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Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal condition caused by a brain infection with JC polyomavirus (JCV). PML develops almost exclusively in immunocompromised patients and has recently been associated with use of fumaric acid esters (FAEs), or fumarates. We reviewed the literature and the Dutch and European pharmacovigilance databases in order to identify all available FAE-associated PML cases and distinguish possible common features among these patients. A total of 19 PML cases associated with FAE use were identified. Five cases were associated with FAE use for multiple sclerosis and 14 for psoriasis. Ten patients were male and nine were female. The median age at PML diagnosis was 59 years. The median duration of FAE therapy to PML symptom onset or appearance of first PML lesion on brain imaging was 31 months (range 6–110). In all cases a certain degree of lymphocytopenia was reported. The median duration of lymphocytopenia to PML symptom onset was 23 months (range 6–72). The median lymphocyte count at PML diagnosis was 414 cells/µL. CD4 and CD8 counts were reported in ten cases, with median cell count of 137 and 39 cells/µL, respectively. Three patients died (16% mortality). The association between occurrence of PML in patients with low CD4 and CD8 counts is reminiscent of PML cases in the HIV population and suggests that loss of T cells is the most important risk factor.

HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.

Fumarates (fumaric acid esters, FAEs) are orally administered systemic agents used for the treatment of psoriasis and multiple sclerosis. In 1994, a proprietary combination of FAEs was licensed for psoriasis by the German Drug Administration for use within Germany. Since then, fumarates have been established as one of the most commonly used treatments for moderate-to-severe psoriasis in Germany and other countries. The licensed FAE formulation contains dimethyl fumarate (DMF), as well as calcium, zinc, and magnesium salts of monoethyl fumarate (MEF). While the clinical efficacy of this FAE mixture is well established, the combination of esters on which it is based, and its dosing regimen, was determined empirically. Since the mid-1990s, the modes of action and contribution of the different FAEs to their overall therapeutic effect in psoriasis, as well as their adverse event profile, have been investigated in more detail. In this article, the available clinical data for DMF are reviewed and compared with data for the other FAEs. The current evidence substantiates that DMF is the main active compound, via its metabolic transformation to monomethyl fumarate (MMF). A recent phase III randomized and placebo-controlled trial including more than 700 patients demonstrated therapeutic equivalence when comparing the licensed FAE combination with DMF alone, in terms of psoriasis clearance according to the Psoriasis Area and Severity Index (PASI) and Physician’s Global Assessment (PGA). Thus, DMF as monotherapy for the treatment of psoriasis is as efficacious as in combination with MEF, making the addition of such fumarate derivatives unnecessary.

Rhizopus oryzae is a filamentous fungus belonging to the Zygomycetes. It is among others known for its ability to produce the sustainable platform chemicals l-(+)-lactic acid, fumaric acid, and ethanol. During glycolysis, all fermentable carbon sources are metabolized to pyruvate and subsequently distributed over the pathways leading to the formation of these products. These platform chemicals are produced in high yields on a wide range of carbon sources. The yields are in excess of 85 % of the theoretical yield for l-(+)-lactic acid and ethanol and over 65 % for fumaric acid. The study and optimization of the metabolic pathways involved in the production of these compounds requires well-developed metabolic engineering tools and knowledge of the genetic makeup of this organism. This review focuses on the current metabolic engineering techniques available for R. oryzae and their application on the metabolic pathways of the main fermentation products. [PUBLICATION ABSTRACT]

To understand fumaric acid sludge (FAS) systematically and comprehensively and find out how to utilize it, we conducted a series of characterization analyses on FAS. Fourier transform infrared (FT-IR) Spectra shows that the main component of FAS is fumaric acids and also contains a small amount of silicate. The nuclear magnetic resonance hydrogen (1H-NMR) spectrum also shows that fumaric acid accounted for a large proportion of FAS. The X-ray diffraction (XRD) shows that the main phase in FAS is fumaric acid, and there is also a small amount of Kaliophilite. After gas chromatography and mass spectrometry (GC-MS) and pyrolysis gas chromatography and mass spectrometry (Py-GC-MS) analysis, it indicates that the possible volatiles and pyrolysis products in FAS are fumaric acid, maleic acid, maleic anhydride, phthalic acid, etc. In the test of Liquid chromatography and mass spectrometry (LC-MS), we determined the contents of phthalic acid, fumaric acid, and maleic acid in FAS. The detailed mass content of each component in FAS is as follows: phthalic acid is about 0.10–0.15%; maleic anhydride is about 0.40–0.80%; maleic acid is about 18.40–19.0%; fumaric acid is about 55.00–56.90%; succinic anhydride is about 0.06–0.08%; acrylic acid is about 0.06–0.08%; malic acid is about 0.90–1.00%; acetic acid is about 0.10–0.20%; silicate is about 0.25–0.30%; phthalic anhydride is about 0.20–0.30%; water is about 24.30–24.80%. The filtrate loss reducer (PAAF) used in oilwell drilling fluids synthesized by FAS not only has excellent temperature and complex saline resistance, the API filtration loss (FL) was only 13.2 mL/30 min in the complex saline based mud, but is also cost-effective.

Merkel cell carcinoma (MCC) is a rare, difficult-to-treat skin cancer once immunotherapy has failed. MCC is associated either with the clonal integration of the Merkel cell polyomavirus (MCPyV) or mutagenic UV-radiation. Fumaric acid esters, including dimethyl fumarate (DMF), have been shown to inhibit cell growth in cutaneous melanoma and lymphoma. We aimed to explore the effects of DMF on MCPyV-negative MCC cell lines. Three MCC cell lines (MCC13, MCC14.2, and MCC26) were treated with different doses of DMF. The cytotoxic effects and cell proliferation were assessed by the MTT cytotoxicity assay and BrdU proliferation assay at different time points. A significant reduction in cell viability and proliferation were demonstrated for all the cell lines used, with DMF proving to be effective.

This study investigated the potential of using steam-exploded oil palm empty fruit bunches (EFB) as a renewable feedstock for producing fumaric acid (FA), a food additive widely used for flavor and preservation, through a separate hydrolysis and fermentation process using the fungal isolate K20. The efficiency of FA production by free and immobilized cells was compared. The maximum FA concentration (3.25 g/L), with 0.034 g/L/h productivity, was observed after incubation with the free cells for 96 h. Furthermore, the production was scaled up in a 3-L air-lift fermenter using oil palm EFB-derived glucose as the substrate. The FA concentration, yield, and productivity from 100 g/L initial oil palm EFB-derived glucose were 44 g/L, 0.39 g/g, and 0.41 g/L/h, respectively. The potential for scaling up the fermentation process indicates favorable results, which could have significant implications for industrial applications.

Spinal cord injury (SCI) causes permanent changes in motor, sensory, and autonomic functions. Unfortunately, there are no stable cures and current treatments include surgical decompression, methylprednisolone, and hemodynamic control that lead to modest function recovery. Fumaric acid esters (FAEs) were firstly used in the management of an immunological skin disorder, such as psoriasis. Because of their potent anti-inflammatory effects, they have been introduced in multiple sclerosis (MS). Investigation has shown not only an anti-inflammatory, but also supposed neuroprotective mechanism of action. The goal of the present work was to evaluate the potential beneficial effects of dimethyl fumarate (DMF) and monomethyl fumarate (MMF) in a mouse model of traumatic SCI. SCI was produced by extradural compression for 1 min of the spinal cord at the T6–7 level using an aneurysm clip, and DMF and MMF (both at 30 mg/kg) were administered by oral gavage to the mice 1 and 6 h after SCI. For locomotor activity, study mice were treated with FAEs once daily for 10 days. We observed that mice treated with DMF exhibited a significant and sustained recovery of motor function. FAEs significantly reduced the severity of inflammation by a modulation of pro-inflammatory cytokines and apoptosis factors, and increased neutrophic factors such as anti-brain-derived neurotrophic factor (BDNF), anti-glial cell-derived neurotrophic factor (GDNF), and neurotrophin-3 (NT3). Our results showed important protective effects of DMF in an animal model of SCI, considerably improving recovery of motor function, possibly by reducing the secondary inflammation and tissue injury that characterize this model. DMF may constitute a promising target for future SCI therapies.

Multicomponent crystals have great scientific potential because of their amenability to crystal engineering in terms of composition and structure, and hence their properties can be easily modified. More and more research areas are employing the design of multicomponent materials to improve the known or induce novel physicochemical properties of crystals, and recently they have been explored as materials with abnormal pressure behaviour. The cocrystal of 1,2-bis(4'-pyridyl)ethane and fumaric acid (ETYFUM) exhibits a negative linear compressibility behaviour comparable to that of framework and metal-containing materials, but overcomes many of their deficiencies restricting their use. Herein ETYFUM was investigated at low temperature to reveal negative thermal expansion behaviour. Additionally, a cocrystal isostructural with ETYFUM, based on 1,2-bis(4'-pyridyl)ethane and succinic acid (ETYSUC), was exposed to high pressure and low temperature, showing that its behaviour is similar in nature to that of ETYFUM, but significantly differs in the magnitude of both effects. It was revealed that the minor structural difference between the acid molecules does not significantly affect the packing under ambient conditions, but has far-reaching consequences when it comes to the deformation of the structure when exposed to external stimuli. Keywords: negative linear compressibility; NLC; cocrystals; negative thermal expansion; NTE; crystal engineering; multicomponent crystals.

Fumaric acid sludge (FAS) by-produced from phthalic anhydride production wastewater treatment contains a large amount of refractory organic compounds with a complex composition, which will cause environmental pollution unless it is treated in a deep, harmless manner. FAS included saturated carboxylic acid, more than 60%, and unsaturated carboxylic acid, close to 30%, which accounted for the total mass of dry sludge. A new oil well drilling fluid filtrate loss reducer, poly(AM-AMPS-FAS) (PAAF), was synthesized by copolymerizing FAS with acrylamide (AM) and 2-acrylamide-2-methyl propane sulfonic acid (AMPS). Without a refining requirement for FAS, it can be used as a polymerizable free radical monomer for the synthesis of PAAF after a simple drying process. The copolymer PAAF synthesis process was studied, and the optimal monomer mass ratio was determined to be AM:AMPS:FAS = 1:1:1. The temperature resistance of the synthesized PAAF was significantly improved when 5% sodium silicate was added as a cross-linking agent. The structural characterization and evaluation of temperature and complex saline resistance performance of PAAF were carried out. The FT-IR results show that the structure of PAAF contained amide groups and sulfonic acid groups. The TGA results show that PAAF has good temperature resistance. As an oilfield filtrate loss reducer, the cost-effective copolymer PAAF not only has excellent temperature and complex saline resistance, the API filtration loss (FL) was only 13.2 mL/30 min after 16 h of hot rolling and aging at 150 °C in the complex saline-based mud, which is smaller compared with other filtrate loss reducer copolymers, but it also has little effect on the rheological properties of drilling fluid.