ABSTRACT
Semicarbazide-sensitive amine oxidase (SSAO) is an enzyme with a unique dual function in controlling inflammation as well as reactive oxygen species (ROS) generation. We have demonstrated benefit of SSAO inhibition in acute kidney fibrosis. However the function of SSAO in chronic kidney disease (CKD) and diabetic kidney disease (DKD) is yet to be determined. We aimed to assess the effectiveness of a SSAO inhibitor (SSAOi; PXS-4728A) as an antifibrotic agent using a diabetic model of CKD. Diabetic mice were treated with SSAOi for 24 weeks and outcomes compared with untreated diabetic mice and telmisartan treated animals as a standard of care comparator. Extracellular matrix markers, fibronectin and oxidative stress, were downregulated in diabetic mice treated with SSAOi compared with untreated diabetic mice. Expression of the pan-leukocyte marker CD45 was also supressed by SSAOi. SSAO inhibition in diabetic mice resulted in a significant reduction in glomerulosclerosis and associated albuminuria compared to untreated diabetic mice. However, the effect of SSAO inhibition was less obvious in the tubulointerstitial compartment than in the glomeruli. Therefore, SSAO may be a potential target for diabetic glomerulosclerosis.
Subject(s)
Albuminuria/drug therapy , Allylamine/analogs & derivatives , Amine Oxidase (Copper-Containing)/antagonists & inhibitors , Benzamides/therapeutic use , Diabetic Nephropathies/drug therapy , Enzyme Inhibitors/therapeutic use , Kidney Glomerulus/pathology , Kidney Tubules/pathology , Renal Insufficiency, Chronic/drug therapy , Allylamine/pharmacology , Allylamine/therapeutic use , Animals , Benzamides/pharmacology , Diabetes Mellitus, Experimental , Diabetic Nephropathies/pathology , Enzyme Inhibitors/pharmacology , Fibronectins/metabolism , Fibrosis , Kidney Glomerulus/drug effects , Kidney Tubules/drug effects , Leukocyte Common Antigens/metabolism , Male , Mice , Mice, Inbred C57BL , Oxidative Stress/drug effects , Renal Insufficiency, Chronic/pathology , Telmisartan/pharmacology , Telmisartan/therapeutic useABSTRACT
Benign biliary strictures can be difficult to manage. Untreated biliary strictures can lead to complications, such as chronic cholestasis, jaundice, recurrent sepsis, and secondary biliary cirrhosis, which can have severe ramifications. The management landscape is constantly evolving, with the development of modifiable self-expandable metal stents and biodegradable stents. This review critically appraises current endoscopic treatment strategies, in particular focusing on the shortfalls, such as stent migration and stricture recurrence. It also proposes a treatment algorithm based on aetiologias and the location of the strictures.
ABSTRACT
INTRODUCTION: Polycystic liver disease (PLD) is characterized by the presence of multiple cholangiocyte-derived hepatic cysts that progressively replace liver tissue. They are classified as an inherited ciliopathy /cholangiopathy as pathology exists at the level of the primary cilia of cholangiocytes. Aberrant expression of the proteins in primary cilia can impair their structures and functions, thereby promoting cystogenesis. Areas covered: This review begins by looking at the epidemiology of PLD and its natural history. It then describes the pathophysiology and corresponding potential treatment strategies for PLD. Expert commentary: Traditionally, therapies for symptomatic PLD have been limited to symptomatic management and surgical interventions. Such techniques are not completely effective, do not alter the natural history of the disease, and are linked with high rate of re-accumulation of cysts. As a result, there has been a push for drugs targeted at abnormal cellular signaling cascades to address deregulated proliferation, cell dedifferentiation, apoptosis and fluid secretion. Currently, the only available drug treatments that halt disease progression and improve quality of life in PLD patients are somatostatin analogues. Numerous preclinical studies suggest that targeting components of the signaling pathways that influence cyst development can ameliorate growth of hepatic cysts.
