Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress

Aim. Nonalcoholic steatohepatitis (NASH) is the consequence of insulin resistance, fatty acid accumulation, oxidative stress, and lipotoxicity.We hypothesize that an increase in the inflammatory adipokine NOV decreases antioxidant Heme Oxygenase 1 (HO- 1) levels in adipose and hepatic tissue, resulting in the development of NASH in obese mice. Methods. Mice were fed a high fat diet (HFD) and obese animals were administered an HO-1 inducer with or without an inhibitor of HO activity to examine levels of adipose-derived NOV and possible links between increased synthesis of inflammatory adipokines and hepatic pathology. Results. NASH mice displayed decreased HO-1 levels and HO activity, increased levels of hepatic heme, NOV, MMP2, hepcidin, and increased NAS scores and hepatic fibrosis. IncreasedHO-1 levels are associated with a decrease in NOV, improved hepatic NAS score, ameliorated fibrosis, and increases in mitochondrial integrity and insulin receptor phosphorylation. Adipose tissue function is disrupted in obesity as evidenced by an increase in proinflammatory molecules such as NOV and a decrease in adiponectin. Importantly, increased HO-1 levels are associated with a decrease of NOV, increased adiponectin levels, and increased levels of thermogenic and mitochondrial signaling associated genes in adipose tissue. Conclusions.These results suggest that the metabolic abnormalities in NASH are driven by decreased levels of hepatic HO-1 that is associated with an increase in the adipose-derived proinflammatory adipokine NOV in our obese mouse model of NASH. Concurrently, induction of HO-1 provides protection against insulin resistance as seen by increased insulin receptor phosphorylation. Pharmacological increases in HO-1 associated with decreases in NOV may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NASH

The Terracol and Ardouin developmental model of frontal sinus drainage pathway and surrounding spaces: a radiologic validation

The complexity of the frontal sinus drainage pathway (FSDP) can be challenging even for expert surgeons. Several classifications have been proposed to simplify the understanding of FSDP, whose anatomical variability can be simplified based on the knowledge of its developmental mechanisms

Stress proteins in experimental nephrotoxicity: a ten year experience

Heat shock proteins and glucose­regulated proteins represent an extraordinary mechanism of defense induced in the kidney by chemicals or drugs and essential to survive. Here we resume our experience on the presence and regulation of stress proteins into acute and chronic nephrotoxic models in rodents and in vitro. In acute renal damage, induced in rats by a single injection of inorganic mercury, stress proteins enhanced in a dose-dependent manner to recover cytoskeleton and mitochondria and maintain nuclear activity. When we pre-treated mercury injected-rats with antioxidant melatonin or with bimoclomol, a stress proteins-coinducer, stress proteins expression was modulated together with tubular recovery. Similar data were obtained in ischemia-reperfusion in rats treated with stannous chloride, that provided cytoprotection stimulating heme oxygenase induction. During nephrotoxicity induced by administration of cyclosporine A at therapeutic dosage for 1-2 months, stress protein overexpression well correlated with oxidative and cell death, but decreased if we counteracted renal damage using antioxidants. In aluminium intoxication through drinking water for 3-6 months, we detected a time-dependent stress response in the rat kidney that was organ specific and different from the liver. In vitro studies on rat tubular proximal cells exposed to heavy metals demonstrated that stress protein expression was related to peculiar mechanisms of action of each metal. In conclusion, experimental studies on the renal chaperones can greatly contribute to understand their role, and agents able to modulate the stress response might be considered promising therapeutic tools to reduce nephrotoxicity

Expression of endothelial nitric oxide synthase in blood vessels and silicic acid consumption

NO produces by endothelial nitric oxide synthase (eNOS) represents one of the most representative vasoactive molecules able to regulate vascular tone; it is released by endothelial cells and it diffuses to adjacent vascular smooth muscle cells causing vasorelaxation. In addition, endothelium-derived NO is know to be involved in multiple ways to prevent the progression of age-related vascular diseases. Senescent endothelial cells are characterized by a decreased production of endothelium-derived NO due to a decrease of eNOS activity that could be attributable to a reduction in eNOS protein expression as well as in eNOS phosphorylation (Matsushita et al., 2001). Previous studies showed that silicon, mainly as silicic acid, plays an important role as protective factor against the development of age-related vascular diseases, maintaining integrity, stability and elastic properties of arterial walls (Schwarz et al., 1977). So, the aim of this study was to evaluate the relationship between the expression of eNOS and silicic acid consumption in a mouse model of early physiological aging. We evaluated qualitatively and quantitatively by immunohistochemical method, the expression of eNOS in the vessel wall of aorta and renal vessels in relation with the administration of silicic acid in drinking water. The results showed that loss of eNOS expression was prevented by regular consumption of silicic acid rich water, supporting the potential protective role of silicon against age related-vascular disorders

Ethmoidal arteries variability: an anatomical and radiological study

Understanding the location of ethmoidal arteries (EAs) is crucial during endo- scopic sinus surgery or skull base surgery. The aim of this study was to evaluate the anatomical variability of EAs, considering their presence and position within the ethmoid bone and their position in relation to the skull base (SB) and the frontal sinus (FS). Fourteen human heads underwent a cone-beam CT scan and an endoscopic dissection was carried out to evaluate the anatomy of the EAs. Several features were assessed both radiologically and in the lab setting: presence; position according to the “5 doors theory” (1); position respect to the SB; distance from the SB; relation with the FS (2); dehiscence of the bony canal. Anterior EA and posterior EA were present in all cases, whereas the prevalence of the middle EA was 28.57±16.73%. Anterior EA was most frequently found (64.29%) in the basal lamella of the middle turbinate; it originated from the SB in 60.71% of cases and it was separated from the FS by a single bony lamella in 46.43%. Its canal was dehiscent in 46.43±18.47%. Posterior EA was almost equally found posterior to the basal lamella of the middle turbinate, in the basal lamella of the superior turbinate and posterior to it. It was found in the SB in 82.14% of the cases and its canal was dehiscent in the 28.57±16.73%. Middle EA was found posterior to the basal lamella of the middle turbinate in 62.50% of cas- es and it was found in the SB in 75.00% of the cases. These data demonstrate that, despite their constant presence, anterior and posterior EAs showed a variable position and relationship with the SB; in addition, the data showed a non-negligible number of cases in which the middle MEA was present. Therefore, because of these several anatomical variability in EAs, a high-spatial-resolution CT should be provided for the preoperative anatomical assessment

Platelet preparations in neuronal cell differentiation

Concentrated Growth Factors (CGF) is a platelet rich preparation that has the important feature of a tight fibrin network and containing a large number of growth factors possessing great regenerative potentialities [1]. The regeneration of nervous system is one of the mail goal of regenerative medicine. The aim of this study is to test the in vitro CGF effects on both differentiated and undifferentiated SH-SY5Y cells, derived from human neuroblastoma. To induce differentiation, SH-SY5Y cells have been treated with Retinoic Acid (RA) 10µM, in both basal and complete medium and in the presence and absence of CGF. After 72 hours, different parameters have been investigated: the morphological characteristics of the cells, the cell proliferation, the cellular vitality using the MTT test, the CGF and/or RA differentiation property and the immunocytochemical analysis of neuronal specific markers (NeuN, Sinaptophisine, β-III-tubulin, Nestin). Moreover the NGF (Nerve Growth Factor) and BDNF (Brain Derived Growth Factor) release have been assayed by ELISA test. Our results obtained suggest that treatment with CGF, also used alone, positively affects cell differentiation and neuronal phenotype regulating the expression of the neuronal markers and improving the outgrowth of neurites. Taken together these results seems to be promised into new approaches for neuronal regeneration using platelet preparations

The anastomotic network around the anterior superior alveolar nerve: an anatomical and radiological study

Innervation of superior teeth is supplied by the posterior (PSAN), anterior (ASAN) and sometimes by middle superior alveolar nerve (MSAN). PSAN arises from the maxillary nerve and passes through the posterolateral maxillary wall towards the posterior teeth. ASAN arises from the anterior portion of the infraorbital nerve and courses within the infraorbital canal passing nearby the piriform aperture and premaxilla. When present, MSAN arises from the posterior portion of the infraorbital nerve and runs along the lateral maxillary wall. However, an additional nasopalatine or sublabial injection is frequently required to obtain a complete anesthesia of the maxillary teeth due to rich anastomotic network (1-2). With the aim to better describe the complexity of the superior alveolar nerve network, fifty-seven high-definition sinonasal cone-beam CT (CBCT) were analyzed. PSAN, ASAN and MSAN were detected by specific bony landmarks/canals and nervous anastomoses were accurately evaluated. In addition, medial anastomotic branches from the palatal and/or nasal nervous plexi were also considered. PSAN and ASAN were identified in 100% of cases whereas MSAN in 19.6% of cases. Anastomotic branch versus ASAN was identified in all cases from MSAN and in 60.3% from PSAN. Medial anastomotic branch was detected in 62.0% of cases from the nasal plexus and in 6.2% from the palatal plexus: the former passed through a bony defect in the floor of the piriform aperture or at the base of the nasal septum; the latter passed through a tiny canal in the interface between maxilla and premaxilla. These data confirm that maxillary teeth innervation, especially for incisor teeth, could be provided not only by alveolar nerves but also from palatal and nasal plexi via small branches running within maxillary bony canals. These results support the need of additional anesthetic injection to obtain adequate anesthesia of the maxillary teeth; moreover, the role of CBCT in the identification of the nervous pattern was underlined

The frontoethmoidal architecture: a developmental point of view

The anatomy of frontal sinus drainage pathway (FSDP) and surrounding spaces is extremely complex and variable. Its anatomical variability can be simplified based on the knowledge of the developmental mechanism of the frontal recess. The frontal sinus develops from the 13th week of intrauterine life to the age of twenty through a number of well-known steps of progressive extension within the frontal bone. Its development results from an upward epithelial migration of the anterior ethmoidal cells that penetrate the inferior aspect of the frontal bone between its two diploic plates. Even though this developmental theory is almost universally accepted, only few Authors focused on the formation of FSDP prior to the extramural pneumatization (1-2). The results of the present study conducted on 14 human heads match with the developmental model proposed by Terracol and Ardouin (2), in fact a number of significant associations are conform to the process of growing of the frontal sinus from one out of the three primordial cells (i.e. orbital, nasal, or bullar cell). In this model, renewed in view of the observation of the present study, the hierarchical order of growing among primordial cells determines the final frontoethmoidal architecture

3D gelatin-chitosan hybrid hydrogels combined with human platelet lysate highly support human mesenchymal stem cell proliferation and osteogenic differentiation

Bone marrow and adipose tissue human mesenchymal stem cells were seeded in highly performing 3D gelatin–chitosan hybrid hydrogels of varying chitosan content in the presence of human platelet lysate and evaluated for their proliferation and osteogenic differentiation. Both bone marrow and adipose tissue human mesenchymal stem cells in gelatin–chitosan hybrid hydrogel 1 (chitosan content 8.1%) or gelatin–chitosan hybrid hydrogel 2 (chitosan 14.9%) showed high levels of viability (80%–90%), and their proliferation and osteogenic differentiation was significantly higher with human platelet lysate compared to fetal bovine serum, particularly in gelatin–chitosan hybrid hydrogel 1. Mineralization was detected early, after 21 days of culture, when human platelet lysate was used in the presence of osteogenic stimuli. Proteomic characterization of human platelet lysate highlighted 59 proteins mainly involved in functions related to cell adhesion, cellular repairing mechanisms, and regulation of cell differentiation. In conclusion, the combination of our gelatin–chitosan hybrid hydrogels with hPL represents a promising strategy for bone regenerative medicine using human mesenchymal stem cells