Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of morbidity and mortality in neonates. Because of high concentrations of sensitive immature cells, metal-catalyzed free radicals, non-saturated fatty acids, and low concentrations of antioxidant enzymes, the brain requires high levels of oxygen supply and is, thus, extremely sensitive to hypoxia. Strong evidence indicates that oxidative stress plays an important role in pathogenesis and progression. Following hypoxia and ischemia, reactive oxygen species (ROS) production rapidly increases and overwhelms antioxidant defenses. A large excess of ROS will directly modify or degenerate cellular macromolecules, such as membranes, proteins, lipids, and DNA, and lead to a cascading inflammatory response, and protease secretion. These derivatives are involved in a complex interplay of multiple pathways (e.g., inflammation, apoptosis, autophagy, and necrosis) which finally lead to brain injury. In this review, we highlight the molecular mechanism for oxidative stress in HIE, summarize current research on therapeutic strategies utilized in combating oxidative stress, and try to explore novel potential clinical approaches.

Hydrogen exerts beneficial effects in disease animal models of ischemia-reperfusion injury as well as inflammatory and neurological disease. Additionally, molecular hydrogen is useful for various novel medical and therapeutic applications in the clinical setting. In the present study, the hydrogen concentration in rat blood and tissue was estimated. Wistar rats were orally administered hydrogen super-rich water (HSRW), intraperitoneal and intravenous administration of hydrogen super-rich saline (HSRS) and inhalation of hydrogen gas. A new method for determining the hydrogen concentration was then applied using high-quality sensor gas chromatography, after which the specimen was prepared via tissue homogenization in airtight tubes. This method allowed for the sensitive and stable determination of the hydrogen concentration. The hydrogen concentration reached a peak at 5 minutes after oral and intraperitoneal administration, compared to 1 minute after intravenous administration. Following inhalation of hydrogen gas, the hydrogen concentration was found to be significantly increased at 30 minutes and maintained the same level thereafter. These results demonstrate that accurately determining the hydrogen concentration in rat blood and organ tissue is very useful and important for the application of various novel medical and therapeutic therapies using molecular hydrogen.

Cytokines play important roles in all stages of steatohepatitis, including hepatocyte injury, the inflammatory response, and the altered function of sinusoidal cells. This study examined the involvement of a major inflammatory cytokine, interferon-γ (IFN-γ), in the progression of steatohepatitis. In a steatohepatitis model by feeding a methionine- and choline-deficient high-fat (MCDHF) diet to both wild-type and IFN-γ-deficient mice, the liver histology, expression of genes encoding inflammatory cytokines, and fibrosis-related markers were examined. To analyze the effects of IFN-γ on Kupffer cells in vitro, we examined the tumor necrosis factor-α (TNF-α) production by a mouse macrophage cell line. Forty two days of MCDHF diet resulted in weight loss, elevated aminotransferases, liver steatosis, and inflammation in wild-type mice. However, the IFN-γ-deficient mice exhibited less extensive changes. RT-PCR revealed that the expression of tumor necrosis factor-α (TNF-α), transforming growth factor-β, inducible nitric oxide synthase, interleukin-4 and osteopontin were increased in wild-type mice, although they were suppressed in IFN-γ-deficient mice. Seventy days of MCDHF diet induced much more liver fibrosis in wild-type mice than in IFN-γ-deficient mice. The expression levels of fibrosis-related genes, α-smooth muscle actin, type I collagen, tissue inhibitor of matrix metalloproteinase-1, and matrix metalloproteinase-2, were dramatically increased in wild-type mice, whereas they were significantly suppressed in IFN-γ-deficient mice. Moreover, in vitro experiments showed that, when RAW 264.7 macrophages were treated with IFN-γ, they produced TNF-α in a dose-dependent manner. The present study showed that IFN-γ deficiency might inhibit the inflammatory response of macrophages cells and subsequently suppress stellate cell activation and liver fibrosis. These findings highlight the critical role of IFN-γ in the progression of steatohepatitis.

During aortic surgery, interruption of spinal cord blood flow might cause spinal cord ischemia-reperfusion injury (IRI). The incidence of spinal cord IRI after aortic surgery is up to 28%, and patients with spinal cord IRI might suffer from postoperative paraplegia or paraparesis. Spinal cord IRI includes two phases. The immediate spinal cord injury is related to acute ischemia. And the delayed spinal cord injury involves both ischemic cellular death and reperfusion injury. Inflammation is a subsequent event of spinal cord ischemia and possibly a major contributor to spinal cord IRI. However, the development of inflammatory mediators is incompletely demonstrated. And treatments available for inflammation in spinal cord IRI are insufficient. Improved understanding about spinal cord IRI and the development of inflammatory cells and cytokines in this process will provide novel therapeutic strategies for spinal cord IRI. Inflammatory cytokines (e.g., TNF-αand IL-1) may play an important role in spinal cord IRI. For treatment of several intractable autoimmune diseases (e.g., rheumatoid arthritis), where inflammatory cytokines are involved in disease progression, anti-inflammatory cytokine antagonist is now available. Hence, there is great potential of anti-inflammatory cytokine antagonist for therapeutic use of spinal cord IRI. We here review the mediators and several possibilities of treatment in spinal cord IRI.

5-Aminolevulinic acid (5-ALA) is a naturally occurring amino acid and precursor of heme and protoporphyrin IX (PpIX). Exogenously administrated 5-ALA increases the accumulation of PpIX in tumor cells specifically due to the compromised metabolism of 5-ALA to heme in mitochondria. PpIX emits red fluorescence by the irradiation of blue light and the formation of reactive oxygen species and singlet oxygen. Thus, performing a photodynamic diagnosis (PDD) and photodynamic therapy (PDT) using 5-ALA have given rise to a new strategy for tumor diagnosis and therapy. In addition to the field of tumor therapy, 5-ALA has been implicated in the treatment of inflammatory disease, autoimmune disease and transplantation due to the anti-inflammation and immunoregulation properties that are elicited with the expression of heme oxygenase (HO)-1, an inducible enzyme that catalyzes the rate-limiting step in the oxidative degradation of heme to free iron, biliverdin and carbon monoxide (CO), in combination with sodium ferrous citrate (SFC), because an inhibitor of HO-1 abolishes the effects of 5-ALA. Furthermore, NF-E2-related factor 2 (Nrf2), mitogen-activated protein kinase (MAPK), and heme are involved in the HO-1 expression. Biliverdin and CO are also known to have anti-apoptotic, anti-inflammatory and immunoregulatory functions. We herein review the current use of 5-ALA in inflammatory diseases, transplantation medicine, and tumor therapy.

IgA nephropathy (IgAN) is the most prevalent primary glomerulonephritis worldwide, with diverse clinical manifestations characterized by recurrent gross hematuria or microscopic hematuria, and pathological changes featuring poorly O-galactosylated IgA1 deposition in the glomerular mesangium. Pathogenesis has always been the focus of IgAN studies. After 50 years of research, most scholars agree that IgAN is a group of clinicopathological syndromes with certain common immunopathological characteristics, and multiple mechanisms are involved in its pathogenesis, including immunology, genetics, and environmental or nutritional factors. However, the precise pathogenetic mechanisms have not been fully determined. One hypothesis about the pathogenesis of IgAN suggests that immunological factors are engaged in all aspects of IgAN development and play a critical role. A variety of immune cells (e.g., dendritic cells, NK cells, macrophages, T-lymphocyte subsets, and B-lymphocytes, etc.) and molecules (e.g., IgA receptors, Toll-like receptors, complements, etc.) in innate and adaptive immunity are involved in the pathogenesis of IgAN. Moreover, the abnormality of mucosal immune regulation is the core of IgAN immunopathogenesis. The roles of tonsil immunity or intestinal mucosal immunity, which have received more attention in recent years, are supported by mounting evidence. In this review, we will explore the latest research insights on the role of immune modulation in the pathogenesis of IgAN. With a better understanding of immunopathogenesis of IgAN, emerging therapies will soon become realized.