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The gut microbiota and its metabolites, as components of the gut–bone axis, play a pivotal role in regulating skeletal homeostasis through the bidirectional communication network. In this systematic review, evidence was collected from mainstream databases following standardized inclusion/exclusion criteria for screening, to comprehensively retrieve and screen eligible studies from multiple mainstream databases according to standardized inclusion and exclusion criteria, and systematically summarize current research progress on plant-derived bioactive compounds targeting the gut–bone axis for skeletal health regulation. This review systematically explores the underlying mechanisms of the gut–bone axis and critically evaluates the regulatory effects and therapeutic potential of plant-derived bioactive compounds. Particular attention is given to targeted interventions involving prebiotics, probiotics, synbiotics, and plant-rich diets or functional foods. Among these interventions, synbiotics represent the most successful strategy and show the most prominent therapeutic possibilities in bone-related disorders. Different from single prebiotics (only nourish endogenous intestinal microbes), individual probiotics (easy to be degraded in gastrointestinal tract with poor colonization) and ordinary plant-rich diets (unfixed effective dosage and weak targeting property), synbiotics combine prebiotic carriers and viable probiotic strains to produce complementary advantages, which is the core reason for its outstanding therapeutic prospect against bone diseases. Synbiotics exert synergistic effects on gut microecology, mineral absorption, and immune regulation, leading to more robust and consistent improvements in bone health than single prebiotics, probiotics, or general plant-rich diets. They have been verified in preclinical and clinical studies to ameliorate osteoporosis and related skeletal diseases via the gut–bone axis. These strategies offer novel insights into the prevention and treatment of bone metabolic disorders, such as osteoporosis, by targeting the gut–bone axis with phytochemicals. Key outcomes of this review include that synbiotics, soy isoflavones, naringin, curcumin, and resveratrol effectively improve bone mineral density, restore gut microbiota balance, and inhibit pathological bone resorption via the gut–bone axis. Collectively, the above bioactive substances realize bone protection mainly by reshaping gut flora, elevating mineral uptake and suppressing excessive osteoclast activity. Representative cases include soy isoflavones mitigating estrogen-deficient bone loss in OVX models, naringin improving the trabecular microarchitecture, and probiotic BL-11 promoting longitudinal bone growth in children. Future directions will focus on clarifying dose–response relationships, developing standardized synbiotic formulations, constructing microbiome-guided precision diets, and conducting large-sample randomized controlled trials to translate plant-derived compounds into clinical therapies. Full article

Children in residential care constitute a particularly vulnerable group at high risk of developing emotional and behavioral difficulties as a consequence of adverse experiences and dysfunctional family environments. Identifying risk and protective factors is essential for designing interventions tailored to their needs; however, the available research remains limited and does not always provide the evidence required to guide effective programs within the child protection system. The aim of this study was to examine the prevalence of emotional and behavioral problems among children in residential care and to analyze the role of family factors, sex, and age in these difficulties. The sample consisted of 210 children aged 6 to 18 years institutionalized in residential care centers and supervised apartments. A cross-sectional design was employed, administering the Strengths and Difficulties Questionnaire (SDQ) along with an ad hoc questionnaire to collect socio-family variables. The results reveal a high prevalence of emotional and behavioral difficulties. The multivariable models explained between 8.1% and 29.4% of the variance in emotional and behavioral functioning and showed that age, sex, exposure to gender-based violence, parental substance use, and parental intellectual disability were associated with specific emotional and behavioral dimensions. The study highlights the need to develop and implement educational and therapeutic programs aimed at strengthening children’s emotional regulation, addressing behavioral difficulties, and considering family-related adversity in intervention planning. Full article

Background/Objectives: Dysphagia is a prevalent consequence of neurological conditions, particularly stroke and Parkinson’s disease, leading to aspiration pneumonia and reduced quality of life. Currently, there are no specific recommendations for pharmacological therapy, although studies indicate that elevated substance P levels may improve swallowing function. While nicergoline is known to increase substance P, the role of its major metabolite, 10-methoxy-dihydro-lysergol (MDL), in this therapeutic effect remains unclear. This study examined the therapeutic effects of nicergoline and its correlation with substance P and MDL levels. Methods: This study conducted an open-label pilot study with historical controls in neurogenic patients with dysphagia. The primary outcome was improvement in the Gugging Swallowing Screen (GUSS) scores at week 12. Secondary outcomes included choking frequency, serum substance P levels, and the correlation between serum MDL levels and dysphagia enhancement. Inverse Probability Weighting (IPW) was employed to adjust for baseline confounders. Results: A total of 92 patients were analyzed: 26 in the nicergoline group (20 or 60 mg/day) and 66 in the historical control group. Compared to controls, the nicergoline group exhibited significantly higher median of GUSS scores (20 (IQR: 19–20) vs. 15 (IQR: 9–19), p < 0.001) and significantly lower median of choking frequency (6.43 (IQR 0–17) vs. 108 (IQR 13–201) 105.22, p < 0.001). The median substance P concentration in the therapy group was 4089.15 (IQR: 3336.13–4468.26) pg/mL. Patients receiving nicergoline showed a statistically significant elevation in substance P from baseline (p < 0.001). Pearson analysis revealed a negligible correlation between serum MDL and substance P levels (R² = 0.0349). Conclusions: Preliminary findings suggest that nicergoline may be associated with improvements in swallowing function in neurogenic dysphagia and a potential increase in substance P levels. The lack of correlation with serum MDL suggests that efficacy may not linearly depend on circulating metabolite concentrations. Further large-scale randomized controlled trials are warranted. Full article

Water solubility is a key physicochemical property during drug development, yet about 90% of new drug candidates exhibit low solubility. Numerous approaches have been proposed to enhance drug solubility, including physical modification and the use of solubilizing agents, formulation modifications, and nanotechnology techniques. Increasing both the solubility and dissolution rate of the drug substance is an important element of drug formulation technology, aimed at improving therapeutic efficacy and bringing economic benefits—both in the production process and by reducing the cost of therapy for the patient. Moreover, enhancing solubility helps reduce dosing, which is key to combating antibiotic overuse and resistance. This article reviews the newest methods and effects for increasing solubility and the dissolution rate of antibacterial substances in biopharmaceutics classification system (BCS) class IV, characterized by low water solubility and limited intestinal permeability. Particular attention was paid to summarizing the newest strategies to guide future formulation development and critically evaluate the literature. Full article

Biofilms are structured communities of microorganisms embedded in a self-produced extracellular polymeric substance (EPS) matrix, whose development significantly enhances microbial resistance to antibiotics, disinfectants, and host immune defenses, posing major challenges in clinical, industrial, and environmental settings. Compared with planktonic cells, biofilm-associated microorganisms can exhibit up to 10- to 1000-fold increased tolerance to antimicrobial agents, contributing to the persistence of biofilm-associated infections (BAIs). These infections remain difficult to eradicate due to reduced penetration, altered metabolic states, and the presence of dormant or persister cells. Anti-biofilm strategies can be broadly classified into physical approaches (e.g., ultrasound, mechanical stress, and light-based approaches) that target biofilm structure; chemical and enzymatic methods (e.g., EPS-degrading enzymes) that destabilize the matrix; and biological and molecular strategies (e.g., quorum-sensing (QS) inhibitors, anti-virulence agents, bacteriophages, phage-derived antimicrobial molecules, antimicrobial peptides, and natural bioactive compounds) that modulate biofilm development and integrity by targeting regulatory pathways and matrix stability through distinct mechanisms of action. Natural compounds, including lactoferrin, lactoferrin-derived peptides, and probiotic and postbiotic fractions of lactic acid bacteria (LAB), as well as plant-derived metabolites, have shown promising anti-biofilm effects, with efficacy often enhanced through complementary or potentially synergistic interactions. However, despite these advancements, clinical translation remains limited. For example, BAIs account for approximately 80% of chronic infections, with high recurrence rates and therapeutic failure reported in device-associated infections and chronic wounds. These limitations highlight the need for clinically translatable, multimodal approaches that integrate structural biofilm disruption, antimicrobial targeting, and host response modulation to design more effective and sustainable anti-biofilm strategies. Full article

Cancer is still one of the world’s major causes of morbidity and mortality; thus, safer and more efficient treatment approaches are required. The structural variety, multitargeted mechanisms, and generally good safety profiles of plant-derived polyphenols have made them attractive anticancer medicines. Flavonoids (like quercetin), stilbenes (like resveratrol), phenolic acids and curcuminoids (like curcumin) are major classes that have shown strong anticancer action against a variety of cancers, including prostate, colorectal and breast cancers. Through targets including PI3K/Akt, MAPK, NF-κB, and p53 signaling networks, these substances influence important molecular pathways involved in tumor initiation and development, including oxidative stress, inflammation, apoptosis, cell cycle control, angiogenesis and metastasis. The clinical translation of polyphenols is still constrained by poor bioavailability, fast metabolism, low aqueous solubility and inefficient pharmacokinetic characteristics, which lead to insufficient systemic exposure and therapeutic efficacy despite strong preclinical data. Their therapeutic applicability is further complicated by variations in absorption and possible dose-related restrictions. To overcome these limitations, the anticancer efficacy of polyphenols has been enhanced via delivery technologies like polymeric nanoparticles, lipid-based carriers, nanoemulsions and phytosome complexes, which have shown improved stability, increased bioavailability and targeted delivery to tumor tissues. This review provides a comprehensive and integrative analysis of plant-derived polyphenols by linking molecular mechanisms, pharmacokinetic limitations and emerging delivery strategies within a translational framework. By bridging these interconnected domains, this review highlights the potential of polyphenols as viable candidates in next-generation cancer therapeutics and underscores the need for well-designed clinical studies to facilitate their successful integration into oncology practice. Full article

The growing field of nanobiotechnology could provide an alternative platform for the development of new therapeutic agents. A potential means for achieving these goals are nanoparticles of rare-earth metals, for example, nanoceria. According to the results of numerous in vitro and in vivo studies, not only oxide forms of lanthanides can demonstrate a pharmacological effect. A promising nano-object for biomedical application is cerium phosphate, which exhibits both properties characteristic of cerium dioxide and its own unique properties, due to the diversity of morphology. However, at present, a unified methodological approach has not been formulated that would make it possible to formulate principles for obtaining a compound with specified properties. This review was conducted on using the international databases PubMed, PubChem, Scopus and Google Scholar, and included original studies and reviews. The literature describes the preparation of cerium phosphate nanoparticles by the hydrothermal, chemical precipitation, microwave, and sol–gel methods. It was established that reaction temperature, pH value of the medium, use of organic solvents, ratio of reagents, and precursors have a direct influence on the size, shape, and structure of the obtained nano-object, making it possible to synthesize nanospheres, nanorods, and nanoneedles by regulating these parameters. In addition, the strategy of obtaining nano-objects with specified properties can be implemented by using excipients of predominantly polymer nature. The use of auxiliary substances is capable both of exerting a stabilizing effect and improving adherence to the nanoscale range, and of influencing pharmacological activity. The literature describes the possibility of using cerium phosphate as a redox-active, regenerative, antibacterial, sunscreen, and antitumor agent. However, the insufficient amount of data on the toxicological profile, as well as the results of in vivo studies, remains a significant limitation for the introduction of cerium phosphate into clinical practice. Thus, the purpose of the present review is to identify patterns that make it possible to formulate recommendations for the synthesis of cerium phosphate with specified properties, to assess factors affecting its suitability for use in biomedicine, and to consider its prospects and limitations. Full article

Mori Cortex Radicis (MCR), which is abundant in resources and low in cost, is a Chinese herbal medicine with antitussive, anti-inflammatory, analgesic, and hypoglycemic effects; however, its application in the prevention and control of aquatic pathogens remains understudied. In this study, a MCR water extract (MCR-WE) was prepared, and its contents of polysaccharides, polyphenols, and proteins were found to be 0.63%, 1.17%, and 2.79%, respectively. LC-MS metabolomics revealed that L(+)-Arginine, 9,12,13-Todea, Citric acid, 1-Deoxynojirimycin, and 4-Guanidinobutanoic acid were the most abundant compounds. Subsequently, by feeding the MCR-WE to crucian carp (Carassius auratus) and challenging them with Aeromonas veronii, it was found that the MCR-WE enhanced the activities of immune factors (AKP, ACP, LZM) and the phagocytic activity of leukocytes (p < 0.05). Furthermore, the MCR-WE improved the survival rate of crucian carp (p < 0.05), reduced the bacterial load in the kidneys (p < 0.05), decreased the mRNA expression of inflammatory factors (IL-6, IL-1β, TNF-α), and lowered the expression levels of antioxidant-related factors (CAT, GSH-Px, SOD, MDA) and the mRNAs of oxidative stress pathway factors (Nrf2, HO-1, Keap1) (p < 0.05). Histopathological sections and immunofluorescence assays showed that the MCR-WE maintained the structural integrity of internal organs and reduced renal cell apoptosis and DNA damage. Therefore, MCR-WE is rich in immunologically active substances, can activate the immune response of crucian carp, reduce fish mortality, exert anti-inflammatory and antioxidant activities, and maintain the structural and functional integrity of internal organs. Thus, the MCR-WE holds promise as a therapeutic agent against A. veronii infection in fish. Full article

Wound healing remains a persistent health problem with no definitive solution. It is crucial to characterize the complex wound healing process and the various growth factors, cytokines, and polypeptides involved. Transforming growth factor beta1 (rhTGF-β1) stimulates different cell types, providing multifunctionality in the wound healing process. Since proteins are sensitive to proteases, drug delivery systems are needed. Developed polymeric carrier systems are as important as the active substance. The carrier systems used in our study aim to contribute to wound healing in addition to the rhTGF-β1. We hypothesized that PLGA nanoparticles embedded in PVA/Chitosan (PVA/Chi) hydrogels could enhance the therapeutic effect of rhTGF-β1. PVA/Chitosan hydrogels were prepared by the freezing/thawing method. Several characterization studies (Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), texture analysis, and cell culture) were performed to investigate the potential of the prepared formulations to enhance the therapeutic effect of rhTGF-β1. Hydrogel formulations reduced the inhibitory effect of rhTGF-β1 on keratinocytes. The H5 hydrogel exhibited a proliferative effect on fibroblast cells, which play a crucial role in wound healing, resulting in a 78.8% increase compared to the control. As the PVA content in the hydrogel formulations increased, bioadhesion and viscosity also increased. Although TGF-β1 inhibited keratinocytes, it induced migration of both NIH-3T3 and HACAT cell lines. The formulations developed exhibit the potential to improve the therapeutic efficacy of rhTGF-β1 in wound healing. A small amount of the protein can have the same therapeutic efficacy and fewer side effects because the developed polymeric carrier systems contribute to the therapeutic efficacy. Full article

Dormancy is an important factor influencing colorectal cancer (CRC) metastasis through diverse metabolic pathways and cell types. To elucidate its molecular mechanisms, bulk transcriptomic pathway scoring was integrated with single-cell RNA sequencing of epithelial, cancer stem, and immune cells to identify CRC dormancy-associated genes (CDAGs). Twenty-three CDAGs were identified. These genes were found to play a regulatory role in dormancy by participating in metabolic processes affecting energy supply or substance synthesis. In two independent CRC cohorts (GSE41258, GSE41568), machine learning models using these genes distinguished metastatic samples with area under the curve (AUC) of 0.79–0.87. High CDAG expression was associated with better recurrence-free survival in GSE41258 (p = 0.005), which remained significant after adjusting for age, sex, and adjuvant chemotherapy (p = 0.037). The prognostic value was validated in The Cancer Genome Atlas (TCGA) Colon and Rectal Cancer for progression-free survival (p = 0.004). Moreover, 20 CRC dormancy-associated drugs were identified, 12 of which were reported to be associated with CRC, two with experimental evidence of inhibiting CRC metastasis or recurrence. This study provided metabolic-oriented genes for characterizing CRC dormancy, which could distinguish metastatic samples and had independent prognostic value, and offered a foundation for further development of targeted therapeutic strategies. Full article

Background: Sapropelic mud from Techirghiol Lake has been used therapeutically under medical supervision for more than 170 years; however, its comprehensive physicochemical characterization under application-relevant conditions remains insufficiently documented. This study aimed to evaluate the physicochemical properties, mineral and organic composition, ion-exchange capacity, and potential therapeutic mechanisms of Techirghiol sapropelic mud. Methods: Mud samples were analyzed using standardized physicochemical and analytical techniques to determine pH, water content, granulometry, mineral composition, organic fraction, and trace elements. Results: The results indicate that Techirghiol mud is a highly hydrated alkaline peloid characterized by a complex mineral–organic system. Major elements included sodium, calcium, and magnesium, while trace elements such as manganese, iron, and zinc were present in relevant concentrations. The organic fraction, composed of humic substances, lipids, and proteins, reflected advanced but incomplete humification processes. Conclusions: The findings demonstrate the complex physicochemical composition of Techirghiol sapropelic mud and provide a scientific basis for further studies regarding its properties and applications. Full article

Background: Enterococcus faecalis is one of the most frequent causes of catheter-associated urinary tract infections, largely due to its ability to form biofilms on indwelling urinary catheter surfaces, which enhance bacterial persistence and antimicrobial tolerance. Sub-minimum inhibitory concentrations (sub-MICs) of antimicrobials frequently occur in clinical settings, and growing evidence suggests that such suboptimal exposures can induce bacterial biofilm formation. We hypothesized that exposure to sub-MICs of amoxicillin, ciprofloxacin, and nitrofurantoin, antimicrobials commonly employed in the treatment of urinary tract infections, would enhance the biofilm-forming capacity of E. faecalis strains. Objective: To investigate the effects of sub-MICs of amoxicillin, ciprofloxacin, and nitrofurantoin on biofilm formation and biofilm-associated gene expression. The study focused on key biofilm-related genes, including those encoding aggregation substance protein (asa1), collagen adhesin (ace), E. faecalis surface protein (esp), gelatinase (gelE), cytolysin activator A (cylA), endocarditis antigen A (efaA), and the endocarditis- and biofilm-associated pili subunit A (ebpA) in E. faecalis. Methods: Two strains, E. faecalis ATCC 29212 and strain 54, were exposed to 1/8× and 1/4× MIC of amoxicillin, ciprofloxacin, and nitrofurantoin in either artificial urine medium (AUM) or tryptone soya broth (TSB). Bacterial growth kinetics were monitored by optical density measurements, while biofilm formation was quantified using a microtiter plate biofilm assay. The expression of biofilm-associated genes was analyzed using quantitative reverse transcription PCR (RT-qPCR) at 24 and 48 h following exposure to sub-MICs of amoxicillin under flow conditions mimicking the urinary tract milieu. Results: Exposure to sub-MICs of the three antimicrobials did not significantly affect bacterial growth in either strain or culture medium. Sub-MICs of amoxicillin significantly enhanced biofilm formation, with the most pronounced effect observed at 1/4× MIC in both AUM and TSB. In contrast, ciprofloxacin and nitrofurantoin exerted inhibitory effects on biofilm formation across both media. Gene expression analysis demonstrated time- and strain-dependent responses to amoxicillin exposure. E. faecalis ATCC 29212 exhibited a moderate, coordinated upregulation of adhesion- and biofilm-associated genes, particularly at 48 h. By comparison, E. faecalis strain 54 showed a stronger and more dynamic transcriptional response, characterized by early and sustained induction of key biofilm-related genes, including esp and gelE, as well as a pronounced late upregulation of ebpA. Conclusions: These findings emphasize the importance of maintaining therapeutically effective antimicrobial concentrations, as sub-inhibitory amoxicillin exposure may promote biofilm-associated persistence and potentially compromise treatment efficacy. Full article

Opioids comprise a class of substances characterized by a narrow therapeutic window and significant euphoric effects. Opioid-related mortality remains a critical global health issue, primarily resulting from respiratory depression associated with full μ-opioid receptor agonists. Buprenorphine is distinguished by its pharmacological profile as a partial μ-opioid receptor agonist, exhibiting a ceiling effect on both respiratory depression and euphoria. These characteristics render buprenorphine particularly valuable in opioid replacement therapy for opioid use disorder and in the management of both chronic and acute pain. Current literature indicates that, due to these properties, buprenorphine possesses a superior safety profile compared to other opioids. This narrative review evaluates whether buprenorphine can cause fatal overdose despite its protective ceiling effect and examines cases of buprenorphine-related fatalities. The review synthesizes data from pre-clinical, clinical, pharmacological, and toxicological studies. Current literature supports the consensus that the established ceiling effect on respiratory depression does not fully eliminate the risk of fatal overdose. Polysubstance use, particularly co-ingestion of other central nervous system depressants, significantly increases this risk, and most buprenorphine-related deaths involve such combinations. Additionally, buprenorphine’s safety is reduced in vulnerable populations, including opioid-naive individuals, children, and patients with pre-existing respiratory compromise. While buprenorphine alone presents a substantially lower fatality risk compared to other opioids, the ceiling effect is pharmacodynamic rather than absolute, and toxicity or fatal overdose may still occur. Current data gathered from clinical and pre-clinical studies suggest that buprenorphine is safer than full μ-opioid receptor agonists, but it is not without risk. The ceiling effect’s protective benefits depend on context. Therefore, despite its improved safety profile, buprenorphine should not be regarded as risk-free. Full article

Background: Allergic rhinitis (AR) is a common inflammatory disorder with an unclear role of lytic cell death (LCD). This study aimed to identify LCD-associated genes associated with AR and investigate their underlying regulatory pathways. Methods: Transcriptomic data from AR patients (GSE19187, GSE206149) were retrieved from public repositories, and LCD-associated genes were collected from the literature. A combination of differential expression analysis, machine learning techniques, validation of expression levels, and ROC curve analysis was employed to screen for biomarkers. These biomarkers were then subjected to comprehensive functional characterization via GSEA, subcellular localization prediction, immune infiltration profiling, construction of molecular regulatory networks, and drug prediction. Finally, clinical relevance was confirmed through expression levels in patient specimens. Results: Two key indicators, ALOX15 and TIMP1, were successfully pinpointed. GSEA revealed significant enrichment of ALOX15 and TIMP1 in several biological processes, specifically chromatin organization, immune system response, and extracellular substance transport. Subcellular distribution studies showed that ALOX15 predominantly localized in the cytosol and plasma membrane, while TIMP1 was mainly detected extracellularly. Immune infiltration studies demonstrated notable modifications in seven immune cell populations, with significant associations with megakaryocyte–erythroid progenitors and conventional dendritic cells. Based on these findings, a regulatory network composed of transcription factors and microRNAs was established, and several potential therapeutic candidates (e.g., quercetin) were identified through prediction. Consistent with predictions, mRNA expression levels of both genes were significantly upregulated in the AR group compared to controls (p < 0.01), confirming reliability. Conclusions: In summary, ALOX15 and TIMP1 were identified as exploratory biomarkers associated with AR, providing preliminary insights into its molecular mechanisms and potential therapeutic implications. Full article

Cisplatin-induced acute kidney injury (AKI) poses a significant clinical challenge lacking specific therapeutic drugs. Arundina graminifolia, a traditional Dai medicine, exhibits notable renoprotective effects; however, its in vivo pharmacodynamic material basis and molecular mechanisms remain unclear. This study aimed to explore its mechanisms against AKI from the perspective of authentic kidney-migrating components. A cisplatin-induced mouse AKI model was established to evaluate the renoprotective effects of the A. graminifolia extract (BYJ) via biochemical markers and histopathology. UPLC-Q-TOF-MS/MS was employed to comparatively analyze the blood and kidney-migrating components between normal and AKI mice. Network pharmacology and molecular docking were subsequently applied to predict and validate the core signaling pathways based on the specific components detected in the injured kidneys. Results showed that BYJ administration significantly ameliorated renal dysfunction, restored antioxidant capacity, and alleviated tubular necrosis. MS analysis identified 93 chemical components in vitro. In vivo tracking revealed a “pathological targeted recruitment” characteristic: only 6 prototype components entered normal kidneys, whereas 16 prototypes penetrated the AKI kidneys, highly enriched in lipophilic flavonoid aglycones such as kaempferol and apigenin. Network pharmacology predicted that these targeted components could potentially interact with 124 key targets (including AKT1, PIK3CA, and EGFR) to putatively exert anti-apoptotic and anti-inflammatory effects via the PI3K-Akt, TNF, and MAPK pathways. Molecular docking confirmed excellent binding affinities between these aglycones and core target proteins (e.g., kaempferol with PIK3CA at −8.9 kcal/mol). Based on actual in vivo distribution, this study reveals the specific accumulation of polyhydroxy flavonoid aglycones in injured kidneys, providing a reliable scientific basis for defining the pharmacodynamic substances of A. graminifolia. Full article