The unique characteristics of the tumor vasculature offer the possibility to selectively target tumor growth and vascularization using tubulin-destabilizing agents. Evidence accumulated with ...combretastatin A-4 (CA-4) and its prodrug CA-4P support the therapeutic value of compounds sharing this mechanism of action. However, the chemical instability and poor solubility of CA-4 demand alternative compounds that are able to surmount these limitations. This Perspective illustrates the different classes of compounds that behave similar to CA-4, analyzes their binding mode to αβ-tubulin according to recently available structural complexes, and includes described approaches to improve their delivery. In addition, dissecting the mechanism of action of CA-4 and analogues allows a closer insight into the advantages and drawbacks associated with these tubulin-destabilizing agents that behave as vascular disrupting agents (VDAs).
The aim of this study was to evaluate whether dietary behaviours of the Spanish adult population were changed during the COVID-19 outbreak confinement. For that purpose, an online questionnaire, ...based on 44 items including socio-demographic data, Mediterranean diet (MedDiet) Adherence Screener (MEDAS) as a reference of a healthy diet, processed foods intake, changes in their usual food choices and weight gain was distributed using social media and snowball sampling. A total of 7514 participants (37% aged below 35 years, 70.6% female, 77.9% university-level education or higher) from all the Spanish territory completed the questionnaire. Results outlined healthier dietary behaviours during the confinement when compared to previous habits. Overall, the MEDAS score (ranging from 0 to 14, whereby higher a scoring reflects greater adherence to the MedDiet) increased significantly from 6.53 ± 2 to 7.34 ± 1.93 during the confinement. Multivariate logistic regression models, adjusted for age, gender, region and other variables, showed a statistically significant higher likelihood of changing the adherence to the MedDiet (towards an increase in adherence) in those persons who decreased the intake of fried foods, snacks, fast foods, red meat, pastries or sweet beverages, but increased MedDiet-related foods such as olive oil, vegetables, fruits or legumes during the confinement. COVID-19 confinement in Spain has led to the adoption of healthier dietary habits/behaviours in the studied population, as reflected by a higher adherence to the MedDiet. This improvement, if sustained in the long-term, could have a positive impact on the prevention of chronic diseases and COVID-19-related complications.
Metastasis development represents an important threat for melanoma patients, even when diagnosed at early stages and upon removal of the primary tumor. In this scenario, determination of prognostic ...biomarkers would be of great interest. Serum contains information about the general status of the organism and therefore represents a valuable source for biomarkers. Thus, we aimed to define serological biomarkers that could be used along with clinical and histopathological features of the disease to predict metastatic events on the early‐stage population of patients. We previously demonstrated that in stage II melanoma patients, serum levels of dermcidin (DCD) were associated with metastatic progression. Based on the relevance of the immune response on the cancer progression and the recent association of DCD with local and systemic immune response against cancer cells, serum DCD was analyzed in a new cohort of patients along with interleukin 4 (IL‐4), IL‐6, IL‐10, IL‐17A, interferon γ (IFN‐γ), transforming growth factor‐β (TGF‐ β), and granulocyte–macrophage colony‐stimulating factor (GM‐CSF). We initially recruited 448 melanoma patients, 323 of whom were diagnosed as stages I‐II according to AJCC. Levels of selected cytokines were determined by ELISA and Luminex, and obtained data were analyzed employing machine learning and Kaplan–Meier techniques to define an algorithm capable of accurately classifying early‐stage melanoma patients with a high and low risk of developing metastasis. The results show that in early‐stage melanoma patients, serum levels of the cytokines IL‐4, GM‐CSF, and DCD together with the Breslow thickness are those that best predict melanoma metastasis. Moreover, resulting algorithm represents a new tool to discriminate subjects with good prognosis from those with high risk for a future metastasis.
Melanoma displays a remarkable capacity for dissemination even when detected at early stages. We developed a decision rule that considers Breslow thickness of the removed malignant lesion and IL‐4, GM‐CSF, and DCD serum levels in order to foresee the risk for future metastasis development of those stage I‐II patients. This algorithm may represent a tool to design more personalized follow‐up strategies.
In May, 2022, several European countries reported autochthonous cases of monkeypox, which rapidly spread globally. Early reports suggest atypical presentations. We aimed to investigate clinical and ...virological characteristics of cases of human monkeypox in Spain.
This multicentre, prospective, observational cohort study was done in three sexual health clinics in Madrid and Barcelona, Spain. We enrolled all consecutive patients with laboratory-confirmed monkeypox from May 11 to June 29, 2022. Participants were offered lesion, anal, and oropharynx swabs for PCR testing. Participant data were collected by means of interviews conducted by dermatologists or specialists in sexually transmitted infections and were recorded using a standard case report form. Outcomes assessed in all participants with a confirmed diagnosis were demographics, smallpox vaccination, HIV status, exposure to someone with monkeypox, travel, mass gathering attendance, risk factors for sexually transmitted infections, sexual behaviour, signs and symptoms on first presentation, virological results at multiple body sites, co-infection with other sexually transmitted pathogens, and clinical outcomes 14 days after the initial presentation. Clinical outcomes were followed up until July 13, 2022.
181 patients had a confirmed monkeypox diagnosis and were enrolled in the study. 166 (92%) identified as gay men, bisexual men, or other men who have sex with men (MSM) and 15 (8%) identified as heterosexual men or heterosexual women. Median age was 37·0 years (IQR 31·0–42·0). 32 (18%) patients reported previous smallpox vaccination, 72 (40%) were HIV-positive, eight (11%) had a CD4 cell count less than 500 cells per μL, and 31 (17%) were diagnosed with a concurrent sexually transmitted infection. Median incubation was 7·0 days (IQR 5·0–10·0). All participants presented with skin lesions; 141 (78%) participants had lesions in the anogenital region, and 78 (43%) in the oral and perioral region. 70 (39%) participants had complications requiring treatment: 45 (25%) had a proctitis, 19 (10%) had tonsillitis, 15 (8%) had penile oedema, six (3%) an abscess, and eight (4%) had an exanthem. Three (2%) patients required hospital admission. 178 (99%) of 180 swabs from skin lesions collected tested positive, as did 82 (70%) of 117 throat swabs. Viral load was higher in lesion swabs than in pharyngeal specimens (mean cycle threshold value 23 SD 4 vs 32 6, absolute difference 9 95% CI 8–10; p<0·0001). 108 (65%) of 166 MSM reported anal-receptive sex. MSM who engaged in anal-receptive sex presented with proctitis (41 38% of 108 vs four 7% of 58, absolute difference 31% 95% CI 19–44; p<0·0001) and systemic symptoms before the rash (67 62% vs 16 28%, absolute difference 34% 28–62; p<0·0001) more frequently than MSM who did not engage in anal-receptive sex. 18 (95%) of 19 participants with tonsillitis reported practising oral-receptive sex. The median time from onset of lesions to formation of a dry crust was 10 days (IQR 7–13).
In our cohort, monkeypox caused genital, perianal, and oral lesions and complications including proctitis and tonsillitis. Because of the variability of presentations, clinicians should have a low threshold for suspicion of monkeypox. Lesion swabs showed the highest viral loads, which, combined with the history of sexual exposure and the distribution of lesions, suggests close contact is probably the dominant transmission route in the current outbreak.
None.
Chikungunya virus (CHIKV) is a re-emerging Alphavirus that is transmitted to humans by Aedes mosquitoes. Currently, there are still no drugs or vaccines available for the treatment or prevention of ...this disease. Although traditionally restricted to Africa and Asia, the adaptation of the virus to Aedes albopictus, a mosquito species with an almost worldwide distribution, has contributed to the geographical spread of this virus in the past decade. Here, we report on a new family of compounds named 1,2,3triazolo4,5-dpyrimidin-7(6H)-ones that inhibit CHIKV replication in the low micromolar range with no toxicity to the host (Vero) cells. The most potent compound in this series has an EC50 value below 1 μM with no cytotoxicity detected up to 668 μM, therefore affording a selectivity index greater than 600. Interestingly, the compounds have little or no antiviral activity on the replication of other members of the Togaviridae family. The exploration and study of this class of selective inhibitors of CHIKV replication will contribute to deeper insights into the CHIKV life cycle and may be a first step toward the development of a clinical drug candidate.
Most nitroaromatic compounds are toxic and mutagenic for living organisms, but some microorganisms have developed oxidative or reductive pathways to degrade or transform these compounds. Reductive ...pathways are based either on the reduction of the aromatic ring by hydride additions or on the reduction of the nitro groups to hydroxylamino and/or amino derivatives. Bacterial nitroreductases are flavoenzymes that catalyze the NAD(P)H-dependent reduction of the nitro groups on nitroaromatic and nitroheterocyclic compounds. Nitroreductases have raised a great interest due to their potential applications in bioremediation, biocatalysis, and biomedicine, especially in prodrug activation for chemotherapeutic cancer treatments. Different bacterial nitroreductases have been purified and their biochemical and kinetic parameters have been determined. The crystal structure of some nitroreductases have also been solved. However, the physiological role(s) of these enzymes remains unclear. Nitroreductase genes are widely spread within bacterial genomes, but are also found in archaea and some eukaryotic species. Although studies on regulation of nitroreductase gene expression are scarce, it seems that nitroreductase genes may be controlled by the MarRA and SoxRS regulatory systems that are involved in responses to several antibiotics and environmental chemical hazards and to specific oxidative stress conditions. This review covers the microbial distribution, types, biochemical properties, structure and regulation of the bacterial nitroreductases. The possible physiological functions and the biotechnological applications of these enzymes are also discussed.
This systematic review evaluates pneumolysin (PLY) as a target for new treatments against pneumococcal infections. Pneumolysin is one of the main virulence factors produced by all types of ...pneumococci. This toxin (53 kDa) is a highly conserved protein that binds to cholesterol in eukaryotic cells, forming pores that lead to cell destruction.
The databases consulted were MEDLINE, Web of Science, and Scopus. Articles were independently screened by title, abstract, and full text by two researchers, and using consensus to resolve any disagreements that occurred. Articles in other languages different from English, patents, cases report, notes, chapter books and reviews were excluded. Searches were restricted to the years 2000 to 2021. Methodological quality was evaluated using OHAT framework.
Forty-one articles describing the effects of different molecules that inhibit PLY were reviewed. Briefly, the inhibitory molecules found were classified into three main groups: those exerting a direct effect by binding and/or blocking PLY, those acting indirectly by preventing its effects on host cells, and those whose mechanisms are unknown. Although many molecules are proposed as toxin blockers, only some of them, such as antibiotics, peptides, sterols, and statins, have the probability of being implemented as clinical treatment. In contrast, for other molecules, there are limited studies that demonstrate efficacy in animal models with sufficient reliability.
Most of the studies reviewed has a good level of confidence. However, one of the limitations of this systematic review is the lack of homogeneity of the studies, what prevented to carry out a statistical comparison of the results or meta-analysis.
A panel of molecules blocking PLY activity are associated with the improvement of the inflammatory process triggered by the pneumococcal infection. Some molecules have already been used in humans for other purposes, so they could be safe for use in patients with pneumococcal infections. These patients might benefit from a second line treatment during the initial stages of the infection preventing acute respiratory distress syndrome and invasive pneumococcal diseases. Additional research using the presented set of compounds might further improve the clinical management of these patients.
Orthorexia nervosa (ON) is characterized by an obsession with healthy eating, which may lead to severe physical, psychological and social disorders. It is particularly important to research this ...problem in populations that do not receive clinical care in order to improve early detection and treatment.
The aim of this study was to research the prevalence of ON in a population of Spanish university students and to analyze the possible associations between ON and psychological traits and behaviors that are common to ED.
A cross-sectional study with 454 students from the University of Castilla La Mancha, Spain. In total, 295 women and 159 men participated, aged between 18 and 41 years. The ORTO-11-ES questionnaire and the Eating Disorder Inventory (EDI-2) were used for this study. The chi squared test was used to compare the homogeneity among the different groups.
The scores on the ORTO-11-ES suggested that 17% of students were at risk of ON. The scores on the EDI-2 for the group at risk of ON were significant, compared to the remaining individuals, regarding their drive for thinness (17.1% vs 2.1%), bulimia (2.6% vs 0%), body dissatisfaction (26.3% vs. 12.4%), perfectionism (14.5% vs 4.8%), interoceptive awareness (13.2% vs 1.3%), asceticism (15.8% vs 3.7%) and impulsiveness (9.2% vs 1.9%).
These findings suggest that many of the psychological and behavioral aspects of ED are shared by people who are at risk of ON. Future research should use longitudinal data, examining the temporal relationship among these variables or other underlying variables that may contribute to the concurrence of ED and ON.
Lactoferrin (LF) is a multifunctional protein that exerts important activities in the neonate through its presence in milk, and also in other external mucosas, acting as a defense protein of innate ...immunity. The addition of bovine LF to infant formula and also to other functional products and cosmetics has increased during the last decades. Consequently, it is essential to know the effect that the technological processes, necessary to elaborate those products, have on LF activity. In this study, we have revised the effect of classical treatments on lactoferrin structure and activity, such as heat treatment or drying, and also of emerging technologies, like high pressure or pulsed electric field. The results of the studies included in this review indicate that LF stability is dependent on its level of iron-saturation and on the characteristics of the treatment media. Furthermore, the studies revised here reveal that the non-thermal treatments are interesting alternatives to the traditional ones, as they protect better the structure and activity of lactoferrin. It is also clear the need for research on LF encapsulation by different ways, to protect its properties before it reaches the intestine. All this knowledge would allow designing processes less harmful for LF, thus maintaining all its functionality.
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•Lactoferrin has great potential to be used in functional products.•Some heat treatments have great impact on the structure and activity of lactoferrin.•Non-thermal treatments are an alternative to heating for products with lactoferrin.•PEF changes on lactoferrin are lower compared with those produced by heating.
Films have undoubtedly seen the most significant advances in their development in recent years of all the pharmaceutical forms for the vaginal administration of drugs. Films combine the advantages of ...gels and solid pharmaceutical forms, and their great versatility is largely determined by the numerous polymers that can be used for their fabrication. They may be based on many natural polymers, and cellulose derivatives, polyvinyl alcohol or acrylic derivatives – among others – are also frequently used. The combination of different polymers and the inclusion of plasticizing agents makes them extremely versatility for responding to a range of therapeutic needs. The techniques used to produce films have also undergone substantial development. Although the solvent casting technique is by far the most widely used in fabrication, alternative options have also emerged such as electrospinning, moulding extrusion and 3D printing. Various research groups have proposed a proliferation of assays to characterise vaginal films in recent years, which highlight the importance of the preliminary evaluation and determination of the films' uniformity, in addition to tests to determine their permeability and hydrophilic/hydrophobic coefficient and their mechanical properties, the application of imaging techniques and thermal analysis, and especially the evaluation of the mucoadhesive properties and control over the drug release. This article offers a critical overview of the advances in the development and fabrication of films intended for vaginal drug delivery, and summarises current clinical applications for vaginal films.
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•Film technology provides platforms adaptable to the desired drug release profile.•Several natural and synthetic polymers have been considered to obtain vaginal films.•Plasticisers and other excipients allow modifying the relevant properties of films.•Solvent casting is the most common manufacturing method, but others are emerging.•Films could be useful against STDs, unintended pregnancy and other FGT disorders.
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