Search Results (4,802)

Background/Objectives: Calcium hydroxyapatite (CaHA)-based injectable materials are widely used as dermal biostimulators. In vitro models allow for controlled comparison of cellular responses and particle characteristics across formulations. This study aimed to compare two commercially available CaHA-based materials in terms of fibroblast metabolic activity, extracellular matrix-related gene expression, and microsphere morphology. Methods: Primary human dermal fibroblasts were exposed to two CaHA-based materials (Sample R and Sample S) at 10 mg/mL. Metabolic activity was assessed using the MTT assay at 24, 36, 48, and 72 h. Type I collagen and elastin gene expression were evaluated by RT-qPCR at 72 h. Microsphere morphology was analyzed by scanning electron microscopy (SEM). Results: Both materials increased fibroblast metabolic activity compared with the control at all time points. Early responses were similar, whereas Sample S showed higher activity at 48 and 72 h. At 72 h, both materials increased collagen and elastin gene expression versus the control, with greater responses observed for Sample S. SEM analysis showed predominantly spherical microspheres in both materials, with qualitative differences in surface microtopography. Conclusions: Under controlled in vitro conditions, both CaHA-based materials were biocompatible and modulated fibroblast metabolic activity and extracellular matrix-related gene expression. Differences in particle surface characteristics may contribute to the observed biological profiles. These findings support further studies incorporating extended incubation periods and protein-level analyses. Full article

The safety profile for bio-derived phenols post-oxidation and their related antioxidant/redox potential remain largely under-explored. Oxidation by fungi, in terms of environmental impacts via fungal oxidation by enzymes, remains an attractive strategy under milder conditions, since it is one route by which many naturally occurring lignocellulosic phenols are modified; thus, an immediate need still exists for characterizing the effects that these modified phenolic compounds may have. Methodology: We examined four different biomass-derived phenolics—vanillin, ferulic acid, syringaldehyde and guaiacol—that were oxidized with fungal laccase and characterized their effects on normal human lung fibroblasts and levels of cellular oxidative stress. Laccase activity was evaluated via the ABTS method and through simple observation and UV-Vis spectroscopic scanning of the phenolics in question, and compared with the untreated version of each phenolic. In addition to assessing the cytotoxic effect and oxidative stress generated by the phenols alone, an ELISA-based measurement assay was used to investigate the relative abundance of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH) in the human normal lung fibroblast cell line under varying treatment regimes, complemented by phase-contrast microscopy. Scores integrating the biomarkers were analyzed via clustering, PCA, radar and Pearson correlation analyses, to discern distinct trends in antioxidant potential after laccase conversion. Observations: Each of the four tested phenolics demonstrated the presence of laccase activity, leading to substantial differences in visible appearance compared with the control and characteristic absorbance shifts at differing wavelengths from the original molecule. Cell viability dropped dramatically as phenol concentration was increased and the untreated phenolics resulted in diminished confluence and induced greater levels of oxidative damage, from guaiacol and syringaldehyde. Laccase treatment resulted in higher MTT reduction activity and improved cellular morphology compared with the corresponding untreated phenolic compounds. Untreated phenols induced the highest levels of MDA, while decreasing SOD, CAT, GPx and GSH levels. Post-oxidation with laccase, there were lower amounts of lipid peroxidation, along with improved levels of antioxidant activity compared with the control phenol. Multi-technique analyses show clear distinctness between the untreated and laccase-converted phenolic groups. Clustering with multivariate techniques separated all cell groups in line with control samples, grouping the laccase-converted treatments towards the middle and displaying an inverse relationship between MDA and the antioxidant markers. Conclusions: Laccase conversion markedly decreases the adverse effects that bio-derived phenols have on normal cell viability and induces fewer detrimental effects on the cellular redox balance. This is a critical discovery in terms of finding greener methods by which to upgrade bio-derived substances as we research these lignocellulosic phenols. By employing ELISA-based measurements along with multiple analysis techniques, we present a suitable paradigm for studying biological effects in all bio-based goods intended for pharmaceuticals, packaging materials, nutraceuticals or a host of different applications. Full article

Background/Objectives: Autophagy is a key degradative pathway involved in orthodontic tooth movement. DNA damage-regulated autophagy modulator 1 (DRAM1), a protein that plays a central role in the degradation of autophagic cargo, exhibits differential regulation in human periodontal ligament (hPDL) fibroblasts under compressive force. Single-nucleotide polymorphisms (SNPs) may influence force-induced gene expression. Therefore, this study investigated the impact of DRAM1 SNPs on its expression in hPDL fibroblasts under compression force. Methods: The hPDL sample comprised cells of 59 patients. A physiological compressive strain of 2 g/cm³ was used to simulate orthodontic tooth movement. Total RNA from hPDL fibroblasts was isolated to determine DRAM1 relative gene expression under loaded conditions and in a physiological control. Furthermore, a genotyping analysis of six SNPs within the DRAM1 gene (rs756534 (G/T), rs2138257 (C/T), rs2176092 (C/T), rs4622329 (A/G), rs10860812 (A/G), and rs4764657 (A/G)) was performed using real-time polymerase chain reaction. DRAM1 expression was com-pared among genotypes of each SNP using an alpha of 5%. Linear regression analysis was then employed to evaluate SNP-SNP interaction. Results: The relative DRAM1 gene expression was not statistically significantly different (p > 0.05) according to the geno-types. The SNP-SNP interaction did not demonstrate any statistically significant associ-ation either. Conclusions: DRAM1 gene expression in hPDL fibroblasts under orthodontic compression may not be regulated by the studied intronic SNPs in the gene encoding DRAM1. Full article

Background/Objectives: Schistosomiasis, a parasitic disease caused by Schistosoma worms with freshwater snails as intermediate hosts, affects over 250 million people. The current control relies solely on praziquantel, which raises concerns on drug resistance and highlights the need for new therapeutic alternatives. Our bioprospection studies have focused on marine macroalgae as an unexplored source of antischistosomal metabolites with promising results. Guided by WHO recommendations to target both the parasite and its transmission vectors, this study aimed to investigate Ochtodes secundiramea to: (i) isolate active metabolites; (ii) evaluate the isolated compounds against adult worms and oviposition to identify leads for drug development; and (iii) perform an independent screening of their effects against the environmental transmission stages on cercariae and B. glabrata embryos. Methods: A dichloromethane extract of O. secundiramea was submitted to an NMR–biomonitored guided fractionation against Schistosoma mansoni adult worms. Active fractions were further purified through HPLC and characterized by ¹H and ¹³C NMR spectroscopy to identify the isolated compounds. Results: Three halogenated monoterpenes were isolated: ochtodene 1 (4-bromo-1,6,8-trichloro-2,3-ochtodene), ochtodene 2 (2-chloro-1,6,8-tribromo-3,8-ochtodene), and the novel natural product ochtodene 3 [2,6-dibromo-4-(2-chloroethylidene)-1,1dimethylcyclohexane]. Ochtodene 1 was the primary active metabolite against Schistosoma mansoni adult worms, with IC₅₀/96 h values of 47.2 and 46.1 µM for male and female worms respectively, and totally suppressed egg laying with 60 µM, while showing no toxicity toward human fibroblasts. Notably, all metabolites, including the novel ochtodene 3, caused 100% mortality in cercariae and embryos at low concentrations. Conclusions: The discovery of the novel ochtodene 3 and the identification of distinct leads for host treatment and transmission elimination position O. secundiramea as a promising source for integrated schistosomiasis control. Full article

Background/Objectives: Peri-implant diseases, encompassing peri-implant mucositis and peri-implantitis, affect 43% and 18.8–23% of implant-bearing patients, respectively, representing significant clinical challenges in implant dentistry. While mechanical debridement remains foundational, biologically active materials offer promising adjunctive regenerative strategies. This narrative review synthesises current evidence regarding five biologically active materials: enamel matrix derivative (EMD), platelet-rich fibrin (PRF), fibroblast growth factor-2 (FGF-2), recombinant human platelet-derived growth factor-BB (rhPDGF-BB/GEM 21S^®), and polynucleotide–hyaluronic acid combinations (Regenfast^®). Methods: The relevant literature was identified using electronic databases, including MEDLINE, PubMed, Scopus, and Google Scholar. This review focused on clinical studies and randomised controlled trials with a minimum follow-up of six months investigating biologically active materials in peri-implant disease management. Material mechanisms, clinical efficacy, therapeutic limitations, and evidence quality were systematically evaluated. Attention was directed toward identifying genuine biological distinctions between peri-implant and periodontal disease contexts. Results: EMD demonstrates efficacy exclusively within multimodal surgical protocols, with isolated application yielding limited benefits. rhPDGF-BB shows superior periodontal regenerative capacity; however, dedicated peri-implantitis trials remain absent. FGF-2 exhibits paradoxical osteogenic suppression despite bone fill achievement, limiting peri-implant applicability. PRF and Regenfast^® demonstrate a mechanistically sound rationale yet lack substantive peri-implant disease validation. The critical findings revealed that peri-implant regeneration fundamentally differs from periodontal regeneration: implants lack periodontal ligament anatomy, rendering ligamentogenic differentiation-promoting agents biologically inappropriate. Conclusions: Contemporary biologically active materials demonstrate compelling periodontal efficacy yet remain inadequately validated for peri-implantitis management. This disparity reflects authentic biological distinctions rather than insufficient investigation. Until multicentre randomised controlled trials stratify efficacy across distinct peri-implant disease presentations, practitioners must prioritise evidence-based surgical fundamentals—meticulous decontamination, strategic grafting, and optimised wound healing—integrating biologically active materials judiciously within comprehensive, anatomy-respecting treatment protocols. Full article

Background: Solriamfetol, a dopamine and norepinephrine reuptake inhibitor widely used in narcolepsy management, has not been thoroughly investigated for its anti-fibrotic and anti-inflammatory properties. Herein, we investigated its potential therapeutic applications and underlying mechanisms in both cellular and murine models of pulmonary fibrosis. Methods: To induce fibrosis, C57BL/6 male mice (six-week-old) were administered bleomycin via the intratracheal route. These animals subsequently received solriamfetol orally once per day at dosages of 3 or 10 mg/kg. Histological and immunohistochemical techniques were employed to evaluate inflammatory cell infiltration, collagen accumulation, and α-smooth muscle actin (α-SMA) expression in bronchoalveolar lavage samples and lung tissue sections. Cytokine levels were measured by ELISA, and gene/protein expression of pro-fibrotic markers, A_2A/A_2B adenosine receptors (ARs), adenylate cyclases (ACs), Epac, K_Ca3.1, and adenosine deaminase (ADA) were assessed via quantitative PCR and Western blot. Electrophysiological recordings evaluated K_Ca3.1 channel activity. Purified ADA and normal human lung fibroblasts (NHLFs) were treated with solriamfetol to assess effects on ADA activity and levels of cAMP and adenosine, respectively. Results: Solriamfetol significantly reduced inflammatory cell infiltration, collagen accumulation, and α-SMA expression in fibrotic lungs. Solriamfetol restored downregulated A_2AAR, A_2BAR, ACs, and Epac, while suppressing ADA expression and activity, resulting in elevated extracellular adenosine and intracellular cAMP. The intervention potentiated Epac signaling and inhibited fibroblast activation. Solriamfetol inhibited the K_Ca3.1 current in fibroblasts and reduced K_Ca3.1 protein expression levels in TGFβ-treated fibroblasts and lung tissues from bleomycin-challenged mice. Notably, these effects were abolished by A_2AAR or A_2BAR antagonists, implying that they occur through AR-mediated pathways. Conclusions: Solriamfetol inhibits ADA and reinforces adenosine–cAMP signaling, suppressing pathological fibroblast activation. These findings suggest its therapeutic utility as a novel anti-fibrotic compound for various fibrotic diseases, including pulmonary fibrosis. Full article

Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is strongly associated with atrial structural remodeling driven by activated cardiac fibroblasts. Autophagy has been implicated in AF-related atrial remodeling; however, the non-coding RNA mechanisms that govern autophagic activation in atrial fibroblasts under rapid electrical stress remain poorly understood. Methods: Human cardiac fibroblasts from adult atria (HCF-aa) were subjected to rapid electrical stimulation (RES) at 0.5 V/cm and 10 Hz. Expression levels of exosomal metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), cytoplasmic miR-204-5p, and microtubule-associated protein light chain 3B (LC3B) were measured using quantitative real-time PCR and Western blot analyses. Luciferase reporter assays were performed to confirm direct molecular interactions. The functional roles of MALAT1 siRNA, miR-204-5p mimics/antagomirs, rapamycin, and 3-methyladenine (3-MA) on LC3B expression and autophagic activation were assessed by Western blot and immunofluorescence confocal microscopy for LC3B puncta formation. Results: RES significantly induced exosomal MALAT1 expression in a voltage- and time-dependent manner, peaking at 2 h post-stimulation, while cytoplasmic MALAT1 levels remained unchanged. Cytoplasmic miR-204-5p exhibited an initial transient rise followed by a significant decline at 2 h, inversely correlating with peak MALAT1 levels. LC3B mRNA and protein expression subsequently increased, peaking at 6 and 16 h, respectively. Luciferase reporter assays confirmed that miR-204-5p directly binds both the MALAT1 transcript and the 3′-UTR of LC3B mRNA. MALAT1 knockdown augmented miR-204-5p levels and suppressed LC3B expression, while miR-204-5p overexpression attenuated RES-induced LC3B upregulation and LC3B puncta accumulation. Conversely, miR-204-5p inhibition further enhanced autophagic activation, as evidenced by increased LC3B puncta density. Conclusions: In HCF-aa subjected to RES, MALAT1 functions intracellularly as a competing endogenous RNA to putatively sequester miR-204-5p, thereby de-repressing LC3B expression and promoting autophagic activation. Concurrent exosomal secretion of MALAT1 may additionally serve as a paracrine signal to neighboring cells, though this requires future conditioned-media transfer experiments to confirm. Full article

Type XVII collagen (COL17) is crucial for skin integrity but difficult to produce. To achieve high-level secretory expression, a human COL17 segment was designed and cloned into the pPIC9K vector with six different α-mating factor signal peptides and integrated into Komagataella phaffii GS115. Fed-batch fermentation in a 5 L bioreactor yielded 4.7 g/L of recombinant COL17. Functional assays showed that it promoted the proliferation of human skin fibroblast (HFF) and immortalized keratinocytes (HaCaT), upregulated COL1A1, COL3A1, and TIMP1 in HFF cells, and enhanced skin barrier-related genes (KRT1, KRT5, KRT10, KRT14, IVL, LOR, FLG) in HaCaT cells. In a UVB-induced photoaging model, COL17 reduced reactive oxygen species (ROS) and matrix metalloproteinase 3 (MMP3) activity. This recombinant collagen exhibits photoprotective, regenerative, and barrier-enhancing activities, offering potential for skincare and tissue engineering. Full article

Sponge spicules have emerged as promising biomaterial scaffolds due to their biocompatibility and unique structural properties; however, achieving stable and bioactive functionalization remains a key challenge. The tripeptide GHK is known to promote collagen synthesis and wound repair, yet its therapeutic efficacy is often limited by rapid diffusion and instability. Here, we report ALTUM, a thiol-functionalized sponge spicule composite in which GHK is covalently conjugated via disulfide linkage to enable controlled and redox-responsive peptide delivery. ALTUM exhibited sustained GHK retention under physiological and storage conditions, while exposure to reduced glutathione (GSH) selectively accelerated peptide release through disulfide bond cleavage. This dual release behavior—long-term stability combined with reduction-triggered activation—distinguishes ALTUM from conventional delivery systems. The composite also demonstrated structural stability under thermal, cyclic, and photostability conditions. In an artificial human skin model, ALTUM enhanced dermal penetration of GHK and significantly increased collagen deposition in the dermal layer, demonstrating its capacity to promote collagen production within deeper skin tissue, compared to simple spicule–peptide mixtures. ALTUM was fabricated at an optimized spicule-to-peptide ratio of 3% (w/w), preserving the needle-shaped spicule morphology after surface modification. In vitro, ALTUM exhibited a sustained release profile, with GHK release markedly accelerated in the presence of 10 mM glutathione (GSH) compared with non-reductive conditions, reaching approximately 60% cumulative release over 35 days. In the bioprinted artificial human skin model, ALTUM delivered 9.72 ng/cm² of GHK, more than five-fold higher than the physical mixture of spicules and free GHK (1.9 ng/cm²), and significantly increased type I collagen expression in human dermal fibroblasts. Mechanistically, ALTUM-mediated delivery was associated with increased TGF-β expression and engagement of the SMAD signaling pathway, as indicated by increased phosphorylation of SMAD2/3, consistent with involvement of the TGF-β–SMAD axis in the observed collagen induction. Collectively, these findings establish ALTUM as a structurally stable, redox-responsive dermal delivery platform that enhances collagen synthesis and skin regeneration. Full article

Melittin (Mel) is a membrane-active peptide with potential anticancer activity, but its direct therapeutic application may be limited by nonspecific toxicity and delivery-related challenges. The study aimed to assess melittin-functionalized magnetic nanoparticles (MNPs-Mel) as a strategy to enhance antitumor activity in Caco-2 cells, with/without magnetic hyperthermia (MH) association. BJ fibroblasts were used as a normal human in vitro cellular model. The effects of free Mel (2.5 µg/mL), MNPs, and MNPs-Mel (50 µg/mL both) + MH (30 min at 355 kHz and 25 kA/m) were assessed using colorimetry (for viability), luminescence (ATP), and spectrophotometry (lactate) following different exposure conditions. The mechanism of apoptosis induction was evaluated by ELISA (caspase 8 and 9 levels). Transmission electron microscopy (TEM) was also used to evaluate nanoparticle morphology and treatment-associated cellular ultrastructural changes. Free Mel reduced viability in both cell lines, with Caco-2 cells showing greater sensitivity at lower concentrations. MNPs (with/without MH) produced limited and less consistent effects, whereas MNPs-Mel significantly reduced Caco-2 viability and ATP levels and increased LDH and caspase 9. MH further enhanced the effects of MNPs-Mel: reduced viability (57–58% of the control at 24 h and 72 h), decreased ATP levels (67% of the control at 24 h and 53% at 72 h), increased LDH levels (206% of the control at 24 h and 301% at 72 h), and induced the mitochondrial apoptotic pathway (caspase 9 increased with 2164% of the control at 72 h). TEM proved the internalization of both MNPs and MNPs-Mel and revealed extensive ultrastructural alterations concerning mitochondria and lysosomes produced by MNPs-Mel, particularly in the Caco-2 cells. These modifications were heavily increased by MNPs-Mel + MH exposure. Overall, these findings demonstrate that Mel functionalization increases the antitumor activity of Mel at lower doses and that MH further potentiates this effect in Caco-2 cells. Full article

The skin serves as the body’s first line of defense against environmental threats, acting as a barrier between external aggressors and internal systems. Current evidence regarding the roles of sulfur dioxide (SO₂) in biology and medicine is limited. Environmental pollutants, including SO₂, can increase the production of reactive oxygen species in the skin, leading to oxidative damage that may worsen various dermatological conditions. Endogenous SO₂, proposed as the fourth member of the gasotransmitter family, functions as a biological signaling molecule. It is generated in various human skin cells, including vascular smooth muscle cells, endothelial cells, mast cells, keratinocytes, macrophages, adipocytes, fibroblasts, dermal immune cell population, etc, where it performs multiple functions at physiologically relevant concentrations. Endogenous SO₂ plays a crucial role in regulating cell signaling and maintaining skin homeostasis through its antioxidant, anti-inflammatory, and cytoprotective effects. Abnormal generation and metabolism of SO₂ are linked to several critical processes in the skin, including vascular biology, immune response, cell proliferation, pigmentation, malignancy, protective barriers, senescence, and resistance to stress. This paper provides a narrative review of the significant roles of SO₂ in skin health and disease. A comprehensive understanding of the complex molecular effects and mechanisms mediated by SO₂ in human skin, along with the development of gas therapy, will be essential for translating fundamental research into clinical applications. Full article

UVA radiation affects communication between the cells that create the human skin. To prevent UVA-induced damage, there is a constant search for compounds protecting all skin cells and homeostasis in their communication. Therefore, the aim of this study was to evaluate the effect of 24 h incubation with 3-O-ethyl ascorbic acid (EAA; 150 µM) on the intracellular proteome of co-cultured keratinocytes and fibroblasts after UVA irradiation (total dose 15 J/cm²), and on the protein profiles released into the medium by both cell types. A proteomic approach (nanoHPLC/QOrbiTrap) allowed the identification of proteins significantly modified by UVA and EAA. In keratinocytes, UVA radiation enhanced expression of pro-inflammatory and pro-proliferative/keratinizing proteins and decreased expression of antiapoptotic and antioxidant proteins, while in fibroblasts, UVA radiation induced expression mainly of pro-inflammatory proteins, simultaneously decreasing levels of proteins involved in the antioxidant response and growth factors. Increased pro-inflammatory protein and decreased growth factor levels were also observed in the medium. EAA restored the levels of these proteins compared to control cultures. The results of this study show that EAA may protect epidermal and dermal cells by reducing levels of pro-inflammatory proteins, increasing antioxidant system activity in skin keratinocytes and fibroblasts, and normalizing intercellular signaling. Full article

The valorization of culinary by-products into functional bioactive resources represents a significant advancement in sustainable biotechnology. This study characterizes an extract derived from “battuto toscano” by-products, a traditional blend of garlic, onion, carrot, and celery trimmings, recovered through circular economy principles. Comprehensive antioxidant profiling was performed alongside biological evaluations on human cell lines and anti-glycation assays. Results from Folin–Ciocalteu, FRAP, and TEAC assays confirmed a high concentration of secondary metabolites with significant scavenging capacity. In vitro testing on primary human fibroblasts and HaCaT keratinocytes revealed a concentration- and time-dependent biological response, with lower concentrations showing better compatibility and transiently enhancing HaCaT metabolic activity. Furthermore, BTE reduced AGE-associated fluorescence in the BSA–glucose model, particularly at 5 mg/mL, supporting its potential anti-glycation activity. These findings establish “battuto toscano” by-products as a reservoir of sustainable biomolecules. This study offers a transformative resource for the pharma/nutraceutical sectors by bridging culinary tradition with biomedical innovation. Full article

Protease-activated receptor 1 (PAR1), a G protein-coupled receptor, plays a central role in coordinating multiple phases of cutaneous wound healing, including hemostasis, cell proliferation, migration, and extracellular matrix remodeling. Despite its therapeutic potential, PAR1-selective positive allosteric modulators (PAMs) remain limited. Here, we characterized the wound healing efficacy of gestodene, a third-generation progestin previously identified as a selective PAM of PAR1. Gestodene exhibited no intrinsic agonist activity but selectively potentiated PAR1-activating peptide (PAR1-AP)-induced calcium signaling without affecting PAR2 or PAR4 responses. Consistently, gestodene induced a concentration-dependent leftward shift in the PAR1-AP dose–response curve. Notably, gestodene enhanced PAR1-dependent cell proliferation, migration, and ERK1/2 activation, effects abolished by PAR1 knockout or pharmacological inhibition with vorapaxar in human keratinocytes (HaCaT) and dermal fibroblasts (HDF). Gestodene also potentiated the expression of wound healing-associated genes, including matrix metalloproteinases (MMP-1, -2, -3, -10), fibronectin, and type I collagen (COL1A1). In a murine wound model, topical administration of gestodene accelerated wound closure, achieving complete re-epithelialization by Day 8 and significantly enhancing collagen deposition, effects reversed by vorapaxar. Collectively, these findings demonstrate that gestodene accelerates cutaneous wound healing through PAR1-selective positive allosteric modulation and supports its potential as a drug repositioning candidate for wound repair. Full article

Calcium hydroxyapatite (CaHA)-based dermal fillers have been shown to help counteract and potentially reverse certain aspects of skin aging. By applying isolated CaHA microspheres, we investigated the importance of the direct contact of dermal cells to microspheres and their role for the expression of extracellular matrix (ECM) components. To this end, human dermal fibroblasts were cultured in the presence of CaHA microspheres. Cell migration, cell–microsphere interaction, and CaHA dose-dependent effects on the expression of ECM proteins were examined using microscopy, mRNA and protein expression analysis. Our results indicated that fibroblasts established direct and close contact to CaHA microspheres. This interaction was associated with a time- and dose-dependent increase in ECM protein expression, including collagen-1, emilin-1, elastin, fibulin-5, fibronectin, and the proteoglycans—lumican and versican. These observations indicate that direct contact between fibroblasts and CaHA microspheres promotes ECM protein expression, suggesting a role for this interaction in supporting skin regeneration and counteracting age-related changes, potentially augmented in vivo by immunomodulatory effects. Full article