The role of tocotrienol in protecting against metabolic diseases

Obesity is a major risk factor for diabetes, and these two metabolic conditions cause significant healthcare burden worldwide. Chronic inflammation and increased oxidative stress due to exposure of cells to excess nutrients in obesity may trigger insulin resistance and pancreatic β- cell dysfunction. Tocotrienol, as a functional food component with anti-inflammatory, antioxidant, and cell signaling-mediating effects, may be a potential agent to complement the current management of obesity and diabetes. The review aimed to summarize the current evidence on the anti-obesity and antidiabetic effects of tocotrienol. Previous studies showed that tocotrienol could suppress adipogenesis and, subsequently, reduce body weight and fat mass in animals. This was achieved by regulating pathways of lipid metabolism and fatty acid biosynthesis. It could also reduce the expression of transcription factors regulating adipogenesis and increase apoptosis of adipocytes. In diabetic models, tocotrienol was shown to improve glucose homeostasis. Activation of peroxisome proliferator-activated receptors was suggested to be responsible for these effects. Tocotrienol also prevented multiple systemic complications due to obesity and diabetes in animal models through suppression of inflammation and oxidative stress. Several clinical trials have been conducted to validate the antidiabetic of tocotrienol, but the results were heterogeneous. There is no evidence showing the anti-obesity effects of tocotrienol in humans. Considering the limitations of the current studies, tocotrienol has the potential to be a functional food component to aid in the management of patients with obesity and diabetes. Keywords: adipose; diabetes; insulin resistance; metabolic syndrome; obesity; overweight; vitamin

Berberine for prevention of dementia associated with diabetes and its comorbidities: A systematic review

Background A growing number of epidemiological studies indicate that metabolic syndrome (MetS) and its associated features play a key role in the development of certain degenerative brain disorders, including Alzheimer’s disease and vascular dementia. Produced by several different medicinal plants, berberine is a bioactive alkaloid with a wide range of pharmacological effects, including antidiabetic effects. However, it is not clear whether berberine could prevent the development of dementia in association with diabetes. Objective To give an overview of the therapeutic potential of berberine as a treatment for dementia associated with diabetes. Search strategy Database searches A and B were conducted using PubMed and ScienceDirect. In search A, studies on berberine’s antidementia activities were identified using “berberine” and “dementia” as search terms. In search B, recent studies on berberine’s effects on diabetes were surveyed using “berberine” and “diabetes” as search terms. Inclusion criteria Clinical and preclinical studies that investigated berberine’s effects associated with MetS and cognitive dysfunction were included. Data extraction and analysis Data from studies were extracted by one author, and checked by a second; quality assessments were performed independently by two authors. Results In search A, 61 articles were identified, and 22 original research articles were selected. In search B, 458 articles were identified, of which 101 were deemed relevant and selected. Three duplicates were removed, and a total of 120 articles were reviewed for this study. The results demonstrate that berberine exerts beneficial effects directly in the brain: enhancing cholinergic neurotransmission, improving cerebral blood flow, protecting neurons from inflammation, limiting hyperphosphorylation of tau and facilitating β-amyloid peptide clearance. In addition, evidence is growing that berberine is effective against diabetes and associated disorders, such as atherosclerosis, cardiomyopathy, hypertension, hepatic steatosis, diabetic nephropathy, gut dysbiosis, retinopathy and neuropathy, suggesting indirect benefits for the prevention of dementia. Conclusion Berberine could impede the development of dementia via multiple mechanisms: preventing brain damages and enhancing cognition directly in the brain, and indirectly through alleviating risk factors such as metabolic dysfunction, and cardiovascular, kidney and liver diseases. This study provided evidence to support the value of berberine in the prevention of dementia associated with MetS

Targeting pathological changes in the gut protects the CNS from neuropathology.

There is growing evidence that the health of the gut microbiome (GM) has an important role on multiple host organ systems. Ethanol-related neuropathologies and Alzheimer’s disease (AD) currently have no effective clinical treatment. Therefore, we developed a novel mouse model of fecal matter transplantation (FMT) utilizing the microbiome from alcoholic hepatitis (AH) patients, characterized by a loss of butyrogenic potential. Minimal neuroinflammation occurred in AH-FMT mice, but significant increases in the endoplasmic reticulum stress response (ERSR) across the majority of neurons in the prefrontal cortex and hippocampus were observed. In the cerebellum, Purkinje cells were specifically affected. Targeting the loss of butyrate reduced the ERSR as well as low-grade inflammation. The AD 3xTg mouse model was assessed for the development of dysbiosis. At 12 months these mice developed dysbiosis, characterized by the loss of butyrate-producing bacteria. Butyrate supplementation did positively impact inflammation, oxidative stress, and neurofibrillary tangle formation. Functionally, cognitive decline was ameliorated in butyrate-supplemented mice. Aldose reductase (AR) is the rate-limiting enzyme in the polyol pathway. Biproducts of this pathway yield increases in inflammatory products and decreases in antioxidants. Lipopolysaccharide (LPS) was injected intraperitoneally in mice to mimic endotoxemia. The brains and livers of AR knock-out mice (ARKO) showed markedly reduced inflammation. While microglial activation remained the same, a significant reduction in macrophage-related cytokines was observed. Macrophages treated with Epalrastat, an AR inhibitor, showed reduced CNS inflammatory gene expression in response to LPS, indicating the role of AR in LPS-induced inflammation. These studies implicate the GM in the CNS pathology of neurological-related diseases. The loss of butyrate has a critical role in the health of neurons and targeting this loss reduced or prevented neuropathology. Finally, we identified AR as a critical mediator of LPS-induced inflammation indicating that Epalrastat may aid in the treatment of CNS disease driven by endotoxemia

Immune Cells and Inflammation in Diabetic Nephropathy

Diabetic nephropathy (DN) is a serious complication of diabetes. At its core, DN is a metabolic disorder which can also manifest itself in terms of local inflammation in the kidneys. Such inflammation can then drive the classical markers of fibrosis and structural remodeling. As a result, resolution of immune-mediated inflammation is critical towards achieving a cure for DN. Many immune cells play a part in DN, including key members of both the innate and adaptive immune systems. While these cells were classically understood to primarily function against pathogen insult, it has also become increasingly clear that they also serve a major role as internal sensors of damage. In fact, damage sensing may serve as the impetus for much of the inflammation that occurs in DN, in a vicious positive feedback cycle. Although direct targeting of these proinflammatory cells may be difficult, new approaches that focus on their metabolic profiles may be able to alleviate DN significantly, especially since dysregulation of the local metabolic environment may well be responsible for triggering inflammation to begin with. In this review, the authors consider the metabolic profile of several relevant immune types and discuss their respective roles

Roles and Mechanisms of Astragaloside IV in Combating Neuronal Aging

Aging can lead to changes in the cellular milieu of the brain. These changes may exacerbate, resulting in pathological phenomena (including impaired bioenergetics, aberrant neurotransmission, compromised resilience and neuroplasticity, mitochondrial dysfunction, and the generation of free radicals) and the onset of neurodegenerative diseases. Furthermore, alterations in the energy-sensing pathways can accelerate neuronal aging but the exact mechanism of neural aging is still elusive. In recent decades, the use of plant-derived compounds, including astragaloside IV, to treat neuronal aging and its associated diseases has been extensively investigated. This article presents the current understanding of the roles and mechanisms of astragaloside IV in combating neuronal aging. The ability of the agent to suppress oxidative stress, to attenuate inflammatory responses and to maintain mitochondrial integrity will be discussed. Important challenges to be tacked for further development of astragaloside IV-based pharmacophores will be highlighted for future research

Aldose reductase deficiency protects the retinal neurons in a mouse model of retinopathy of prematurity

Poster Presentation: P64PURPOSE: Retinopathy of prematurity (ROP) is a common retinal disease occurred in premature babies. It is found to be related to oxidative stress while dysfunction of the neural retina has also been documented. We previously showed that genetic deletion or pharmacological inhibition of aldose reductase (AR), a rate- limiting enzyme in the polyol pathway, prevented ischemia-induced retinal ganglion cell (RGC) loss and oxidative stress. Here, we assessed the effects of AR deletion on retinal neurons using a mouse model of ROP. METHODS: Seven-day-old mouse pups were exposed to 75% oxygen for five days and returned to room air. The pathological neuronal changes were examined and compared between wild-type (WT) and AR-deficient retinae on P14 and P17 (P, postnatal). Retinal thickness was measured and immunohistochemistry for calbindin, calretinin, PKCα, Tuj1, glial fibrillary acidic protein (GFAP), nitrotyrosine (NT), as well as poly(ADP-ribose) (PAR) was performed. RESULTS: After hyperoxia exposure, significantly reduced inner nuclear layer (INL) and inner plexiform layer (IPL) thickness were found in both genotypes. The intensity of calbindin staining for horizontal cells in INL was reduced in the WT retinae but not in AR-deficient retinae. In addition, significant reduction was found in calretinin-positive amacrine cell bodies in central INL especially in WT retinae. Serious distortion was also observed in the three calretinin-positive strata along IPL in the WT retinae but not AR-deficient retinae on P17. Moreover, increased GFAP intensity across IPL indicating Müller cell processes was observed in AR-deficient retinae on P14 and in WT retinae on P17. Furthermore, increased NT immunoreactivity in INL and nuclear or para-nuclear PAR staining along GCL were observed in WT retina while these changes were not apparent in AR-deficient retina. CONCLUSION: Our observations demonstrated morphological changes of retinal neurons in the mouse model of ROP and indicated that AR deficiency showed neuronal protection in the retina, possibly through modulating glial responses and reducing oxidative stress.postprin

Research Progress on the Treatment of Related Diseases With Astragalus

Xinyu Zhang,1,* Bingying Lin,2,* Xiaoqian Wang,1 Ninɡji Fanɡ,2 Lifei Wu,3 Haitong Wan,2,4 Huifen Zhou2 1School of Life Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 2School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 3Department of Physical Education, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China; 4Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan Province, 450046, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huifen Zhou, School of Basic Medical Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Email [email protected] Haitong Wan, School of Basic Medical Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou, 310053, People’s Republic of China, Email [email protected]: Astragalus mongholicus Bunge [Fabaceae; Astragali radix] is an herb widely used in traditional Chinese medicine. It has diuretic, anti-aging, antihypertensive, immune-boosting, liver-protective, anti-stress and other extensive pharmacological effects. In recent years, Astragalus and its extract have been used to treat lung and stomach qi deficiency as well as general qi deficiency. This paper summarizes the mode of action and mechanisms of Astragalus in treating various diseases, and provides valuable insights for the future application, development, and improvement of Astragalus. In this paper, literature on the use of Astragalus in treating related diseases over the past five years was collected from PubMed and CNKI databases, and the pathogenic mechanisms of Astragalus and its extracts were reviewed. Its mechanism of action is primarily involved in antioxidant protection, anti-inflammatory effects, and anti-apoptotic properties. This provides a new research direction for future studies and clinical treatments using Astragalus.Keywords: Astragalus, active ingredient, Astragalus extract, traditional Chinese medicin

How to reprogram microglia toward beneficial functions

Microglia, brain cells of nonneural origin, orchestrate the inflammatory response to diverse insults, including hypoxia/ischemia or maternal/fetal infection in the perinatal brain. Experimental studies have demonstrated the capacity of microglia to recognize pathogens or damaged cells activating a cytotoxic response that can exacerbate brain damage. However, microglia display an enormous plasticity in their responses to injury and may also promote resolution stages of inflammation and tissue regeneration. Despite the critical role of microglia in brain pathologies, the cellular mechanisms that govern the diverse phenotypes of microglia are just beginning to be defined. Here we review emerging strategies to drive microglia toward beneficial functions, selectively reporting the studies which provide insights into molecular mechanisms underlying the phenotypic switch. A variety of approaches have been proposed which rely on microglia treatment with pharmacological agents, cytokines, lipid messengers, or microRNAs, as well on nutritional approaches or therapies with immunomodulatory cells. Analysis of the molecular mechanisms relevant for microglia reprogramming toward pro-regenerative functions points to a central role of energy metabolism in shaping microglial functions. Manipulation of metabolic pathways may thus provide new therapeutic opportunities to prevent the deleterious effects of inflammatory microglia and to control excessive inflammation in brain disorders

MOLECULAR MECHANISM OF AUTOPHAGY-BASED UNCONVENTIONAL SECRETION OF IL-β

Proteins without signal peptides can still be released into extracellular space via ER/Golgi-independent unconventional secretory pathway(s) that remain to be revealed. A class of leaderless proteins including the pro-inflammatory cytokine interleukin-β (IL-β) is processed in the cytosol by proteolytic machineries such as the inflammasome prior to secretion. Studies in yeast uncovered a new unconventional secretory pathway that is dependent on GRASP (Golgi Reassembly and Stacking Protein) and autophagy proteins. The purpose of this work was to determine whether this autophagy-based unconventional secretory pathway (secretory autophagy) is conserved in mammals, how this secretory autophagy differs from the traditional degradative autophagy, and how GRASP intersects with the autophagy pathways. Here, we provide the first evidence that autophagy mediates unconventional secretion of IL-β in an inflammasome, GRASP55, and Rab8-dependent manner in mouse bone marrow-derived macrophages, a route which also applies to IL-18 and non-inflammasome substrate HMGB1. GRASP55 was also found to be mediating autophagosome formation possibly making secretory autophagosomes. We also give initial insights to the divergence between degradative autophagy and this secretory autophagy pathway, which preferentially utilizes some of the autophagy-related proteins, LC3A, GABARAP, and p62, but not LC3B, NBR1, TBK1, and ULK1. We also discuss the way that GRASP55, the conserved player of unconventional secretion, negatively regulates removal of damaged mitochondria by mitophagy, which might be due to competition between secretory and degradative autophagy. Taken together, these data indicate there is a conserved, unconventional secretory pathway involving GRASP and autophagy. It also suggests that although secretory and degradative autophagy share some core components, secretory autophagy also involves specialized molecular machinery to execute its unconventional secretory function and balance with degradative autophagy

Structure-function study of ubiquitin c-terminal hydrolase L1 (UCH-L1) by NMR spectroscopy - insights into UCH-L1 mutation's association with the risk of Parkinson's disease

Poster Presentation: P72Protein ubiquitination and deubiquitination, play important roles in many aspects of cellular mechanisms. Its defective regulation results in diseases that range from developmental abnormalities to neurodegenerative diseases and cancer. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) is a protein of 223 amino acids, which is highly abundant in brain, constituting up to 2% of total brain proteins. Although it was originally characterized as a deubiquitinating enzyme, recent studies indicate that it also functions as a ubiquitin ligase and a mono-Ub stabilizer. Down-regulation and extensive oxidative modifications of UCH-L1 have been observed in the brains of Alzheimer’s disease and Parkinson’s disease (PD) patients. Of importance, I93M and S18Y point mutations in the UCH-L1 gene have been reported to be linked to susceptibility to and protection from PD respectively. Hence, the structure of UCH-L1 and the effects of disease associated mutations on the structure and function are of considerable interest. Our circular dichroism studies suggest that the S18Y point mutation only slightly perturbs the structure while a significant decrease in the α-helical content is observed in the I93M mutant. We have determined the solution structure of S18Y and mapping its interaction with ubiquitin by chemical shift perturbation approach. The electrostatic surface potential analysis reveals that the interaction between ubiquitin and UCH-L1-S18Y is primarily electrostatic in nature, with negatively charged residues on the surface of UCH-L1-S18Y interacting with the positively charged residues on the basic face of ubiquitin. Although the active site and the L8 loop in UCH-L1-S18Y adopts conformations similar to that observed in the crystal structure of UCH-L1-WT, both the altered hydrogen bond network and surface charge distributions have demonstrated that the S18Y substitution could lead to profound structural changes. In particular, the difference in the dimeric interfaces of the wild-type and the S18Y mutant has shown that mutation can significantly affect the distribution of the surface-exposed residues involved in the dimeric interface. Such observed difference might weaken the stability of the UCH-L1 dimer and hence may explain the reduced dimerization-dependent ligase activity of UCH-L1-S18Y in comparison to UCH-L1-WT.postprin