A complex antioxidant system has been developed in mammals to relieve oxidative stress. However, excessive reactive species derived from oxygen and nitrogen may still lead to oxidative damage to tissue and organs. Oxidative stress has been considered as a conjoint pathological mechanism, and it contributes to initiation and progression of liver injury. A lot of risk factors, including alcohol, drugs, environmental pollutants and irradiation, may induce oxidative stress in liver, which in turn results in severe liver diseases, such as alcoholic liver disease and non-alcoholic steatohepatitis. Application of antioxidants signifies a rational curative strategy to prevent and cure liver diseases involving oxidative stress. Although conclusions drawn from clinical studies remain uncertain, animal studies have revealed the promising in vivo therapeutic effect of antioxidants on liver diseases. Natural antioxidants contained in edible or medicinal plants often possess strong antioxidant and free radical scavenging abilities as well as anti-inflammatory action, which are also supposed to be the basis of other bioactivities and health benefits. In this review, PubMed was extensively searched for literature research. The keywords for searching oxidative stress were free radicals, reactive oxygen, nitrogen species, anti-oxidative therapy, Chinese medicines, natural products, antioxidants and liver diseases. The literature, including ours, with studies on oxidative stress and anti-oxidative therapy in liver diseases were the focus. Various factors that cause oxidative stress in liver and effects of antioxidants in the prevention and treatment of liver diseases were summarized, questioned, and discussed.

/pdf/the-role-of-oxidative-stress-and-antioxidants-in-liver-3pnddyz5af.pdf

The Role of Oxidative Stress and Antioxidants in Liver Diseases

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

Heavy metals, which have widespread environmental distribution and originate from natural and anthropogenic sources, are common environmental pollutants. In recent decades, their contamination has increased dramatically because of continuous discharge in sewage and untreated industrial effluents. Because they are non-degradable, they persist in the environment; accordingly, they have received a great deal of attention owing to their potential health and environmental risks. Although the toxic effects of metals depend on the forms and routes of exposure, interruptions of intracellular homeostasis include damage to lipids, proteins, enzymes and DNA via the production of free radicals. Following exposure to heavy metals, their metabolism and subsequent excretion from the body depends on the presence of antioxidants (glutathione, α-tocopherol, ascorbate, etc.) associated with the quenching of free radicals by suspending the activity of enzymes (catalase, peroxidase, and superoxide dismutase). Therefore, this review was written to provide a deep understanding of the mechanisms involved in eliciting their toxicity in order to highlight the necessity for development of strategies to decrease exposure to these metals, as well as to identify substances that contribute significantly to overcome their hazardous effects within the body of living organisms.

Heavy Metals and Human Health: Mechanistic Insight into Toxicity and Counter Defense System of Antioxidants

Superoxide, O2•–, is formed in all living organisms that come in contact with air, and, depending upon its biological context, it may act as a signaling agent, a toxic species, or a harmless intermediate that decomposes spontaneously Its levels are limited in vivo by two different types of enzymes, superoxide reductase (SOR) and superoxide dismutase (SOD) Although superoxide has long been an important factor in evolution, it was not so when life first emerged on Earth at least 35 billion years ago At that time, the early biosphere was highly reducing and lacking in any significant concentrations of dioxygen (O2), very different from what it is today Consequently, there was little or no O2•– and therefore no reason for SOR or SOD enzymes to evolve Instead, the history of biological O2•– probably commences somewhere around 24 billion years ago, when the biosphere started to experience what has been termed the “Great Oxidation Event”, a transformation driven by the increase in O2 levels, formed by cyanobacteria as a product of oxygenic photosynthesis1 The rise of O2 on Earth caused a reshaping of existing metabolic pathways, and it triggered the development of new ones2 Its appearance led to the formation of the so-called “reactive oxygen species” (ROS), for example, superoxide, hydrogen peroxide, and hydroxyl radical, and to a need for antioxidant enzymes and other antioxidant systems to protect against the growing levels of oxidative damage to living systems


Dioxygen is a powerful four-electron oxidizing agent, and the product of this reduction is water




1


When O2 is reduced in four sequential one-electron steps, the intermediates formed are the three major ROS, that is, O2•–, H2O2, and HO•




2





3





4





5



Each of these intermediates is a potent oxidizing agent The consequences of their presence to early life must have been an enormous evolutionary challenge In the case of superoxide, we find the SOD and SOR enzymes to be widely distributed throughout current living organisms, both aerobic and anaerobic, suggesting that, from the start of the rise of O2 on Earth, the chemistry of superoxide has been an important factor during evolution


The SORs and three very different types of SOD enzymes are redox-active metalloenzymes that have evolved entirely independently from one another for the purpose of lowering superoxide concentrations SORs catalyze the one-electron reduction of O2•– to give H2O2, a reaction requiring two protons per superoxide reacted as well as an external reductant to provide the electron (eq 6) SODs catalyze the disproportionation of superoxide to give O2 and H2O2, a reaction requiring one proton per superoxide reacted, but no external reductant (eq 7)




6





7



All of the SOR enzymes contain only iron, while the three types of SODs are the nickel-containing SODs (NiSOD), the iron- or manganese-containing SODs (FeSOD and MnSOD), and the copper- and zinc-containing SODs (CuZnSOD) Although the structures and other properties of these four types of metalloenzymes are quite different, they all share several characteristics, including the ability to react rapidly and selectively with the small anionic substrate O2•– Consequently, there are some striking similarities between these otherwise dissimilar enzymes, many of which can be explained by considering the nature of the chemical reactivity of O2•– (see below)

Numerous valuable reviews describing the SOD and SOR enzymes have appeared over the years, but few have covered and compared all four classes of these enzymes, as we attempt to do here Thus, the purpose of this Review is to describe, compare, and contrast the properties of the SOR and the four SOD enzymes; to summarize what is known about their evolutionary pathways; and to analyze the properties of these enzymes in light of what is known of the inherent chemical reactivity of superoxide

Superoxide dismutases and superoxide reductases

Cell culture is an important tool for biological research. Two-dimensional cell culture has been used for some time now, but growing cells in flat layers on plastic surfaces does not accurately model the in vivo state. As compared to the two-dimensional case, the three-dimensional (3D) cell culture allows biological cells to grow or interact with their surroundings in all three dimensions thanks to an artificial environment. Cells grown in a 3D model have proven to be more physiologically relevant and showed improvements in several studies of biological mechanisms like: cell number monitoring, viability, morphology, proliferation, differentiation, response to stimuli, migration and invasion of tumor cells into surrounding tissues, angiogenesis stimulation and immune system evasion, drug metabolism, gene expression and protein synthesis, general cell function and in vivo relevance. 3D culture models succeed thanks to technological advances, including materials science, cell biology and bioreactor design.

Three-Dimensional Cell Culture: A Breakthrough in Vivo

It has become increasingly apparent that the pain threshold of females and males varies in an estrogen dependent manner. To investigate the modulation of pain by estrogen and the molecular mechanisms involved in this process. A total of 48 rats were ovariectomized (OVX). At 14 and 20 days after OVX, rats were divided into eight groups: groups 1–4 were administered drugs intravenously (IV); groups 5–8 were administered through intrathecal (IT) catheter. Hind paw incision was made in all animals to determine incisional pain. Paw withdraw threshold (PWT) was tested prior to and 24 h after incision. The test drugs were applied 24 h after the incision. Rats were either IV or IT administered with: 17-β-estradiol (E2), G protein-coupled estrogen receptor (GPER)-selective agonist (G1), GPER-selective antagonist (G15) and E2 (G15 + E2), or solvent. Before and 30 min after IV drug administration and 20 min during the IT catheter administration, PWT was tested and recorded. 24 h after incisional surgery, the PWT of all rats significantly decreased. Both in the IV group and IT group: administration of E2 and G1 significantly decreased PWT. Neither administration of G15 + E2 nor solvent significantly changed PWT. Estrogen causes rapid reduction in the mechanical pain threshold of OVX rats via GPER.

Estrogen Rapidly Enhances Incisional Pain of Ovariectomized Rats Primarily through the G Protein-Coupled Estrogen Receptor

Six-month efficacy of the Ketogenic diet is predicted after 3 months and is unrelated to clinical variables

Background There is a large population of people with spinal muscular atrophy (SMA) in China, and new disease-modifying therapies have become available recently. However, comprehensive data on the management and profile of treatment-naive SMA patients in China are still lacking. Methods As a retrospective study, a large cohort of treatment-naive patients with clinical and genetic diagnoses of 5q SMA were enrolled, ranging from neonatal to 18 years old, from the Neurology Department of Children's Hospital of Fudan University between January 2013 and December 2020. The data regarding their clinical presentations, genetic defects, motor function assessment results, and follow ups were reviewed. Results We enrolled 392 SMA patients (male: female = 189: 203): 1a = 46, 1b = 44, 1c = 31, 2a = 119, 2b = 56, 3a = 52, 3b = 14, from 27 of the 34 administrative districts in China, and 389 patients harbored homozygous deletion of exon 7 in the SMN1 gene (99.2%). The median age of onset was 0.08 (range: 0–0.30), 0.25 (0.06–0.60), 0.42 (0.08–1.50), 0.67 (0.07–5.08), 1.0 (0.40–1.83), 1.5 (1.00–3.00), and 4.04 (1.80–12.00) years old for SMA 1a, 1b, 1c, 2a, 2b, 3a, and 3b patients, while the median age of first assessment was 0.25 (0.08–2.60), 0.42 (0.17–1.90), 0.80 (0.17–4.5), 2.50 (0.5–15.83), 2.92 (1.08–13.42), 4.25 (1.58–17.33), and 7.34 (3.67–14.00) years old, respectively. Patients were followed up with for up to 15.8 years. The median event-free survival time was 7 months, 15 months, and indeterminate in SMA 1a, 1b, and 1c patients (p < 0.0001), with a better survival situation for higher SMN2 copies (p = 0.0171). The median age of sitting loss was 5.75 years and 13.5 years in SMA 2a and 2b (p = 0.0214) and that of ambulation loss was 9.0 years and undefined in SMA 3a and 3b (p = 0.0072). Cox regression analysis showed that higher SMN2 copies indicated better remaining ambulation in SMA 3. The median time to develop orthopedic deformities was 4.5, 5.2, and 10.1 years in SMAs 1c, 2, and 3, respectively (p < 0.0001), with a possible trend of better preservation of joint function for patients under regular rehabilitation (p = 0.8668). Conclusion Our study elucidated insight into the comprehensive management and profile of different types of SMA patients in China, providing a clinical basis for assessing the efficacy of new therapies.

Comprehensive profile and natural history of pediatric patients with spinal muscular atrophy: A large retrospective study from China

Background Glycosylphosphatidylinositols (GPI) are glycolipids that act as membrane anchors of many cell surface proteins. The phosphatidylinositol glycan class S (PIGS) gene encodes an essential component of the multi-subunit, membrane-bound, GPI transamidase that comprises 4 other proteins including PIGK, GPAA1, PIGT, and PIGU. To date, 13 patients with PIGS variants have been identified with developmental delay, seizures, and hypotonia, and only one canonical splicing variant has been reported. Case Description This case study describes a boy with very early onset refractory seizures, developmental delay, hypotonia, ventricular septal defect, nystagmus, and some facial dysmorphism. His seizures were responsive to vitamin B6 administration. Compound heterozygous variants (c.1141_1164dup and c.935-6C>G) in PIGS were identified in the proband by trio whole exome sequencing (WES). The c.1141_1164dup has been previously reported in two unrelated patients with PIGS variants. The skipping of exon 10 was observed in the proband by RNA analysis, and the pathogenicity of the splicing variant c. 935-6C>G was confirmed. Conclusions Our identification of the c. 935-6C>G variant enlarges the variant spectrum in the PIGS gene. It is a novel splicing variant which leads to the skipping of exon 10 in the PIGS gene. Furthermore, the phenotypic spectrum of PIGS variants has also been expanded, with ventricular septal defect in heart being reported in patients with PIGS variants for the first time.

Identification of a novel splicing variant in the phosphatidylinositol glycan class S (PIGS) gene that is associated with early onset epilepsy, severe developmental delay, and ventricular septal defect: a case report

Abstract Background Spinal Muscular Atrophy (SMA) is a severe neuromuscular disorder due to a defect in the survival motor neuron 1 ( SMN1 ) gene. Hypoplasia of the corpus callosum is underdevelopment or thinness of the corpus callosum. SMA and callosal hypoplasia are relatively rare, and there is limited information sharing the diagnosis and treatment for SMA patients with callosal hypoplasia. Case description A boy with callosal hypoplasia, small penis, and small testes had been perceived with motor regression at 5 months. He was referred to the rehabilitation department and neurology department at 7 months. Physical examination showed absent deep tendon reflexes, proximal weakness and significant hypotonia. He was recommended to perform trio whole-exome sequencing (WES) and array comparative genomic hybridization (aCGH) for his complicated conditions. The subsequent nerve conduction study revealed some characteristics of motor neuron diseases. We identified a homozygous deletion in exon 7 of the SMN1 gene by multiplex ligation-dependent probe amplification and failed to find further pathogenic variations responsible for multiple malformations by trio WES and aCGH. He was diagnosed as SMA. Despite some concerns, he received the therapy of nusinersen for nearly 2 years. He gained the milestone of sitting without support, which he had never accomplished, after the seventh injection, and he continued to improve. During follow-up, there were no adverse events reported and no signs of hydrocephalus. Conclusions Some extra features which could not belong to neuromuscular manifestation made the diagnosis and treatment of SMA more complicated. 

/pdf/spinal-muscular-atrophy-with-hypoplasia-of-the-corpus-1sqknpac.pdf

Spinal muscular atrophy with hypoplasia of the corpus callosum: a case report

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