valorization
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Dermatomyositis (DM) is a rare and debilitating, systemic, autoimmune disease. While heterogenous in presentation and severity, DM is primarily characterised by a spectrum of skin and muscle disease, which may include proximal muscle weakness and recalcitrant cutaneous eruptions. DM may also be associated with joint pain and stiffness, inflammatory arthritis, dysphagia, fatigue, and calcinosis. The current standard of care for DM includes glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIg). Unfortunately, these medications are not uniformly effective and can lead to adverse events, particularly with chronic use, necessitating discontinuation of therapy. Therefore, a substantial unmet need exists for more tailored and efficacious therapies that target DM pathogenesis. Brepocitinib is an oral, once-daily, novel, and specific TYK2/JAK1 inhibitor. Brepocitinib's potent inhibition of TYK2 and JAK1 reduces the signalling of pro-inflammatory cytokines, including IFN-α/β, IL-12, IL-23, and IFNγ, that have been implicated in the pathogenesis of DM. Other JAK inhibitors have been used off-label in both case series and open-label clinical trials in patients with DM; and brepocitinib has demonstrated efficacy in phase 2 clinical trials of several other autoimmune diseases, including plaque psoriasis, psoriatic arthritis, Crohn's disease, hidradenitis suppurativa, and ulcerative colitis. Therefore, there is a strong scientific and clinical rationale for the utility and potential effectiveness of brepocitinib in the treatment of DM patients. Currently, the safety, tolerability, and efficacy of brepocitinib is being evaluated in the largest (n=225) double-blind placebo-controlled phase 3 trial in DM patients to date (VALOR - NCT0543726).
- MeSH
- dermatomyozitida * farmakoterapie diagnóza imunologie MeSH
- inhibitory proteinkinas * terapeutické užití škodlivé účinky MeSH
- Janus kinasa 1 * antagonisté a inhibitory MeSH
- kinasa TYK2 * antagonisté a inhibitory MeSH
- lidé MeSH
- signální transdukce účinky léků MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The correct diagnosis is fundamental for the appropriate treatment to be employed in a particular pathology. The best treatment is not the one that solves only local problems, fragmenting the patient, and therefore, it is necessary to integrate the entire systemic condition of the individual before initiating any local treatment. This context inevitably requires dentistry to participate in a multidisciplinary approach, where the role of the dentist is expanded in concepts that encompass ethics, human dignity, and professional valorization. This article describes a clinical case of a patient with mucopolysaccharidosis type I, whose treatment of cystic lesions present in the mandible was exclusively performed through marsupialisation. The objective of this study is to demonstrate, within the complexity of this rare syndrome, the difficulties of diagnosis and the need for evaluation of the patient beyond the limits of the oral cavity, as well as to report two cases of large dentigerous cysts, surgically treated conservatively through marsupialisation, without the need for re-approach for enucleation and without recurrences over a 20-year period.
Cílem práce je popsat aktuální léčebný algoritmus obstrukční formy hypertrofické kardiomyopatie (HCM), kde je novinkou zařazení inhibitoru srdečního myosinu mavakamtenu. Klasické sarkomerické formy HCM se z patofyziologického hlediska vyznačují hyperkontraktilitou sarkomery, poruchou relaxace a variabilním výskytem obstrukce výtokového traktu (left ventricular outflow tract, LVOT). Na molekulární úrovni je příčinou těchto změn deplece superrelaxované formy hlavic těžkého řetězce srdečního myosinu, zvýšený počet aktin-myosinových interakcí a zvýšená spotřeba energie. Inhibice ATPázy srdečního myosinu mavakamtenem korigovala hyperkontraktilitu a porušenou relaxaci kardiomyocytů v tkáňových a zvířecích modelech genetických forem HCM. Klinický program s mavakamtenem tyto výsledky replikoval a v randomizovaných studiích fáze III (Explorer-HCM, Valor-HCM) vedl k následujícím závěrům. U obstrukční HCM mavakamten zlepšoval symptomatologii a toleranci zátěže, dále snižoval gradient ve LVOT a potřebu invazivní septální ablace. Mavakamten byl proto jako první inhibitor srdečního myosinu zařazen do algoritmu léčby symptomatických pacientů s HCM a přetrvávající významnou obstrukcí LVOT na konvenční léčbě beta-blokátory, disopyramidem, verapamilem nebo diltiazemem. Rizikem léčby inhibitory srdečního myosinu je vznik reverzibilní systolické dysfunkce levé komory, proto je nezbytná pečlivá titrace dávky léčiva a dlouhodobé echokardiografické sledování nemocných ve specializovaných centrech. Základní informace z farmakologie mavakamtenu, s ohledem na možnost interakcí s jídlem a léky, jsou uvedeny v závěrečné části tohoto textu.
We aimed to describe the contemporary recommendations for management of obstructive form of hypertrophic cardiomyopathy (HCM), which newly incorporates inhibition of cardiac myosin. Pathophysiology of classical sarcomeric forms of HCM is characterized by hypercontractility of sarcomere, its impaired relaxation and a variable occurrence of left ventricular outflow tract (LVOT) obstruction. At the molecular level, these abnormalities are related to depletion of super-relaxed conformation of cardiac myosin heavy chain molecules, increased actin-myosin interactions and exaggerated myocardial oxygen consumption. Inhibition of ATPase of cardiac myosin with mavacamten corrected hypercontractility and abnormal relaxation of cardiomyocytes in tissue and animal models of genetic forms of HCM. Mavacamten clinical program replicated these results and showed in randomized phase III clinical trials (Explorer-HCM, Valor-HCM) the following findings. In obstructive HCM, mavacamten improved symptoms and exercise tolerance; in addition, it reduced obstruction in LVOT and the need for invasive septal reduction therapy. Mavacamten thus became the first cardiac myosin inhibitor which was introduced into the management of symptomatic HCM patients with persistent significant obstruction in LVOT despite the conventional treatment with beta-blockers, disopyramide, verapamil or diltiazem. The treatment with cardiac myosin inhibitors may be complicated by a reversible left ventricular systolic dysfunction. Therefore, a careful titration of target mavacamten dose and long-term echocardiographic follow-up of patients under treatment are required. Basic information about mavacamten pharmacology is shown in the final part of the manuscript. It includes potential food and drug interactions of mavacamten.
In this study, we have focused on a multiparametric microbiological analysis of the antistaphylococcal action of the iodinated imine BH77, designed as an analogue of rafoxanide. Its antibacterial activity against five reference strains and eight clinical isolates of Gram-positive cocci of the genera Staphylococcus and Enterococcus was evaluated. The most clinically significant multidrug-resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S. aureus (VRSA), and vancomycin-resistant Enterococcus faecium, were also included. The bactericidal and bacteriostatic actions, the dynamics leading to a loss of bacterial viability, antibiofilm activity, BH77 activity in combination with selected conventional antibiotics, the mechanism of action, in vitro cytotoxicity, and in vivo toxicity in an alternative animal model, Galleria mellonella, were analyzed. The antistaphylococcal activity (MIC) ranged from 15.625 to 62.5 μM, and the antienterococcal activity ranged from 62.5 to 125 μM. Its bactericidal action; promising antibiofilm activity; interference with nucleic acid, protein, and peptidoglycan synthesis pathways; and nontoxicity/low toxicity in vitro and in vivo in the Galleria mellonella model were found to be activity attributes of this newly synthesized compound. In conclusion, BH77 could be rightfully minimally considered at least as the structural pattern for future adjuvants for selected antibiotic drugs. IMPORTANCE Antibiotic resistance is among the largest threats to global health, with a potentially serious socioeconomic impact. One of the strategies to deal with the predicted catastrophic future scenarios associated with the rapid emergence of resistant infectious agents lies in the discovery and research of new anti-infectives. In our study, we have introduced a rafoxanide analogue, a newly synthesized and described polyhalogenated 3,5-diiodosalicylaldehyde-based imine, that effectively acts against Gram-positive cocci of the genera Staphylococcus and Enterococcus. The inclusion of an extensive and comprehensive analysis for providing a detailed description of candidate compound-microbe interactions allows the valorization of the beneficial attributes linked to anti-infective action conclusively. In addition, this study can help with making rational decisions about the possible involvement of this molecule in advanced studies or may merit the support of studies focused on related or derived chemical structures to discover more effective new anti-infective drug candidates.
- MeSH
- antibakteriální látky farmakologie chemie MeSH
- antiinfekční látky * farmakologie MeSH
- Enterococcus MeSH
- methicilin rezistentní Staphylococcus aureus * MeSH
- mikrobiální testy citlivosti MeSH
- rafoxanid farmakologie MeSH
- Staphylococcus aureus MeSH
- Staphylococcus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Lignins are the most abundant biopolymers that consist of aromatic units. Lignins are obtained by fractionation of lignocellulose in the form of "technical lignins". The depolymerization (conversion) of lignin and the treatment of depolymerized lignin are challenging processes due to the complexity and resistance of lignins. Progress toward mild work-up of lignins has been discussed in numerous reviews. The next step in the valorization of lignin is the conversion of lignin-based monomers, which are limited in number, into a wider range of bulk and fine chemicals. These reactions may need chemicals, catalysts, solvents, or energy from fossil resources. This is counterintuitive to green, sustainable chemistry. Therefore, in this review, we focus on biocatalyzed reactions of lignin monomers, e.g., vanillin, vanillic acid, syringaldehyde, guaiacols, (iso)eugenol, ferulic acid, p-coumaric acid, and alkylphenols. For each monomer, its production from lignin or lignocellulose is summarized, and, mainly, its biotransformations that provide useful chemicals are discussed. The technological maturity of these processes is characterized based on, e.g., scale, volumetric productivities, or isolated yields. The biocatalyzed reactions are compared with their chemically catalyzed counterparts if the latter are available.
Polyhydroxyalkanoates (PHAs) are polyesters of significant interest due to their biodegradability and properties similar to petroleum-derived plastics, as well as the fact that they can be produced from renewable sources such as by-product streams. In this study, brewer's spent grain (BSG), the main by-product of the brewing industry, was subjected to a set of physicochemical pretreatments and their effect on the release of reducing sugars (RS) was evaluated. The RS obtained were used as a substrate for further PHA production in Burkholderia cepacia, Bacillus cereus, and Cupriavidus necator in liquid cultures. Although some pretreatments proved efficient in releasing RS (acid-thermal pretreatment up to 42.1 gRS L-1 and 0.77 gRS g-1 dried BSG), the generation of inhibitors in such scenarios likely affected PHA production compared with the process run without pretreatment (direct enzymatic hydrolysis of BSG). Thus, the maximum PHA accumulation from BSG hydrolysates was found in the reference case with 0.31 ± 0.02 g PHA per g cell dried weight, corresponding to 1.13 ± 0.06 g L-1 and a PHA yield of 23 ± 1 mg g-1 BSG. It was also found that C. necator presented the highest PHA accumulation of the tested strains followed closely by B. cepacia, reaching their maxima at 48 h. Although BSG has been used as a source for other bioproducts, these results show the potential of this by-product as a no-cost raw material for producing PHAs in a waste valorization and circular economy scheme.
It is estimated that more than 20% of processed apples and grapes are discarded as waste, which is dominated by pomace rich in malic acid that could be converted to high-value organic acids or other chemicals. A total of 98 yeast strains isolated from apple, grape, and plum wastes were evaluated for their ability to degrade malic acid relative to known yeast strains. Most (94%) of the new isolates degraded malic acid efficiently (> 50%) in the presence and absence of exogenous glucose, whereas only 14% of the known strains could do so, thus confirming the value of exploring (and exploiting) natural biodiversity. The best candidates were evaluated in synthetic media for their ability to convert malic acid to other valuable products under aerobic and oxygen-limited conditions, with two strains that produced ethanol and acetic acid as potential biorefinery products during aerobic cultivations and oxygen-limited fermentations on sterilized apple and grape pomace. Noteworthy was the identification of a Saccharomyces cerevisiae strain that is more efficient in degrading malic acid than other members of the species. This natural strain could be of value in the wine-making industry that often requires pH corrections due to excess malic acid.
Lignin, the term commonly used in literature, represents a group of heterogeneous aromatic compounds of plant origin. Protolignin or lignin in the cell wall is entirely different from the commercially available technical lignin due to changes during the delignification process. In this paper, we assess the status of lignin valorization in terms of commercial products. We start with existing knowledge of the lignin/protolignin structure in its native form and move to the technical lignin from various sources. Special attention is given to the patents and lignin-based commercial products. We observed that the technical lignin-based commercial products utilize coarse properties of the technical lignin in marketed formulations. Additionally, the general principles of polymers chemistry and self-assembly are difficult to apply in lignin-based nanotechnology, and lignin-centric investigations must be carried out. The alternate upcoming approach is to develop lignin-centric or lignin first bio-refineries for high-value applications; however, that brings its own technological challenges. The assessment of the gap between lab-scale applications and lignin-based commercial products delineates the challenges lignin nanoparticles-based technologies must meet to be a commercially viable alternative.
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The bacterium Pseudomonas putida KT2440 is gaining considerable interest as a microbial platform for biotechnological valorization of polymeric organic materials, such as lignocellulosic residues or plastics. However, P. putida on its own cannot make much use of such complex substrates, mainly because it lacks an efficient extracellular depolymerizing apparatus. We seek to address this limitation by adopting a recombinant cellulosome strategy for this host. In this work, we report an essential step in this endeavor-a display of designer enzyme-anchoring protein "scaffoldins", encompassing cohesin binding domains from divergent cellulolytic bacterial species on the P. putida surface. Two P. putida chassis strains, EM42 and EM371, with streamlined genomes and differences in the composition of the outer membrane were employed in this study. Scaffoldin variants were optimally delivered to their surface with one of four tested autotransporter systems (Ag43 from Escherichia coli), and the efficient display was confirmed by extracellular attachment of chimeric β-glucosidase and fluorescent proteins. Our results not only highlight the value of cell surface engineering for presentation of recombinant proteins on the envelope of Gram-negative bacteria but also pave the way toward designer cellulosome strategies tailored for P. putida.
- MeSH
- beta-glukosidasa metabolismus MeSH
- celulosa metabolismus MeSH
- celulozómy metabolismus MeSH
- chromozomální proteiny, nehistonové chemie MeSH
- Escherichia coli metabolismus MeSH
- genom bakteriální * MeSH
- membránové proteiny metabolismus MeSH
- metabolické inženýrství metody MeSH
- proteinové domény MeSH
- proteiny buněčného cyklu chemie MeSH
- proteiny z Escherichia coli metabolismus MeSH
- Pseudomonas putida genetika metabolismus MeSH
- rekombinantní proteiny metabolismus MeSH
- vnější bakteriální membrána metabolismus MeSH
- zelené fluorescenční proteiny metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
