Polyesters containing 2,4-dihydroxy-6-(2-hydroxypropyl)benzoate and 3-hydroxybutyrate moieties have been isolated from many fungal species. Talaromyces stipitatus was previously reported to produce a similar polyester, talapolyester G. The complete genome sequence and the development of bioinformatics tools have enabled the discovery of the biosynthetic potential of this microorganism. Here, a putative biosynthetic gene cluster (BGC) of the polyesters encoding a highly reducing polyketide synthase (HR-PKS) and nonreducing polyketide synthase (NR-PKS), a cytochrome P450 and a regulator, was identified. Although talapolyester G does not require an oxidative step for its biosynthesis, further investigation into the secondary metabolite production of T. stipitatus resulted in isolating two new metabolites called talarodioxadione and talarooxime, in addition to three known compounds, namely 6-hydroxymellein, 15G256α and transtorine that have never been reported from this organism. Interestingly, the biosynthesis of the cyclic polyester 15G256α requires hydroxylation of an inactive methyl group and thus could be a product of the identified gene cluster. The two compounds, talarooxime and transtorine, are probably the catabolic metabolites of tryptophan through the kynurenine pathway. Tryptophan metabolism exists in almost all organisms and has been of interest to many researchers. The biosynthesis of the new oxime is proposed to involve two subsequent N-hydroxylation of 2-aminoacetophenone. Full article

The effect of dimethyl sulfoxide (DMSO) in rheumatoid arthritis (RA) human fibroblast-like synoviocytes (FLSs) has been studied on five different samples harvested from the joints (fingers, hands and pelvis) of five women with RA. At high concentrations (>5%), the presence of DMSO induces the cleavage of caspase-3 and PARP-1, two phenomena associated with the cell death mechanism. Even at a 0.5% concentration of DMSO, MTT assays show a strong toxicity after 24 h exposure (≈25% cell death). Therefore, to ensure a minimum impact of DMSO on RA FLSs, our study shows that the concentration of DMSO has to be below 0.05% to be considered safe. Full article

The essential fatty acid alpha-linolenic acid (ALA) is present in high amounts in oils such as flaxseed, soy, hemp, rapeseed, chia, and perilla, while stearidonic acid is abundant in echium oil. ALA is metabolized to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by desaturases and elongases in humans. The conversion of ALA to EPA and DHA is limited, and these long-chain n−3 polyunsaturated fatty acids (PUFAs) are mainly provided from dietary sources (fish and seafood). This review provides an overview of studies that explored the effects of dietary supplementation with ALA in obesity and related diseases. The obesity-associated changes of desaturase and elongase activities are summarized, as they could influence the metabolic conversion of ALA. Generally, supplementation with ALA or ALA-rich oils leads to an increase in EPA levels and has no effect on DHA or omega-3 index. According to the literature data, stearidonic acid could enhance conversion of ALA to long-chain n−3 PUFA in obesity. Recent studies confirm that EPA and DHA intake should be considered as a primary dietary treatment strategy for improving the omega-3 index in obesity and related diseases. Full article

The nano-drug delivery system has gained greater acceptability for poorly soluble drugs. Alogliptin (ALG) is a FDA-approved oral anti-hyperglycemic drug that inhibits dipeptidyl peptidase-4. The present study is designed to prepare polymeric ALG nanoparticles (NPs) for the management of diabetes. ALG-NPs were prepared using the nanoprecipitation method and further optimized by Box–Behnken experimental design (BBD). The formulation was optimized by varying the independent variables Eudragit RSPO (A), Tween 20 (B), and sonication time (C), and the effects on the hydrodynamic diameter (Y1) and entrapment efficiency (Y2) were evaluated. The optimized ALG-NPs were further evaluated for in vitro release, intestinal permeation, and pharmacokinetic and anti-diabetic activity. The prepared ALG-NPs show a hydrodynamic diameter of between 272.34 nm and 482.87 nm, and an entrapment efficiency of between 64.43 and 95.21%. The in vitro release data of ALG-NPs reveals a prolonged release pattern (84.52 ± 4.1%) in 24 h. The permeation study results show a 2.35-fold higher permeation flux than pure ALG. ALG-NPs exhibit a significantly (p < 0.05) higher pharmacokinetic profile than pure ALG. They also significantly (p < 0.05) reduce the blood sugar levels as compared to pure ALG. The findings of the study support the application of ALG-entrapped Eudragit RSPO nanoparticles as an alternative carrier for the improvement of therapeutic activity. Full article

Endophytes, microorganisms that live in the internal tissues and organs of the plants, are known to produce numerous bioactive compounds, including, at times, some phytochemicals of their host plant. For such reason, endophytes have been quoted as a potential source for discovering bioactive compounds, particularly, of medical interest. Currently, many non-communicable diseases are threatening global human health, noticeably: diabetes, neurodegenerative diseases, cancer, and other ailment related to chronic inflammation and ageing. Intriguingly, the pathogenesis and development of these diseases have been linked to an excessive formation and accumulation of advanced glycation end products (AGEs). AGEs are a heterogeneous group of compounds that can alter the conformation, function, and lifetime of proteins. Therefore, compounds that prevent the formation and consequent accumulation of AGEs (AntiAGEs compounds) could be useful to delay the progress of some chronic diseases, and/or harmful effects of undue AGEs accumulation. Despite the remarkable ability of endophytes to produce bioactive compounds, most of the natural antiAGEs compounds reported in the literature are derived from plants. Accordingly, this work covers 26 plant antiAGEs compounds and some derivatives that have been reported as endophytic metabolites, and discusses the importance, possible advantages, and challenges of using endophytes as a potential source of antiAGEs compounds. Full article

Various chitosan (CS)-based nanoparticles (CS-NPs) of ciprofloxacin hydrochloride (CHCl) have been investigated for therapeutic delivery and to enhance antimicrobial efficacy. However, the Box–Behnken design (BBD)-supported statistical optimization of NPs of CHCl has not been performed in the literature. As a result, the goal of this study was to look into the key interactions and quadratic impacts of formulation variables on the performance of CHCl-CS-NPs in a systematic way. To optimize CHCl-loaded CS-NPs generated by the ionic gelation process, the response surface methodology (RSM) was used. The BBD was used with three factors on three levels and three replicas at the central point. Tripolyphosphate, CS concentrations, and ultrasonication energy were chosen as independent variables after preliminary screening. Particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), and in vitro release were the dependent factors (responses). Prepared NPs were found in the PS range of 198–304 nm with a ZP of 27–42 mV. EE and drug release were in the range of 23–45% and 36–61%, respectively. All of the responses were optimized at the same time using a desirability function based on Design Expert^® modeling and a desirability factor of 95%. The minimum inhibitory concentration (MIC) of the improved formula against two bacterial strains, Pseudomonas aeruginosa and Staphylococcus aureus, was determined. The MIC of the optimized NPs was found to be decreased 4-fold compared with pure CHCl. The predicted and observed values for the optimized formulation were nearly identical. The BBD aided in a better understanding of the intrinsic relationship between formulation variables and responses, as well as the optimization of CHCl-loaded CS-NPs in a time- and labor-efficient manner. Full article

The development of any commercial product should also be aimed at reducing the risk associated with it, according to the safe-by-design concept; that is, risk assessment should always be at the center of the design, and the impact on human and environmental health should be assessed and eliminated during the product development phase and not afterwards. Unfortunately, even today, most operators in any production sector implement the philosophy of “risk management” or rather of managing the problem when it occurs, using spot interventions instead of changing the approach. This argument is also valid in the production of solar filters, which have reached a satisfactory degree of efficiency in the face of a substantial underestimation of the risks associated with their possible environmental fate. In fact, solar filters have been found in bathing waters and their environmental fate may depend on various factors such as the pH of the water, the presence of organic material, metal ions and light, and, above all, the chemical agents used in the disinfection of the water itself. Thus, during disinfection processes, the generation of dozens of products with a lower molecular weight and generally of an aromatic nature has been tested, where some of them did not receive an exact structural definition and a precise evaluation of their precise toxicological profile. Therefore, it is interesting to draw a complete picture of organic sunscreens and of the byproducts obtained under different conditions and their related ecotoxicological profile. Full article

Based on the acid–base neutralization, the (1-methylimidazolium)(tetrazol-1-yl)borane was successfully synthesized by taking advantage of the acidity of the tetrazole and the basicity of the 1-methylimidazole borane complex. Through HRMS, NMR, and FT−IR, the structure of synthetic compounds was characterized in detail. Concerning about the (1-methylimidazolium)(tetrazol-1-yl)borane, it had an ignition−delay time of about 25 ms and a density specific impulse over 351 s·g/cm³, making it a suitable candidate for green hypergolic fuels. Moreover, it also demonstrated that introducing tetrazole into the borane could be an appropriate strategy to adjust the performance of the energy of those borane compounds. Full article

Gynecologic cancers are one of the main health concerns of women throughout the world, and the early diagnosis and effective therapy of gynecologic cancers will be particularly important for the survival of female patients. As a current hotspot, carbon nanomaterials have attracted tremendous interest in tumor theranostics, and their application in gynecologic cancers has also been developed rapidly with great achievements in recent years. This Overview Article summarizes the latest progress in the application of diverse carbon nanomaterials (e.g., graphenes, carbon nanotubes, mesoporous carbon, carbon dots, etc.) and their derivatives in the sensing, imaging, drug delivery, and therapy of different gynecologic cancers. Important research contributions are highlighted in terms of the relationships among the fabrication strategies, architectural features, and action mechanisms for the diagnosis and therapy of gynecologic cancers. The current challenges and future strategies are discussed from the viewpoint of the real clinical application of carbon-based nanomedicines in gynecologic cancers. It is anticipated that this review will attract more attention toward the development and application of carbon nanomaterials for the theranostics of gynecologic cancers. Full article

Dodonaea viscosa is a medicinal plant which has been used to treat various diseases in humans. However, the anti-insect activity of extracts from D. viscosa has not been evaluated. Here, we found that the total saponins from D. viscosa (TSDV) had strong antifeedant and growth inhibition activities against 4th-instar larvae of Spodoptera litura. The median antifeeding concentration (AFC₅₀) value of TSDV on larvae was 1621.81 μg/mL. TSDV affected the detoxification enzyme system of the larvae and also exerted antifeedant activity possibly through targeting the γ-aminobutyric acid (GABA) system. The AFC₅₀ concentration, the carboxylesterase activity, glutathione S-transferases activity, and cytochrome P450 content increased to 258%, 205%, and 215%, respectively, and likewise the glutamate decarboxylase activity and GABA content to 195% and 230%, respectively, in larvae which fed on TSDV. However, D. viscosa saponin A (DVSA) showed better antifeedant activity and growth inhibition activity in larvae, compared to TSDV. DVSA also exerted their antifeedant activity possibly through targeting the GABA system and subsequently affected the detoxification enzyme system. Further, DVSA directly affected the medial sensillum and the lateral sensillum of the 4th-instar larvae. Stimulation of Spodoptera litura. with DVSA elicited clear, consistent, and robust excitatory responses in a single taste cell. Full article

Alzheimer’s disease (AD) is a common age-related neurodegenerative disease that strikes millions worldwide. Herein, we demonstrate a new approach based on network target to identify anti-AD compounds from Danshen. Network pharmacology and molecular docking were employed to establish the DS-AD network, which mainly involved apoptosis of neuron cells. Then network scoring was confirmed via Connectivity Map analysis. M308 (Danshenxinkun D) was an anti-AD candidate with a high score (p < 0.01). Furthermore, we conducted ex vivo experiments with H₂O₂-treated PC12 cells to verify the neuroprotective effect of Salvia miltiorrhiza-containing plasma (SMP), and UPLC-Q-TOF/MS and RT-qPCR were performed to demonstrate the anti-AD activity of M308 from SMP. Results revealed that SMP could enhance cell viability and level of acetylcholine. AO/EB staining and Mitochondrial membrane potential (MMP) analysis showed that SMP significantly suppressed apoptosis, which may be due to anti-oxidative stress activity. Moreover, the effects of M308 and SMP on expressions of PSEN1, DRD2, and APP mRNA were consistent, and M308 can significantly reverse the expression of PSEN1 and DRD2 mRNA in H₂O₂-treated PC12 cells. The strategy based on the network could be employed to identify anti-AD compounds from Chinese herbs. Notably, M308 stands out as a promising anti-AD candidate for development. Full article

The fruit of Tetradium ruticarpum (TR) is commonly used in Chinese herbal medicine and it has known antiproliferative and antitumor activities, which can serve as a good source of functional ingredients. Although some antiproliferative compounds are reported to be present in TR fruit, most studies only focused on a limited range of metabolites. Therefore, in this study, the antiproliferative activity of different extracts of TR fruit was examined, and the potentially antiproliferative compounds were highlighted by applying an untargeted liquid chromatography–tandem mass spectrometry (LC-MS/MS)-based multi-informative molecular networking strategy. The results showed that among different extracts of TR fruit, the EtOAc fraction F2-3 possessed the most potent antiproliferative activity against HL-60, T24, and LX-2 human cell lines. Through computational tool-aided structure prediction and integrating various data (sample taxonomy, antiproliferative activity, and compound identity) into a molecular network, a total of 11 indole alkaloids and 47 types of quinolone alkaloids were successfully annotated and visualized into three targeted bioactive molecular families. Within these families, up to 25 types of quinolone alkaloids were found that were previously unreported in TR fruit. Four indole alkaloids and five types of quinolone alkaloids were targeted as potentially antiproliferative compounds in the EtOAc fraction F2-3, and three (evodiamine, dehydroevodiamine, and schinifoline) of these targeted alkaloids can serve as marker compounds of F2-3. Evodiamine was verified to be one of the major antiproliferative compounds, and its structural analogues discovered in the molecular network were found to be promising antitumor agents. These results exemplify the application of an LC-MS/MS-based multi-informative molecular networking strategy in the discovery and annotation of bioactive compounds from complex mixtures of potential functional food ingredients. Full article

Cherry is a fleshy drupe, and it is grown in temperate regions of the world. It is perishable, and several biotic and abiotic factors affect its yield. During April–May 2021, a severe fruit rot of cherry was observed in Swat and adjacent areas. Diseased fruit samples were collected, and the disease-causing pathogen was isolated on PDA. Subsequent morphological, microscopic, and molecular analyses identified the isolated pathogen as Aspergillus flavus. For the control of the fruit rot disease of cherry, iron oxide nanoparticles (Fe₂O₃ NPs) were synthesized in the leaf extract of Calotropis procera and characterized. Fourier transform infrared (FTIR) spectroscopy of synthesized Fe₂O₃ NPs showed the presence of capping and stabilizing agents such as alcohols, aldehydes, and halo compounds. X-ray diffraction (XRD) analysis verified the form and size (32 nm) of Fe₂O₃ NPs. Scanning electron microscopy (SEM) revealed the spinal-shaped morphology of synthesized Fe₂O₃ NPs while X-ray diffraction (EDX) analysis displayed the occurrence of main elements in the samples. After successful preparation and characterization of NPs, their antifungal activity against A. flavus was determined by poison technique. Based on in vitro and in vivo antifungal activity analyses, it was observed that 1.0 mg/mL concentration of Fe₂O₃ can effectively inhibit the growth of fungal mycelia and decrease the incidence of fruit rot of cherry. The results confirmed ecofriendly fungicidal role of Fe₂O₃ and suggested that their large-scale application in the field to replace toxic chemical fungicides. Full article

Despite the recent advances in the prediction of protein structures by deep neutral networks, the elucidation of protein-folding mechanisms remains challenging. A promising theory for describing protein folding is a coarse-grained statistical mechanical model called the Wako-Saitô-Muñoz-Eaton (WSME) model. The model can calculate the free-energy landscapes of proteins based on a three-dimensional structure with low computational complexity, thereby providing a comprehensive understanding of the folding pathways and the structure and stability of the intermediates and transition states involved in the folding reaction. In this review, we summarize previous and recent studies on protein folding and dynamics performed using the WSME model and discuss future challenges and prospects. The WSME model successfully predicted the folding mechanisms of small single-domain proteins and the effects of amino-acid substitutions on protein stability and folding in a manner that was consistent with experimental results. Furthermore, extended versions of the WSME model were applied to predict the folding mechanisms of multi-domain proteins and the conformational changes associated with protein function. Thus, the WSME model may contribute significantly to solving the protein-folding problem and is expected to be useful for predicting protein folding, stability, and dynamics in basic research and in industrial and medical applications. Full article

Vitamin B12, only found naturally in animal-based foods, is essential for brain functions and various chemical reactions in the human body. Insufficient vitamin B12 leads to vitamin B12 deficiency, common among strict vegetarians due to their limited intake of animal-based foods. Nevertheless, extensive studies have demonstrated that macroalgae, specifically the Ulva lactuca species, are rich in vitamin B12 and could be further exploited in future dietary applications. In the current study, the ideal extraction method of vitamin B12 from dried U. lactuca was developed and optimised to achieve the maximum vitamin B12 yield. The effects of several extraction parameters, including the solvent-to-solvent, methanol:water (MeOH:H₂O), and solute-to-solvent ratios, and pH on the total vitamin B12 content were analysed through a two-level factorial and central composite design. The highest vitamin B12 content, particularly cyanocobalamin (CN-Cbl), was recovered through the ultrasonic-assisted extraction (UAE) of oven-dried U. lactuca at 3 g:60 mL of solute-to-solvent and 25:75% of MeOH to H₂O ratios at pH 4. The extraction of CN-Cbl from oven-dried U. lactuca that employed the UAE method has elevated CN-Cbl content recovery compared to other extraction methods. Full article