzyme active site in order to get insights into the binding mode and energy.

     

Persistent Moderate-to-Weak Mediterranean Diet Adherence and Low Scoring for Plant-Based Foods across Several Southern European Countries: Are We Overlooking the Mediterranean Diet Recommendations?

The Mediterranean diet (MD) has been sponsored worldwide as a healthy and sustainable diet. Our aim was to update and compare MD adherence and food choices across several Southern European countries: Spain (SP), Portugal (PT), Italy (IT), Greece (GR), and Cyprus (CY) (MED, Mediterranean), and Bulgaria (BG) and the Republic of North Macedonia (NMK) (non-MED, non-Mediterranean). Participants (N = 3145, ≥18 y) completed a survey (MeDiWeB) with sociodemographic, anthropometric, and food questions (14-item Mediterranean Diet Adherence Screener, 14-MEDAS). The MED and non-MED populations showed moderate (7.08 ± 1.96) and weak (5.58 ± 1.82) MD adherence, respectively, with significant yet small differences across countries (SP > PT > GR > IT > CY > BG > NMK, p-value < 0.001). The MED participants scored higher than the non-MED ones for most of the Mediterranean-typical foods, with the greatest differences found for olive oil (OO) and white meat preference. In most countries, ≥70% of the participants reported quantities of red meat, butter, sweet drinks, and desserts below the recommended cutoff points, whereas <50% achieved the targets for plant-based foods, OO, fish, and wine. Being a woman and increasing age were associated with superior adherence (p-value < 0.001), but differences were rather small. Our results suggest that the campaigns carried out to support and reinforce the MD and to promote plant-based foods have limited success across Southern Europe, and that more hard-hitting strategies are needed.     

Hydro-distillation and microwave-assisted distillation of Sideritis raeseri: Comparison of the composition of the essential oil,hydrolat and residual water extract

Sideritis raeseri is widely used as a tea in the traditional medicine of many Mediterranean, Balkan, and Middle East countries. In this study, microwave-assisted hydro-distillation (MAHD) at different power levels (180 W, 360 W, and 600 W) of Sideritis raeseri essential oil was compared in terms of extraction time, yield, qualitative analysis, and operational cost with the conventional method of hydro-distillation (HD). Obtained essential oil, as well as hydrolats and residual water extracts, were chemically characterized. An extraction time of 16–32 min with MAHD at different powers provided yields of 0.61–0.67%, while HD gave 0.01% after 141 min. The main constituents in all essential oils were oxygenated sesquiterpenes, and their content was higher in MAHD (32.93–51.42%) than in oil from HD (17.62%). HD oil was characterized by higher concentration of oxygenated monoterpenes (14.95%) in relation to MAHD oil (8.87–14.16%). The essential oil obtained by MAHD at 600 W has a higher content of diterpenes (13.26%) than HD oil (8.59%). All hydrolats displayed the highest content of oxygenated monoterpenes. The highest contents of 8-hydroxyflavone 7-allosylglucosides compounds in residual water extracts were obtained by applying higher (600 W) microwave power. MAHD could be selected as a more appropriate extraction technique for S. reaseri essential oil than HD with respect to the extraction time, quality, and energy savings above 99%.     

PCL/Si-Doped Multi-Phase Calcium Phosphate Scaffolds Derived from Cuttlefish Bone

Increasing attention is focused on developing biomaterials as temporary scaffolds that provide a specific environment and microstructure for bone tissue regeneration. The aim of the present work was to synthesize silicon-doped biomimetic multi-phase composite scaffolds based on bioactive inorganic phases and biocompatible polymers (poly(ε-caprolactone), PCL) using simple and inexpensive methods. Porous multi-phase composite scaffolds from cuttlefish bone were synthesized using a hydrothermal method and were further impregnated with (3-aminopropyl)triethoxysilane 1–4 times, heat-treated (1000 °C) and coated with PCL. The effect of silicon doping and the PCL coating on the microstructure and mechanical and biological properties of the scaffolds has been investigated. Multi-phase scaffolds based on calcium phosphate (hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate) and calcium silicate (wollastonite, larnite, dicalcium silicate) phases were obtained. Elemental mapping revealed homogeneously dispersed silicon throughout the scaffolds, whereas silicon doping increased bovine serum albumin protein adsorption. The highly porous structure of cuttlefish bone was preserved with a composite scaffold porosity of ~78%. A compressive strength of ~1.4 MPa makes the obtained composite scaffolds appropriate for non-load-bearing applications. Cytocompatibility assessment by an MTT assay of human mesenchymal stem cells revealed the non-cytotoxicity of the obtained scaffolds.     

The European response to control and manage multi- and extensively drug-resistant Neisseria gonorrhoeae

Because cefixime and ceftriaxone resistance in Neisseria gonorrhoeae and gonorrhoea treatment failures were increasing, a response plan to control and manage multidrug-resistant N. gonorrhoeae (MDR-NG) in Europe was published in 2012. The three main areas of the plan were to: (i) strengthen surveillance of antimicrobial resistance (AMR), (ii) implement monitoring of treatment failures and (iii) establish a communication strategy to increase awareness and disseminate AMR results. Since 2012, several additional extensively drug-resistant N. gonorrhoeae (XDR-NG) strains have emerged, and strains with high-level ceftriaxone resistance spread internationally. This prompted an evaluation and review of the 2012 European Centre for Disease Prevention and Control (ECDC) response plan, revealing an overall improvement in many aspects of monitoring AMR in N. gonorrhoeae; however, treatment failure monitoring was a weakness. Accordingly, the plan was updated in 2019 to further support European Union/European Economic Area (EU/EEA) countries in controlling and managing the threat of MDR/XDR-NG in Europe through further strengthening of AMR surveillance and clinical management including treatment failure monitoring. The plan will be assessed biennially to ensure its effectiveness and its value. Along with prevention, diagnostic, treatment and epidemiological surveillance strategies, AMR surveillance is essential for effective control of gonorrhoea.     

Biomarkers in Pancreatic Cancer as Analytic Targets for Nanomediated Imaging and Therapy

As the increase in therapeutic and imaging technologies is swiftly improving survival chances for cancer patients, pancreatic cancer (PC) still has a grim prognosis and a rising incidence. Practically everything distinguishing for this type of malignancy makes it challenging to treat: no approved method for early detection, extended asymptomatic state, limited treatment options, poor chemotherapy response and dense tumor stroma that impedes drug delivery. We provide a narrative review of our main findings in the field of nanoparticle directed treatment for PC, with a focus on biomarker targeted delivery. By reducing drug toxicity, increasing their tumor accumulation, ability to modulate tumor microenvironment and even improve imaging contrast, it seems that nanotechnology may one day give hope for better outcome in pancreatic cancer. Further conjugating nanoparticles with biomarkers that are overexpressed amplifies the benefits mentioned, with potential increase in survival and treatment response.     

Prevalence of HIV infection among inpatients and outpatients in Department of Veterans Affairs health care systems: implications for screening programs for HIV

Objectives. We sought to determine the prevalence of HIV in both inpatient and outpatient settings in 6 Department of Veterans Affairs (VA) health care sites.Methods. We collected demographic data and data on comorbid conditions and then conducted blinded, anonymous HIV testing. We conducted a multivariate analysis to determine predictors of HIV infection.Results. We tested 4500 outpatient blood specimens and 4205 inpatient blood specimens; 326 (3.7%) patients tested positive for HIV. Inpatient HIV prevalence ranged from 1.2% to 6.9%; outpatient HIV prevalence ranged from 0.9% to 8.9%. Having a history of hepatitis B or C infection, a sexually transmitted disease, or pneumonia also predicted HIV infection. The prevalence of previously undocumented HIV infection varied from 0.1% to 2.8% among outpatients and from 0.0% to 1.7% among inpatients.Conclusions. The prevalence of undocumented HIV infection was sufficiently high for routine voluntary screening to be cost effective in each of the 6 sites we evaluated. Many VA health care systems should consider expanded routine voluntary HIV screening.Early identification of HIV infection through screening substantially lengthens the life of the person identified and provides an important public health benefit from reduced HIV transmission.1 HIV screening in health care settings is also cost effective, even when the prevalence of HIV infection is as low as 0.05% to 0.1%.1^–3 Newly revised guidelines for HIV screening from the Centers for Disease Control and Prevention (CDC) recommend one-time screening in all health care settings unless the prevalence of undiagnosed HIV infection is documented to be less than 0.1%.4The prevalence of undiagnosed HIV infection has been documented in few health care settings in the era of highly active antiretroviral therapy. The Sentinel Hospital Study, which assessed HIV prevalence in a probability sample of nonfederal US hospitals, showed that the prevalence of HIV infection ranged from 0.1% to 7.8% among sentinel hospital populations (inpatients and outpatients combined) in 1989; however, currently, few people with HIV are hospitalized, so both inpatient and outpatient prevalence rates may differ from previous estimates. Although total HIV prevalence has been evaluated in many settings, the most important factor in determining the usefulness of an HIV screening program is the prevalence of unidentified, rather than known, HIV infection.The preferred method for determining an unbiased estimate of prevalence in a population is a blinded (anonymous) serological survey, an approach recommended by the CDC.6^,7 In a blinded serological survey, blood that is drawn for other purposes is stripped of identifiers and tested for HIV. Because the patient’s identity cannot be determined, informed consent is not required. Other approaches that depend on patients’ acceptance of screening are limited by selection bias that occurs when patients decline testing.8^–10 This selection bias can be substantial, and the prevalence of HIV among patients who have declined testing may be either higher or lower than the prevalence among patients who accept testing.11 Blinded serological surveys have been used widely, most notably in the Sentinel Hospital Study.5We conducted a blinded serological survey to determine the prevalence of HIV infection among outpatients and inpatients in 6 Department of Veterans Affairs (VA) health care systems. The VA is one of the largest integrated health care systems and the largest provider of HIV care in the United States. Our goal was to assess the prevalence of both documented and undocumented HIV infection and to assess demographic and clinical predictors of documented and undocumented infection. Although predictors of undocumented HIV infection have been evaluated in emergency departments,12^,13 they have not been well studied in VA populations.