Differential Cardiac Responses after Passive Leg Raising.

This study retrospectively examined the hemodynamic effects of passive leg raising (PLR) in mechanically ventilated patients during fluid removal before spontaneous breathing trials. In previous studies, we noticed varying cardiac responses after PLR completion, particularly in positive tests. Using a bioreactance monitor, we recorded and analyzed hemodynamic parameters, including stroke volume and cardiac index (CI), before and after PLR in post-acute ICU patients. We included 27 patients who underwent 60 PLR procedures. In preload-unresponsive patients, no significant CI changes were observed (CI_t-6 = 3.7 [2.6; 4.7] mL/min/m2 vs. CI_t9 = 3.3 [2.5; 3.4] mL/min/m2; p = 0.306), while in preload-responsive patients, two distinct CI response types to PLR were identified: a transient peak with immediate return to baseline (CI_t-6 = 2.7 [2.5; 3.1] mL/min/m2 vs. 3.3 [2.6; 3.8] L/min/m2; p = 0.119) and a sustained CI elevation lasting beyond the PLR maneuver (CI_t-6 = 2.8 [2.3; 2.9] L/min/m2 vs. 3.3 [2.8; 3.9] ml/min/m2; p = 0.034). The latter was particularly noted when ΔCI during PLR exceeded 25%. Our findings suggest that in certain preload-responsive patients, PLR can induce a more sustained increase in CI, indicating a possible persistent hemodynamic effect. This effect could be due to a combination of autotransfusion and sympathetic activation affecting venous return and vascular tone. Further research in larger cohorts and more comprehensive hemodynamic assessments are warranted to validate these observations and elucidate the possible underlying mechanisms.The Fluid unLoading On Weaning (FLOW) study was prospectively registered under the ID NCT04496583 on 2020-07-29 at ClinicalTrials.gov.

Dynamic changes of hepatic vein Doppler velocities predict preload responsiveness in mechanically ventilated critically ill patients.

BACKGROUND: Assessment of dynamic parameters to guide fluid administration is one of the mainstays of current resuscitation strategies. Each test has its own limitations, but passive leg raising (PLR) has emerged as one of the most versatile preload responsiveness tests. However, it requires real-time cardiac output (CO) measurement either through advanced monitoring devices, which are not routinely available, or echocardiography, which is not always feasible. Analysis of the hepatic vein Doppler waveform change, a simpler ultrasound-based assessment, during a dynamic test such as PLR could be useful in predicting preload responsiveness. The objective of this study was to assess the diagnostic accuracy of hepatic vein Doppler S and D-wave velocities during PLR as a predictor of preload responsiveness. METHODS: Prospective observational study conducted in two medical-surgical ICUs in Chile. Patients in circulatory failure and connected to controlled mechanical ventilation were included from August to December 2023. A baseline ultrasound assessment of cardiac function was performed. Then, simultaneously, ultrasound measurements of hepatic vein Doppler S and D waves and cardiac output by continuous pulse contour analysis device were performed during a PLR maneuver. RESULTS: Thirty-seven patients were analyzed. 63% of the patients were preload responsive defined by a 10% increase in CO after passive leg raising. A 20% increase in the maximum S wave velocity after PLR showed the best diagnostic accuracy with a sensitivity of 69.6% (49.1-84.4) and specificity of 92.8 (68.5-99.6) to detect preload responsiveness, with an area under curve of receiving operator characteristic (AUC-ROC) of 0.82 ± 0.07 (p = 0.001 vs. AUC-ROC of 0.5). D-wave velocities showed worse diagnostic accuracy. CONCLUSIONS: Hepatic vein Doppler assessment emerges as a novel complementary technique with adequate predictive capacity to identify preload responsiveness in patients in mechanical ventilation and circulatory failure. This technique could become valuable in scenarios of basic hemodynamic monitoring and when echocardiography is not feasible. Future studies should confirm these results.

Antifungal Activity, Mode of Action, and Cytotoxicity of 4-chlorobenzyl p-coumarate: a Promising New Molecule.

Fungal infections represent a serious health problem worldwide. The study evaluated the antifungal activity of 4-chlorobenzyl p-coumarate, an unprecedented semi-synthetic molecule. Docking molecular and assay experiments were conducted to determine the Minimum Inhibitory Concentration (MIC) and Minimum Fungicidal Concentration (MFC), mode of action, effect on growth, fungal death kinetics, drug association, effects on biofilm, micromorphology, and against human keratinocytes. The investigation included 16 strains of Candida spp, including C. albicans, C. krusei, C. glabrata, C. tropicalis, C. dubliniensis, C. lusitaniae, C. utilis, C. rugosa, C. guilhermondi, and C. parapsilosis. Docking analysis predicted affinity between the molecule and all tested targets. MIC and MFC values ranged from 3.9 µg/mL (13.54 µM) to 62.5 µg/mL (217.01 µM), indicating a probable effect on the plasma membrane. The molecule inhibited growth from the first hour of testing. Association with nystatin proved to be indifferent. All concentrations of the molecule reduced fungal biofilm. The compound altered fungal micromorphology. The tested compound exhibited an IC50 of 7.90 ± 0.40 µg/mL (27.45 ± 1.42 µM) for keratinocytes. 4-chlorobenzyl p-coumarate showed strong fungicidal effects, likely through its action on the plasma membrane and alteration of fungal micromorphology, and mildly cytotoxic to human keratinocytes.

Capillary refill time response to a fluid challenge or a vasopressor test: an observational, proof-of-concept study.

BACKGROUND: Several studies have validated capillary refill time (CRT) as a marker of tissue hypoperfusion, and recent guidelines recommend CRT monitoring during septic shock resuscitation. Therefore, it is relevant to further explore its kinetics of response to short-term hemodynamic interventions with fluids or vasopressors. A couple of previous studies explored the impact of a fluid bolus on CRT, but little is known about the impact of norepinephrine on CRT when aiming at a higher mean arterial pressure (MAP) target in septic shock. We designed this observational study to further evaluate the effect of a fluid challenge (FC) and a vasopressor test (VPT) on CRT in septic shock patients with abnormal CRT after initial resuscitation. Our purpose was to determine the effects of a FC in fluid-responsive patients, and of a VPT aimed at a higher MAP target in chronically hypertensive fluid-unresponsive patients on the direction and magnitude of CRT response. METHODS: Thirty-four septic shock patients were included. Fluid responsiveness was assessed at baseline, and a FC (500 ml/30 mins) was administered in 9 fluid-responsive patients. A VPT was performed in 25 patients by increasing norepinephrine dose to reach a MAP to 80-85 mmHg for 30 min. Patients shared a multimodal perfusion and hemodynamic monitoring protocol with assessments at at least two time-points (baseline, and at the end of interventions). RESULTS: CRT decreased significantly with both tests (from 5 [3.5-7.6] to 4 [2.4-5.1] sec, p = 0.008 after the FC; and from 4.0 [3.3-5.6] to 3 [2.6 -5] sec, p = 0.03 after the VPT. A CRT-response was observed in 7/9 patients after the FC, and in 14/25 pts after the VPT, but CRT deteriorated in 4 patients on this latter group, all of them receiving a concomitant low-dose vasopressin. CONCLUSIONS: Our findings support that fluid boluses may improve CRT or produce neutral effects in fluid-responsive septic shock patients with persistent hypoperfusion. Conversely, raising NE doses to target a higher MAP in previously hypertensive patients elicits a more heterogeneous response, improving CRT in the majority, but deteriorating skin perfusion in some patients, a fact that deserves further research.

Cytotoxicity and Biological Activities of Geopopolis Extract from the Stingless bee (Melipona scutellaris) in Isolates of Staphylococcus aureus.

Geopropolis resins are produced by stingless bees (Meliponinae), developed from the collection of resinous materials, waxes and exudates, from the flora of the region where stingless bees are present, in addition to the addition of clay or earth in its composition. Several biological activities are attributed to Ethanol Extracts of Geopropolis (EEGP). The bioactive properties are associated with the complex chemical composition that the samples have. This work aims to evaluate the biological activities of the EEGP, in order to contribute with a natural therapeutic alternative, to face infections, mainly those caused by resistant strains of Staphylococcus aureus. The EEGP MIC tests showed antibacterial activity against two strains of S. aureus, both at concentrations of 550 µg/mL. The MBC performed with the inhibition values showed that the EEGP has bacteriostatic activity in both strains. Biofilm inhibition rates exhibited an average value greater than 65 % at the highest concentration. The EEGP antioxidant potential test showed good antioxidant activity (IC50) of 11.05±1.55 µg/mL. In the cytotoxicity test against HaCat cells, after 24 hours, EEGP induced cell viability at the three tested concentrations (550 µg/mL: 81.68±3.79 %; 1100 µg/mL: 67.10±3.76 %; 2200 µg/mL: 67.40±1.86 %). In view of the above, the safe use of EEGP from the brazilian northeast could be proven by the cytotoxicity test, and its use as an antioxidant and antibacterial agent has proven to be effective, as an alternative in combating oxidative stress and microorganisms such as S. aureus, which, through the spread and ongoing evolution of drug resistance, generates an active search for effective solutions.

Fluid Responsiveness Is Associated with Successful Weaning after Liver Transplant Surgery.

A positive fluid balance may evolve to fluid overload and associate with organ dysfunctions, weaning difficulties, and increased mortality in ICU patients. We explored whether individualized fluid management, assessing fluid responsiveness via a passive leg-raising maneuver (PLR) before a spontaneous breathing trial (SBT), is associated with less extubation failure in ventilated patients with a high fluid balance admitted to the ICU after liver transplantation (LT). We recruited 15 LT patients in 2023. Their postoperative fluid balance was +4476 {3697, 5722} mL. PLR maneuvers were conducted upon ICU admission (T1) and pre SBT (T2). Cardiac index (CI) changes were recorded before and after each SBT (T3). Seven patients were fluid-responsive at T1, and twelve were responsive at T2. No significant differences occurred in hemodynamic, respiratory, and perfusion parameters between the fluid-responsive and fluid-unresponsive patients at any time. Fluid-responsive patients at T1 and T2 increased their CI during SBT from 3.1 {2.8, 3.7} to 3.7 {3.4, 4.1} mL/min/m2 (p = 0.045). All fluid-responsive patients at T2 were extubated after the SBTs and consolidated extubation. Two out of three of the fluid-unresponsive patients experienced weaning difficulties. We concluded that fluid-responsive patients post LT may start weaning earlier and achieve successful extubation despite a high postoperative fluid balance. This highlights the profound impact of personalized assessments of cardiovascular state on critical surgical patients.

The Controlled Release of Abscisic Acid (ABA) Utilizing Alginate-Chitosan Gel Blends: A Synergistic Approach for an Enhanced Small-Molecule Delivery Controller.

The integration of abscisic acid (ABA) into a chitosan-alginate gel blend unveils crucial insights into the formation and stability of these two substances. ABA, a key phytohormone in plant growth and stress responses, is strategically targeted for controlled release within these complexes. This study investigates the design and characterization of this novel controlled-release system, showcasing the potential of alginate-chitosan gel blends in ABA delivery. Computational methods, including molecular dynamics simulations, are employed to analyze the structural effects of microencapsulation, offering valuable insights into complex behavior under varying conditions. This paper focuses on the controlled release of ABA from these complexes, highlighting its strategic importance in drug delivery systems and beyond. This controlled release enables targeted and regulated ABA delivery, with far-reaching implications for pharmaceuticals, agriculture, and plant stress response studies. While acknowledging context dependency, the paper suggests that the liberation or controlled release of ABA holds promise in applications, urging further research and experimentation to validate its utility across diverse fields. Overall, this work significantly contributes to understanding the characteristics and potential applications of chitosan-alginate complexes, marking a noteworthy advancement in the field of controlled-release systems.

Anticandida and antibiofilm activities of extract from Schinopsis brasiliensis Engl. against Candida spp.

The pathogenic nature of infections caused by Candida spp. underscores the necessity for novel therapeutic agents. Extracts of Schinopsis brasilienses Engl are \ a promising source of agents with antifungal effects. This study aimed to assess the antifungal potential of the leaf extract of S. brasilienses. The antifungal activity was evaluated by determining the minimum inhibitory concentrations and fungicide concentrations (MIC and MFC). The antibiofilm potential was assessed by counting colony-forming units/mL. The study examined the inhibition kinetics of fungal growth and potential synergism between gallic acid or the extract and nystatin using the Checkerboard method. Cytotoxicity was evaluated through the MTT assay. The extract exhibited antifungal effect against all tested strains, with MIC and MFC ranging from 31.25-250 µg/mL. Gallic acid, the main isolated compound, displayed a MIC of 2000 µg/mL. The extract of S. brasilienses at 31.25 µg/mL inhibited the formation of biofilm by C. albicans and significantly reduced the mass of mature biofilm after 24 and 48 h (p < 0. 05). At a concentration of 125 µg/mL, the extract demonstrated significant inhibition of fungal growth after 6 hours. The combination of gallic acid or extract with nystatin did not exhibit synergistic or antagonistic effect. Furthermore, the extract did not induce cytotoxicity to a human cell line. The extract of S. brasiliensis demonstrates antifungal activity against Candida, generally exhibiting fungicidal action and capacity to inhibit biofilm formation as well as reduce mature biofilms. Additionally, the extract showed low cytotoxicity to human cells.

Coexistence of a fluid responsive state and venous congestion signals in critically ill patients: a multicenter observational proof-of-concept study.

BACKGROUND: Current recommendations support guiding fluid resuscitation through the assessment of fluid responsiveness. Recently, the concept of fluid tolerance and the prevention of venous congestion (VC) have emerged as relevant aspects to be considered to avoid potentially deleterious side effects of fluid resuscitation. However, there is paucity of data on the relationship of fluid responsiveness and VC. This study aims to compare the prevalence of venous congestion in fluid responsive and fluid unresponsive critically ill patients after intensive care (ICU) admission. METHODS: Multicenter, prospective cross-sectional observational study conducted in three medical-surgical ICUs in Chile. Consecutive mechanically ventilated patients that required vasopressors and admitted < 24 h to ICU were included between November 2022 and June 2023. Patients were assessed simultaneously for fluid responsiveness and VC at a single timepoint. Fluid responsiveness status, VC signals such as central venous pressure, estimation of left ventricular filling pressures, lung, and abdominal ultrasound congestion indexes and relevant clinical data were collected. RESULTS: Ninety patients were included. Median age was 63 [45-71] years old, and median SOFA score was 9 [7-11]. Thirty-eight percent of the patients were fluid responsive (FR+), while 62% were fluid unresponsive (FR-). The most prevalent diagnosis was sepsis (41%) followed by respiratory failure (22%). The prevalence of at least one VC signal was not significantly different between FR+ and FR- groups (53% vs. 57%, p = 0.69), as well as the proportion of patients with 2 or 3 VC signals (15% vs. 21%, p = 0.4). We found no association between fluid balance, CRT status, or diagnostic group and the presence of VC signals. CONCLUSIONS: Venous congestion signals were prevalent in both fluid responsive and unresponsive critically ill patients. The presence of venous congestion was not associated with fluid balance or diagnostic group. Further studies should assess the clinical relevance of these results and their potential impact on resuscitation and monitoring practices.

Unveiling Novel Urease Inhibitors for Helicobacter pylori: A Multi-Methodological Approach from Virtual Screening and ADME to Molecular Dynamics Simulations.

Helicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.

An In Silico Approach to Exploring the Antinociceptive Biological Activities of Linalool and its Metabolites.

Pain is characterized by the unpleasant sensory and emotional sensation associated with actual or potential tissue damage, whereas nociception refers to the mechanism by which noxious stimuli are transmitted from the periphery to the CNS. The main drugs used to treat pain are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics, which have side effects that limit their use. Therefore, in the search for new drugs with potential antinociceptive effects, essential oils have been studied, whose constituents (monoterpenes) are emerging as a new therapeutic possibility. Among them, linalool and its metabolites stand out. The present study aims to investigate the antinociceptive potential of linalool and its metabolites through a screening using an in silico approach. Molecular docking was used to evaluate possible interactions with important targets involved in antinociceptive activity, such as α2-adrenergic, GABAergic, muscarinic, opioid, adenosinergic, transient potential, and glutamatergic receptors. The compounds in the investigated series obtained negative energies for all enzymes, representing satisfactory interactions with the targets and highlighting the multi-target potential of the L4 metabolite. Linalool and its metabolites have a high likelihood of modulatory activity against the targets involved in nociception and are potential candidates for future drugs.

Evaluation of antifungal activity, mechanisms of action and toxicological profile of the synthetic amide 2-chloro-N-phenylacetamide.

Aspergillus niger causes infections such as otitis and pulmonary aspergillosis in immunocompromised individuals. Treatment involves voriconazole or amphotericin B, and due to the increase in fungal resistance, the search for new compounds with antifungal activity has intensified. In the development of new drugs, cytotoxicity and genotoxicity assays are important, as they allow predicting possible damage that a molecule can cause, and in silico studies predict the pharmacokinetic properties. The aim of this study was to verify the antifungal activity and the mechanism of action of the synthetic amide 2-chloro-N-phenylacetamide against Aspergillus niger strains and toxicity. 2-Chloro-N-phenylacetamide showed antifungal activity against different strains of Aspergillus niger with minimum inhibitory concentrations between 32 and 256 µg/mL and minimum fungicides between 64 and 1024 µg/mL. The minimum inhibitory concentration of 2-chloro-N-phenylacetamide also inhibited conidia germination. When associated with amphotericin B or voriconazole, 2-chloro-N-phenylacetamide had antagonistic effects. Interaction with ergosterol in the plasma membrane is the probable mechanism of action.2-Chloro-N-phenylacetamide has favorable physicochemical parameters, good oral bioavailability and absorption in the gastrointestinal tract, crosses the blood-brain barrier and inhibits CYP1A2. At concentrations of 50 to 500 µg/mL, it has little hemolytic effect and a protective effect for type A and O red blood cells, and in the cells of the oral mucosa it promotes little genotoxic change. It is concluded that 2-chloro-N-phenylacetamide has promising antifungal potential, favorable pharmacokinetic profile for oral administration and low cytotoxic and genotoxic potential, being a promising candidate for in vivo toxicity studies.

Mechanisms Involved in the Therapeutic Effect of Cannabinoid Compounds on Gliomas: A Review with Experimental Approach.

INTRODUCTION: Brain tumors have high morbidity and mortality rates, accounting for 1.4% of all cancers. Gliomas are the most common primary brain tumors in adults. Currently, several therapeutic approaches are used; however, they are associated with side effects that affect patients'quality of life. Therefore, further studies are needed to develop novel therapeutic protocols with a more favorable side effect profile. In this context, cannabinoid compounds may serve as potential alternatives. OBJECTIVE: This study aimed to review the key enzymatic targets involved in glioma pathophysiology and evaluate the potential interaction of these targets with four cannabinoid derivatives through molecular docking simulations. METHODS: Molecular docking simulations were performed using four cannabinoid compounds and six molecular targets associated with glioma pathophysiology. RESULTS: Encouraging interactions between the selected enzymes and glioma-related targets were observed, suggesting their potential activity through these pathways. In particular, cannabigerol showed promising interactions with epidermal growth factor receptors and phosphatidylinositol 3- kinase, while Δ-9-tetrahydrocannabinol showed remarkable interactions with telomerase reverse transcriptase. CONCLUSION: The evaluated compounds exhibited favorable interactions with the analyzed enzymatic targets, thus representing potential candidates for further in vitro and in vivo studies.

Antifungal activity against Candida albicans of methyl 3,5-dinitrobenzoate loaded nanoemulsion.

The objective of this study was to evaluate the antifungal activity of free methyl 3,5 dinitrobenzoate (MDNB) and its nanoemulsion (MDNB-NE) against strains of Candida albicans. Additionally, a molecular modeling study was also carried out to propose the mechanism of action and toxicity of MDNB. These results demonstrated the MDNB-NE presented a droplet size of 181.16 ± 3.20 nm and polydispersity index of 0.30 ± 0.03. MDNB and MDNB-NE inhibited the growth of all strains with minimum inhibitory concentrations of 0.27-1.10 mM. The biological results corroborated the molecular model, which pointed to a multi-target antifungal mechanism of action for MDNB in C. albicans. The study could serve as a basis for further research involving compounds with nitro groups with antifungal.

Anticandida and antibiofilm activities of extract from Schinopsis brasiliensis Engl. against Candida spp

Abstract The pathogenic nature of infections caused by Candida spp. underscores the necessity for novel therapeutic agents. Extracts of Schinopsis brasilienses Engl are / a promising source of agents with antifungal effects. This study aimed to assess the antifungal potential of the leaf extract of S. brasilienses. The antifungal activity was evaluated by determining the minimum inhibitory concentrations and fungicide concentrations (MIC and MFC). The antibiofilm potential was assessed by counting colony-forming units/mL. The study examined the inhibition kinetics of fungal growth and potential synergism between gallic acid or the extract and nystatin using the Checkerboard method. Cytotoxicity was evaluated through the MTT assay. The extract exhibited antifungal effect against all tested strains, with MIC and MFC ranging from 31.25-250 μg/mL. Gallic acid, the main isolated compound, displayed a MIC of 2000 μg/mL. The extract of S. brasilienses at 31.25 μg/mL inhibited the formation of biofilm by C. albicans and significantly reduced the mass of mature biofilm after 24 and 48 h (p < 0. 05). At a concentration of 125 μg/mL, the extract demonstrated significant inhibition of fungal growth after 6 hours. The combination of gallic acid or extract with nystatin did not exhibit synergistic or antagonistic effect. Furthermore, the extract did not induce cytotoxicity to a human cell line. The extract of S. brasiliensis demonstrates antifungal activity against Candida, generally exhibiting fungicidal action and capacity to inhibit biofilm formation as well as reduce mature biofilms. Additionally, the extract showed low cytotoxicity to human cells.

Study of electrospun nanofibers loaded with Ru(ii) phenanthroline complexes as a potential material for use in dye-sensitized solar cells (DSSCs).

Dye-sensitized solar cells (DSSCs) are an increasingly attractive alternative energy source because of their low cost. Therefore, researchers have intensified efforts over the past decade to increase their energy conversion efficiency by employing new materials in each DSSC component. The present research focuses on synthesizing electrospun nanofibers as a potential new material as a counter electrode in DSSCs. Two Ru(ii) half sandwich 1,10 phenanthroline (phen) Ru-1 and 5-amino- phen Ru-2 complexes were prepared for its functionalization. As a deposition medium, poly(caprolactone) (PCL) dissolved in chloroform was used. Different Ru(ii) complex concentrations were made at 0.1% wt., 0.5% wt., and 1% wt. Thermal characterization studies using differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were conducted to evaluate the behavior and weight loss of the samples with temperature variations. Fourier transform infrared spectroscopy (FTIR) measurements were taken to observe the bond interaction of the ruthenium complexes and the PCL. Finally, scanning electron microscopy (SEM) was used to structurally and morphologically evaluate the fiber distribution and porosity. These fibers have a homogeneous morphology, without bulbs, but with evident solid inlays on the surface, with fibers between ∼0.58 to 2.47 µm and percentages of porosity ∼45%. TGA and DSC thermograms show minor temperature variations that demonstrate the incorporation of the Ru(ii) complexes into the fiber. Furthermore, the melting and degradation temperature of the fibers is suitable for use in a DSSC approach. The incorporation of the ruthenium compounds into PCL fibers, along with the addition of the NH2 group into complex Ru-2, resulted in a higher current density for both anodic and cathodic peaks in Cyclic Voltammetry (CV). It is noteworthy that from I-V curves, PCL-Ru2 1% fibers demonstrated a conductivity of 0.461 µS cm-1, which is comparable to other PCL fibers carrying a higher metal load. Future studies will delve into the mechanical properties of these fibers to highlight their potential for application in this field.

Derivative of 7-hydroxycoumarin has antifungal potential against Candida species and low cytotoxicity against human cells: In silico studies and biological evaluation.

This study investigates the antifungal and cytotoxic properties of 7-(pentyloxy)-2H-chromen-2-one. Through molecular docking and dynamics simulations, we explored the compound's interactions with fungal cell protein targets. Notably, it exhibited strong affinities for 1,3ß-glucan synthase, squalene epoxidase, δ-14-sterol reductase, 14-α-demethylase, and thymidylate synthase, with binding energies ranging from -100.39 to -73.15 kcal/mol. Molecular dynamics simulations confirmed its stable binding at active targets. The MIC and MFC values ranged from 67.16 µM (15.6 µg/mL) to 537.28 µM (125.0 µg/mL). The compound displayed promising antifungal effects, inhibiting fungal growth for at least 24 hours. Fungal plasma membrane function alteration likely contributed to these antifungal mechanisms. Additionally, the combination of the compound with nystatin, fluconazole, and caspofungin showed indifferent effects on antifungal activity. Cytotoxicity assessment in human keratinocyte cells (HaCaT) revealed an IC50 of 100 µM, which was approximately 1.5 times higher than the MIC for C. krusei. Thus, the compound exhibited strongly in silico and in vitro antifungal activity with low cytotoxicity in HaCaT cells. These findings support its potential as a candidate for further development as an antifungal compound.

Obesity influences the development of bisphosphonate-induced osteonecrosis in Wistar rats.

Medication-related osteonecrosis of the jaw (MRONJ) is characterized by bone exposure for more than eight weeks in patients who have used or been treated with antiresorptive or antiangiogenic drugs, without a history of radiation therapy or metastatic diseases in the jaws. Obesity is associated with changes in periodontal tissues and oral microbiota that are linked to bone alterations. This study aimed to analyze the influence of obesity on the development of bisphosphonate-induced osteonecrosis. The experiment randomly and simply divided 24 male Wistar rats (Rattus norvegicus) into four groups: healthy, with osteonecrosis, obese, and obese with osteonecrosis (n=6 per group). Osteonecrosis was induced through weekly intraperitoneal injection for eight weeks at a dose of 250 µg/kg of zoledronic acid in a 4 mg/5 mL solution, combined with trauma (exodontia). Obesity was induced through a high glycaemic index diet. Each group was qualitatively and quantitatively evaluated regarding the development of models and pathological anatomy of the lesions. The results were expressed in mean percentage and standard deviation and statistically analyzed using one-way analysis of variance (ANOVA) followed by Tukey's post-hoc test, with a significance level of 5% (p<0.05) to establish differences found between the groups. Animals in the osteonecrosis group and the obese with osteonecrosis group presented larger necrosis areas (averages: 172.83±18,19 µm2 and 290.33±15,77 µm2, respectively) (p<0,0001). Bone sequestration, hepatic steatosis, and increased adipocyte size were observed in the obese group (average: 97.75±1.91 µm2) and in the obese with osteonecrosis group (average: 98.41±1.56 µm2), indicating greater tissue damage in these groups (p<0,0001). All parameters analyzed (through histological, morphometric, and murinometric analyses) increased for the obese and obese with osteonecrosis groups, suggesting a possible influence of obesity on the results. However, further studies are needed to confirm the role of obesity in the possible exacerbation of osteonecrosis and understand the underlying mechanisms.

Methyleugenol Has an Antidepressant Effect in a Neuroendocrine Model: In Silico and In Vivo Evidence.

Major depressive disorder is a severe mood disorder characterized by different emotions and feelings. This study investigated the antidepressant activity of the phenylpropanoid methyleugenol (ME) in adult female mice exposed to a stress model induced by dexamethasone. The animals were randomly divided into groups containing eight animals and were pre-administered with dexamethasone (64 µg/kg subcutaneously). After 165 and 180 min, they were treated with ME (25, 50 and 100 mg/kg intraperitoneally) or imipramine (10 mg/kg intraperitoneally) after 45 min and 30 min, respectively; they were then submitted to tests which were filmed. The videos were analyzed blindly. In the tail suspension test, ME (50 mg/kg) increased latency and reduced immobility time. In the splash test, ME (50 mg/kg) decreased grooming latency and increased grooming time. In the open field, there was no statistical difference for the ME groups regarding the number of crosses, and ME (50 mg/kg) increased the number of rearing and time spent in the center. Regarding in silico studies, ME interacted with dopaminergic D1 and α1 adrenergic pathway receptors and with tryptophan hydroxylase inhibitor. In the in vivo evaluation of the pathways of action, the antidepressant potential of ME (50 mg/kg) was reversed by SCH23390 (4 mg/kg intraperitoneally) dopaminergic D1 receptor, Prazosin (1 mg/kg intraperitoneally) α1 adrenergic receptor, and PCPA (4 mg/kg intraperitoneally) tryptophan hydroxylase inhibitor. Our findings indicate that ME did not alter with the locomotor activity of the animals and shows antidepressant activity in female mice with the participation of the D1, α1 and serotonergic systems.

A quality by design framework for developing nanocrystal bioenabling formulations.

The present study aims to outline a rational framework for the design and development of a 1.0% (w/v) hydrocortisone nanocrystal-based formulation, resorting to a simple, efficient, and scalable nanonization methodology, based on the high-pressure homogenization (HPH) technique. Accordingly, the innovative product was comprehensively optimized following a Quality by Design (QbD) approach. The thorough selection of formulation composition was driven by a dual purpose: improving skin permeation and stability. In the early stage of development, a Failure Mode, Effects and Criticality Analysis (FMECA) diagram was employed to identify the most impactful variables for the critical quality attributes (CQAs). In this sense, a rotatable, three-factor and five-level circumscribed central composite design (CCCD) was applied to investigate how squalene concentration (x1), soluplus concentration (x2) and HPH-time (x3) influence physicochemical properties, performance and physical stability of the formulation. A robust Design Space (DS) was defined, establishing the optimal settings for the critical variables, whose combination meets the requirements set in the quality target product profile (QTPP). Morphological analysis revealed the cuboidal shape of hydrocortisone nanocrystals. In what concerns colloidal properties, the most promising formulation disclosed a small particle size (Dx(50) = 311.8 ± 1.5 nm), along with narrow size distribution (span value = 1.91 ± 0.17). Zeta potential results (-2.19 ± 0.15 mV--12.1 ± 0.4 mV) suggested a steric hindrance stabilization. FTIR spectra showed no chemical interactions between drug and formulation components. XRD diffractograms confirmed loss of crystallinity during the downsizing process. In vitro studies revealed an improvement on drug release rate (316 ± 21-516 ± 35 µg/cm2/√t), compared to the coarse suspension and commercial products, and a straight dependence on the stabilizer concentration and HPH time. The permeation flux across the skin (0.16 ± 0.02-1.2 ± 0.5 µg/cm2/h) appeared to be dependent on the drug physicochemical properties, in particular saturation solubility. Further characterization of the experimental formulations pointed out the role of the stabilizing component to prevent against physical instability phenomena. This organic solvent-free, and therefore "green" nanocrystal production technology offers great potential for pharmaceutical R&D and drug delivery by enabling the development of new forms of conventional drugs with optimal physicochemical properties and performance.