Tannic acid-layered hydroxide salt hybrid: assessment of antibiofilm formation and foodborne pathogen growth inhibition.

Pathogenic bacteria in food are a public health problem worldwide. Polyphenolic bioactive compounds with antimicrobial activity and antioxidant capacity represent a tangible alternative to overcome this problem. To preserve the biological functions of phenolic compounds such as tannic acid, which has been described to possess antioxidant and antimicrobial activity, this study describes the synthesis of a zinc nanohydroxide to stabilize its properties. Characterization by XRD, FT-IR, SEM, DLS, and UV-vis evidenced the presence of tannic acid in the nanohybrid TA-Zn-LHS which was further confirmed by DPPH, ABTS and FRAP antioxidant activity techniques. Bacterial growth inhibition of Escherichia coli ATCC 8739, Salmonella Enteritidis, and Staphylococcus aureus ATCC 25923 was over 80% at 50 mg/mL of the TA-Zn-LHS and over 90% with Zn-LHS. Antibiofilm evaluation of these same strains showed biofilm formation inhibition > 90% and > 80% for Zn-LHS and TA-Zn-LHS, respectively. The toxicity evaluation of the materials in Artemia salina showed a classification of the materials as non-toxic to slightly toxic in concentrations up to 1 mg/mL. These results allow us to introduce a new nanohybrid useful for food safety with safe biological functions.

Taenia solium: Socioeconomic changes and prevalence evolution in four endemic communities in northwestern Mexico.

In Mexico, for the past 30 years, a continuous decrease in the incidence of clinical taeniosis/cysticercosis has been documented. This work aimed to determine the influence of improvement in socioeconomic conditions on the prevalence of Taenia solium in four endemic communities in northwestern Mexico. This study was carried out in two phases. First, documentary information (1989-2018) was collected about the prevalence of Theridion solium in the federal entity of Sinaloa State. Second, a pilot study was performed in four communities of Sinaloa, which had an endemic history of Taenia transmission. In each community, a risk factor questionnaire was applied, and serum and stool samples were collected for convenience in a non-probabilistic way. Anti-cysticercus antibodies and adult worm coproantigen were determined. The documentary analysis showed the incidence of taeniosis and cysticercosis to have decreased by 98 and 53%, respectively, while the human development index increased by 5% (1992-2017). Our data suggest that the risk of parasitic transmission is low, although female sex was a risk factor for reporting tremors or seizures (prevalence rate 2.1336, CI: 1.1821-3.8508) and background of tapeworm infection (prevalence rate 1.2893, CI: 0.9795-1.6972). No tapeworms or eggs were found while examining stool samples, but protozoa cysts were observed in four samples. Unexpectedly, only one of the 79 stool samples was positive for coproantigens. This positive result was confirmed in a second sample. However, the evaluation of a third sample was negative. No antibodies were found in human (n = 377) or pig (n = 69) samples. These data suggest parasite transmission has been interrupted and could be possibly associated with improving socioeconomic conditions. Further studies are needed to determine the real prevalence of zoonoses in Mexico.

Heparan Sulfate and Sialic Acid in Viral Attachment: Two Sides of the Same Coin?

Sialic acids and heparan sulfates make up the outermost part of the cell membrane and the extracellular matrix. Both structures are characterized by being negatively charged, serving as receptors for various pathogens, and are highly expressed in the respiratory and digestive tracts. Numerous viruses use heparan sulfates as receptors to infect cells; in this group are HSV, HPV, and SARS-CoV-2. Other viruses require the cell to express sialic acids, as is the case in influenza A viruses and adenoviruses. This review aims to present, in a general way, the participation of glycoconjugates in viral entry, and therapeutic strategies focused on inhibiting the interaction between the virus and the glycoconjugates. Interestingly, there are few studies that suggest the participation of both glycoconjugates in the viruses addressed here. Considering the biological redundancy that exists between heparan sulfates and sialic acids, we propose that it is important to jointly evaluate and design strategies that contemplate inhibiting the interactions of both glycoconjugates. This approach will allow identifying new receptors and lead to a deeper understanding of interspecies transmission.

Sea urchins: an update on their pharmacological properties.

Sea urchins are a group of benthic invertebrates characterized by having rigid globose bodies, covered in spines, and have an innate immune system that has allowed them to survive in the environment and defend against many pathogens that affect them. They are consumed for their unique flavor, but also for possessing a rich source of bioactive compounds which make them a source for a wide array of medicinal properties. Thus, these may be used to discover and develop new drugs such as anti-bacterials, anti-carcinogenics and anti-virals. Precisely for those reasons, this revision is centered on the known biological activities in various sea urchin species. Recently, the potential pharmacological benefits of nine sea urchin species [Diadema antillarum (Philippi 1845), Echinometra mathaei (de Blainville), Evechinus chloroticus (Valenciennes), Mesocentrotus nudus (Agassiz, 1863), Paracentrotus lividus (Lamarck, 1816), Scaphechinus mirabilis (Agazzis, 1863), Stomopneustes variolaris (Lamarck, 1816), Tripneustes depressus (Agassiz, 1863), and Tripneustes ventricosus (Lamarck, 1816)] have been evaluated. Our work includes a comprehensive review of the anti-fungal, anti-parasitic, anti-inflammatory, hepatoprotective, anti-viral, anti-diabetic, anti-lipidemic, gastro-protective and anti-cardiotoxic effects. Furthermore, we revised the compounds responsible of these pharmacological effects. This work was intended for a broad readership in the fields of pharmacology, drugs and devices, marine biology and aquaculture, fisheries and fish science. Our results suggest that organic extracts, as well as pure compounds obtained from several parts of sea urchin bodies are effective in vitro and in vivo pharmacological models. As such, these properties manifest the potential use of sea urchins to develop emergent active ingredients.

Protective Effects of a synthetic glycosaminoglycan mimetic (OTR4132) in a rat immunotoxic lesion model of septohippocampal cholinergic degeneration.

Using a partial hippocampal cholinergic denervation model, we assessed the effects of the RGTA® named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial septum/diagonal band of Broca (0.37 µg); vehicle injections served as controls. Immediately after surgery, OTR4132 was injected into the lateral ventricles (0.25 µg/5 µl/rat) or intramuscularly (1.5 mg/kg). To determine whether OTR4132 reached the lesion site, some rats received intracerebroventricular (ICV) or intramuscular (I.M.) injections of fluorescent OTR4132. Rats were sacrificed at 4, 10, 20, or 60 days post-lesion (DPL). Fluorescein-labeled OTR4132 injected ICV or I.M. was found in the lesion from 4 to 20 DPL. Rats with partial hippocampal cholinergic denervation showed decreases in hippocampal acetylcholinesterase reaction products and in choline acetyltransferase-positive neurons in the medial septum. These lesions were the largest at 10 DPL and then remained stable until 60 DPL. Both hippocampal acetylcholinesterase reaction products and choline acetyltransferase-positive neurons in the medial septum effects were significantly attenuated in OTR4132-treated rats. These effects were not related to competition between OTR4132 and 192 IgG-saporin for the neurotrophin receptor P75 (p75NTR), as OTR4132 treatment did not alter the internalization of Cy3-labelled 192 IgG. OTR4132 was more efficient at reducing the acetylcholinesterase reaction products and choline acetyltransferase-positive neurons than a comparable heparin dose used as a comparator. Using the slice superfusion technique, we found that the lesion-induced decrease in muscarinic autoreceptor sensitivity was abolished by intramuscular OTR4132. After partial cholinergic damage, OTR4132 was able to concentrate at the brain lesion site possibly due to the disruption of the blood-brain barrier and to exert structural and functional effects that hold promises for neuroprotection/neurotrophism.

APP deficiency and HTRA2 modulates PrPc proteostasis in human cancer cells.

Cellular protein homeostasis (proteostasis) requires an accurate balance between protein biosynthesis, folding, and degradation, and its instability is causally related to human diseases and cancers. Here, we created numerous engineered cancer cell lines targeting APP (amyloid ß precursor protein) and/or PRNP (cellular prion) genes and we showed that APP knocking-down impaired PRNP mRNA level and vice versa, suggesting a link between their gene regulation. PRNPKD, APPKD and PRNPKD/APPKD HeLa cells encountered major difficulties to grow in a 3D tissue-like environment. Unexpectedly, we found a cytoplasmic accumulation of the PrPc protein without PRNP gene up regulation, in both APPKD and APPKO HeLa cells. Interestingly, APP and/or PRNP gene ablation enhanced the chaperone/serine protease HTRA2 gene expression, which is a protein processing quality factor involved in Alzheimer's disease. Importantly, HTRA2 gene silencing decreased PRNP mRNA level and lowered PrPc protein amounts, and conversely, HTRA2 overexpression increased PRNP gene regulation and enhanced membrane-anchored and cytoplasmic PrPc fractions. PrPc, APP and HTRA2 destabilized membrane-associated CD24 protein, suggesting changes in the lipid raft structure. Our data show for the first time that APP and the dual chaperone/serine protease HTRA2 protein could modulate PrPc proteostasis hampering cancer cell behavior.

Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation.

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of high-mobility group proteins during transcription initiation remain unclear. Here we show that high-mobility group AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support the concept that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure genome integrity.

Performance of Indocyanine-Green Imaging for Sentinel Lymph Node Mapping and Lymph Node Metastasis in Esophageal Cancer: Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Lymphatic mapping with indocyanine-green (ICG) and near-infrared light fluorescent imaging is widely used for sentinel lymph node staging in different types of cancer but is not fully accepted for all procedures because studies have reported heterogeneous results. This study aimed to assess the detection rate (DR) of ICG imaging for sentinel lymph node mapping (SLNM) and lymph node metastases (LNMs) in esophageal cancer. METHODS: A systematic search was performed to identify relevant studies examining the use of ICG imaging for SLNM in patients with esophageal cancer. Extracted results were pooled in a single-proportion meta-analysis, with a random-effects model, presented as forest plots. RESULTS: Six studies were included in the analysis. The ICG DR for SLNM was 89% [95% confidence interval (CI) 71%-96%]. The pooled sensitivity and specificity values for the detection of LNMs were 84% (95% CI 64%-94%) and 15% (95% CI 3%-45%), respectively. A trend towards a lower DR was found with increasing mean latency time between ICG injection and SLNM. CONCLUSIONS: ICG imaging is a technique that potentially could improve lymph node yield excision and, as a consequence, improve the detection of lymph node metastases.

Testing the effectiveness of physical activity advice delivered via text messaging vs. human phone advisors in a Latino population: The On The Move randomized controlled trial design and methods.

Physical inactivity is a key risk factor for a range of chronic diseases and conditions, yet, approximately 50% of U.S. adults fall below recommended levels of regular aerobic physical activity (PA). This is particularly true for ethnic minority populations such as Latino adults for whom few culturally adapted programs have been developed and tested. Text messaging (SMS) represents a convenient and accessible communication channel for delivering targeted PA information and support, but has not been rigorously evaluated against standard telehealth advising programs. The objective of the On The Move randomized controlled trial is to test the effectiveness of a linguistically and culturally targeted SMS PA intervention (SMS PA Advisor) versus two comparison conditions: a) a standard, staff-delivered phone PA intervention (Telephone PA Advisor) and b) an attention-control arm consisting of a culturally targeted SMS intervention to promote a healthy diet (SMS Nutrition Advisor). The study sample (N = 350) consists of generally healthy, insufficiently active Latino adults ages 35 years and older living in five northern California counties. Study assessments occur at baseline, 6, and 12 months, with a subset of participants completing 18-month assessments. The primary outcome is 12-month change in walking, and secondary outcomes include other forms of PA, assessed via validated self-report measures and supported by accelerometry, and physical function and well-being variables. Potential mediators and moderators of intervention success will be explored to better determine which subgroups do best with which type of intervention. Here we present the study design and methods, including recruitment strategies and yields. Trial Registration: clinicaltrial.gov Identifier = NCT02385591.

Catalizando cambios sociales y bioculturales sobre el cáncer. Diseño de acciones transdisciplinarias contra la pandemia / Catalyzing biocultural and social changes about cancer. Design of transdisciplinary actions against the pandemic

RESUMEN Objetivo Diseñar y analizar una experiencia de formación y organización transdisciplinaria sobre el cáncer, en la que expertos de múltiples disciplinas y actores con diferentes horizontes convergen en un diagnóstico y un panorama de intervención en múltiples escalas. Método Se diseñó e implementó un diplomado de 140 horas con más de 60 ponentes y 50 actores relevantes en torno al cáncer. Se llevó a cabo un taller transversal de 20 horas, usando como mediación las metodologías del diseño para la transición, que proponen estrategias para la construcción de diagnósticos e intervenciones en problemáticas complejas y conflictivas. Resultados Se logró construir un mapa de actores, preocupaciones, conflictos, causas-raíces, escenarios ideales y modelos potenciales de intervención con base en un trabajo colegiado. Se generaron recursos visuales que funcionan como mapas y estructuras donde se ubican los factores bioculturales que facilitan o impiden la efectiva implementación de estrategias de intervención. Las infografías y tablas funcionaron como mediaciones transdisciplinarias en tanto que posibilitaron que el espacio político (múltiples actores) fuera también un espacio pedagógico (múltiples epistemologías) situado en un contexto económico y ecológico concreto (interdependencia material de actores y ambientes). Conclusión Con la metodología del diseño para la transición se logró catalizar un trabajo transdisciplinario entre expertos y actores sociales en torno al cáncer. A través de las mediaciones visuales como mapas, infografías y tablas, se logró sintetizar y usar un diagnóstico compartido y avanzar así en intervenciones más incluyentes que reconozcan la complejidad biocultural de esta pandemia.(AU)

ABSTRACT Objective Design and analyze a transdisciplinary training and organization experience on cancer, where experts from multiple disciplines and actors with different horizons converge on a diagnosis and intervention horizon on multiple scales. Method A 140-hour diploma course with more than 60 speakers and 50 relevant actors around cancer was designed and implemented. A 20-hour transversal workshop was developed, using the Design for Transition methods as mediation of collaborative strategies for the construction of diagnoses and interventions in complex and conflict situations. Results It was possible to build a series of maps with a common view of stakeholders, concerns, conflicts, root causes, ideal scenarios and potential models of intervention, based on diverse participant's input. The visual resources generated were able to function as guides and structures that made possible the identification of biocultural factors that facilitate or impede implementation of strategies and interventions. Infographic material functioned as transdisciplinary mediations that enabled a diverse political (multiple-actors) and pedagogical (multiple-epistemologies) space to act upon an economic and ecological context (material interdependence of actors and environments). Conclusion The Design for Transition methodology catalized transdisciplinary work by enabling cancer experts and social actors interactions. Through visual mediations such as maps, infographics and tables, it was possible to synthesize and use a shared diagnosis and thus advance towards more inclusive interventions that recognize the biocultural complexity of this pandemic.(AU)

[Catalyzing biocultural and social changes about cancer. Design of transdisciplinary actions against the pandemic]. / Catalizando cambios sociales y bioculturales sobre el cáncer. Diseño de acciones transdisciplinarias contra la pandemia.

OBJECTIVE: Design and analyze a transdisciplinary training and organization experience on cancer, where experts from multiple disciplines and actors with different horizons converge on a diagnosis and intervention horizon on multiple scales. METHOD: A 140-hour diploma course with more than 60 speakers and 50 relevant actors around cancer was designed and implemented. A 20-hour transversal workshop was developed, using the Design for Transition methods as mediation of collaborative strategies for the construction of diagnoses and interventions in complex and conflict situations. RESULTS: It was possible to build a series of maps with a common view of stakeholders, concerns, conflicts, root causes, ideal scenarios and potential models of intervention, based on diverse participant's input. The visual resources generated were able to function as guides and structures that made possible the identification of biocultural factors that facilitate or impede implementation of strategies and interventions. Infographic material functioned as transdisciplinary mediations that enabled a diverse political (multiple-actors) and pedagogical (multiple-epistemologies) space to act upon an economic and ecological context (material interdependence of actors and environments). CONCLUSION: The Design for Transition methodology catalized transdisciplinary work by enabling cancer experts and social actors interactions. Through visual mediations such as maps, infographics and tables, it was possible to synthesize and use a shared diagnosis and thus advance towards more inclusive interventions that recognize the biocultural complexity of this pandemic.

OBJETIVO: Diseñar y analizar una experiencia de formación y organización transdisciplinaria sobre el cáncer, en la que expertos de múltiples disciplinas y actores con diferentes horizontes convergen en un diagnóstico y un panorama de intervención en múltiples escalas. MÉTODO: Se diseñó e implementó un diplomado de 140 horas con más de 60 ponentes y 50 actores relevantes en torno al cáncer. Se llevó a cabo un taller transversal de 20 horas, usando como mediación las metodologías del diseño para la transición, que proponen estrategias para la construcción de diagnósticos e intervenciones en problemáticas complejas y conflictivas. RESULTADOS: Se logró construir un mapa de actores, preocupaciones, conflictos, causas-raíces, escenarios ideales y modelos potenciales de intervención con base en un trabajo colegiado. Se generaron recursos visuales que funcionan como mapas y estructuras donde se ubican los factores bioculturales que facilitan o impiden la efectiva implementación de estrategias de intervención. Las infografías y tablas funcionaron como mediaciones transdisciplinarias en tanto que posibilitaron que el espacio político (múltiples actores) fuera también un espacio pedagógico (múltiples epistemologías) situado en un contexto económico y ecológico concreto (interdependencia material de actores y ambientes). CONCLUSIÓN: Con la metodología del diseño para la transición se logró catalizar un trabajo transdisciplinario entre expertos y actores sociales en torno al cáncer. A través de las mediaciones visuales como mapas, infografías y tablas, se logró sintetizar y usar un diagnóstico compartido y avanzar así en intervenciones más incluyentes que reconozcan la complejidad biocultural de esta pandemia.

Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and highly lethal lung disease with unknown etiology and poor prognosis. IPF patients die within 2 years after diagnosis mostly due to respiratory failure. Current treatments against IPF aim to ameliorate patient symptoms and to delay disease progression. Unfortunately, therapies targeting the causes of or reverting IPF have not yet been developed. Here we show that reduced levels of miRNA lethal 7d (MIRLET7D) in IPF compromise epigenetic gene silencing mediated by the ribonucleoprotein complex MiCEE. In addition, we find that hyperactive EP300 reduces nuclear HDAC activity and interferes with MiCEE function in IPF. Remarkably, EP300 inhibition reduces fibrotic hallmarks of in vitro (patient-derived primary fibroblast), in vivo (bleomycin mouse model), and ex vivo (precision-cut lung slices, PCLS) IPF models. Our work provides the molecular basis for therapies against IPF using EP300 inhibition.

Glycosaminoglycans from Alzheimer's disease hippocampus have altered capacities to bind and regulate growth factors activities and to bind tau.

Glycosaminoglycans (GAGs), including heparan sulfates and chondroitin sulfates, are major components of the extracellular matrix. Upon interacting with heparin binding growth factors (HBGF), GAGs participate to the maintaintenance of tissue homeostasis and contribute to self-healing. Although several processes regulated by HBGF are altered in Alzheimer's disease, it is unknown whether the brain GAG capacities to bind and regulate the function of HBGF or of other heparin binding proteins, as tau, are modified in this disease. Here, we show that total sulfated GAGs from hippocampus of Alzheimer's disease have altered capacities to bind and potentiate the activities of growth factors including FGF-2, VEGF, and BDNF while their capacity to bind to tau is remarkable increased. Alterations of GAG structures and capacities to interact with and regulate the activity of heparin binding proteins might contribute to impaired tissue homeostasis in the Alzheimer's disease brain.

SLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects.

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7-/- mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7-/- mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development.

New tools for carbohydrate sulfation analysis: heparan sulfate 2-O-sulfotransferase (HS2ST) is a target for small-molecule protein kinase inhibitors.

Sulfation of carbohydrate residues occurs on a variety of glycans destined for secretion, and this modification is essential for efficient matrix-based signal transduction. Heparan sulfate (HS) glycosaminoglycans control physiological functions ranging from blood coagulation to cell proliferation. HS biosynthesis involves membrane-bound Golgi sulfotransferases, including HS 2-O-sulfotransferase (HS2ST), which transfers sulfate from the cofactor PAPS (3'-phosphoadenosine 5'-phosphosulfate) to the 2-O position of α-l-iduronate in the maturing polysaccharide chain. The current lack of simple non-radioactive enzyme assays that can be used to quantify the levels of carbohydrate sulfation hampers kinetic analysis of this process and the discovery of HS2ST inhibitors. In the present paper, we describe a new procedure for thermal shift analysis of purified HS2ST. Using this approach, we quantify HS2ST-catalysed oligosaccharide sulfation using a novel synthetic fluorescent substrate and screen the Published Kinase Inhibitor Set, to evaluate compounds that inhibit catalysis. We report the susceptibility of HS2ST to a variety of cell-permeable compounds in vitro, including polyanionic polar molecules, the protein kinase inhibitor rottlerin and oxindole-based RAF kinase inhibitors. In a related study, published back-to-back with the present study, we demonstrated that tyrosyl protein sulfotranferases are also inhibited by a variety of protein kinase inhibitors. We propose that appropriately validated small-molecule compounds could become new tools for rapid inhibition of glycan (and protein) sulfation in cells, and that protein kinase inhibitors might be repurposed or redesigned for the specific inhibition of HS2ST.

Heparan sulfate 3-O-sulfotransferase 2 (HS3ST2) displays an unexpected subcellular localization in the plasma membrane.

BACKGROUND: Heparan sulfate (HS) 3-O-sulfation can be catalysed by seven 3-O-sulfotransferases (HS3STs) in humans, still it is the rarest modification in HS and its biological function is yet misunderstood. HS3ST2 and HS3ST3B exhibit the same activity in vitro. They are however differently expressed in macrophages depending on cell environment, which suggests that they may be involved in distinct cellular processes. Here, we hypothesized that both isozymes might also display distinct subcellular localizations. METHODS: The subcellular distribution of HS3ST2 and HS3ST3B was analysed by using overexpression systems in HeLa cells. The localization of endogenous HS3ST2 was confirmed by immunostaining in primary macrophages. RESULTS: We found that HS3ST3B was only localized in the Golgi apparatus and no difference between full-length enzyme and truncated construct depleted of its catalytic domain was observed. In contrast, HS3ST2 was clearly visualized at the plasma membrane. Its truncated form remained in the Golgi apparatus, meaning that the catalytic domain might support correct addressing of HS3ST2 to cell surface. Moreover, we found a partial co-localization of HS3ST2 with syndecan-2 in HeLa cells and primary macrophages. Silencing the expression of this proteoglycan altered the localization of HS3ST2, which suggests that syndecan-2 is required to address the isozyme outside of the Golgi apparatus. CONCLUSIONS: We demonstrated that HS3ST3B is a Golgi-resident isozyme, while HS3ST2 is addressed to the plasma membrane with syndecan-2. GENERAL SIGNIFICANCE: The membrane localization of HS3ST2 suggests that this enzyme may participate in discrete processes that occur at the cell surface.

Heparan sulfate proteoglycans as key regulators of the mesenchymal niche of hematopoietic stem cells.

The complex microenvironment that surrounds hematopoietic stem cells (HSCs) in the bone marrow niche involves different coordinated signaling pathways. The stem cells establish permanent interactions with distinct cell types such as mesenchymal stromal cells, osteoblasts, osteoclasts or endothelial cells and with secreted regulators such as growth factors, cytokines, chemokines and their receptors. These interactions are mediated through adhesion to extracellular matrix compounds also. All these signaling pathways are important for stem cell fates such as self-renewal, proliferation or differentiation, homing and mobilization, as well as for remodeling of the niche. Among these complex molecular cues, this review focuses on heparan sulfate (HS) structures and functions and on the role of enzymes involved in their biosynthesis and turnover. HS associated to core protein, constitute the superfamily of heparan sulfate proteoglycans (HSPGs) present on the cell surface and in the extracellular matrix of all tissues. The key regulatory effects of major medullar HSPGs are described, focusing on their roles in the interactions between hematopoietic stem cells and their endosteal niche, and on their ability to interact with Heparin Binding Proteins (HBPs). Finally, according to the relevance of HS moieties effects on this complex medullar niche, we describe recent data that identify HS mimetics or sulfated HS signatures as new glycanic tools and targets, respectively, for hematopoietic and mesenchymal stem cell based therapeutic applications.

Genetic Polymorphisms of Tumor Necrosis Factor Alpha and Susceptibility to Dengue Virus Infection in a Mexican Population.

To evaluate the association of the -308 and -238 tumor necrosis factor alpha (TNF-α) gene polymorphisms with clinical manifestations of dengue and TNF-α serum levels in a northwestern Mexican population. The study populations included dengue fever (DF) and dengue hemorrhagic fever (DHF) patients, and a group of healthy controls (HCs) without history of dengue. Polymerase chain reaction-restriction fragment length polymorphism and Enzyme-Linked Immunosorbent Assay were performed to determine genotypes and serum concentration of TNF-α, respectively. There were no significant differences in alleles, genotypes, and haplotype frequencies between patients and HCs. However, when patients were separated into DF and DHF, there was an increased prevalence of the -308 GA genotype in HCs compared to DHF (odds ratio [OR] = 0.129, 95% confidence interval [CI] = 0.018-0.945, p = 0.025), as well as the GG haplotype (OR = 0.49, 95% CI = 0.273-0.880, p = 0.01757) in DF. The genotypes of both polymorphisms were not associated with hematologic manifestations. Serum TNF-α levels were significantly higher in patients than in HCs (p = 0.004). Our results suggest a minimal effect of the -308 and -238 TNF-α gene polymorphisms in dengue patients and that their increased serum levels of TNF-α are independent of genotypes.