Search

Dithiolopyrrolones (DTPs), such as holomycin, are natural products that hold promise as scaffolds for antibiotics as they exhibit inhibitory activity against antibiotic-resistant pathogens. They consist of a unique bicyclic core containing a disulfide that is crucial for their biological activity. Herein, we establish the DTPs as prochelators. We show that the disulfides are reduced at cellular gluathione levels. This activates the drugs and initiates interactions with targets, particularly metal coordination. In addition, we report an expedient synthesis for the DTPs thiolutin and aureothricin, providing facile access to important natural DTPs and derivatives thereof.

Worldwide, health systems and care approaches vary widely due to local reality, distance to facilities, cultural norms, resources, staff availability, geography, and politics. Consequently, globally maternal-newborn dyad care and outcomes are highly variable, leading to approximately 800 maternal deaths daily with a 100-fold difference among high- and low-resource countries. Irrespective of where care is received, maternal safety and wellbeing should be preserved. Despite ongoing efforts, however, this is not the case. Large gaps exist between spending and clinical outcomes. Segmented health care, coupled with poor planning and inadequate resource distribution, results in failure to provide essential life-saving treatment. The proposed solution is a regional integrated care model from midwife to advanced level III/IV care and the newborn unit, achieved through effective coordination by site, staff, and clinicians. This model has been successfully implemented in high- to low-resource countries in the past 20 years. In the large diverse population of the United States, constructive steps have been implemented to reduce high maternal mortality in black and rural communities. The COVID-19 pandemic demonstrates the feasibility of rapid resources coordination to provide effective advanced care. The proposed integration of resources will have a major positive impact on the maternal-newborn dyad.

l-Kynurenine is an endogenous metabolite generated by the catabolic pathway of l-tryptophan and it could be a potential biomarker to test the efficacy of several checkpoint inhibitors that have already reached the clinical trials in the antitumor therapy. Thus, a molecularly imprinted polymer specific for the recognition of this metabolite was synthesized and used as innovative system in solid-phase extraction technique for the specific extraction and quantification of l-kynurenine in human urine. The off-line system was firstly tested on l-kynurenine standard solutions, allowing recoveries up to 97.7% (relative standard deviation = 2.2%) and then applied to fortified and deproteinated human urine samples, where a recovery of 84.1% (relative standard deviation = 3.1%) was obtained. The method was validated and it revealed a good linearity in the range of 0.157-20 μg/mL (r2 = 0.9992). The optimized procedure demonstrated a good feasibility on biological samples, allowing a ready quantification of l-kynurenine in the human urine, where the metabolite was found at a very low concentration (0.80 μg/mL). The extraction system developed could attract attention of pharmaceutical industries for l-kynurenine production as potential drug in the treatment of autoimmune disorders through its extraction and purification from biological matrixes.

Background Salmonella are bacteria of the family Enterobacteriaceae with a wide host range. Infection in birds causes subclinical disease to mass mortality events. Wild birds may act as healthy carriers posing a hazard to livestock and humans. The present study investigated the occurrence of Salmonella in wild birds admitted to a rehabilitation centre in order to assess the exposure of the staff to this zoonotic pathogen. Methods Faecal swabs of 552 avian patients (68 species) were collected over the course of 12 months. Each sample was propagated in enrichment broth and subsequently incubated on a RAPID'Salmonella plate. Salmonella isolates were serotyped, and antimicrobial susceptibility testing was performed. Results Six Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) and 1 S. Schleissheim were detected; all were pansusceptible to the antibiotics tested. Conclusion Despite the low positive rate in the tested population, the authors recommend applying protective equipment and hygiene measures when handling wild birds.

BACKGROUND Short implants have been presented as an option for posterior rehabilitation in cases of poor bone height. PURPOSE To compare the survival rate of short implants and standard implants when used in posterior single crowns, in addition to reporting marginal bone loss, prosthetic failures, and surgical complications. MATERIALS AND METHODS Electronic search (PubMed, LILACS, Cochrane Library, Scopus, and Web of Science) and hand search were performed to identify all randomized controlled trials (RCTs) and controlled clinical trials (CCTs) that evaluated both short and standard implants in posterior single crowns. RESULTS Out of 345 articles identified by both electronic and hand search, four studies were selected (one CCT and three RCTs). The meta-analysis for the survival rate showed that there was no significant difference between the short implants and the standard ones (P = 1.00; RR:1.00; CI:0.97-1.03) performed with three RCTs for a one-year follow-up. The mean marginal bone loss ranged from 0.1 mm to 0.54 mm. Only one study reported the presence of prosthetic failures and surgical complications. CONCLUSIONS The survival rate of short implants was similar to the standard ones in posterior single crowns, for the one-year follow-up period. They also presented low surgical complications, prosthetic failures and marginal bone loss, being a predictable treatment for single rehabilitation in posterior tooth loss.

This review covers photochemical approaches aimed at supplementing surgical instruments with handheld photodynamic therapy (PDT) instruments. PDT is not widely used in hospitals, because of the laser equipment and expertise needed, and because insurance policies often do not cover the procedure. Accordingly, this review focuses on advances in photochemistry, photophysics, nanotechnology and miniaturization techniques that may likely inspire the use of handheld instruments in PDT. A takeaway point is that the advent of photochemical scalpels or lancets that deliver reactive oxygen species (ROS) on site may better equip medical practitioners and allow for eradication of tumors or infections in general. Specifically, the review is divided into several sections: sensitizer types, multiphoton and plasmonic topics, sensitizer delivery, light delivery, dosimetry, fiber optics and handheld implements in PDT.

Aims Pulmonary hypertension (PH) is a relevant complication of left heart disease (LHD). The 2015 ESC/ERS PH guidelines report two different haemodynamic subsets of PH due to LHD (PH-LHD) based on levels of pulmonary vascular resistance (PVR) and diastolic pressure gradient (DPG): isolated post-capillary PH (Ipc-PH) and combined post- and pre-capillary PH (Cpc-PH). The objective of this study is to evaluate the prognostic value of Ipc-PH and Cpc-PH. Methods and results Data from 276 consecutive incident patients with PH-LHD were included. According to the guidelines, Ipc-PH is defined by DPG 3 WU. Using this definition, we identified three patient groups: Ipc-PH with both normal PVR and DPG (108 patients); Cpc-PH with both increased PVR and DPG (66 patients); and an intermediate group with either increased PVR or DPG (102 patients). Survival was estimated using the Kaplan–Meier method and compared between groups using the log-rank test. Patients with Ipc-PH had better survival compared with the group of patients with Cpc-PH (P = 0.026) and the intermediate group (P = 0.025). No survival difference was detected between patients with Cpc-PH and the intermediate group (P = 0.891). Patients with normal PVR had a better survival compared with those with elevated PVR (P = 0.012); while no difference was observed according to the level of DPG (P = 0.253). Conclusion Patients with Ipc-PH have a better prognosis compared with patients with Cpc-PH and with patients with isolated increase of PVR or DPG. Pulmonary vascular resistance has a better predictive value than DPG in patients with PH-LHD.

Electrospray Ionization and collision induced dissociation tandem mass spectrometry are usually employed to obtain compound identification through a mass spectra match. Different algorithms have been developed for this purpose (for example the nist match algorithm). These approaches compare the tandem mass spectra of the unknown analyte with the tandem mass spectra spectra of known compounds inserted in a database. The compounds are usually identified on the basis of spectral match value associated with a probability of recognition. However, this approach is not usually applied to multiple reaction monitoring transition spectra achieved by means of triple quadrupole apparatus, mainly due to the lack of a transition spectra database. The Surface Activated Chemical Ionization-Electrospray-NIST Bayesian model database search (SANIST) platform has been recently developed for new potential metabolite biomarker discovery, to confirm their identity and to use them for clinical and diagnostic applications. Here, we present an improved version of the SANIST platform that extends its application to forensic, pharmaceutical, and food analysis studies, where the compound identification rules are strict. The European Union (EU) has set directives for compound identification (EU directive 2002/657/EC). We have applied the SANIST method to identification of 11-nor-9-carboxytetrahydro-cannabinol in urine samples (an example of a forensic application), circulating levels of the immunosuppressive drug tacrolimus in blood (an example of a pharmaceutical application) and glyphosate in fruit juice (an example of a food analysis application) that meet the EU directive requirements. Copyright © 2016 John Wiley & Sons, Ltd.

Nutrigenomics data on the functional components of olive oil are still sparse, but rapidly increasing. Olive oil is the main source of fat and health-promoting component of the Mediterranean diet. Positive effects have been observed on genes involved in the pathobiology of most prevalent age- and lifestyle-related human conditions, such as cancer, cardiovascular disease and neurodegeneration. Other effects on health-promoting genes have been identified for bioactive components of olives and olive leafs. Omics technologies are offering unique opportunities to identify nutritional and health biomarkers associated with these gene responses, the use of which in personalized and even predictive protocols of investigation, is a main breakthrough in modern medicine and nutrition. Gene regulation properties of the functional components of olive oil, such as oleic acid, biophenols and vitamin E, point to a role for these molecules as natural homeostatic and even hormetic factors with applications as prevention agents in conditions of premature and pathologic aging. Therapeutic applications can be foreseen in conditions of chronic inflammation, and particularly in cancer, which will be discussed in detail in this review paper as major clinical target of nutritional interventions with olive oil and its functional components. © 2016 BioFactors, 43(1):17-41, 2017.

While often considered as harmful for cultural heritage, microorganisms can also be used for its safeguarding. Two research projects (BIOPATINAS and MAIA) using the capabilities of microorganisms for the conservation-restoration of metal artistic and archaeological objects are presented in this study. The objective of the BIOPATINAS project is to propose an alternative biological treatment for copper alloys artefacts. Taking advantage of unique properties of carefully selected fungal strains, the project relies on the conversion of existing corrosion patinas into more stable copper oxalates. The results demonstrated a different weathering behavior of the biopatina compared to standard treatments such as waxes or inhibitors. In the MAIA project, the unique capacities of some fungi and bacteria are studied for the stabilization of archeological iron. Based on the results achieved, a synergetic microbial consortium will be designed for the formation of stable iron compounds and the simultaneous removal of chloride ions that are the instigators of further corrosion after excavation. A careful assessment of the methodology is currently carried out over iron- and chloride-rich phases.

In ephemeral ponds, the hatching asynchrony of resting eggs may be adaptive and the result of a maternal bet-hedging strategy. A mother can influence the progeny phenology through conditions experienced during life cycle even in early development stages. We investigated the consequences of a hatching delay for offspring and compared early and late maternal effects in a clonal lineage of Heterocypris incongruens. We used females from genetically identical, 40 months old, resting eggs that hatched, asynchronically, after a first (FI) or a second (SI) inundation event. Maternal origin (FI or SI) was considered an early effect involving the maternal response to hatching stimuli during the embryological dormant stage. Maternal age at deposition and egg size were considered late effects that account for maternal conditions during active stage. We compared size and development time of eggs produced by FI and SI females under laboratory condition (24°C 12:12 L:D photoperiod). Maternal origin affected development time to adulthood which was later in FI than in SI females, and fecundity that was higher in FI than in SI females. SI eggs were smaller than FI eggs: size was affected by maternal age at deposition and was directly related to the egg development time. Development time varied from 1 to 117 days and was shorter in SI eggs than in FI eggs. Our results showed that maternal response during embryological stage affects the performance in successive active stages and suggested that hatching asynchrony may be considered a risk spread strategy. J. Exp. Zool. 323A: 382–391, 2015. © 2015 Wiley Periodicals, Inc.

Hepatocyte growth factor (HGF) is involved in the pathogenesis of Kaposi's sarcoma (KS), the most frequent neoplasia in patients with AIDS, characterized by proliferating spindle cells, infiltrating inflammatory cells, angiogenesis, edema, and invasiveness. In vitro, this factor sustains the biological behavior of KS derived cells, after activation of its receptor and the downstream MAPK and AKT signals. In other cell types, namely endothelial and epithelial cells, movement, proliferation, and survival stimulated by HGF and other growth factors and cytokines depend on diacylglycerol kinases (DGK). In an effort to identify new intracellular transducers operative in KS cells, which could represent therapeutic targets, we investigated the role of DGK in KS cell movement and proliferation by treating cells with the DGK pharmacological inhibitor R59949. We report that R59949 strongly inhibits HGF-induced KS motility, proliferation, and anchorage-independent growth with only a partial effect on cell adhesion and spreading. R59949 does not affect cell survival, HGF receptor activation, or the classical MAPK and AKT signalling pathways. Furthermore, we carried out an siRNA screen to characterize the DGK isoforms involved in KS motility and anchorage independent growth. Our data indicate a strong involvement of DGK-δ in KS motility and of DGK-ι in anchorage-independent growth. These results indicate that DGK inhibition is sufficient to impair in vitro KS cell proliferation and movement and suggest that selected DGK represent new pharmacological targets to interfere with the malignant properties of KS, independently from the well-known RAS/MAPK and PI3K/AKT pathways. © 2011 Japanese Cancer Association.

Summary Traditional local treatment of non-infectious uveitis was limited to steroids with side effects such as cataract and ocular hypertension. Intravitreal (IVT) sirolimus is a novel, non-steroid, locally delivered mTOR inhibitor under investigation. The SAKURA Program, which represents the largest study of non-infectious uveitis to date, was comprised of two Phase III (one pivotal, one supportive) multinational randomized double-masked studies evaluating sirolimus 440 μg vs 44 μg active control in subjects with active NIU-PS. 80% of subjects had Multiple Measures of Inflammation (MMI) at baseline, defined as vitreous haze (VH) ≥1.5+ and ≥1 of the following: systemic corticosteroids (overall prednisone-equivalent dose ≥7.5 mg/day), BCVA ≤ 75 ETDRS letters, and/or presence of macular edema. In the integrated ITT population, 21.2% vs 13.5% of subjects receiving 440 μg vs 44 μg achieved VH=0 at Month 5 (p = 0.0381). Among subjects with MMI at baseline, 21.1% vs 8.0% in 440 and 44 μg, respectively, achieved VH = 0 (p = 0.0007). In the SAKURA Program, treatment with 440 μg IVT sirolimus demonstrated statistically significant improvements in VH in subjects with active NIU-PS, including in subjects with MMI at baseline.

The human white adipose tissue (WAT) contains progenitors with cooperative roles in breast cancer (BC) angiogenesis, local and metastatic progression. The biguanide Metformin (Met), commonly used for Type 2 diabetes, might have activity against BC and was found to inhibit angiogenesis in vivo. We studied Met and another biguanide, phenformin (Phe), in vitro and in vivo in BC models. In vitro, biguanides activated AMPK, inhibited Complex 1 of the respiratory chain and induced apoptosis of BC and WAT endothelial cells. In coculture, biguanides inhibited the production of several angiogenic proteins. In vivo, biguanides inhibited local and metastatic growth of triple negative and HER2+ BC in immune-competent and immune-deficient mice orthotopically injected with BC. Biguanides inhibited local and metastatic BC growth in a genetically engineered murine model model of HER2+ BC. In vivo, biguanides increased pimonidazole binding (but not HIF-1 expression) of WAT progenitors, reduced tumor microvessel density and altered the vascular pericyte/endothelial cell ratio, so that cancer vessels displayed a dysplastic phenotype. Phe was significantly more active than Met both in vitro and in vivo. Considering their safety profile, biguanides deserve to be further investigated for BC prevention in high-risk subjects, in combination with chemo and/or targeted therapy and/or as post-therapy consolidation or maintenance therapy for the prevention of BC recurrence.

The photostability of guaiazulene (1,4-dimethyl-7-isopropylazulene; GA), a natural azulenic compound used in cosmetic and health-care products, as well as in pharmaceutical preparations, was investigated in solution (methanol, ethanol, acetonitrile), by different techniques: gas chromatography/mass spectrometry (GC/MS) and high-performance liquid chromatography combined with atmospheric pressure chemical ionization mass spectrometry and UV detection (LC/APCI-MS and HPLC/UV). A solar simulator (xenon-arc lamp) was used as UV-A radiation source. The study involved: monitoring compound decomposition, identifying products of photodegradation (PPs), assessing the role of oxygen and evaluating the kinetics of the process. Minor PPs are volatile compounds and were characterized by GC/MS, while oligomeric polyoxygenated compounds, tentatively characterized on the basis of MS and MS/MS spectra, were found to be the main photoproducts. The photodegradation was found to be enhanced by the presence of oxygen; nevertheless, determination of the singlet oxygen quantum yield for GA gave a lower value than that for the reference standard Rose Bengal. The obtained results and the developed stability-indicating methods (GC/MS and LC/MS) are of interest for stability studies and/or quality control purposes of GA as raw material or cosmetic products.