Search Results (3,129)

Objective: This study aimed to design and clinically evaluate a bespoke cosmetic formulation tailored to individual skin characteristics and user preferences, focusing on hydration and barrier recovery in mature, therapy-affected skin. In addition, this study aimed to explore the feasibility and short-term outcomes of a structured, biometry-driven personalization approach applied within a single-subject case study design. Materials and Methods: A personalized dermato-cosmetic formulation incorporating melatonin, astaxanthin, low-molecular-weight hyaluronic acid, allantoin, yarrow oil (Achillea millefolium), lecithin, cholesterol, and arginine was developed based on objective biophysical assessment of the skin. A clinical case evaluation was conducted in a male subject over 55 years of age (Fitzpatrick phototype III) presenting persistent xerosis and dehydration following completed oncologic therapy. Quantitative skin biometry was performed at baseline and after 28 days of daily application, assessing hydration at six anatomical sites, sebum secretion, pigmentation and erythema indices, elasticity, and stratum corneum turnover and scaling. Results: After 28 days, sebum secretion increased by more than 100%, indicating partial restoration of the lipid barrier. Hyperpigmented areas decreased from 7.2% to 2.3%, while skin elasticity improved from 25% to 44%. A reduction of 8% in the erythema index suggested decreased vascular reactivity. Hydration levels improved consistently across all evaluated sites, and epidermal renewal was enhanced, as evidenced by reduced scaling and smoother skin surface. The melanin index remained stable throughout the study period. Conclusions: This pilot evaluation shows that bespoke cosmetic formulations, customized to individual skin biometry and preferences, can yield measurable improvements in hydration, barrier repair, elasticity, pigmentation uniformity, and epidermal renewal within 28 days, even in skin compromised by previous oncologic therapy. Given the single-subject nature of this pilot evaluation, these findings cannot be generalized to broader populations but rather highlight the importance of personalization and objective skin assessment in guiding individualized dermato-cosmetic formulation strategies. Personalized dermato-cosmetology using objective biophysical assessment may be a promising future strategy for effective, consumer-centered skincare. Full article

Candida albicans is a major fungal pathogen associated with vulvovaginal candidiasis, and rapid, sensitive detection remains challenging, particularly in amplification-free formats. Here, we report NaPddCas, a microfluidic-free, droplet-based CRISPR/Cas12a detection strategy for qualitative identification of Candida albicans DNA. Unlike conventional bulk CRISPR assays, NaPddCas partitions the reaction mixture into vortex-generated polydisperse droplets, enabling spatial confinement of Cas12a activation events and effective suppression of background fluorescence. This compartmentalization substantially enhances detection sensitivity without nucleic acid amplification or microfluidic devices. Using plasmid and genomic DNA templates, NaPddCas achieved reliable detection at concentrations several orders of magnitude lower than bulk CRISPR/Cas12a reactions. The assay further demonstrated high specificity against non-target bacterial and fungal species and was successfully applied to clinical vaginal secretion samples. Importantly, NaPddCas is designed as a qualitative or semi-qualitative droplet-dependent digital detection method rather than a quantitative digital assay. Owing to its simplicity, sensitivity, and amplification-free workflow, NaPddCas represents a practical approach for laboratory-based screening of Candida albicans infections. Full article

Traditional polysaccharide extraction suffers from low efficiency and high energy consumption, while deep eutectic solvents (DESs) are promising sustainable solvents. This study used DES ChCl-LA (1:2) with ultrasonic assistance to extract polysaccharides from red alga A.taxiformis. Optimized via single-factor experiments and response surface methodology (350 W, 1:30 g/mL, 75 °C), the yield reached 11.28% ± 0.50% (1.5 times higher than that obtained by water extraction). Structural characterization revealed that the DES extract was an acidic polysaccharide, mainly composed of galactose (89.2%), glucose (4.9%), xylose (4.9%), and glucuronic acid (1.0%), with a weight-average molecular weight of 99.88 kDa. Density functional theory and molecular dynamics simulations showed that ChCl-LA enhanced galactose solubility via stronger hydrogen bonding (−25.33 vs. −5.06 kcal/mol for water). Notably, the immunological activity of the DES-extracted polysaccharide was significantly compromised compared to the water-extracted counterpart (p < 0.05). At a concentration of 0.25 mg/mL, the water-extracted polysaccharide-treated group exhibited a 33.98% higher neutral red phagocytosis rate in macrophages, a nitric oxide (NO) secretion level of 34.14 μmol/L (94.98% higher) compared with the DES-extracted polysaccharide group, as well as significantly higher secretion levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The observed disparity in bioactivity is likely due to the distinct chemical profiles resulting from the two extraction methods, including the significantly reduced molecular weight and potential alterations of sulfation degree, monosaccharide composition, and protein content in the DES-extracted polysaccharide. This mechanistic perspective is supported by the relevant literature on the structure–activity relationships of polysaccharides. This study demonstrates the potential of ChCl-LA and elucidates the complex effects of extraction methods on polysaccharide’s structure and function, thereby informing the high-value utilization of A. taxiformis in functional foods. Full article

Glioblastoma multiforme (GBM) is characterized by aggressive growth, extensive vascularization, high metabolic malleability, and a striking capacity for therapy resistance. Current treatments involve surgical resection and concomitant radiation therapy and chemotherapy, prolonging survival times marginally due to the therapy resistance that is built up by the tumor cells. A growing body of research has identified exosomes as critical enablers of therapy resistance. These nanoscale vesicles enable GBM cells to disseminate oncogenic proteins, nucleic acids, and lipids that collectively promote angiogenesis, maintain autophagy under metabolic pressure, and suppress apoptosis. As interest grows in targeting tumor communication networks, exosome-based therapeutic strategies have emerged as promising avenues for improving therapeutic outcomes in GBM. This review integrates current insights into two complementary therapeutic strategies: inhibiting exosome biogenesis and secretion, and engineering exosomes as precision vehicles for the delivery of anti-tumor molecular cargo. Key molecular regulators of exosome formation—including the endosomal sorting complex required for transport (ESCRT) machinery, tumor susceptibility gene 101 (TSG101) protein, ceramide-driven pathways, and Rab GTPases—govern the sorting and release of factors that enhance GBM survival. Targeting these pathways through pharmacological or genetic means has shown promise in suppressing angiogenic signaling, disrupting autophagic flux via modulation of autophagy-related gene (ATG) proteins, and sensitizing tumor cells to apoptosis by destabilizing mitochondria and associated survival networks. In parallel, advances in exosome engineering—encompassing siRNA loading, miRNA enrichment, and small-molecule drug packaging—offer new routes for delivering therapeutic agents across the blood–brain barrier with high cellular specificity. Engineered exosomes carrying anti-angiogenic, autophagy-inhibiting, or pro-apoptotic molecules can reprogram the tumor microenvironment and activate both the intrinsic mitochondrial and extrinsic ligand-mediated apoptotic pathways. Collectively, current evidence underscores the potential of strategically modulating endogenous exosome biogenesis and harnessing exogenous engineered therapeutic exosomes to interrupt the angiogenic and autophagic circuits that underpin therapy resistance, ultimately leading to the induction of apoptotic cell death in GBM. Full article

Drug- and alcohol-induced liver injury involves impaired bile acids or bilirubin secretion, but it is not known how senescence influences the secretion of hepatocytes exposed to drugs and alcohol. In this study, the toxic effects of ritonavir, lopinavir, and alcohol on hepatocyte transporters and the secretion of bile acids and bilirubin were investigated in hydrogen peroxide-induced senescent HepG2 and doxorubicin-induced senescent primary human hepatocytes. In HepG2, intracellular conjugated bilirubin increased upon senescence and extracellular conjugated bilirubin in culture medium was decreased by ritonavir and lopinavir treatment. In the primary hepatocytes, intracellular bile acids or medium bilirubin were not significantly changed upon senescence. However, intracellular bile acids were increased, and medium conjugated bilirubin were decreased in senescent primary hepatocytes treated with alcohol and the two drugs. Transcriptional expressions of adenosine triphosphate (ATP)-binding cassette (ABC) transporters (ABCB4, ABCC6, ABCB11, and ABCD3) were decreased whereas UDP-glucuronosyltransferase (UGT1A1) was increased by ritonavir and lopinavir in senescent HepG2. In senescent primary hepatocytes, expressions of ABCB11, ABCC1, ABCC2, ABCC3, ABCC4, and ABCC6 were apparently reduced whereas UGT1A1 and the cytochrome P450 enzyme CYP7A1 were markedly increased by alcohol combined with ritonavir and lopinavir. Selective ABCC6 knockdown in the primary hepatocytes altered expressions of two senescence markers, Lamin A/C and cyclin-dependent kinase inhibitor CKI (p21), increased expressions of CYP7A1 and hydroxy methyl glutaryl-CoA reductase (HMGCR), and increased intracellular bile acids. Further, anti-cholestasis agents, ursodeoxycholic acid and glycyrrhizin, significantly ameliorated the impaired secretions of bile acids and bilirubin as well as reducing intracellular lipid accumulation and cell death caused by ritonavir, lopinavir, and alcohol in the primary hepatocytes with ABCC6 knockdown. These results indicate that senescence moderately impairs the ABC transporters of hepatocytes and secretion of bile acids or bilirubin, which become worse in the presence of the drugs and alcohol but could be improved by anti-cholestasis agents. Full article

Calcium (Ca²⁺)signaling dysfunction is a central contributor to neuronal hyperexcitability and seizure propagation in epilepsy, yet the intracellular mechanisms underlying the actions of valproic acid (VPA) remain incompletely understood. In this study, we investigated whether VPA modulates Ca²⁺ homeostasis at the level of the endoplasmic reticulum (ER) and how this action influences cytosolic Ca²⁺ dynamics associated with epileptiform activity. ER Ca²⁺ levels were directly measured using ER-targeted aequorin in HeLa and PC12 cells, while cytosolic Ca²⁺ signals were monitored by fura-2 fluorescence imaging in bovine chromaffin cells exposed to veratridine, a model of sustained sodium channel activation and Ca²⁺ oscillations. VPA induced a concentration-dependent release of Ca²⁺ from the ER, with an IC₅₀ of approximately 17 µM. This effect was preserved in permeabilized cells and exhibited activation kinetics comparable to those elicited by inositol 1,4,5-trisphosphate (InsP₃). Pharmacological inhibition of InsP₃ receptors (InsP₃Rs), but not ryanodine receptors or SERCA, abolished VPA-induced ER Ca²⁺ release, supporting a selective InsP₃R-mediated mechanism. Functionally, VPA suppressed the repetitive cytosolic Ca²⁺ oscillations induced by veratridine, while simultaneously producing a sustained elevation of cytosolic Ca²⁺ originating from ER stores and facilitating depolarization-evoked catecholamine secretion. Together, these results support the conclusion that VPA induces InsP₃R-mediated Ca²⁺ mobilization from the endoplasmic reticulum and identify ER Ca²⁺ release as a previously unrecognized intracellular mechanism contributing to its modulatory effects on Ca²⁺ signaling and excitability in epilepsy. Full article

Caffeoyl hexapeptide-9 (CH-9) is a novel cosmetic peptide designed by conjugating hexapeptide-9 (H-9), a known collagen-mimetic peptide with established skin anti-aging activity, with caffeic acid (CA) via an amide bond, leveraging peptide-drug conjugate (PDC) design principles. In ultraviolet (UV)-irradiated cellular and skin models, CH-9 outperformed H-9 in preserving cell viability, restoring collagen types I, III, and IV, and suppressing interleukin-6 and -8 secretion. Additionally, its direct antioxidant activity, absent in H-9, was demonstrated in vitro by scavenging of hydroxyl and peroxyl radicals. Molecular docking indicated CH-9 interacted with the catalytic domain of matrix metalloproteinase 2 (MMP2), a key enzyme in collagen degradation during photoaging, suggesting a potential inhibition of its activity. Molecular dynamics (MD) simulations revealed an improved insertion of CH-9 into a stratum corneum (SC) lipid bilayer compared to H-9, consistent with enhanced skin permeation in vivo. Moreover, CH-9 exhibited improved aqueous and cosmetic serum stability over CA. In a 28-day clinical study, topical application of CH-9 significantly improved skin elasticity and firmness compared to H-9. This work demonstrates that the PDC-based conjugate CH-9 combines enhanced anti-photoaging efficacy with improved transdermal permeation and stability, highlighting a promising strategy for the development of advanced cosmetic ingredients. Full article

Background: The incidence of dementia, especially Alzheimer’s disease (AD), is rising, with over 55 million affected globally. Therefore, this disease, for which there is no adequate treatment, is more frequent and prevalent in women. Royal jelly, a bee secretion, is known for its health benefits and contains proteins, carbohydrates, lipids, minerals, polyphenols, enzymes, and B vitamins, as well as anti-inflammatory and antioxidant properties relevant to AD. Thus, we aimed to investigate the chemical compounds in royal jelly extract and their effect on neurobehavioral changes in an AD female model. Methods: In vitro studies were used to investigate the chemical and physicochemical properties of the royal jelly extract. In vivo studies, we divided female mice into five groups (n = 25): Control (C), Alzheimer (ALZ), ALZ standard (ALZ-STD, rivastigmine 1 mg/Kg), ALZ-D1 (royal jelly 150 mg/kg), and ALZ-D2 (royal jelly 300 mg/kg). The mice received the treatments orally at 45 days. We induced the AD model by orally administering aluminum chloride at 100 mg/kg and intraperitoneally injecting D-galactose at 120 mg/kg for 45 consecutive days, after which we subjected the animals to the radial arm maze, Morris water maze, elevated plus maze, and forced swim tests. Results: Analyses showed moderate acidity and a rich bioactive profile, with flavonoids being more prevalent. Antioxidant activity tests indicated moderate efficacy, while FTIR-ATR analysis revealed the chemical complexity of royal jelly. The royal jelly extract used in the study did not induce toxicity in vivo. Notably, royal jelly improved cognitive deficits, neurodegeneration, and reduced anxiety in AD. Conclusions: The study suggests that royal jelly extract has promising neuroprotective properties and could be a viable natural therapeutic option for AD. Full article

Lactoferrin (LF) is an iron-binding immunoprotein of the mammary gland whose levels increase during mastitis and may be influenced by the metabolic status of the cow. During early lactation, dairy cows are exposed to a negative energy balance (NEB) and the associated increase in susceptibility to mastitis. However, the extent to which the metabolic profile influences LF secretion in milk during the postpartum period remains unclear. The objective of this study was to assess the associations between metabolic status and milk LF contents in Holstein cows (n = 122) in the first twenty days of lactation. Based on the milk LF contents, the cows were categorized into two groups: LF-LOW (≤123 mg/L; n = 81) and LF-HIGH (>123 mg/L; n = 41). Serum indicators of energy and nitrogen metabolism, hepatic function, and selected macro-/microelements were measured; urine electrolytes and net acid–base excretion (U-ABB) were assessed; and milk composition, including somatic cell count (SCC), was determined. LF-HIGH cows showed higher SCC (p = 0.0516) and serum glucose (p < 0.001), together with lower serum triglycerides (p = 0.0101) versus LF-LOW cows. Milk beta-hydroxybutyric acid (BHB) content was lower in the LF-HIGH group (trend, p ≈ 0.062). LF-HIGH also exhibited significantly greater natriuresis (p = 0.0078) and a more negative U-ABB (p < 0.001), indicating higher acid–base load. In conclusion, elevated LF contents during the postpartum period were associated with the activation of local mammary gland immune defence and concurrent compensatory metabolic processes related to NEB, rather than with pronounced alterations in basic milk composition. Milk LF content may therefore be considered as a specific indicator of immunometabolic compensation during the early postpartum period, rather than as a general marker of overall cow health. Full article

We present a simplified phenomenological computational framework that integrates the GABA shunt into established metabolic mechanisms underlying pancreatic beta cell insulin secretion. The GABA shunt introduces carbon into the tricarboxylic acid (TCA) cycle via succinate, thereby functioning as an anaplerotic pathway. This anaplerotic input is coupled to oscillatory cataplerotic fluxes, primarily involving α-ketoglutarate, whose effective extrusion requires coordinated counter-fluxes of malate and aspartate. Within the model, these cataplerotic exchanges are facilitated by UCP2-mediated transport processes and necessitate complementary anaplerotic replenishment through pyruvate carboxylase (PC). Based on this functional interdependence, we introduce the Dual Anaplerotic Model (DAM), which conceptually links two anaplerotic routes—the GABA shunt-mediated pathway and the glucose-dependent PC pathway—into a unified metabolic response module. DAM describes a coordinated, breathing-like redistribution of carbon between mitochondrial and cytosolic metabolite pools, while efficient oxidative metabolism of glucose-derived carbon entering the TCA cycle via pyruvate dehydrogenase is maintained. The model is driven by experimentally observed ATP/ADP and Ca²⁺ dynamics and is not intended to generate autonomous oscillations. Instead, it enables qualitative, phase-dependent visualization of how dual anaplerotic fluxes constrain and shape oscillatory metabolic states in beta cells. DAM provides an integrative conceptual scaffold for interpreting experimental observations and for motivating future quantitative modeling and experimental studies addressing metabolic regulation in physiological and pathophysiological contexts. Full article

The liver plays a central role in numerous physiological processes, with one of its most critical functions being the regulation of lipid homeostasis through both the biogenesis and secretion of very low-density lipoproteins (VLDLs) and fatty acid oxidation. By forming and secreting VLDLs, the liver mitigates the influx of potentially toxic free fatty acids from the bloodstream and repurposes them for energy utilization throughout the body. Fatty acid oxidation is equally essential for maintaining hepatic lipid balance, and its disruption can lead to lipid accumulation and metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD). Even subtle alterations in these processes can have profound health consequences, contributing to chronic liver diseases and atherosclerosis—the leading cause of cardiovascular morbidity and mortality worldwide. Despite their importance, many aspects of hepatic VLDL formation, secretion, and fatty acid oxidation remain poorly understood. This narrative review highlights the pivotal role of the liver in maintaining lipid balance, summarizes current knowledge on fatty acid uptake and processing, provides an in-depth analysis of VLDL biogenesis and secretion, and underscores the need for continued research in this critical area of human health. Full article

The present study involves the isolation, structural elucidation, and biological evaluation of eight compounds from Pouzolzia zeylanica. From the n-hexane and ethyl acetate extracts of the plant, eight compounds were successfully isolated and identified: oleanolic acid (1), ursolic acid (2), 2α-hydroxyursolic acid (3), 3β-O-acetyl-12-oleanen-28-oic acid (4), 5-hydroxy-6,7-dimethoxyflavanone (5), 4′-methoxytectochrysin (6), 3,4′,5,7-tetrahydroxyflavanone-3-O-L-rhamnopyranoside (7), and 3,3′,5,5′,7-pentahydroxyflavanone-3-O-L-rhamnopyranoside (8). These compounds were evaluated for in vitro antioxidant activity using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) and lipid peroxidation inhibition (TBARS) assays, as well as anti-inflammatory activity via inhibition of nitric oxide (NO) production and the secretion of pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in RAW 264.7 macrophages. It was observed that compound 3 exhibited the strongest antioxidant activity with IC₅₀ values of 18.52 ± 1.50 µM (DPPH) and 10.34 ± 0.93 µM (TBARS), whereas compounds 2, 5, and 6 showed moderate to weak effects. Meanwhile, compound 8 demonstrated the most potent anti-inflammatory effect with IC₅₀ values of 16.25 ± 0.95 µM (NO inhibition), 12.97 ± 0.88 µM (TNF-α inhibition), and 22.52 ± 1.98 µM (IL-6 inhibition). Furthermore, in silico approaches were employed, including density functional theory (DFT) calculations to predict the antioxidant mechanisms of compounds 1 and 3 and molecular docking to assess the cyclooxygenase-2 (COX-2) and phosphodiesterase-4B (PDE4B) inhibitory potentials of compounds 4, 7, and 8. Computational results aligned well with experimental data, supporting the potential of these compounds as natural antioxidant and anti-inflammatory agents. Full article

(E)-Flavokawain A (FKA), the primary chalcone constituent of Piper methysticum, exhibits diverse pharmacological properties and holds significant potential for therapeutic development. Objectives: This study aims to investigate the anti-colorectal cancer effects and mechanisms of FKA. Methods: Using AOM/DSS-induced colorectal cancer models in C57 mice, the research examines the impact of different FKA doses, employing 16S rRNA and metabolomics to explore the potential mechanism. Results: The findings indicated that FKA significantly inhibited the progression of colorectal cancer in C57 mice by modulating the composition of the gut microbiota. This modulation involved the suppression of endotoxin secretion by pathogenic bacteria and the concurrent augmentation of beneficial bacteria. Furthermore, in the context of metabolic pathways, FKA regulates lipid metabolism and arachidonic acid metabolism, thereby mitigating the inflammatory transformation associated with colorectal cancer. Conclusions: These findings provide valuable insights supporting the potential of FKA as a viable preventive strategy against CRC. Full article

Pathogenic bacteria utilize a type III secretion system (T3SS) to inject type III effectors (T3Es) into plant cells, suppressing plant immunity and facilitating colonization. Paracidovorax citrulli, the causal agent of bacterial fruit blotch (BFB) of Cucurbitaceae crops, harbors a functional T3SS like many other plant pathogens. The expression of its T3SS and T3Es is regulated by the two-component system response regulators HrpG and HrpX. Here, we demonstrate that the aspartic acid (Asp) residues at positions 52 and 60 in P. citrulli HrpG are essential for its complete function. Plasmid-mediated complementation of the ΔhrpG mutant with hrpG carrying Asp52→alanine (Ala) or Asp60→Ala mutations failed to restore the ability of P. citrulli to induce a hypersensitive response (HR) in tobacco, whereas the Asp46→Ala mutation fully rescued this phenotype. Furthermore, genomic hrpG point mutations generating strains Aac5 (D52A) and Aac5 (D60A) abolish the activation of hrpX transcription, resulting in decreased HrpX accumulation. Collectively, Asp 52 and Asp 60 in P. citrulli HrpG are essential for transcriptional activation activity of hrpX and HR induction, serving as a potential phosphorylation site (Asp 52) for upstream histidine kinases and a Mg²⁺ coordination site (Asp 60). Given that conserved Asp residues often function as phosphorylation sites in two-component system response regulators, this study provides a foundation for identifying upstream histidine kinases that modulate HrpG activity in P. citrulli. Full article

Ergot alkaloids derived from lysergic acid have impacted humankind significantly as toxins in agriculture and as the foundations of several pharmaceuticals. Few fungi capable of producing lysergic acid derivatives have been found outside the family Clavicipitaceae. Based on its phylogenetic placement, we hypothesized the recently described fungus Aspergillus aspearensis (Aspergillaceae) would synthesize lysergic acid amides. Cultures of A. aspearensis produced abundant lysergic acid α-hydroxyethylamide (LAH) and lesser amounts of other lysergic acid derivatives. Conidia contained high concentrations of ergot alkaloids, whereas sclerotia contained significantly less. Approximately half of the ergot alkaloids produced were secreted into the culture medium. When spores of A. aspearensis were injected into larvae of the model insect Galleria mellonella, larvae died at a significantly faster rate than control larvae. The fungus produced ergot alkaloids during insect pathogenesis and later produced conidia and sclerotia on cadavers, indicating it can complete its life cycle in an insect. The genome of A. aspearensis contained two complete ergot alkaloid synthesis gene clusters, similar to those of A. leporis; however, unlike its sister species, none of the ergot cluster genes were pseudogenized. Aspergillus aspearensis is a newly discovered source of ergot alkaloids and may be useful for studying and producing these important chemicals. Full article