Abstract
Widespread use of herbicides results in the global increase in weed resistance. The rotational use of herbicides according to their modes of action (MoAs) and discovery of novel phytotoxic ...molecules are the two strategies used against the weed resistance. Herein, Random Forest modeling was used to build predictive models and establish comprehensive characterization of structure–activity relationships underlying herbicide classifications according to their MoAs and weed selectivity. By combining the predictive models with herbicide-likeness rules defined by selected molecular features (numbers of H-bond acceptors and donors, logP, topological and relative polar surface area, and net charge), the virtual stepwise screening platform is proposed for characterization of small weight molecules for their phytotoxic properties. The screening cascade was applied on the data set of phytotoxic natural products. The obtained results may be valuable for refinement of herbicide rotational program as well as for discovery of novel herbicides primarily among natural products as a source for molecules of novel structures and novel modes of action and translocation profiles as compared with the synthetic compounds.
Glyphosate has remained the leading herbicide on the global market to date, despite the continuous debate between consumers, scientific community, and regulatory agencies over its carcinogenicity, ...genotoxicity, environmental persistence, and the role in the development of neurodegenerative disorders. Chemically, glyphosate belongs to a large family of organophosphorus pesticides, which exert a neurotoxic effect by inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes of the cholinergic system essential for maintaining neurotransmission. Although research shows that glyphosate is a weak cholinesterase inhibitor in fish and mammals compared to other OP compounds, no conclusive data exist concerning the inhibition of human AChE and BChE. In our study we analysed its inhibitory potency on human AChE and BChE, by establishing its IC
and reversible inhibition in terms of dissociation inhibition constants. Glyphosate concentration of 40 mmol/L caused near total inhibition of enzyme activity (approx. 10 % activity remaining). Inhibition dissociation constants (
) of glyphosate-AChE and -BChE complexes were 28.4±2.7 mmol/L and 19.3±1.8 mmol/L, respectively. In conclusion, glyphosate shows a slight binding preference for BChE but exhibits inhibition only in a high concentration range. Our results are in line with studies reporting that its neurotoxic effect is not primarily linked to the cholinergic system.
Psoriatic arthritis (PsA) is influenced by a complex genetic predisposition. In patients with PsA, interleukin (IL)-17A plays a key role in triggering a complex autoimmune/autoinflammatory immune ...response in conjunction with other pro-inflammatory cytokines (such as tumor necrosis factor-alpha, IL-23, monocyte chemotactic protein-1, and IL-6). PsA manifests with various clinical symptoms, including musculoskeletal diseases and extra-articular manifestations. In particular, mediated by the soluble IL-17A presents a higher cardiovascular risk, suggesting connection between inflammation and cardiovascular diseases beyond the traditional risk factors. Moreover, studies have shown that patients with psoriasis are ten times at higher risk of developing dilated cardiomyopathy than those without psoriasis. Therefore, owing to the prominent role of IL-17A and psoriasis in the pathogenesis of PsA and endothelial dysfunction, we hypothesized that IL-17A is crucial in the early development of diastolic dysfunction (DD) and could serve as a tool to identify patients with asymptomatic DD and PsA. Although transthoracic echocardiography is the primary evaluation method for DD, it requires skilled personnel, routine parameters assessment, such as mitral inflow, and tissue Doppler imaging. As a result, assessing parameters such as left atrial deformity using novel techniques could be valuable for a more specific evaluation and diagnosis of DD. Clinical characteristics and laboratory parameters of PsA activity, cardiac ultrasound parameters, or cardiac functional markers like N-terminal pro-brain natriuretic peptide (NT-pro-BNP) can be correlated with the concentration of serum IL-17A. Moreover, determining the diagnostic accuracy of circulating IL-17A for early DD can also serve as a laboratory biomarker for diagnosing DD in asymptomatic patients. Thus, if the diagnostic accuracy of IL-17A for DD can be proven, the identification of biological drugs that inhibit IL-17A could be advantageous in treating patients with PsA and echocardiography-verified asymptomatic DD.
We aimed to evaluate the diagnostic accuracy of the proinflammatory monocyte chemotactic protein-1 (MCP-1) in the diagnosis of asymptomatic diastolic dysfunction (DD) in patients with psoriatic ...arthritis (PsA). The disease activity in psoriatic arthritis (DAPSA) was determined using clinical and laboratory parameters, and echocardiography was performed to estimate DD. Serum MCP-1 concentrations were elevated in PsA patients with DD diagnosed with ultrasound (median (25th percentile, 75th percentile): 366.6 pg/mL (283, 407.1 pg/mL) vs. 277.5 pg/mL (223.5, 319.1 pg/mL) in controls; P<0.0017). PsA patients with serum MCP-1 concentration higher than the cut-off value of 347.6 pg/mL had a 7.74-fold higher chance of developing DD than PsA patients with lower serum MCP-1 concentrations (controls), with a specificity of 86.36% and sensitivity of 55%, as verified using ultrasound. The group with MCP-1 concentrations above the cut-off value also showed a higher late peak diastolic mitral inflow velocity, A-wave value (P=0.000005), E/E′ ratio (P=0.00005), and a lower E/A ratio (P=0.000002), peak systolic left atrial reservoir strain, SA value (P=0.0066), early peak diastolic displacement of the mitral septal annulus, E′ wave value (P=0.003), than controls. Systolic blood pressure (P=0.01), LDL cholesterol concentration (P=0.012), glucose concentration (P=0.011), and DAPSA (P=0.0000) increased in the PsA group with higher MCP-1 concentrations, although there were no differences in comorbidities and therapy between the groups compared. Thus, the serum MCP-1 concentration was a significant and independent prognostic indicator for asymptomatic DD in PsA patients (area under the curve=0.730, P=0.001). The DAPSA score in PsA patients might indicate the need for echocardiography and adjustment of anti-inflammatory treatment in terms of DD prevention.
Amiodarone is a potent antiarrhythmic medication used to treat life-threatening ventricular arrhythmias; however, its well-established adverse effect is a thyroid disorder. Amiodarone-induced ...thyroiditis (AIT), a clinical entity involving two types with different etiopathology and treatment approaches, may occur at the beginning or even several years after amiodarone treatment discontinuation. The toxicity profile of amiodarone becomes especially important in young patients with lifelong cardiac disorders, which are often refractory to other antiarrhythmic drugs. Herein, we report the first case of non-sustained ventricular tachycardia (NSVT), an unusual presentation of type II AIT, in a young male patient who was previously diagnosed with left ventricular cardiomyopathy with excessive trabeculation.
A 36-year-old male non-athlete presented with tiredness during regular follow-up. Continuous electrocardiographic monitoring (cECG) revealed NSVT, whereas echocardiography and cardiac magnetic resonance imaging detected discrete structural and functional changes that could not fully explain the observed cECG report. Conversely, an unmeasurably low thyrotropin level on admission and previous exposure to amiodarone pointed the diagnostic pathway in the direction of the thyroid gland. Elevated free thyroxine and undetectable autoantibody titers with unremarkable sonographic findings raised clinical suspicion of type II AIT. Scintigraphic imaging with
Tc-2-methoxyisobutylisonitrile (sestamibi) revealed decreased thyroid uptake; hence, prednisone was introduced for treatment. Clear improvements in both biochemical and electrocardiographic parameters were observed after immunomodulatory treatment of type II AIT in this young patient with cardiomyopathy and excessive trabeculation.
Treatment of reversible causes of cardiac rhythm abnormalities such as type II AIT should be considered before choosing other treatment modalities, particularly in patients with structural cardiac disorders. The importance of a multidisciplinary approach in complex cases such as the one reported, thus, cannot be emphasized enough.
Suvremena sredstva za dekontaminaciju bojnih otrova Tušek, Dragutin; Cetina, Ivana; Pehar, Vesna
Kemija u industriji; časopis kemičara i tehnologa Jugoslavije,
01/2020, Letnik:
69, Številka:
1-2
Journal Article
Recenzirano
Odprti dostop
Metalni oksidi su netoksični spojevi koji se upotrebljavaju kao praškasti dekontaminanti, jednostavni su za primjenu i skladištenje te imaju vrlo visok površinski kapacitet. Metalni oksidi, posebno u ...nanoformi pokazuju odlična fizisorpcijska i kemisorpcijska svojstva za sorpciju toksičnih spojeva uključujući bojne otrove i njihove imitante. Iako se istražuju sorpcijska i dekontaminacijska svojstva mnogih metalnih oksida, najveću komercijalnu iskoristivost pokazali su magnezijev, aluminijev i titanijev oksid. Neki metalni oksidi u nanoformi pokazuju svojstvo destruktivne adsorpcije, što je vrlo interesantno u istraživanju pogodnosti metalnih oksida u svrhu dekontaminacije bojnih otrova i opasnih zagađivala uključujući kemijske, biološke i radiološke tvari. Uz metalne okside istražuju se i metalni kationi kao dopanti drugim metalnim oksidima i zeolitima u svrhu poboljšanja sorpcijskih svojstava dopaniranih spojeva.
Metal oxides are nontoxic compounds that are, in their powder form, used as decontaminating agents; they are simple to use and apply, easy to store, and have very high active surface capacity. Metal oxides, especially in nanoform, show excellent physisorption and chemisorption properties towards toxic compounds like chemical warfare agents and their simulants. Although sorption and decontamination properties of many metal oxides are being researched, only magnesium, aluminum, and titanium oxide showed the greatest commercial usability. Some metal oxides in nanoform show destructive adsorption properties, which is very interesting in research of the metal oxides suitable for decontamination of chemical warfare agents and other chemical, biological, and radiological toxic substances. Besides metal oxides, research focus is also on metal cations used as dopants in other metal oxides and zeolites in order to improve sorption properties.
Suvremena sredstva za dekontaminaciju bojnih otrova Tušek, Dragutin; Cetina, Ivana; Pehar, Vesna
Kemija u industriji; časopis kemičara i tehnologa Jugoslavije,
12/2019, Letnik:
68, Številka:
11-12
Journal Article
Recenzirano
Odprti dostop
Suvremena sredstva za dekontaminaciju bojnih otrova moraju biti djelotvorna i ekološki prihvatljiva. Iz tih razloga novija znanstvena istraživanja usmjerena su na ispitivanje djelotvornosti metalnih ...oksida, prirodnih i sintetskih zeolita te metal-organskih mreža u dekontaminaciji bojnih otrova i drugih toksičnih spojeva poput organofosfornih pesticida. Iako su prvotna istraživanja zeolita kao dekontaminanata bila usmjerena na istraživanje sintetskih zeolita, u posljednje vrijeme sve interesantniji su i prirodni zeoliti, u prvom redu klinoptilolit. Pokazalo se da metal-organske mreže na bazi cirkonija mogu uspješno razgraditi kemijske ratne agense i njihove simulante te da spadaju među najbrže katalizatore za hidrolizu živčanih bojnih otrova. Razvoj suvremenih materijala nije usmjeren samo na istraživanje dekontaminacijskih svojstava nego i u svrhu zaštitnih premaza i slojeva koji mogu imati i samo-dekontaminacijski učinak.
The modern decontaminants for chemical warfare agents must be effective and environmentally acceptable. For these reasons, recent scientific research has focused on the investigation of the efficacy of metal oxides, natural and synthetic zeolites and metal-organic frameworks (MOF) in decontamination of chemical warfare agents and other toxic compounds such as organophosphorus pesticides. Although the first zeolite decontaminants research have been directed to the investigation of synthetic zeolites, the natural zeolites have become more interesting, especially clinoptilolite. It has been shown that zirconium-based metal-organic frameworks (MOF) can successfully break down chemical warfare agents and their simulants and be among the fastest catalysts for the hydrolysis of nerve agents. Development of modern decontamination materials is not intended only to exploring decontamination properties, but also in development of protective coatings and layers with a self-decontamination effect.
Multiple and yet uncertain connections exist between cardiovascular diseases and the nutritional status of patients, particularly in relation to cardiovascular treatments. Proton pump inhibitors ...(PPI) are among the most commonly used group of drugs.
To analyse utilisation of PPI in association with nutritional risk of patients scheduled for rehabilitation after treatment for ischaemic and valvular heart disease.
Retrospective analyses on a consecutive sample of patients, which included drug utilisation of PPI and nutritional risk screening, using a standardised NRS-2002 tool. The patients (n = 536) were divided into groups based on previous cardiovascular treatments and use of PPI.
Nearly half of the patients (244, 46.1%) had PPI in their chronic therapy despite the clinically negligible prevalence of conditions that are their fundamental indications. The odds for using PPI in patients with increased nutritional risk, estimated by logistic regression, were 3.34 (95% confidence intervals CI 2.26-4.94), p < 0.001. Receiver operating curve analyses also revealed significant differences of PPI utilisation in connection with NRS-2002 > 3: positive likelihood-ratio (LR) 2.35 (95% CI 2.10-2.60); negative LR 0.46 (95% CI 0.4-0.6); area under the curve (AUC) 0.720; p < 0.001; as well as the percentage weigh loss history > 6.36% (positive LR 2.22 95% CI 2.00-2.50; negative LR 0.41 95% CI 0.30-0.50; AUC 0.707; p < 0.001).
Utilisation of PPI was found to be of relatively high prevalence and significantly associated with parameters of nutritional risk screening. Furthermore, it was in correlation with the age of patients and the existence of chronic kidney disease, which are well-established predispositions for poor nutritional status. Nutritional risk seems to be additionally negatively challenged by utilisation of PPI due to gastric malabsorption and anaemia.
Sets of 346 herbicides in use and 163 no longer in use were collected from open access online sources and compared in silico with cholinesterases inhibitors (ChI) and drugs in terms of ...physicochemical profile and estimated toxic effects on human health. The screening revealed at least one potential adverse consequence for each herbicide class assigned according to their mode of action on weeds. The classes with most toxic warnings were K1, K3/N, F1 and E. The selection of 11 commercial herbicides for in vitro biological tests on human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes involved in neurotoxicity and detoxification of various xenobiotics, respectively, was based mainly on the structural similarity with inhibitors of cholinesterases. Organophosphate anilofos and oxyacetanilide flufenacet were the most potent inhibitors of AChE (25 μM) and BChE (6.4 μM), respectively. Glyphosate, oxadiazon, tembotrione and terbuthylazine were poor inhibitors with an estimated IC50 above 100 μM, while for glyphosate the IC50 was above 1 mM. Generally, all of the selected herbicides inhibited with a slight preference towards BChE. Cytotoxicity assays showed that anilofos, bensulide, butamifos, piperophos and oxadiazon were cytotoxic for hepatocytes (HepG2) and neuroblastoma cell line (SH-SY5Y). Time-independent cytotoxicity accompanied with induction of reactive oxygen species indicated rapid cell death in few hours. Our results based on in silico and in vitro analyses give insight into the potential toxic outcome of herbicides in use and can be applied in the design of new molecules with a less impact on humans and the environment.
•Computational analysis of herbicides shows potential for neurotoxicity.•Chemical structure of herbicides affects their modes of action and toxicity.•Organophosphates anilofos, bensulide and piperophos inhibit both cholinesterases.•The inhibition is governed by non-covalent and covalent interactions.•Cytotoxicity toward neuronal and hepatic cells was observed for several herbicides.
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