A critical review of consumer responsibility in promoting sustainable cocoa production.

Consumer buying behavior can be defined as all the different steps that consumers follow before purchasing a good or service. Web browser research, involvement in online networking discussions, and a range of other activities might be a part of this process. Despite the negative effects of its production chain on the environment, and on the socio-economical condition of local farmers, chocolate products are among the most distributed food and beverage items in the world. In this review, the consumer responsibility for sustainable cocoa production is described. This study determines the consumer opinions and attitudes on the different operations pursued in the production chain of chocolate, from the collection of cocoa beans to their processing into different final products. For this, data on life cycle assessment from some studies was gathered to identify and investigate links between the production chain of different types of chocolate (dark, white, milk) and its impact on natural resources so that the sensitivity of consumers to purchase more sustainable products can be evaluated. This approach revealed that consumers will not only purchase chocolate because of its good quality or health benefits, but they also consider it the most sustainable product.

Comparative in silico analysis of CNS-active molecules targeting the blood-brain barrier choline transporter for Alzheimer's disease therapy.

This study investigated the blood‒brain barrier (BBB) permeability of the central nervous system (CNS)-active compounds donepezil (DON), methionine (MET), and memantine (MEM) by employing a comprehensive in silico approach. These compounds are of particular interest for Alzheimer's disease (AD) therapy. Rigid-flexible molecular docking simulations indicated favorable binding affinities of all the compounds with BBB-ChT, with DON exhibiting the highest binding affinity (ΔGbind = -10.26 kcal/mol), predominantly mediated by significant hydrophobic interactions. In silico kinetic profiling suggested the stability of the DON/BBB-ChT complex, with ligand release prompted by conformational changes. 3D molecular alignment corroborated a minor conformational shift for DON in its minimal binding energy pose. Predictions indicated that active transport mechanisms notably enhance the brain distribution of donepezil compared to that of MET and MEM. Additionally, DON and MEM exhibited low mutagenic probabilities, while MET was identified as highly mutagenic. Overall, these findings highlight the potential of donepezil for superior BBB penetration, primarily through active transport mechanisms, underscoring the need for further validation through in vitro and in vivo studies for effective AD treatment. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00245-w.

The release of host-derived antibodies bound to the variant surface glycoprotein (VSG) of Trypanosoma brucei cannot be explained by pH-dependent conformational changes of the VSG dimer.

Background: Trypanosoma brucei is a protozoan parasite that evades the mammalian host's adaptive immune response by antigenic variation of the highly immunogenic variant surface glycoprotein (VSG). VSGs form a dense surface coat that is constantly recycled through the endosomal system. Bound antibodies are separated in the endosome from the VSG and destroyed in the lysosome. For VSGs it has been hypothesized that pH-dependent structural changes of the VSG could occur in the more acidic environment of the endosome and hence, facilitate the separation of the antibody from the VSG. Methods: We used size exclusion chromatography, where molecules are separated according to their hydrodynamic radius to see if the VSG is present as a homodimer at both pH values. To gain information about the structural integrity of the protein we used circular dichroism spectroscopy by exposing the VSG in solution to a mixture of right- and left-circularly polarized light and analysing the absorbed UV spectra. Evaluation of protein stability and molecular dynamics simulations at different pH values was performed using different computational methods. Results: We show, for an A2-type VSG, that the dimer size is only slightly larger at pH 5.2 than at pH 7.4. Moreover, the dimer was marginally more stable at lower pH due to the higher affinity (ΔG = 353.37 kcal/mol) between the monomers. Due to the larger size, the predicted epitopes were more exposed to the solvent at low pH. Moderate conformational changes (ΔRMSD = 0.35 nm) in VSG were detected between the dimers at pH 5.2 and pH 7.4 in molecular dynamics simulations, and no significant differences in the protein secondary structure were observed by circular dichroism spectroscopy. Conclusions: Thus, the dissociation of anti-VSG-antibodies in endosomes cannot be explained by changes in pH.

Synergistic Effects of Weight Loss and Catheter Ablation: Can microRNAs Serve as Predictive Biomarkers for the Prevention of Atrial Fibrillation Recurrence?

In atrial fibrillation (AF), multifactorial pathologic atrial alterations are manifested by structural and electrophysiological changes known as atrial remodeling. AF frequently develops in the context of underlying cardiac abnormalities. A critical mechanistic role played by atrial stretch is played by abnormal substrates in a number of conditions that predispose to AF, including obesity, heart failure, hypertension, and sleep apnea. The significant role of overweight and obesity in the development of AF is known; however, the differential effect of overweight, obesity, cardiovascular comorbidities, lifestyle, and other modifiable risk factors on the occurrence and recurrence of AF remains to be determined. Reverse remodeling of the atrial substrate and subsequent reduction in the AF burden by conversion into a typical sinus rhythm has been associated with weight loss through lifestyle changes or surgery. This makes it an essential pillar in the management of AF in obese patients. According to recently published research, microRNAs (miRs) may function as post-transcriptional regulators of genes involved in atrial remodeling, potentially contributing to the pathophysiology of AF. The focus of this review is on their modulation by both weight loss and catheter ablation interventions to counteract atrial remodeling in AF. Our analysis outlines the experimental and clinical evidence supporting the synergistic effects of weight loss and catheter ablation (CA) in reversing atrial electrical and structural remodeling in AF onset and in recurrent post-ablation AF by attenuating pro-thrombotic, pro-inflammatory, pro-fibrotic, arrhythmogenic, and male-sex-associated hypertrophic remodeling pathways. Furthermore, we discuss the promising role of miRs with prognostic potential as predictive biomarkers in guiding approaches to AF recurrence prevention.

Social, ethical, environmental, economic and technological aspects of rabbit meat production - A critical review.

Rabbit (RM) has become a valuable source of nutrients since the 1970s, helping to transform the European food industry into the largest RM producer in the world. However, the RM industry is experiencing a critical period of ethical imbalance. This trend, described as feed conversion ratio, impacts the environmental and financial performance of RM farms, which could lead to an increase production of industrial waste. In addition, the loss of corporate ethical responsibility and sustainable development by RM-oriented companies has further exacerbated the situation. Our objective was to summarize current trends in the RM industry and markets, highlighting possible strengths and weaknesses. This review shows current approaches in sustainable techniques in RM production processes, ethical issue, environmental and processing responsibility of RM producers, as well as social responsibilities and ethical practices of slaughterhouses and RM producers, sustainable environmental practices of slaughterhouses, technological aspects and safety of RM and social drivers in RM market. The analysis of reviewed literature revealed the potential strategies for sustainable RM production.

Unraveling the binding interactions between two Pt(II) complexes of aliphatic glycine derivatives with human serum albumin: A comprehensive computational and multi-spectral investigation.

This article delves into the interaction between HSA protein and synthesized platinum complexes, with formula: [Pt(Propyl-NH2)2(Propylglycine)]NO3 and [Pt(Tertpentyl-NH2)2(Tertpentylglycine)]NO3, through a range of methods, including spectroscopic (UV-visible, fluorescence, synchronous fluorescence and CD) analysis and computational modeling (molecular docking and MD simulation). The binding constants, the number of binding sites, and thermodynamic parameters were obtained at 25 to 37 °C. The study found that both complexes could bind with HSA (moderate affinity for Tertpentyl and strong affinity for Propyl derivatives) and occupied one binding site in HSA (validated with, Stern-Volmer, Job-plots, and molecular docking investigations) located in subdomain IIA. The binding mechanisms of both mentioned Pt(II) agents were different, with the Propyl derivative predominantly using van der Waals forces and hydrogen bond interactions with a static quenching mechanism and the Tertpentyl derivative mainly utilizing hydrophobic force with a dynamic quenching mechanism. However, the two ligands affected protein differently; the Tertpentyl complex did not significantly alter the protein structure upon binding, as evidenced by synchronous fluorescence spectroscopy (SFS), CD spectroscopy, and MD analysis. The outcome helps in understanding the binding mechanisms and structural modifications induced by the ligands, which could aid in the innovation of more effective and stable Pt(II)-based drugs.

Protecting the Brain: Novel Strategies for Preventing Breast Cancer Brain Metastases through Selective Estrogen Receptor ß Agonists and In Vitro Blood-Brain Barrier Models.

Breast cancer brain metastasis (BCBM) is a challenging condition with limited treatment options and poor prognosis. Understanding the interactions between tumor cells and the blood-brain barrier (BBB) is critical for developing novel therapeutic strategies. One promising target is estrogen receptor ß (ERß), which promotes the expression of key tight junction proteins, sealing the BBB and reducing its permeability. In this study, we investigated the effects of 17ß-estradiol (E2) and the selective ERß agonist diarylpropionitrile (DPN) on endothelial and cancer cells. Western blot analysis revealed the expression patterns of ERs in these cell lines, and estrogen treatment upregulated claudin-5 expression in brain endothelial cells. Using in vitro models of the BBB, we found that DPN treatment significantly increased BBB tightness about suppressed BBB transmigration activity of representative Her2-positive (BT-474) and triple-negative (MDA-MB-231) breast cancer cell lines. However, the efficacy of DPN treatment decreased when cancer cells were pre-differentiated in the presence of E2. Our results support ERß as a potential target for the prevention and treatment of BCBM and suggest that targeted vector-based approaches may be effective for future preventive and therapeutic implications.

Meta-Analysis of the Effects of Overexpressed bZIP Transcription Factors in Plants under Drought Stress.

The bZIP (basic leucine zipper) transcription factors have been identified as key regulators of plant responses to drought stress, which limits plant growth and yield. Overexpression of bZIP genes has shown potential in enhancing drought tolerance in various plant species. However, the constrained types of individual studies and inconsistencies among experimental approaches has resulted in a lack of statistical significance and limited the extrapolation of bZIP transcription factor overexpression for plant improvement. We conducted a meta-analysis to evaluate ten measured parameters of drought tolerance in bZIP transcription factor-expressing plants as well as moderators affecting the performance of transgenic plants. The results showed that seven parameters, including survival rate as well as the content of regulatory substances (proline accumulation, H2O2 concentration, CAT activity, POD activity, SOD activity and MDA accumulation), were most affected while the impact on physiological status indicators is not significant. In addition, donor/recipient species, treatment medium, duration and methods of simulating drought stress all significantly impacted the degree of drought stress tolerance in plants to some extent among the considered moderators. The findings underscore the potential of bZIP transcription factors as key targets for genetic engineering approaches aimed at improving plant resilience to water scarcity.

NeuroClick: software for mimicking click reaction to generate drug-like molecules permeating the blood-brain barrier.

Background: Traditional methods for chemical library generation in virtual screening often impose limitations on the accessible chemical space or produce synthetically irrelevant structures. Incorporating common chemical reactions into generative algorithms could offer significant benefits. Materials & methods: In this study, we developed NeuroClick, a graphical user interface software designed to perform in silico azide-alkyne cycloaddition, a widely utilized synthetic approach in modern medicinal chemistry. Results & conclusion: NeuroClick facilitates the generation and filtering of large combinatorial libraries at a remarkable rate of 10,000 molecules per minute. Moreover, the generated products can be filtered to identify subsets of pharmaceutically relevant compounds based on Lipinski's rule of five and blood-brain barrier permeability prediction. We demonstrate the utility of NeuroClick by generating and filtering several thousand molecules for dopamine D3 receptor ligand screening.

Analyzing the Effects of Single Nucleotide Polymorphisms on hnRNPA2/B1 Protein Stability and Function: Insights for Anticancer Therapeutic Design.

Heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1) is a pivotal player in m6A recognition, RNA metabolism, and antiviral responses. In the context of cancer, overexpression of hnRNPA2/B1, abnormal RNA levels, and m6A depositions are evident. This study focuses on two significant nonsynonymous single nucleotide polymorphisms (nsSNPs) within hnRNPA2/B1, namely, F66L and E92K. Our structural analyses reveal decreased stability in these mutants, with E92K being predicted to undergo destabilizing post-translational methylation. Furthermore, our extensive analysis of 44,239 tumor samples from the COSMIC database uncovers that amino acid position 92 exhibits the second-highest mutation frequency within hnRNPA2/B1, particularly associated with breast and lung cancers. This experimental data aligns with our theoretical studies, highlighting the substantial impact of the nsSNP at position 92 on hnRNPA2/B1's stability and functionality. Given the critical role of pre-mRNA splicing, transcription, and translation regulation in cellular function, it is important to assess the impact of these nsSNPs on the stability and function of the hnRNPA2/B1 protein to design more efficient anticancer therapeutics.

Calcineurin and mTOR inhibitors in kidney transplantation: integrative metamodeling on transplant survival and kidney function.

In our study, we examined the efficacy of mTOR (mammalian target of rapamycin) inhibitors, specifically rapamycin (Rap), compared to calcineurin inhibitors (CNIs) in kidney transplantation. By conducting a comprehensive search across reputable databases (EMBASE, Scopus, PubMed, Cochrane, and Crossref), we gathered data for a six-month post-transplantation period. Our analysis revealed that mTOR inhibitor administration resulted in improved glomerular filtration rate (GFR) and serum creatinine levels. However, it is important to note that the mTOR inhibitor group had a higher incidence of acute rejection after biopsy. Through molecular modeling, we observed that Rap exhibited a superior binding affinity for mTOR compared to CNIs' binding to calcineurin, probably contributing to the transplant rejection. Our meta-analysis supports the cautious use of an optimal mTOR inhibitor in conjunction with careful consideration of clinical features when minimizing CNIs early in the transplantation process. This is because mTOR inhibitors have complementary mechanisms of action, a low nephrotoxicity profile, and favorable outcomes in serum creatinine and GFR, which contribute to improved transplant survival.

Voronoi Entropy as a Ligand Molecular Descriptor of Protein-Ligand Interactions.

We investigate the correlation between the Voronoi entropy (VE) of ligand molecules and their affinity to receptors to test the hypothesis that less ordered ligands have higher mobility of molecular groups and therefore a higher probability of attaching to receptors. VE of 1144 ligands is calculated using SMILES-based 2D graphs representing the molecular structure. The affinity of the ligands with the SARS-CoV-2 main protease is obtained from the BindingDB Database as half-maximal inhibitory concentration (IC50) data. The VE distribution is close to the Gaussian, 0.4 ≤ Sv ≤ 1.66, and a strong correlation with IC50 is found, IC50 = -275 Sv + 613 nM, indicating the correlation between ligand complexity and affinity. On the contrary, the Shannon entropy (SE) descriptor failed to provide enough evidence to reject the null hypothesis (p-value > 0.05), indicating that the spatial arrangement of atoms is crucial for molecular mobility and binding.

Deciphering Molecular Mechanisms of Carbon TetrachlorideInduced Hepatotoxicity (Fibrosis): A Brief Systematic Review.

The liver plays a critical role in metabolic processes, making it vulnerable to injury. Researchers often study carbon tetrachloride (CCl4)-induced hepatotoxicity in model organisms because it closely resembles human liver damage. This toxicity occurs due to the activation of various cytochromes, including CYP2E1, CYP2B1, CYP2B2, and possibly CYP3A, which produce the trichloromethyl radical (CCl3*). CCl3* can attach to biological molecules such as lipids, proteins, and nucleic acids, impairing lipid metabolism and leading to fatty degeneration. It can also combine with DNA to initiate hepatic carcinogenesis. When exposed to oxygen, CCl3* generates more reactive CCl3OO*, which leads to lipid peroxidation and membrane damage. At the molecular level, CCl4 induces the release of several inflammatory cytokines, including TNF-α and NO, which can either help or harm hepatotoxicity through cellular apoptosis. TGF-ß contributes to fibrogenesis, while IL-6 and IL-10 aid in recovery by minimizing anti-apoptotic activity and directing cells toward regeneration. To prevent liver damage, different interventions can be employed, such as antioxidants, mitogenic agents, and the maintenance of calcium sequestration. Drugs that prevent CCl4- induced cytotoxicity and proliferation or enhance CYP450 activity may offer a protective response against hepatic carcinoma.

Electrochemical Sensor to Detect Antibiotics in Milk Based on Machine Learning Algorithms.

The present study is dedicated to the problem of electrochemical analysis of multicomponent mixtures, such as milk. A combination of cyclic voltammetry facilities and machine learning techniques made it possible to create a pattern recognition system for the detection of antibiotic residues in skimmed milk. A multielectrode sensor including copper, nickel, and carbon fiber was fabricated for the collection of electrochemical data. Processes occurring at the electrode surface were discussed and simulated with the help of molecular docking and density functional theory modeling. It was assumed that the antibiotic fingerprint reveals a potential drift of electrodes, owing to complexation with metal ions present in milk. The gradient boosting algorithm showed the best efficiency in training the machine learning model. High accuracy was achieved for the recognition of antibiotics in milk. The elaborated method may be incorporated into existing milking systems at dairy farms for monitoring the residue concentrations of antibiotics.

Using novel click chemistry algorithm to design D3R inhibitors as blood-brain barrier permeants.

Dopamine receptor D3 (D3R) has gained attention as a promising therapeutic target for neurological disorders. In this study, an innovative in silico click reaction strategy was employed to identify potential D3R binders. The ligand template, 1-phenyl-4-[4-(1H-1,2,3-triazol-5-yl)butyl]piperazine, with substitution at the 1,2,3-triazole ring, served as the starting point. Generated compounds underwent filtration based on their brain-to-blood concentration ratio (logBB), leading to the identification of 1-{4-[1-(decahydronaphthalen-1-yl)-1H-1,2,3-triazol-5-yl]butyl}-4-phenylpiperazine as the most promising candidate, displaying superior D3R affinity and blood-brain barrier (BBB) permeability compared to the reference ligand, eticlopride. Molecular dynamics simulations further supported these findings. This study presents a novel hit for designing D3R ligands and establishes a workflow utilizing in silico click chemistry to screen compounds with BBB permeability. The proposed click reaction-based algorithm holds significant potential as a valuable tool in the development of effective antipsychotic compounds.

Calix[4]arene-pyrazole conjugates as potential cancer therapeutics.

Tumor selectivity is yet a challenge in chemotherapy-based cancer treatment. A series of calixarenes derivatized at the lower rim with 3-phenyl-1H-pyrazole units with variable upper-rim substituent and conformations of macrocyclic core, alkyl chain length between heterocycle and core, as well as phenolic monomer (5-(4-tert-butylphenyloxy)methoxy-3-phenyl-1H-pyrazole) have been synthesized and characterized in a range of therapeutically relevant cellular models (M-HeLa, MCF7, A-549, PC3, Chang liver, and Wi38) from different target organs/systems. Specific cytotoxicity for M-HeLa cells has been observed in tert-butylcalix[4]arene pyrazoles in 1,3-alternate (compound 7b) and partial cone (compound 7c) conformations with low mutagenicity and haemotoxicity and in vivo toxicity in mice. Compounds 7b,c have induced mitochondrial pathway of apoptosis of M-HeLa cells through caspase-9 activation preceded by the cell cycle arrest at G0/G1 phase. A concomitant overexpression of DNA damage markers in pyrazole-treated M-HeLa cells suggests that calixarene pyrazoles target DNA, which was supported by the presence of interactions between calixarenes and ctDNA at the air-water interface.

Blood Biomarkers in Takotsubo Syndrome Point to an Emerging Role for Inflammaging in Endothelial Pathophysiology.

Takotsubo syndrome (TTS), an acute cardiac condition characterized by transient wall motion abnormalities mostly of the left ventricle, results in difficulties in diagnosing patients. We set out to present a detailed blood analysis of TTS patients analyzing novel markers to understand the development of TTS. Significant differences in proinflammatory cytokine expression patterns and sex steroid and glucocorticoid receptor (GR) expression levels were observed in the TTS patient collected. Remarkably, the measured catecholamine serum concentrations determined from TTS patient blood could be shown to be two orders of magnitude lower than the levels determined from experimentally induced TTS in laboratory animals. Consequently, the exposure of endothelial cells and cardiomyocytes in vitro to such catecholamine concentrations did not damage the cellular integrity or function of either endothelial cells forming the blood-brain barrier, endothelial cells derived from myocardium, or cardiomyocytes in vitro. Computational analysis was able to link the identified blood markers, specifically, the proinflammatory cytokines and glucocorticoid receptor GR to microRNA (miR) relevant in the ontogeny of TTS (miR-15) and inflammation (miR-21, miR-146a), respectively. Amongst the well-described risk factors of TTS (older age, female sex), inflammaging-related pathways were identified to add to these relevant risk factors or prediagnostic markers of TTS.

Network pharmacology and multitarget analysis of Nigella sativa in the management of diabetes and obesity: a computational study.

Obesity and diabetes are commonly associated with one another and represent a significant global health issue, with a recent surge in disease incidence. Nigella sativa, also known as black cumin, is believed to possess several health benefits, including anti-diabetic, anticancer, antioxidant, antimicrobial, and anti-obesity properties. In this study, we aimed to identify the active compounds derived from N. sativa, which can potentially inhibit key protein targets and signaling pathways associated with diabesity treatment. We employed an exhaustive in silico search, which led to the identification of 22 potential compounds. Out of these, only five hits were found to be non-toxic, including Arabic and ascorbic acids, dihydrocodeine, catechin, and kaempferol. Our analysis revealed that these hits were associated with genes such as AKT1, IL6, SRC, and EGFR. Finally, we conducted molecular docking and molecular dynamics simulations, which identified kaempferol as the best binder for AKT1 in comparison to the reference molecule. Overall, our in silico integrated pipeline provides a useful approach to identify non-toxic phytocompounds as promising drug candidates to treat diabetes and obesity.Communicated by Ramaswamy H. Sarma.

Chemical Analysis and Molecular Modelling of Cyclodextrin-Formulated Propofol and Its Sodium Salt to Improve Drug Solubility, Stability and Pharmacokinetics (Cytogenotoxicity).

Propofol is a widely used general anesthetic in clinical practice, but its use is limited by its water-insoluble nature and associated pharmacokinetic and pharmacodynamic limitations. Therefore, researchers have been searching for alternative formulations to lipid emulsion to address the remaining side effects. In this study, novel formulations for propofol and its sodium salt Na-propofolat were designed and tested using the amphiphilic cyclodextrin (CD) derivative hydroxypropyl-ß-cyclodextrin (HPßCD). The study found that spectroscopic and calorimetric measurements suggested complex formation between propofol/Na-propofolate and HPßCD, which was confirmed by the absence of an evaporation peak and different glass transition temperatures. Moreover, the formulated compounds showed no cytotoxicity and genotoxicity compared to the reference. The molecular modeling simulations based on molecular docking predicted a higher affinity for propofol/HPßCD than for Na-propofolate/HPßCD, as the former complex was more stable. This finding was further confirmed by high-performance liquid chromatography. In conclusion, the CD-based formulations of propofol and its sodium salt may be a promising option and a plausible alternative to conventional lipid emulsions.

DSF inactivator RpfB homologous FadD upregulated in Bradyrhizobium japonicum under iron limiting conditions.

Phytopathogenic bacteria Xanthomonas campestris pv. campestris (Xcc) causes black rot and other plant diseases. Xcc senses diffusible signal factor (DSF) as a quorum-sensing (QS) signal that mediates mainly iron uptake and virulence. RpfB deactivates DSF in this DSF-QS circuit. We examined differential gene expression profiles of Bradyrhizobium japonicum under low versus high iron conditions and found that fadD and irr were upregulated under low iron (log2 fold change 0.825 and 1.716, respectively). In addition to having similar protein folding patterns and functional domain similarities, FadD shared 58% sequence similarity with RpfB of Xcc. The RpfB-DSF and FadD-DSF complexes had SWISSDock molecular docking scores of - 8.88 kcal/mol and - 9.85 kcal/mol, respectively, and the 100 ns molecular dynamics simulation results were in accord with the docking results. However, significant differences were found between the binding energies of FadD-DSF and RpfB-DSF, indicating possible FadD-dependent DSF turnover. The protein-protein interaction network showed that FadD connected indirectly with ABC transporter permease (ABCtp), which was also upregulated (log2 fold change 5.485). We speculate that the low iron condition may be a mimetic environmental stimulus for fadD upregulation in B. japonicum to deactivate DSF, inhibit iron uptake and virulence of DSF-producing neighbors. This finding provides a new option of using B. japonicum or a genetically improved B. japonicum as a potential biocontrol agent against Xcc, with the added benefit of plant growth-promoting properties.