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© 2019 Published by Elsevier B.V., Acute pancreatitis is an inflammatory process of the pancreatic gland that may lead to dysregulation of the trans-sulfuration pathway. The aims of this work were firstly to study the methionine cycle as well as the trans-sulfuration pathway using metabolomic and proteomic approaches identifying the causes of this dysregulation in an experimental model of acute pancreatitis; and secondly to reveal the effects of S-adenosylmethionine administration on these pathways. Acute pancreatitis was induced by cerulein in mice, and a group of animals received S-adenosylmethionine treatment. Cerulein-induced acute pancreatitis rapidly caused marked depletion of methionine, S-adenosylmethionine, 5′-methylthioadenosine, cystathionine, cysteine, and glutathione levels in pancreas, but S-adenosylhomocysteine and homocysteine remained unchanged. Protein steady-state levels of S-adenosylhomocysteine-hydrolase and cystathionine gamma-lyase diminished but methylthioadenosine phosphorylase levels increased in pancreas with acute pancreatitis. Although cystathionine β-synthase protein levels did not change with acute pancreatitis, Nos2 mRNA and protein levels were markedly up-regulated and caused tyrosine nitration of cystathionine β-synthase in pancreas. S-adenosylmethionine administration enhanced Nos2 mRNA expression and cystathionine β-synthase nitration and triggered homocysteine accumulation in acute pancreatitis. Furthermore, S-adenosylmethionine administration promoted enrichment of the euchromatin marker H3K4me3 in the promoters of Tnf-α, Il-6, and Nos2 and enhanced the mRNA up-regulation of these genes. Accordingly, S-adenosylmethionine administration increased inflammatory infiltrate and edema in pancreas with acute pancreatitis. In conclusion, tyrosine-nitration of cystathionine β-synthase blockades the trans-sulfuration pathway in acute pancreatitis promoting homocysteine accumulation upon S-adenosylmethionine treatment., This work was supported by Grant SAF2015-71208-R with FEDER funds from the Spanish Ministry of Economy and Competitiveness to J.S.

// Adriana C. Vidal 1 , Zinan Chen 2 , Lauren E. Howard 2 , Daniel M. Moreira 3 , Ramiro Castro-Santamaria 4 , Gerald L. Andriole 5 , Emanuela Taioli 6 , Jay H. Fowke 7 , Beatrice Knudsen 8 , Charles G. Drake 9 , J. Curtis Nickel 10 and Stephen J. Freedland 1 1 Department of Surgery, Division of Urology, Cedars Sinai Medical Center, Los Angeles, CA, USA 2 Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA 3 Department of Urology, Mayo Clinic, Rochester, MN, USA 4 GlaxoSmithKline Inc., R&D, King of Prussia, PA, USA 5 Washington University School of Medicine in St. Louis, St. Louis, MO, USA 6 Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA 7 Department of Medicine and Urologic Surgery, Vanderbilt University Medical Center, TN, USA 8 Department of Medicine, Cedars-Sinai Biobank, Cedars Sinai Medical Center, Los Angeles, CA, USA 9 Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, and the Brady Urology Institute, John Hopkins University, Baltimore, MD, USA 10 Department of Urology, Queen’s University, Kingston, ON, Canada Correspondence to: Adriana C. Vidal, email: // Keywords : prostate biopsy, inflammation, race, prostate cancer, acute inflammation Received : May 27, 2016 Accepted : July 07, 2016 Published : July 18, 2016 Abstract Prostate cancer (PC) risk differs between races, and we previously showed prostate inflammation in benign prostate tissue was linked with a lower future PC risk. However, whether prostate tissue inflammation varies by race is unknown. We analyzed baseline acute and chronic prostate inflammation by race in REDUCE, a 4-year, multicenter, placebo-controlled study where all men had a negative prostate biopsy prior to enrollment. We included 7,982 men with standardized central pathology review to determine the presence or absence of chronic or acute inflammation in baseline prostate biopsy tissue. Logistic regression was used to compare prostate inflammation by race, adjusting for confounders. Of 7,982 men, 7,271 were white (91.1%), 180 (2.3%) black, 131 (1.6%) Asian, 319 (4.0%) Hispanic and 81 (1%) unknown. A total of 78% had chronic and 15% had acute inflammation. On multivariable analysis relative to white men, black men were less likely (OR = 0.65, 95%CI: 0.41-1.03, p = 0.07) and Asian men more likely to have acute inflammation (OR = 1.74, 95%CI: 1.14-2.65, p = 0.001). Hispanic men had similar levels of acute inflammation as white men. Chronic inflammation did not significantly differ across races. We identified racial differences in acute inflammation, particularly in Asian men, in benign prostate tissue that inversely mirrored population-level data on PC race disparity. As we showed in REDUCE that acute inflammation is linked with lower future PC risk, if validated in future studies, these data suggest racial differences in prostatic acute inflammation may contribute in part to race differences in PC risk, especially among Asian men.

Chronically inflamed tissues show altered characteristics that include persistent populations of inflammatory leukocytes and remodelling of the vascular network. As the majority of studies on leukocyte recruitment have been carried out in normal healthy tissues, the impact of underlying chronic inflammation on ongoing leukocyte recruitment is largely unknown. Here, we investigate the profile and mechanisms of acute inflammatory responses in chronically inflamed and angiogenic tissues, and consider the implications for chronic inflammatory disorders. We have developed a novel model of chronic ischaemia of the mouse cremaster muscle that is characterized by a persistent population of monocyte‐derived cells (MDCs), and capillary angiogenesis. These tissues also show elevated acute neutrophil recruitment in response to locally administered inflammatory stimuli. We determined that Gr1low MDCs, which are widely considered to have anti‐inflammatory and reparative functions, amplified acute inflammatory reactions via the generation of additional proinflammatory signals, changing both the profile and magnitude of the tissue response. Similar vascular and inflammatory responses, including activation of MDCs by transient ischaemia–reperfusion, were observed in mouse hindlimbs subjected to chronic ischaemia. This response demonstrates the relevance of the findings to peripheral arterial disease, in which patients experience transient exercise‐induced ischaemia known as claudication.These findings demonstrate that chronically inflamed tissues show an altered profile and altered mechanisms of acute inflammatory responses, and identify tissue‐resident MDCs as potential therapeutic targets. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Memory loss is primarily caused by the accumulation of both brain plaques [(consisting of beta-amyloid protein (Aβ) 1–42)] and neurofibrillary tangles (consisting of paired helical and straight filaments containing tau protein). Neuroinflammation is the third key and important factor that leads to accelerated memory loss and eventual dementia. Brain plaques, tangles and inflammation is the trilogy mainly responsible for causing memory loss that has now been documented for over 20 years in the scientific literature. The present investigation used in vitro quantitative methods to directly compare the ability of major memory-support dietary supplements to reduce pre-formed Aβ 1–42 fibrils (21 supplements tested) and tau protein paired helical/straight filaments (13 supplements tested)—two of the three most important targets for memory loss. Additionally, 18 different manufacturers of cat’s claw (Uncaria tomentosa) were directly compared for their ability to inhibit/reduce Aβ 1–42 fibrils and/or tau paired helical/straight filaments based on recent findings that PTI-00703 cat’s claw is a specific and potent inhibitor/reducer of all three targets -brain plaques, tangles and inflammation (Snow et al. in Sci Rep 9:561, 2019). In the present investigation quantitative Thioflavin T fluorometry was used on a comparative weight-to-weight basis at increasing concentrations with ingredients tested from the actual capsules the consumer ingests. Major memory-support dietary supplements were directly compared for their ability to inhibit and disaggregate/reduce both Aβ 1–42 fibrils and/or tau paired helical/straight filaments. Dietary supplements touted to enhance memory comparatively tested included Prevagen, FOCUSfactor, PROCERA AVH, Alpha Brain, NAD+OVIM, BRAIN JUICE, Cebria, EXCELEROL, NOOCUBE, US Doctor’s Clinical Brain Power ADVANCED, healthycell pro, LUMONOL, Brain Awake, BRAIN ARMOR, brainMD (BRAIN & MEMORY POWER BOOST), Brain Support, Clarity (BRAIN HEALTH FORMULA), brainMD (NEUROVITE PLUS), neuriva (Original and Plus) and percepta. This is the first paper to actually comparatively test these memory-support supplements for their ability to reduce Aβ fibrils and tau protein tangles. Percepta (PTI-00703 cat’s claw and a specific oolong tea extract) was determined to be the most effective and potent memory support dietary supplement to disaggregate/disrupt Aβ 1–42 fibrils (range of 25–89%) and tau paired helical/straight filaments (range of 26–86%) at all 3–4 doses tested in comparison to other major memory-support dietary supplements tested. This was at least more than double (> 50%) for percepta reducing Aβ 1–42 fibrils and in comparison to the other 20 memory-support dietary supplements tested. The ranking order for memory-support supplement effects based on reducing Aβ 1–42 fibrils (Aβ 1–42: memory-support supplement at 1:0.1 weight-to-weight in a 3-day study) was percepta (69.6% reduction) >>> Alpha Brain (34.9% reduction) = US Doctor’s Clinical Brain Power ADVANCED (32.4%) = BRAIN JUICE (30.1%) = neuriva Plus (27%) = neuriva Original (27%) > NEUROVITE PLUS (22.9%) = NOOCUBE (19.9%) = EXCELEROL (17.3%) = healthycell pro (17.2%) > Prevagen (12.9%) > PROCERA AVH (6.5%) = FOCUSfactor (5.5%) > Cebria (0%) = Brain Awake (0%) = Brain Support (0%) = brainMD (BRAIN & MEMORY POWER BOOST) (0%) = NAD+OVIM (0%) = BRAIN ARMOR (0%) = LUMONOL (0%). The ranking order for memory support supplement effects on reducing tau paired helical/straight filaments (tau:memory supplement at 1:1 weight-to-weight at 3 days) was percepta (85.7% reduction) >>> neuriva Plus (57.9%) >> BRAIN JUICE (41.9%) = EXCELEROL (41.0%) = neuriva Original (38.4%) = US Doctor’s Clinical Brain Power ADVANCED (38.3%) = healthycell pro (37.6%) >> Alpha Brain (27.9%) >> NOOCUBE (17.6%) >> FOCUSfactor (8.7%) > Cebria (3.6%) = PROCERA AVH (0%) = Prevagen (0%). Congo red staining, Thioflavin S fluorescence, circular dichroism (CD) spectroscopy and electron microscopy confirmed the positive results observed with the supplement percepta. CD spectroscopy demonstrated that percepta caused a marked inhibition of beta-sheet secondary folding of tau protein into paired helical filaments. PTI-00703 cat’s claw (main ingredient in percepta) was also identified as the most potent cat’s claw bark powder (Uncaria tomentosa) to reduce and inhibit Aβ 1–42 fibrils and tau tangles in comparison to 17 other manufacturers of cat’s claw extracts. Although there are thousands of brain memory-support dietary supplements in the marketplace today, none of them have been directly compared and analyzed for their ability to reduce and/or inhibit two major targets of memory loss i.e. Aβ 1–42 fibrils and tau paired helical/straight filaments (major constituents of brain plaques and tangles). In our comparison studies, we show that percepta has the most potent ability to disaggregate/reduce Aβ 1–42 fibrils and tau protein paired helical/straight filaments as demonstrated by a variety of methods most likely due to the specific polyphenol content in PTI-00703 cat’s claw (i.e. polyphenols and proanthocyanidins) as we have previously shown (Snow et al. in Sci Rep 9:561, 2019). Memory-support dietary supplements tested that also contained polyphenols and/or cat’s claw in their product demonstrated some Aβ fibril and tau protein tangle reducing activity, but were much less effective than percepta. Percepta’s main ingredient, PTI-00703 cat’s claw, has previously been shown to reduce brain amyloid plaques and Aβ 1–42/40 insoluble/soluble levels in brain (in plaque-producing transgenic mice) with marked concurrent memory improvements (shown by Morris water maze testing) (Snow et al. in Sci Rep 9:561, 2019). The present investigation further confirms that percepta is one of the best dietary supplements that causes a marked reduction and inhibition of Aβ fibrils and tau tangle filaments -two important major targets for memory-support. In addition, PTI-00703 cat’s claw was the most effective cat’s claw (Uncaria tomentosa) ingredient for reducing /disaggregating and inhibiting Aβ 1–42 fibrils and tau protein paired helical/straight filaments in comparison to 17 other manufacturers of cat’s claw extracts tested.

Acute or chronic inflammatory reactions aim to control lesions, resist to pathogens attack and repair damaged tissue. The therapeutic administration of ozone known as ozone therapy appears as a possible treatment for tissue repair, as it promotes the healing of wounds. It has bactericidal, antiviral and antifungal properties and has been used as a therapeutic resource to treat inflammation. The objective was to carry out an integrative review regarding the use of ozonated oil in acute and chronic inflammations. The keywords “ozone therapy,” “inflammation” and “ozone” were used in the Portuguese, Spanish and English languages. The paper selection was based on inclusion and exclusion criteria. In total, 28 articles were selected. It has been seen that ozonated oil is effective in healing cutaneous wounds. The beneficial effects are due to the healing of wounds, due to the reduction of microbial infection, debridement effect, modulation of the inflammatory phase, stimulation to angiogenesis as well as biological and enzymatic reactions that favor the oxygen metabolism, improving the wound cicatrization. In addition to promoting healing, ozonated oil reduces symptoms related to skin burns, prevents post-lesion hyperpigmentation, and reduces the pain of aphthous ulcers. Therefore, ozonated oil represents an effective and inexpensive therapeutic alternative that must be implanted in the public health system.

Inflammation is a coordinated response of the immune system which is aimed at maintaining or restoring tissue integrity. Sterile inflammation can be triggered by physical, chemical, or metabolic noxious stimuli. The individual stimuli (genomic stress, ER stress, hypoxic stress, nutrient stress, etc.) promote a carefully choreographed set of cell responses to stress. Many types of stress responses exist (e.g., the unfolded protein response, integrated stress response, oxidative stress response, autophagy, etc.), and these can influence each other. Stress responses induce recruitment of inflammatory cells and result in inflammation. When the noxious stimuli persist over and cannot be eliminated or cleared inflammation fails to resolve, resulting in the development of a vicious circle which is part of the pathophysiology of many human diseases, including cancer, autoimmunity, chronic viral infections, chronic graft versus host disease, metabolic syndromes, and several acquired and inborn genetic disorders. Several proximal factors have been identified and proposed to play a role in the individual types of sterile inflammation, including redox responses, the occurrence of damage-associated molecular patterns molecules (DAMPs) and immune stimulatory heat shock proteins, and vascular remodeling. However, the detailed mechanism(s) linking stressful events and the development of inflammation have thus far remained elusive. The identification of the major molecular species in induction, development, and outcome of sterile inflammation, and the illumination of their mechanisms of action are therefore of paramount relevance for the design of effective therapeutic strategies for the treatment of the most common diseases of the Western world. Thus, this Special Topic focuses on articles that can shed new light on the molecular mechanisms of sterile inflammation. This collection of papers, written by experts in this field, addresses the most important current challenges in the topic of sterile inflammation. A significant focus is placed on the factors that mediate sterile inflammation: DAMPs, released during tissue injury, and cytokines of the IL-1 family. In this family, some members such as IL-1β and IL-18 are true cytokines, in that they undergo active secretion by inflammatory cells, highly regulated at the post-translational level by inflammasomes (1) and regulatory receptors (2). Others, such as IL-1α (3), are molecules that are both DAMPs and cytokines, in that they initiate and perpetuate inflammation either after active secretion or when released by stressed cells undergoing necrosis (4). Interestingly, a similar behavior features the prototypic DAMP high mobility group box 1 (HMGB1) (5). In addition, this series describes the most recent observations on the cells involved in the process of sterile inflammation, not only professional inflammatory cells such as myelomonocytic cells but also innate lymphoid cells (6), granulocytes (7), and glial cells (8). Finally, sterile inflammation as a mechanism of disease is illustrated in important in pathologies such as type 2 diabetes (9) and endometriosis (10), in fungal infection, where DAMPs cooperate with pathogen associated molecular pattern molecules (PAMPs) in switching protective versus pathogenic inflammation (11), and in the regulation of physiologic processes such as parturition (12).