Search Results (296)

Background/Objectives: Metabolically dysregulated-associated steatotic liver disease (MASLD) is a complex, multifactorial disorder characterised by hepatic lipid accumulation, insulin resistance, oxidative stress, and dysfunction of the gut–liver axis. Given its intricate pathophysiology, multi-target nutritional strategies represent a promising complementary approach. This study aimed to evaluate the biological effects of a multi-component nutraceutical formulation using an integrated in vitro platform replicating intestinal, hepatic, and pancreatic–liver interactions. Methods: The formulation was tested on Caco-2 intestinal cells to assess cell viability, transepithelial electrical resistance (TEER), probiotic functional properties, and glucose absorption. Intestinally processed metabolites were then applied to HepaRG liver cells under hyperglycemic (glucose) or lipotoxic conditions (oleic acid/palmitic acid) to analyse lipid accumulation, cholesterol biomarkers (HMGR, LDL), bile acid production, and cellular damage (ALT, AST). Finally, a pancreas–liver co-culture model (EndoC-βH5 and HepaRG) was employed to investigate insulin secretion and downstream hepatic metabolic signalling (IRS1, GLUT2, glycogen). Results: The formulation preserved intestinal barrier integrity and enhanced probiotic functionality, including aggregation and hydrophobicity. In hepatic models, the treatment significantly reduced intracellular lipid accumulation and triglycerides, while increasing bile acid production and improving cholesterol profiles. Under steatotic stress, it lowered transaminase levels and downregulated lipogenic signalling. In the pancreas–liver axis model, the formulation restored glucose-stimulated insulin secretion and improved hepatic metabolic signalling by increasing IRS1 levels and glycogen synthesis, indicating enhanced insulin sensitivity. Conclusions: These findings support the biological plausibility of a multi-target nutraceutical approach for MASLD. The formulation demonstrates coordinated beneficial effects on intestinal barrier function, hepatic lipid management, and glucose metabolism, providing a strong rationale for further clinical investigation. Full article

This study characterized lipid accumulation in force-fed mule duck foie gras (fatty liver) and evaluated its association with hepatic physiological status. Thirty-six healthy male mule ducks (67 ± 2 days of age) were randomly assigned to a control group (CON) or force-fed group (O-F). Serum and liver samples were collected for further analysis on days 6, 12, and 18. Compared with the CON group, force-feeding markedly increased liver weight on days 6, 12, and 18, with average increases of 100 g, 200 g, and 430 g, respectively (p < 0.01). No significant differences were observed in hepatic oxidative stress markers, inflammatory cytokines, and biochemical indicators of liver injury on days 6, 12, and 18 between the control and force-fed groups (p > 0.05). Furthermore, both untargeted lipidomic Orthogonal Partial Least Squares—Discriminant Analysis (OPLS-DA) and targeted fatty acid analysis revealed clear metabolic separation between the two groups on day 18. Compared with CON, total hepatic unsaturated fatty acids increased by 60.7% in O-F ducks on day 18 (p < 0.01), with oleic acid, linoleic acid, α-linolenic acid, and eicosapentaenoic acid increasing by approximately 400%, 100%, 300%, and 35%, respectively (p < 0.01). These results indicate that short-term force-feeding alters the hepatic fatty acid profile through lipid accumulation, while circulating markers of liver injury remain unaffected. Full article

Background: Cigarette smoking is a widely recognized risk factor for several diseases and a crucial problem in global health, as it contributes to the development and worsening of various diseases, resulting in an increase in both morbidity and mortality. One of the strategies to reduce the impact of tobacco damage is based on the transition from flammable to non-flammable nicotine products. Objectives: The aim of this narrative review is to summarize the effects of traditional cigarette smoking and non-combustible nicotine products on kidney function. Conclusions: The evidence shows that both combustible and non-combustible nicotine products have harmful effects on kidney health and may promote the onset and progression of kidney dysfunction, leading to chronic kidney disease (CKD). Full article

Mutator-like elements (MULEs) are a major DNA transposon superfamily. The evolutionary profiles of MULE transposons and their impact on arthropod genomes remain largely unexplored. Here, we define the evolutionary landscape—including distribution, diversity, structure, and activity—of MULE transposons across 4268 assembled arthropod genomes. Systematic analysis reveals a divergent evolutionary profile. From the sampled genomes, 222 arthropod species harbor MULE transposons, comprising 322 distinct elements. Phylogenetic analysis divides arthropod MULE transposons into twelve clades. The majority of species (164) carry only one type of MULE transposon, while 51 species contain two or three types, and a few host multiple types (4–9). Copy numbers vary significantly, ranging from 5 to 88 per species. Structural variation is pronounced: full-length MULEs range from 1.4 kb to 10.0 kb, with most falling between 2.5 kb and 5.0 kb. Low Kimura divergence in several species suggests recent MULE activity, noteworthy because most transposons are expected to be inactive. Collectively, our results show that MULEs are widely distributed yet phylogenetically structured across arthropods, with lineage-specific expansions and recent activity in several species. Full article

Background: Dalbavancin (DBV) is a long-acting lipoglycopeptide with activity against Gram-positive pathogens approved for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Its pharmacological profile supports use in infections requiring prolonged therapy, yet its role in osteomyelitis without implantable devices (OM-WoID) remains off-label. This study aims to describe real-world DBV use in a large tertiary care hospital, focusing on its effectiveness in OM-WoID. Methods: This is a monocentric, retrospective analysis including all patients receiving DBV at ASST Spedali Civili di Brescia, Italy, from April 2017 to July 2023. The statistical analysis focused on patients who received DBV for either ABSSSI or OM-WoID, with the latter transitioning to DBV after traditional daily intravenous therapy. Clinical, microbiological, and treatment data were extracted from electronic records and stored in REDCap. Effectiveness was defined as infection resolution or improvement; treatment failure encompassed clinical worsening, recurrence or suppressive therapy. Predictors of failure were identified through univariate and stepwise multivariate logistic regression. Results: During the study period, 157 patients (63.0% male; mean age 62.5 ± 20 years) received at least one dose of DBV, predominantly for off-label indications (66.2%). Early discharge was the most common reason for switching to DBV (66.3%). Focusing specifically on patients treated for ABSSSI (53) and OM-WoID (43), treatment success was achieved in 81.1% of ABSSSI and 90.7% of OM-WoID cases. In the stepwise multivariate logistic regression, older age was independently associated with an increased risk of treatment failure (OR 1.07, 95% CI 1.01–1.13; p = 0.028), while the presence of multimorbidity significantly reduced the risk (OR 0.07, 95% CI 0.01–0.77; p = 0.029). Discussion: Our study offers a comprehensive real-world analysis of DBV use in both approved and off-label indications. Although current clinical experience with DBV remains limited, DBV emerges as a valuable step-down option for the management of invasive Gram-positive infections in our setting. Consistent with previous evidence, older age independently increased the risk of treatment failure, whereas multimorbidity appeared protective, likely due to selection bias and the more intensive monitoring, earlier interventions, and tailored management such patients often receive. Our results support a broader range of approved indications for DBV to allow earlier discharge and more efficient use of healthcare resources. Full article

Treating autosomal dominant polycystic kidney disease (ADPKD) has always been a challenge because the disease is too complex for single-target drugs, which are often held back by side effects. This narrative review explores a different strategy: using plant-derived polyphenols to target multiple disease pathways at the same time. Looking at research from 2005 to 2026, we break down how key compounds like resveratrol, curcumin, naringenin, quercetin, and epigallocatechin-3-gallate (EGCG) actually work. Preclinical studies show these molecules can slow down cyst growth by tackling inflammation, rapid cell division, and tissue scarring all at once, while also resetting the skewed energy metabolism of cystic cells. Some mechanisms are strikingly specific, such as naringenin’s direct interaction with polycystin-2 and quercetin’s ability to clear senescent cells. Yet, the real-world hurdle is poor absorption; a recent clinical trial with standard curcumin fell short simply because the compound could not reach the kidneys in high enough concentrations. Moving forward, the field needs to focus on testing these compounds in realistic animal models, designing smart nanoformulations to improve bioavailability, and exploring combinations that could safely complement current therapies like tolvaptan. Full article

Background/Objectives: Skeletal muscle adaptation to metabolic stress involves a coordinated regulation of inflammatory, bioenergetic, and anabolic signalling pathways. This study aimed to investigate the potential role of whey protein isolate (WPI; commercial name: Volapure) as a modulator of cellular responses to stress in an in vitro model of exercise-mimetic stress over time. Methods: Murine C2C12-differentiated cells were exposed to an Exercise–Mimetic Mix (ExM) to reproduce key biochemical features of muscle stress. Cells were treated with WPI (1 mg/mL) using Pre-exposure (Pre-ExM) and Post-exposure (Post-ExM) protocols at 8 and 24 h. Multiple endpoints were assessed, including cell viability, reactive oxygen species (ROS) production, cytokine release (TNF-α, IL-6, IL-17), intracellular signalling pathways (p38 MAPK, ERK, AMPK, mTOR), bioenergetic markers (ATP, glycogen, lactate), protein synthesis (OPP incorporation), and Ca²⁺/Mg²⁺ fluxes. Results: ExM exposure induced a stress phenotype characterised by increased oxidative and inflammatory markers, impaired bioenergetic status, and reduced anabolic signalling. WPI was associated with modulation of these responses, reducing ROS and pro-inflammatory cytokines, restoring ATP and glycogen levels, and changes in ERK and mTOR-related signalling. The Post-ExM protocol showed greater modulation compared to the Pre-ExM approach, particularly at 24 h. WPI was also associated with the normalisation of ExM-altered Ca²⁺/Mg²⁺ fluxes. These findings should be interpreted as associative rather than causal. Conclusions: WPI was associated with modulation of key pathways involved in cellular adaptation to metabolic stress, supporting recovery of bioenergetic balance and anabolic signalling in C2C12 cells. These findings suggest a potential role for WPI in influencing cellular responses to metabolic stress, supporting recovery of bioenergetic balance and anabolic signalling in C2C12-differentiated-cells. However, further studies are required to confirm the translational relevance of these observations. Full article

The FAR-RED IMPAIRED RESPONSE 1 (FAR1) and FAR-RED ELONGATED HYPOCOTYL 3 (FHY3) transcription factors, together with other members of the FAR1-RELATED SEQUENCE (FRS) and FRS-RELATED FACTOR (FRF) families, represent a striking example of transposable element domestication in plants. Derived from ancient Mutator-like element (MULE) transposases, these proteins have been repurposed as transcriptional regulators throughout the plant kingdom. FHY3 and FAR1 were first identified in Arabidopsis thaliana as positive regulators of phytochrome A (phyA) signaling. They participate in the coordination of light signaling with the circadian clock, chlorophyll biosynthesis, hormone pathways, stress responses, flowering time, shoot branching, leaf senescence, seed dormancy, and phosphate homeostasis. At the molecular level, FHY3 and FAR1 regulate gene expression mainly by binding to the conserved FHY3/FAR1-binding site, FBS, with the sequence CACGCGC, in the promoters of target genes. They also act through protein interactions with key signaling regulators, including HY5, PIFs, EIN3, TOC1, and SPL transcription factors. In this review, we summarize the molecular basis of FHY3/FAR1 gene family function, discuss the roles and mutant phenotypes of characterized family members, and highlight recent advances from other plant species beyond Arabidopsis. Collectively, this gene family illustrates how domesticated transposase-derived proteins have evolved into key regulators of plant development and environmental adaptation. Full article

Research on mule and donkey muscle composition remains limited despite their global importance as working equids. The objective of this study is to identify Mammoth donkey jacks with higher percentage of fast twitch fibers for racing mule production. A total of 33 animals were biopsied; however, only 12 samples were suitable for analysis, including racing mules (n = 7) and male Mammoth donkeys (n = 5). Animals were sedated with detomidine (10 µg/kg body weight) and butorphanol (20 µg/kg body weight). Middle gluteal muscle biopsies were collected using a 6 mm Bergström biopsy needle at a site located 20 cm dorsocaudal to the tuber coxae at a 45° angle to the base of the tail. Collection depth was 7.5 cm in adult mules and 5 cm in donkeys. Samples were prepared aseptically, anesthetized subcutaneously with lidocaine hydrochloride, and frozen in liquid nitrogen. Histochemical analysis included myosin adenosine triphosphatase (ATPase) staining at pH 9.5, 4.6, and 4.3. Fibers were classified as Type I, Type IIA, or Type IIB, and CSA measurements were obtained using NIH ImageJ software. Statistical analysis included group contrasts, summarized as mean ± SD with 95% confidence intervals, while Bayesian ANOVA outputs were presented as exploratory evidence summaries. Type IIA fibers were greater in mules (47.84 ± 7.30%) than donkeys (38.47 ± 4.48%). Results suggest that differences in equid muscle architecture may be associated with variation in Type IIA fiber composition related to work or use. Full article

Background/Objectives: Cervical and lumbar radiculopathy and carpal tunnel syndrome (CTS) are common conditions that are associated with persistent pain, functional impairment, and reduced quality of life. Nutraceutical strategies targeting neuroinflammatory and oxidative stress pathways are being investigated as adjunctive approaches in pain management. This study evaluated the clinical association between supplementation with a Gastrodiae elata Blume-based nutraceutical formulation (Assonal^®) and changes in pain intensity, functional outcomes, symptom burden, and quality of life in patients with radiculopathy and CTS. Methods: A single-centre pragmatic before–after clinical study enrolled adults with cervical or lumbar radiculopathy and/or CTS. Participants received Assonal^® (two tablets daily) for two months. Pain intensity was assessed using the Numerical Pain Rating Scale (NPRS) and Visual Analogue Scale (VAS). Secondary outcomes included the Back Pain Functional Scale (BPFS), the Boston Carpal Tunnel Questionnaire (BCTQ), the Neuropathic Pain Symptom Inventory (NPSI), the EuroQol-5D-5L (EQ-5D-5L), and the Global Perceived Effect (GPE). Longitudinal within-subject changes were analysed using repeated-measures statistical tests. Results: Thirty-four participants completed the study. The observed pain intensity decreased significantly from baseline to two months (NPRS: 7.2 ± 1.3 to 3.6 ± 1.2; VAS: 7.3 ± 2.1 to 3.3 ± 1.7; p < 0.0001) and functional measures showed improvements across BPFS and BCTQ assessments, accompanied by reductions in symptom burden (NPSI). Quality of life increased significantly (EQ-5D-5L index: 0.49 ± 0.23 to 0.81 ± 0.12; p < 0.0001), and most patients reported perceived clinical improvement. Conclusions: In this exploratory real-world study, Assonal^® supplementation was associated with clinically relevant improvements in pain intensity, functional performance, and quality of life in patients with radiculopathy and CTS, suggesting the need for further investigation of these associations in future controlled clinical studies. Full article

The progressive aging of the atrial fibrillation (AF) population, frequently characterized by high ischemic and bleeding risks, has led to a substantial increase in referrals for left atrial appendage occlusion (LAAO). The expansion of indications and the high procedural success rate of LAAO have further contributed to rising procedural volumes. However, this growth introduces important challenges: LAAO candidates are often elderly and frail, with increased anesthesia-related risks, and high-volume catheterization laboratories may face logistical constraints, particularly in centers without dedicated anesthesiology support. The current gold standard approach, transesophageal echocardiography (TEE) under general anesthesia (GA), ensures optimal imaging and procedural control but may increase procedural complexity and perioperative risks. In response, minimalist strategies are increasingly explored, targeting either the anesthetic protocol or the imaging modality. Conscious sedation (CS) protocols have been adopted to reduce anesthesia-related burden while maintaining TEE guidance. Alternatively, imaging-based strategies aim to replace TEE with less invasive modalities, including intracardiac echocardiography (ICE), transesophageal–intracardiac echocardiography (TE-ICE), and MicroTEE. Each approach presents specific advantages and limitations regarding safety, feasibility, operator expertise, and institutional resources. Taken together, these findings support a patient-centered approach to LAAO, whether traditional or minimalist, in which the choice of anesthetic strategy and echocardiographic guidance is driven by institutional resources, operator expertise, and individual patient characteristics rather than by expected differences in procedural or clinical efficacy. This review summarizes current evidence on minimalist LAAO pathways and discusses their role in achieving a tailored, resource-conscious procedural model. Full article

Background/Objectives: Glucagon-like peptide-1 (GLP-1) is a nutritionally regulated incretin involved in the coordination of intestinal, hepatic, and adipose metabolic responses. Although plant-derived extracts are increasingly investigated for their metabolic effects, mechanistic evidence integrating multiple metabolic tissues remains limited. This study aimed to investigate the molecular effects of a combination of plant-derived extracts in an integrated in vitro gut–liver–adipose model. Methods: Differentiated Caco-2 monolayers were exposed to a standardised combination of plant-derived extracts obtained from Gastrodia elata, Morus alba, and Paeonia lactiflora. GLP-1 secretion and epithelial barrier integrity were assessed. Conditioned media from intestinal cells were applied to HepG2 hepatocytes, and downstream effects on lipid metabolism-related pathways were evaluated. Subsequently, conditioned media from hepatic cells were applied to differentiated 3T3-L1 adipocytes to assess lipid accumulation and metabolic signalling. Results: Exposure of intestinal cells to the extract combination significantly increased GLP-1 secretion without altering epithelial barrier integrity. Intestinal conditioned media were associated with reductions in intracellular triglyceride levels in hepatocytes and with modulation of markers linked to lipid handling, including resistin, FGF21, SREBP-1c, NRF2, Src, AMPK, SIRT1, and PGC1α, suggesting GLP-1-associated effects. In adipocytes, hepatic conditioned media decreased lipid accumulation and increased the levels of metabolic markers associated with adipocyte browning-related signalling, including UCP1, NOS, SIRT1, and STAT3. Conclusions: Within the limitations of this in vitro multi-organ model, these findings suggest that the tested combination of plant-derived extracts modulates cellular pathways related to GLP-1-associated metabolic signalling across intestinal, hepatic, and adipose systems. These results should be interpreted as mechanistic and hypothesis-generating, and further in vivo and clinical studies are required to confirm their physiological relevance. Full article

Background/Objectives: Natural multi-component nutraceutical formulations may modulate interconnected pathways involved in metabolic and bone health. This study evaluated, using in vitro models, the effects of a standardized botanical–vitamin formulation on intestinal barrier integrity, osteoblastic activity, and osteoclast differentiation, focusing on intestinal-bone crosstalk, redox-inflammatory signalling, and potential synergistic interactions among components. Methods: A combined in vitro approach using intestinal, osteoblastic, and osteoclastic cell models was applied to assess a formulation containing characterized plant extracts and vitamin D₃. The study evaluated cytocompatibility, intestinal barrier function, cellular uptake, and the modulation of markers related to osteogenesis and osteoclastogenesis, using biochemical, molecular, and enzymatic assays, as well as oxidative stress measurements and synergy analysis. Results: The formulation maintained intestinal barrier integrity and bioavailability without cytotoxicity, promoted osteoblastic differentiation and reduced oxidative stress, while inhibiting osteoclast differentiation and resorptive activity. These effects were associated with modulation of inflammatory and redox-related signalling pathways and showed additive to synergistic interactions among components. Conclusions: These findings support a multi-target nutraceutical approach that can concurrently influence intestinal barrier and bone remodelling in vitro, offering mechanistic evidence for its role in modulating the gut–bone axis, and highlight the need for further studies in advanced models and clinical trials. Full article

This paper examines how scam compounds, money mules and crypto-assets operate as interdependent elements of contemporary money-laundering chains. It assesses whether existing anti-money laundering (AML) and crypto-asset regulatory frameworks are capable of disrupting these chains holistically, rather than addressing individual components in isolation, with particular reference to scam-compound activity in Southeast Asia. The study adopts a qualitative comparative case-study methodology grounded in legal and regulatory analysis. Four empirically grounded cases are examined: two Southeast Asian scam-compound enforcement cases (Cambodia and Myanmar) and two European crypto-asset seizure cases (Ireland and Italy). Judicial decisions, enforcement actions and regulatory instruments are analysed through a chain-based analytical framework aligned with Financial Action Task Force (FATF) standards, the EU Markets in Crypto-Assets Regulation (MiCA) and the Anti-Money Laundering Authority (AMLA) framework. The analysis reveals a structural divergence in enforcement strategies: Southeast Asian responses increasingly prioritise network- and infrastructure-level disruption of scam compounds, whereas European approaches remain largely centred on post-offence crypto-asset seizure through traditional proceeds-of-crime mechanisms. Across all jurisdictions, money mules emerge as a critical yet systematically under-regulated intermediary layer enabling the resilience of crypto-laundering operations. The paper advances existing AML typologies by conceptualising scam compounds, money mules and crypto-assets as interconnected components of a single crypto-laundering chain. This chain-based perspective offers a novel analytical and regulatory lens for understanding organised crypto-enabled fraud. The study is based on a qualitative, case-based design and does not aim for statistical generalisation. However, the analytical framework developed is transferable to other jurisdictions experiencing similar scam-compound and crypto-laundering dynamics. The findings suggest that effective AML enforcement requires coordinated intervention across multiple nodes of the laundering chain, including scam compound infrastructure and money mule networks, alongside traditional asset-seizure mechanisms and CASP supervision. By highlighting the structural links between scam compounds, coercive labour and crypto-laundering mechanisms, the paper underscores the broader social harms of crypto-enabled fraud and the need for integrated regulatory responses that address both financial crime and human exploitation. Full article

Digital mining has become a tangible reality in recent years and the digital revolution enables and requires data exchange for autonomous machines and operational flow management. LoRa technology and its underground propagation behavior can make an important contribution to this digitalization. This paper presents a Data Mule approach that enabled progress in digitalization at refueling stations in active underground mining areas of a mine near Werra, Germany, operated by the K+S Group. This demonstration aimed to automate manual data collection at fuel gauges by using a dynamic LoRa network. We used specially developed LoRa Data Mule modules for operations over many square kilometers. LoRa was chosen for its industrial functionality and long-range capabilities, particularly in underground environments. The Data Mule modules used were in-house-designed units with underground mining-rated casing and connectors, as well as commercial LoRa boards and custom communication protocols. Connectivity between all systems was realized at travel speeds of 20 to 40 km/h, with connection data successfully relayed for 180 to 770 m, despite 90° turns and no line of sight. It was shown that the LoRa Data Mule approach can be used in a network of remote but active data generation points. Full article