Calcitriol attenuates liver fibrosis through hepatitis C virus nonstructural protein 3-transactivated protein 1-mediated TGF β1/Smad3 and NF-κB signaling pathways

BACKGROUND Hepatic fibrosis is a serious condition,and the development of hepatic fibrosis can lead to a series of complications.However,the pathogenesis of hepatic fibrosis remains unclear,and effective therapy options are still lacking.Our group identified hepatitis C virus nonstructural protein 3-transactivated protein 1(NS3TP1) by suppressive subtractive hybridization and bioinformatics analysis,but its role in diseases including hepatic fibrosis remains undefined.Therefore,additional studies on the function of NS3TP1 in hepatic fibrosis are urgently needed to provide new targets for treatment.AIM To elucidate the mechanism of NS3TP1 in hepatic fibrosis and the regulatory effects of calcitriol on NS3TP1.METHODS Twenty-four male C57BL/6 mice were randomized and separated into three groups,comprising the normal,fibrosis,and calcitriol treatment groups,and liver fibrosis was modeled by carbon tetrachloride(CCl4).To evaluate the level of hepatic fibrosis in every group,serological and pathological examinations of the liver were conducted.TGF-β1 was administered to boost the in vitro cultivation of LX-2 cells.NS3TP1,α-smooth muscle actin(α-SMA),collagen I,and collagen Ⅲ in every group were examined using a Western blot and real-time quantitative polymerase chain reaction.The activity of the transforming growth factor beta 1(TGFβ1)/Smad3 and NF-κB signaling pathways in each group of cells transfected with pcDNA-NS3TP1 or siRNA-NS3TP1 was detected.The statistical analysis of the data was performed using the Student’s t test.RESULTS NS3TP1 promoted the activation,proliferation,and differentiation of hepatic stellate cells(HSCs)and enhanced hepatic fibrosis via the TGFβ1/Smad3 and NF-κB signaling pathways,as evidenced by the presence of α-SMA,collagen I,collagen Ⅲ,p-smad3,and p-p65 in LX-2 cells,which were upregulated after NS3TP1 overexpression and downregulated after NS3TP1 interference.The proliferation of HSCs was lowered after NS3TP1 interference and elevated after NS3TP1 overexpression,as shown by the luciferase assay.NS3TP1 inhibited the apoptosis of HSCs.Moreover,both Smad3 and p65 could bind to NS3TP1,and p65 increased the promoter activity of NS3TP1,while NS3TP1 increased the promoter activity of TGFβ1 receptor I,as indicated by coimmunoprecipitation and luciferase assay results.Both in vivo and in vitro,treatment with calcitriol dramatically reduced the expression of NS3TP1.Calcitriol therapy-controlled HSCs activation,proliferation,and differentiation and substantially suppressed CCl4-induced hepatic fibrosis in mice.Furthermore,calcitriol modulated the activities of the above signaling pathways via downregulation of NS3TP1.CONCLUSION Our results suggest that calcitriol may be employed as an adjuvant therapy for hepatic fibrosis and that NS3TP1 is a unique,prospective therapeutic target in hepatic fibrosis.

Recent evidence for subcutaneous drains to prevent surgical site infections after abdominal surgery:A systematic review and metaanalysis

BACKGROUND Surgical site infections(SSIs)increase mortality,hospital stays,additional medical treatment,and medical costs.Subcutaneous drains prevent SSIs in gynecological and breast surgeries;however,their clinical impact in abdominal surgery remains unclear.AIM To investigate whether subcutaneous drains were beneficial in abdominal surgery using a systematic review and meta-analysis.METHODS The database search used PubMed,MEDLINE,and the Cochrane Library.The following inclusion criteria were set for the systematic review:(1)Randomized controlled trial studies comparing SSIs after abdominal surgery with or without subcutaneous drains;and(2)Studies that described clinical outcomes,such as SSIs,seroma formation,the length of hospital stays,and mortality.RESULTS Eight studies were included in this meta-analysis.The rate of total SSIs was significantly lower in the drained group(54/771,7.0%)than in the control group(89/759,11.7%),particularly in gastrointestinal surgery.Furthermore,the rate of superficial SSIs was slightly lower in the drained group(31/517,6.0%)than in the control group(49/521,9.4%).No significant differences were observed in seroma formation between the groups.Hospital stays were shorter in the drained group than in the control group.CONCLUSION Subcutaneous drains after abdominal surgery prevented SSIs and reduced hospital stays but did not significantly affect seroma formation.The timing of drain removal needs to be reconsidered in future studies.

Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apoptosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice.

Isolation and characterization of bioactive fungi from shark Carcharodon carcharias' gill with biopharmaceutical prospects

Until recently,little was known about the fungi found in shark gills and their biomedicinal potential. In this article,we described the isolation,bioactivity,diversity,and secondary metabolites of bioactive fungi from the gill of a shark(Carcharodon carcharias). A total of 115 isolates were obtained and grown in 12 culture media. Fifty-eight of these isolates demonstrated significant activity in four antimicrobial,pesticidal,and cytotoxic bioassay models. Four randomly selected bioactive isolates inhibited human cancer cell proliferation during re-screening. These active isolates were segregated into 6 genera using the internal transcribed spacer-large subunit(ITS-LSU) rDNA-sequence BLAST comparison. Four genera,Penicillium,Aspergillus,Mucor,and Chaetomium were the dominant taxa. A phylogenic tree illustrated their intergenera and intragenera genetic diversity. HPLC-DAD-HRMS analysis and subsequent database searching revealed that nine representative strains produced diverse bioactive compound profiles. These results detail the broad range of bioactive fungi found in a shark's gills,revealing their biopharmaceutical potential. To the best of our knowledge,this is the first study characterizing shark gill fungi and their bioactivity.

Aetiology of Tick-Borne Infections in an Adult Swedish Population—Are Co-Infections with Multiple Agents Common?

In Scandinavia, tick-borne infections affecting humans include Lyme borreliosis (LB), tick-borne encephalitis (TBE) and human granulocytic anaplasmosis (HGA). Each of these infections can present with unspecific symptoms. In this prospective clinical study, we recruited patients based on two independent inclusion criteria;1) patients with unspecific symptoms, i.e. fever (≥38.0℃) or a history of feverishness and/or any combination of headache, myalgia or arthralgia and 2) patients with erythema migrans (EM), following an observed tick bite or tick exposure within one month prior to onset of symptoms. A total of 206 patients fulfilled the study. Among these, we could identify 186 cases of LB (174 with EM), 18 confirmed and two probable cases of HGA and two cases of TBE. Thirteen of the HGA cases presented without fever. Furthermore, 22 of the EM patients had a sub-clinical co-infection with Anaplasma phagocytophilum, based on serology. Both TBE cases had co-infections, one with Borrelia burgdorferi and one with Anaplasma phagocytophilum. We conclude that it is important to consider several causative agents and possible co-infections in the clinical management of infectious diseases where ticks may be suspected as vectors.

Colonization by Superantigen Producing Staphylococcus aureus in Mice Enhances the Capacity to Develop Oral Tolerance

Microbial stimulation in early childhood may be necessary for proper maturation of the immune system. Infants colonized with Staphylococcus aureus have low risk of developing food allergy. Neonatal exposure to staphylococcal superantigen improves oral tolerance and enhances protection in experimental allergy models. Here, we used three wild-type strains of S. aureus, naturally harboring genes for different superantigens (SElM/SElO alone, or in combination with SEA or TSST-1). We first investigated their in vitro stimulatory capacity of splenocytes from germ-free mice. Secondly, germ-free mice were colonized with the strains and their capacity to develop oral tolerance was tested in a food allergy model. In vitro, S. aureus with only SElM/SElO genes promoted the strongest B-cell stimulation. S. aureus carrying gene for SEA induced the highest proportion of CD4+FoxP3+ T cells. The proportion of regulatory T cells was inversely correlated to B-cell proliferation, indicating suppressive ability of these cells. All strains were equally able to colonize the germ-free gut, initially achieving 1010CFU/g faeces, which decreased to 105 over a period of six weeks. Mice colonized with S. aureus carrying genes for SEA or TSST-1 had improved capacity to develop tolerance compared to germ-free mice. These results suggest that colonization by S. aureus producing superantigens may improve active tolerance to gut allergens.

Hypertension Unusual Cause

We expose a case of a woman with hypertension and hypokalemia. The differential diagnosis should include primary hyperaldosteronism, diuretics or lazantes intake, secondary hyperaldosteronism. In this patient, additional tests performed show no cause of hormonal disruption and the whole picture is due to a high intake of licorice. Glycyrrhetinic acid, the active component of licorice, inhibits renal IIbeta-hydroxisteroid dehydrogenase. This allows cortisol to stimulate mineralocorticoid receptors. Licorice ingestion should be considered in the differential diagnosis of hypertension with hypokalemia.

Evolution of Biochemical Effects of Byetta^®in Type 2 Diabetics with Cardiovascular Risk

The objective of this study was to examine longitudinally the effects of exenatide on different physical and biochemical markers, evaluated in adult type 2 diabetic patients with cardiovascular risk. Data were recorded from 10 patients who attended the outpatient primary care health center Mariano Iago Yecla, Murcia province, Spain in the period of December 2009 to October 2011 and who were treated with Byetta®. Differences were statistically significant (p 0.05) in HbA1c from the third month of treatment, and trends of decrease in body weight from the third week of treatment. There was a significant and better glycemic control. Overall effect was interpreted as a sensitizer drug of the parameters evaluated. Randomized studies are recommended with a minimum follow-up of 2 years, to see if the results are maintained over time.

Pleiotropic Effects of GLP-1. Cardiovascular Evidence of Effectiveness

Patients with diabetes are characterized by the development of cardiovascular complications: nephropathy, retinopathy, neuropathy, ischemia or hypertensive etc. Therefore, the cardiovascular involvement is the leading cause of death in patients with Diabetes Mellitus type 2 (DM2). Despite intensive treatment on classical factors of cardiovascular disease (blood pressure levels, LDL cholesterol, etc.), patients with diabetes have a high number of cardiovascular events and the onset and prognosis of these are related to glycemic control parameters, glycosylated hemoglobin (HbA1c). On the other hand, the question of the cardiovascular protective effect of some hypoglycemic treatments has been raised, asking what he has done to know more accurately about the safety and cardiovascular effects of the treatments we have today. The two most important incretin hormones are GIP (gastric inhibitory polypeptide) and GLP-1 (glucagon-like peptide-1). Treatment based on GLP-1 is a novel weapon in T2DM that achieves a reduction in HbA1c with other metabolic effects: weight loss and extra effect in dyslipidemia and blood pressure. In the last years other beneficial actions such a protector effect against myocardium ischemia and other actions in basals were reported. In this article we will try to explain the evidence of GLP-1 treatments and its cardiovascular effects.

Morbid Obesity in Diabetes Mellitus Type 2 and Exenatide

Worldwide, the prevalence of diabetes and obesity is increasing in recent years in developed countries. The first step of treatment is changes in lifestyle and in case of failure to initiate drug treatment. In our case, the patient with morbid obesity and glucose intolerance to metformin therapy was initiated without achieving weight loss and loss of glycemic control after 6 months of treatment. It was decided to add exenatide as an alternative to bariatric surgery. At the end of the study (12 months), it showed a weight reduction of 20.8% (Table 1), 20.83% BMI, glycosylated hemoglobin decrease of 2 points, and improved the lipid profile. So exenatide may be an acceptable option in the use of patient profile. It would be necessary to seek a new alternative treatment with minimal side effects and less healthcare costs.

Review: Surgical Treatment of Type 2 Diabetes

In the last decades we have witnessed a significant increase in the incidence of type 2 diabetes mellitus, and obesity in parallel. So 90% of patients with Diabetes Mellitus type 2 (DM2) are obese. Changes in lifestyle (diet and exercise), behavioral therapies or the use of certain anti-obesity drugs have shown a limited effect and are not maintained over time. Currently, bariatric surgery is the most effective anti-obesity treatment, which is durable and resolves associated comorbidities. The surgical treatment of obesity for the modification of the anatomy of the digestive system is to produce gastric capacity constraints alone or associate with varying degrees of intestinal malabsorption and reduce body weight, improve and maintain the comorbidities associated weight loss by reduced food intake alone or in combination with malabsorption of this. The development of these surgical techniques has occurred in stages. With these techniques, setting to bariatric surgery is an effective, safe and proven procedure for the treatment of obesity and its complications especially DM2, as their post surgery referral mechanisms provide us with information for potential therapeutic treatment aimed at optimizing the control DM2 patients metabolic obese. In this review, we expose the evidence in treatment of DM2 with bariatric surgery and the actual hypothesis trying to explain how it is possible.

Activated Natural Killer Cells Hit Neurogenesis in the Aging Brain

Why neurogenesis is attenuated in elderly individuals is an intriguing question that has raised renewed interest.Mechanisms associated with declined neurogenesis in the aged brain have been attributed to inflammatory cytokines[1].More recently,a specific role for interferon-y(IFN-y)produced by CD8-expressing cytotoxic T cells has been implicated[2].These observations suggest a scenario in which neurogenesis,at least in part,is regulated by immune cells within the aging brain.This raises several interesting questions with regards to the characteristics of specific immune cells within the brain,the signals for their expansion and maintenance,and their role in affecting neurogenesis and cognition during normal brain aging.