The formulation and in vitro evaluation of WS Biotin, a novel encapsulated form of D-Biotin with improved water solubility for hair and skin treatment applications.

OBJECTIVE: To develop and evaluate the efficacy of WS Biotin, a novel water-soluble form of D-Biotin, for cosmetic use. METHODS: A new encapsulated form of D-Biotin was developed with the purpose of improving the water solubility of biotin. This novel form of encapsulated biotin was characterized by its physicochemical properties: particle size, D-Biotin content and solubility in water. Also, proliferation and gene expression in vitro tests in cell culture were performed to evaluate its effectiveness in promoting hair growth, an ELISA test was conducted for hair keratinization and skin lightening property was tested by analysing the intracellular melanin content. RESULTS: The developed WS Biotin microcapsules exhibit a particle size range of 2-30 µm with D-Biotin content of ~50% (w/w). The water solubility of WS Biotin was found to be 20-fold greater than free biotin. The obtained in vitro results indicated that WS Biotin enhances the expression of hair-related keratins in hair follicle keratinocytes, as well as the expression of hair growth-promoting genes in dermal papilla cells. Moreover, the melanin content in UVA-exposed epidermal melanocytes was reduced upon exposure to WS Biotin. CONCLUSION: In this work, a novel form of encapsulated biotin, WS Biotin, was developed in order to improve the water solubility of free biotin and was found to be effective for cosmetic use in both hair and skin applications.

OBJECTIF: Développer et évaluer l'efficacité de la WS Biotin, une nouvelle forme hydrosoluble de D-biotine, à usage cosmétique. MÉTHODES: Une nouveau format gélules de D-biotine a été développé dans le but d'améliorer la propriété d'hydrosolubilité de la biotine. Ce nouveau format de gélules de biotine a été caractérisé pour ses propriétés physicochimiques : taille des particules, teneur en D-biotine et solubilité dans l'eau. En outre, des tests in vitro de prolifération et d'expression génique en culture cellulaire ont été réalisés pour évaluer son efficacité à favoriser la croissance des cheveux, un test ELISA a été réalisé pour la kératinisation des cheveux et la propriété d'éclaircissement de la peau a été testée en analysant la teneur en mélanine intracellulaire. RÉSULTATS: Les microgélules de WS Biotin développées présentent une plage de tailles de particules de 2 à 30 micromètres avec une teneur en biotine D d'environ 50 % (p/p). L'hydrosolubilité de WS Biotin s'est avérée 20 fois plus élevée que celle de la biotine libre. Les résultats in vitro obtenus ont indiqué que WS Biotin améliorait l'expression des kératines capillaires dans les kératinocytes des follicules pileux, ainsi que l'expression des gènes favorisant la croissance dans les cellules papillaires dermiques. En outre, la teneur en mélanine dans les mélanocytes épidermiques exposés aux UVA a été réduite lors de l'exposition à WS Biotin. CONCLUSION: Dans ce travail, une nouvelle forme de biotine en gélule, WS Biotin, a été développée afin d'améliorer l'hydrosolubilité de la biotine libre et s'est avérée efficace pour une utilisation cosmétique dans les applications capillaires et cutanées.

Cyba-deficient mice display an increase in hematopoietic stem cells and an overproduction of immunoglobulins.

The regulation of protein function by reversible oxidation is increasingly recognized as a key mechanism for the control of cellular signaling, modulating crucial biological processes such as cell differentiation. In this scenario, NADPH oxidases must occupy a prominent position. Our results show that hematopoietic stem and progenitor cells express three p22phox-dependent NADPH oxidases members (NOX1, NOX2 and NOX4). By deleting the p22phox coding gene (Cyba), here we have analyzed the importance of this family of enzymes during in vivo hematopoiesis. Cyba-/- mice show a myeloid bias, and an enrichment of hematopoietic stem cell populations. By means of hematopoietic transplant experiments we have also tried to dissect the specific role of the NADPH oxidases. While the absence of NOX1 or NOX2 provides a higher level of reconstitution, a lack of NOX4 rendered the opposite result, suggesting a functional specificity among the different NADPH oxidases. Cyba-/- cells showed a hampered activation of AKT1 and a sharp decrease in STAT5 protein. This is in line with the diminished response to IL-7 shown by our results, which could explain the overproduction of immunoglobulins observed in Cyba-/- mice.

Granuloma Formation in a Cyba-Deficient Model of Chronic Granulomatous Disease Is Associated with Myeloid Hyperplasia and the Exhaustion of B-Cell Lineage.

Haematopoiesis is a paradigm of cell differentiation because of the wide variety and overwhelming number of mature blood cells produced daily. Under stress conditions, the organism must adapt to a boosted demand for blood cells. Chronic granulomatous disease (CGD) is a genetic disease caused by inactivating mutations that affect the phagocyte oxidase. Besides a defective innate immune system, CGD patients suffer from recurrent hyper-inflammation episodes, circumstances upon which they must face emergency haematopoiesis. The targeting of Cybb and Ncf1 genes have produced CGD animal models that are a useful surrogate when studying the pathophysiology and treatment of this disease. Here, we show that Cyba-/- mice spontaneously develop granuloma and, therefore, constitute a CGD animal model to complement the existing Cybb-/- and Ncf1-/- models. More importantly, we have analysed haematopoiesis in granuloma-bearing Cyba-/- mice. These animals showed a significant loss of weight, developed remarkable splenomegaly, bone marrow myeloid hyperplasia, and signs of anaemia. Haematological analyses showed a sharped decrease of B-cells and a striking development of myeloid cells in all compartments. Collectively, our results show that granuloma inflammatory lesions dramatically change haematopoiesis homeostasis. Consequently, we suggest that besides their defective innate immunity, the alteration of haematopoiesis homeostasis upon granuloma may contribute to the dismal outcome of CGD.

A rare cause of intra-abdominal cysts: pancreatic cystic lymphangiomas.

Echenique et al. described a lymphangioma as a rare cystic neoplasm of the pancreas. We present a similar intra-abdominal lesion diagnosed by endoscopic ultrasound (EUS)-fine-needle aspiration (FNA) cytology.

Retrograde enteroclysis by double balloon enteroscopy in a patient with blunt abdominal trauma: small bowel stricture, intraluminal vascular lesion and Crohn's disease.

A 40-year-old male presented to the Emergency Department after a driving accident with blunt abdominal trauma. An abdominal computed tomography (CT) scan revealed a mesenteric injury in the right lower quadrant. He was admitted two months later due to a one-day history of abdominal pain and diarrhea, without fever or blood. The CT angiography showed a pseudoaneurysm located in the proximal ileum and several rigid small bowel (SB) loops with segmental wall thickening of mucosa.

Gastric ulcer due to mucormycosis in a critical patient.

We have read the article published by Sánchez-Velázquez P et al., which described a clinical case of gastrointestinal hemorrhage secondary to gastric ulcer due to Mucor. We present a similar clinical case, as an example of one identified by gastroscopy. The case was a 71-year-old female with multiple organ failure secondary to nosocomial pneumonia who required mechanical ventilation, vasoactive drugs, corticosteroids, antibiotherapy and continuous venovenous hemofiltration. Her room was adjacent to a building under construction. The patient had severe upper gastrointestinal bleeding and therefore, an urgent upper gastrointestinal endoscopy was performed. A small amount of blood was identified, as well as a large ulcer without a white base extending from the fundus to the antrum region of the stomach, with bleeding due to rubbing and nodular edges that suggested degeneration.

Rhabdoid cavitated adenocarcinoma in the jejunum, an exceptional case by enteroscopy.

We have read the article published by Abdulkader I et al., which described two cases of a rhabdoid tumor of the small bowel diagnosed by surgery. We present a similar case in the jejunum diagnosed by double balloon enteroscopy (DBE). We present the case of a 64-year-old patient with multifactorial anemia and transfusional requirements and a flat lesion of 2 cm in the colon, which showed undifferentiated adenocarcinoma on histopathological analysis.

Recurrent small-bowel bleeding from a Dieulafoy's lesion after combined endoscopic treatment.

INTRODUCTION: Dieulafoy's lesion of the small bowel is an uncommon cause of gastrointestinal (GI) bleeding that often recurs after endoscopic treatment. MATERIAL AND METHODS: we report an observational, descriptive, retrospective, single-center study in 15 patients with small bowel bleeding who were diagnosed with a Dieulafoy's lesion by capsule endoscopy or double-balloon enteroscopy. RESULTS AND CONCLUSIONS: all patients underwent combined endoscopic treatment. During a median follow-up of 33.5 months (range, 2-145), three of the 12 cases that stayed in follow-up (25 %) recurred, all within 48 hours after treatment. Two were successfully re-treated with a repeat endoscopic procedure.

Klatskin-mimicking neuroendocrine tumor.

With regard to the article published in your journal by Konstantinos Tsalis et al on Klatskin-mimicking lesions, we recently diagnosed a neuroendocrine tumor (NET) in the proximal biliary tract of a 78-year-old female with obstructive jaundice manifestations. A chest-abdomen-pelvis CT scan identified infiltrating ductal cholangiocarcinoma (Klatskin tumor, type IV in the Bismuth-Corlette classification with cT2N1 staging) and a liver mass in segment IV.

PTPN13 regulates cellular signalling and ß-catenin function during megakaryocytic differentiation.

PTPN13 is a high-molecular weight intracellular phosphatase with several isoforms that exhibits a highly modular structure. Although in recent years different roles have been described for PTPN13, we are still far from understanding its function in cell biology. Here we show that PTPN13 expression is activated during megakaryocytic differentiation at the protein and mRNA level. Our results show that the upregulation of PTPN13 inhibits megakaryocytic differentiation, while PTPN13 silencing triggers differentiation. The ability of PTPN13 to alter megakaryocytic differentiation can be explained by its capacity to regulate ERK and STAT signalling. Interestingly, the silencing of ß-catenin produced the same effect as PTPN13 downregulation. We demonstrate that both proteins coimmunoprecipitate and colocalise. Moreover, we provide evidence showing that PTPN13 can regulate ß-catenin phosphorylation, stability and transcriptional activity. Therefore, the ability of PTPN13 to control megakaryocytic differentiation must be intimately linked to the regulation of ß-catenin function. Moreover, our results show for the first time that PTPN13 is stabilised upon Wnt signalling, which makes PTPN13 an important player in canonical Wnt signalling. Our results show that PTPN13 behaves as an important regulator of megakaryocytic differentiation in cell lines and also in murine haematopoietic progenitors. This importance can be explained by the ability of PTPN13 to regulate cellular signalling, and especially through the regulation of ß-catenin stability and function. Our results hold true for different megakaryocytic cell lines and also for haematopoietic progenitors, suggesting that these two proteins may play a relevant role during in vivo megakaryopoiesis.

Anatomical connectivity changes in the bilingual brain.

How the brain deals with more than one language and whether we need different or extra brain language sub-networks to support more than one language remain unanswered questions. Here, we investigate structural brain network differences between early bilinguals and monolinguals. Using diffusion-weighted MRI (DW-MRI) tractography techniques and a network-based statistic (NBS) procedure, we found two structural sub-networks more connected by white matter (WM) tracts in bilinguals than in monolinguals; confirming WM brain plasticity in bilinguals. One of these sub-networks comprises left frontal and parietal/temporal regions, while the other comprises left occipital and parietal/temporal regions and also the right superior frontal gyrus. Most of these regions have been related to language processing and monitoring; suggesting that bilinguals develop specialized language sub-networks to deal with the two languages. Additionally, a complex network analysis showed that these sub-networks are more graph-efficient in bilinguals than monolinguals and this increase seems to be at the expense of a whole-network graph-efficiency decrease.

Brain hemispheric structural efficiency and interconnectivity rightward asymmetry in human and nonhuman primates.

Evidence for interregional structural asymmetries has been previously reported for brain anatomic regions supporting well-described functional lateralization. Here, we aimed to investigate whether the two brain hemispheres demonstrate dissimilar general structural attributes implying different principles on information flow management. Common left hemisphere/right hemisphere structural network properties are estimated and compared for right-handed healthy human subjects and a nonhuman primate, by means of 3 different diffusion-weighted magnetic resonance imaging fiber tractography algorithms and a graph theory framework. In both the human and the nonhuman primate, the data support the conclusion that, in terms of the graph framework, the right hemisphere is significantly more efficient and interconnected than the left hemisphere, whereas the left hemisphere presents more central or indispensable regions for the whole-brain structural network than the right hemisphere. From our point of view, in terms of functional principles, this pattern could be related with the fact that the left hemisphere has a leading role for highly demanding specific process, such as language and motor actions, which may require dedicated specialized networks, whereas the right hemisphere has a leading role for more general process, such as integration tasks, which may require a more general level of interconnection.

SHP1 and SHP2 inhibition enhances the pro-differentiative effect of phorbol esters: an alternative approach against acute myeloid leukemia.

BACKGROUND: The differentiation-based therapy for acute promyelocytic leukemia (APL) is an inspiring example for the search of novel strategies aimed at treatment of other subtypes of acute myeloid leukemia (AML). Thus, the discovery of new molecular players in cell differentiation becomes a paramount research area to achieve this goal. Here, the involvement of the protein tyrosine phosphatases SHP1 and SHP2 on leukemic cells differentiation is shown, along with the therapeutic possibilities of their targeting to enhance the differentiation induction effect of phorbol esters. METHODS: The oxidation status and enzymatic activity of SHP1 and SHP2 during PMA-induced differentiation of HEL cells was evaluated. Additionally, the effects of RNAi-mediated downregulation of these phosphatases on cell differentiation was studied. Afterwards, the impact of chemical inhibition of SHP1 and SHP2 on differentiation both in the presence and absence of phorbol esters was tested. Finally, the anti-leukemic potential of phorbol esters and chemical inhibitors of SHP1 and SHP2 was addressed in several AML model cell lines, a xenograft mouse model and AML primary cells in vitro. RESULTS: An increase of oxidation with a concomitant decrease of activity was observed for both phosphatases at the onset of PMA-induced differentiation. Consistently, silencing of these proteins favored the process, with an enhanced effect upon their simultaneous downregulation. Moreover, the proteins SRC and ß-catenin were identified as downstream targets of SHP1 and SHP2 in this context. In agreement with these findings, chemical inhibition of the phosphatases promoted cell differentiation itself and enhanced the effect of phorbol esters. Interestingly, treatment with the phorbol ester prostratin and the dual inhibitor of SHP1 and SHP2 NSC87877 synergistically hampered the proliferation of AML cell lines, prolonged the survival of xenografted mice and reduced the clonogenic potential of AML primary cells. CONCLUSIONS: SHP1 and SHP2 are relevant mediators of differentiation in AML cells and their inhibition either alone or in combination with prostratin seems a promising differentiation-based therapeutic strategy against different subtypes of AML beyond APL.

Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side.

Oxidative stress is related to ageing and degenerative diseases, including cancer. However, a moderate amount of reactive oxygen species (ROS) is required for the regulation of cellular signalling and gene expression. A low level of ROS is important for maintaining quiescence and the differentiation potential of haematopoietic stem cells (HSCs), whereas the level of ROS increases during haematopoietic differentiation; thus, suggesting the importance of redox signalling in haematopoiesis. Here, we will analyse the importance of ROS for haematopoiesis and include evidence showing that cells from leukaemia patients live under oxidative stress. The potential sources of ROS will be described. Finally, the level of oxidative stress in leukaemic cells can also be harnessed for therapeutic purposes. In this regard, the reliance of front-line anti-leukaemia chemotherapeutics on increased levels of ROS for their mechanism of action, as well as the active search for novel compounds that modulate the redox state of leukaemic cells, will be analysed.

Automated discrimination of brain pathological state attending to complex structural brain network properties: the shiverer mutant mouse case.

Neuroimaging classification procedures between normal and pathological subjects are sparse and highly dependent of an expert's clinical criterion. Here, we aimed to investigate whether possible brain structural network differences in the shiverer mouse mutant, a relevant animal model of myelin related diseases, can reflect intrinsic individual brain properties that allow the automatic discrimination between the shiverer and normal subjects. Common structural networks properties between shiverer (C3Fe.SWV Mbp(shi)/Mbp(shi), n = 6) and background control (C3HeB.FeJ, n = 6) mice are estimated and compared by means of three diffusion weighted MRI (DW-MRI) fiber tractography algorithms and a graph framework. Firstly, we found that brain networks of control group are significantly more clustered, modularized, efficient and optimized than those of the shiverer group, which presented significantly increased characteristic path length. These results are in line with previous structural/functional complex brain networks analysis that have revealed topologic differences and brain network randomization associated to specific states of human brain pathology. In addition, by means of network measures spatial representations and discrimination analysis, we show that it is possible to classify with high accuracy to which group each subject belongs, providing also a probability value of being a normal or shiverer subject as an individual anatomical classifier. The obtained correct predictions (e.g., around 91.6-100%) and clear spatial subdivisions between control and shiverer mice, suggest that there might exist specific network subspaces corresponding to specific brain disorders, supporting also the point of view that complex brain network analyses constitutes promising tools in the future creation of interpretable imaging biomarkers.