Crohn’s disease:Evidence for involvement of unregulated transcytosis in disease etio-pathogenesis

Crohn’s disease(CD)is a chronic inflammatory bowel disease.Research has identified genetic predisposition and environmental factors as key elements in the development of the disease.However,the precise mechanism that initiates immune activation remains undefined.One pathway for luminal antigenic molecules to enter the sterile lamina propria and activate an immune response is via transcytosis.Transcytosis,although tightly regulated by the cell,has the potential for transepithelial transport of bacteria and highly antigenic luminal molecules whose uncontrolled translocation into the lamina propria can be the source of immune activation.Viewed as a whole,the evidence suggests that unregulated intestinal epithelial transcytosis is involved in the inappropriate presentation of immunogenic luminal macromolecules to the intestinal lamina propria.Thus fulfilling the role of an early pre-morbid mechanism that can result in antigenic overload of the lamina propria and initiate an immune response culminating in chronic inflammation characteristic of this disease.It is the aim of this paper to present evidence implicating enterocyte transcytosis in the early etio-pathogenesis of CD.

Anti-Inflammatory and Anti-Angiogenic Properties of VitD3 in Ovarian Cancer

Ovarian malignancies are the most complicated type among all gynecological cancers.Their etiology is yet unknown;however,they are a heterogeneous,rapidly growing,and very fatal group of cancers.Chronic inflammation and angiogenesis appear to have major contributions in the development and progression of ovarian malignancies.Angiogenesis and inflammation are involved in the pathogenesis of ovarian cancer.Vitamin D3(VitD3)has shown to have anti-inflammatory and anti-angiogenic properties in different types of cancers.The anti-inflammatory and anti-angiogenesis effects of VitD3 on ovarian cancer are investigated in this review.

Metabolic theory of septic shock

Septic shock is a life threatening condition that can develop subsequent to infection. Mortality can reach as high as 80% with over 150000 deaths yearly in the United States alone. Septic shock causes progressive failure of vital homeostatic mechanisms culminating in immunosuppression, coagulopathy and microvascular dysfunction which can lead to refractory hypotension, organ failure and death. The hypermetabolic response that accompanies a systemic inflammatory reaction places high demands upon stored nutritional resources. A crucial element that can become depleted early during the progression to septic shock is glutathione. Glutathione is chiefly responsible for supplying reducing equivalents to neutralize hydrogen peroxide, a toxic oxidizing agent that is produced during normal metabolism. Without glutathione, hydrogen peroxide can rise to toxic levels in tissues and blood where it can cause severe oxidative injury to organs and to the microvasculature. Continued exposure can result in microvascular dysfunction, capillary leakage and septic shock. It is the aim of this paper to present evidence that elevated systemic levels of hydrogen peroxide are present inseptic shock victims and that it significantly contributes to the development and progression of this frequently lethal condition.

Evidence-based pathogenesis and treatment of ulcerative colitis:A causal role for colonic epithelial hydrogen peroxide

In this comprehensive evidence-based analysis of ulcerative colitis(UC),a causal role is identified for colonic epithelial hydrogen peroxide(H_(2)O_(2))in both the pathogenesis and relapse of this debilitating inflammatory bowel disease.Studies have shown that H_(2)O_(2) production is significantly increased in the non-inflamed colonic epithelium of individuals with UC.H_(2)O_(2) is a powerful neutrophilic chemo-tactic agent that can diffuse through colonic epithelial cell membranes creating an interstitial chemotactic molecular“trail”that attracts adjacent intra-vascular neutrophils into the colonic epithelium leading to mucosal inflammation and UC.A novel therapy aimed at removing the inappropriate H_(2)O_(2) mediated chemotactic signal has been highly effective in achieving complete histologic resolution of colitis in patients experiencing refractory disease with at least one(biopsy-proven)histologic remission lasting 14 years to date.The evidence implies that therapeutic intervention to prevent the re-establishment of a pathologic H_(2)O_(2) mediated chemotactic signaling gradient will indefinitely preclude neutrophilic migration into the colonic epithelium constituting a functional cure for this disease.Cumulative data indicate that individuals with UC have normal immune systems and current treatment guidelines calling for the suppression of the immune response based on the belief that UC is caused by an underlying immune dysfunction are not supported by the evidence and may cause serious adverse effects.It is the aim of this paper to present experimental and clinical evidence that identifies H_(2)O_(2) produced by the colonic epithelium as the causal agent in the pathogenesis of UC.A detailed explanation of a novel therapeutic intervention to normalize colonic H_(2)O_(2),its rationale,components,and formulation is also provided.

Sepsis:Evidence-based pathogenesis and treatment

Sepsis can develop during the body’s response to a critical illness leading to multiple organ failure,irreversible shock,and death.Sepsis has been vexing health care providers for centuries due to its insidious onset,generalized metabolic dysfunction,and lack of specific therapy.A common factor underlying sepsis is the characteristic hypermetabolic response as the body ramps up every physiological system in its fight against the underlying critical illness.A hypermetabolic response requires supraphysiological amounts of energy,which is mostly supplied via oxidative phosphorylation generated ATP.A by-product of oxidative phosphorylation is hydrogen peroxide(H2O2),a toxic,membranepermeable oxidizing agent that is produced in far greater amounts during a hypermetabolic state.Continued production of mitochondrial H2O2 can overwhelm cellular reductive(antioxidant)capacity leading to a build-up within cells and eventual diffusion into the bloodstream.H2O2 is a metabolic poison that can inhibit enzyme systems leading to organ failure,microangiopathic dysfunction,and irreversible septic shock.The toxic effects of H2O2 mirror the clinical and laboratory abnormalities observed in sepsis,and toxic levels of blood H2O2 have been reported in patients with septic shock.This review provides evidence to support a causal role for H2O2 in the pathogenesis of sepsis,and an evidence-based therapeutic intervention to reduce H2O2 levels in the body and restore redox homeostasis,which is necessary for normal organ function and vascular responsiveness.

Are M1 and M2 macrophages Effectual Players in Pathological Conditions?

Pathologic inflammatory conditions are frequently correlated with dynamic alterations through macrophage activation,with classically activated Ml cells associated with promoting and sustaining inflammation and M2 cells implicated in resolving or smoldering chronic inflammation.Inflammation is a common feature of various chronic diseases,and it has direct involvement in the emergence and progression of these conditions.Macrophages participate in an autoregulatory loop characterizing inflammatory process,as they produce a wide range of biologically active mediators that exert either deleterious or beneficial effects during inflammation.Therefore,balancing the ratio of M1/M2 macrophages can help to ameliorate the inflammatory landscape of pathological conditions.This review will explore the role of macrophage polarization in distant pathological inflammatory conditions,such as cancer,autoimmunity,renal inflammation,stroke,and atherosclerosis,while sharing macrophage-driven pathogenesis.

Th17 Cells and Tregs in HTLV-1 Infection

HTLV-1(human T-lymphotropic virus type 1)causes chronic infection ofhuman T lymphocytes.HTLV-1 infection is known to be related to multiple diseases,including neoplastic growth of HTLV-1-infected T cells(ATL)and neoplastic inflammatory conditions,such as HTLV-1-associated myelopathy/tropical spastic paraparesis(HAM/TSP),Sjogren's syndrome with arthritis,polymyositis uveitis,and bronchoalveolitis.Regulatory T cells(Tregs)regulate inflammatory cells,such as Th17 cells.The purpose of this study was to evaluate Tregs and Th17 cells,as well as the expression of related transcription factors(ROR-γ1 and FOXP3)and cytokines(IL-10,TGF-β,IL-6,and IL-17A)in HTLV-1 infection.