Long COVID syndrome-associated brain fog.

We investigated the frequency of brain fog in a large cohort of patients with documented coronavirus disease-2019 (COVID-19) who have survived the illness. We also scrutinized the potential risk factors associated with the development of brain fog. Adult patients (18-55 years of age), who were referred to the healthcare facilities anywhere in Fars province from February 19, 2020 to November 20, 2020 were included. All patients had a confirmed COVID-19 diagnosis. In a phone call, at least 3 months after their discharge from the hospital, we obtained their current information. A questionnaire was specifically designed for data collection. In total, 2696 patients had the inclusion criteria; 1680 (62.3%) people reported long COVID syndrome (LCS). LCS-associated brain fog was reported by 194 (7.2%) patients. Female sex (odds ratio [OR]: 1.4), respiratory problems at the onset (OR: 1.9), and intensive care unit (ICU) admission (OR: 1.7) were significantly associated with reporting chronic post-COVID "brain fog" by the patients. In this large population-based study, we report that chronic post-COVID "brain fog" has significant associations with sex (female), respiratory symptoms at the onset, and the severity of the illness (ICU admission).

Design, synthesis, spectroscopic characterization, in vitro tyrosinase inhibition, antioxidant evaluation, in silico and kinetic studies of substituted indole-carbohydrazides.

In the current study, twenty-five indole-carbohydrazide derivatives linked to different aryl substitutions were rationally designed and synthesized. The structures of all derivatives were confirmed using different spectroscopic techniques including 1H NMR, 13C NMR, Mass spectrometry, and elemental analysis. The tyrosinase inhibitory activities of all synthetic compounds exhibited IC50 values in the range of 0.070 to > 100 µM. Structure-activity relationships showed that compounds 4f (R = 4-OH, IC50 = 0.070 µM), 8f (R = 4-OH, IC50 = 0.072 µM), and 19e (IC50 = 0.19 µM) with para-OH substituent at the R position was found to be the most active members of all three tested series. Kinetic studies exhibited that compounds 4f, 8f, and 19e are mixed-type inhibitors. Furthermore, toxicity and cell-based anti-melanogenesis assessments were performed on the most potent derivatives and it was shown that 4f, 8f, and 19e had no toxicity at 8 µM and reduced the percent of melanin content to 68.43, 72.61, 73.47 at 8 µM, respectively. In silico analyses of absorption, distribution, metabolism, and excretion (ADME) profile of synthesized compounds showed that these molecules followed drug-likeness rules and acceptable predictive ADMET features. Results of the docking study were almost in line with biological results with ChemPLP values of 53.56 to 79.33. Also, the docking study showed the critical interactions of potent inhibitors with the active site of the enzyme which affects the potency of the synthesized hybrids. Based on molecular dynamic simulations, compound 4f exhibited pronounced interaction with the critical residues of the tyrosinase active site so that the indole ring participated in H-bond interaction with Gly281 and 4-hydroxy benzylidene recorded another H-bond interaction with Asp289 plus hydrophobic interactions with Phe292. Hydrazide linker also exhibited three H-bond interactions with His263 and Gly281.

Application of isothermal titration calorimetry for characterizing thermodynamic parameters of biomolecular interactions: peptide self-assembly and protein adsorption case studies.

The complex nature of macromolecular interactions usually makes it very hard to identify the molecular-level mechanisms that ultimately dictate the result of these interactions. This is especially evident in the case of biological systems, where the complex interaction of molecules in various situations may be responsible for driving biomolecular interactions themselves but also has a broader effect at the cell and/or tissue level. This review will endeavor to further the understanding of biomolecular interactions utilizing the isothermal titration calorimetry (ITC) technique for thermodynamic characterization of two extremely important biomaterial systems, viz., peptide self-assembly and nonfouling polymer-modified surfaces. The advantages and shortcomings of this technique will be presented along with a thorough review of the recent application of ITC to these two areas. Furthermore, the controversies associated with the enthalpy-entropy compensation effect as well as thermodynamic equilibrium state for such interactions will be discussed.

Targeted drug delivery to the thrombus by fusing streptokinase with a fibrin-binding peptide (CREKA): an in silico study.

Aim: Streptokinase has poor selectivity and provokes the immune response. In this study, we used in silico studies to design a fusion protein to achieve targeted delivery to the thrombus. Materials & methods: Streptokinase was analyzed computationally for mapping. The fusion protein modeling and quality assessment were carried out on several servers. The enzymatic activity and the stability of the fusion protein and its complex with plasminogen were assessed through molecular docking analysis and molecular dynamics simulation respectively. Results: Physicochemical properties analysis, protein quality assessments, protein-protein docking and molecular dynamics simulations predicted that the designed fusion protein is functionally active. Conclusion: Our results showed that this fusion protein might be a prospective candidate as a novel thrombolytic agent with better selectivity.

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Toward a mechanistic understanding of ionic self-complementary peptide self-assembly: role of water molecules and ions.

Ionic self-complementary peptides are considered an important class of self-assembling peptides. In particular, RADARADARADARADA (RADA4) is well-known to form a relatively regular nanofiber structure that has been primarily studied in terms of its physicochemical properties, as related to its biomedical applications. However, the molecular level interactions that are involved in promoting the self-assembly of this peptide into nanofibers have not been fully elucidated. Herein, a thermodynamic analysis of the influences of peptide chemistry upon self-assembly is discussed for RADA4, RADA4-K5, and RADA4-S5. The regular nanofiber structure of the assembled peptides makes it a good candidate for isothermal titration calorimetry (ITC) studies for determining the propensity for self-assembly, the critical assembly concentration (CAC), and the role hydration and ion content play in the assembly of these peptides. First, solutions containing only RADA4-K5 did not self-assemble; illustrating even slight alterations in the asymmetric terminal amino acid chemistry affects assembly. The CAC of the remaining self-assembling peptides was between ~0.1 and ~0.15 mM. Interestingly, we found that self-assembly was entropically driven with hydrophobic forces being the main driving force for RADA4 and hydrogen bonding for RADA4-S5. The role of water molecules and counterions in self-assembly was also highlighted: assembly of RADA4 led to desolvation of interfacial surfaces, whereas the net number of water molecules in the assembled complex increased upon RADA4-S5 self-assembly. Moreover, it was found that counterions did not seem to contribute significantly to self-assembly: a result in contrast to current concepts regarding the role of electrostatic interactions in self-assembly of RADA4-like peptides. A molecular level understanding of peptide self-assembly will allow for further engineering of peptides for a vast array of biomedical applications.

Targeting long noncoding RNAs in neuroblastoma: Progress and prospects.

Neuroblastoma (NB) is the third most prevalent tumor that mostly influences infants and young children. Although different treatments have been developed for the treatment of NB, high-risk patients have been reported to have low survival rates. Currently, long noncoding RNAs (lncRNAs) have shown an attractive potential in cancer research and a party of investigations have been performed to understand mechanisms underlying tumor development through lncRNA dysregulation. Researchers have just newly initiated to exhibit the involvement of lncRNAs in NB pathogenesis. In this review article, we tried to clarify the point we stand with respect to the involvement of lncRNAs in NB. Moreover, implications for the pathologic roles of lncRNAs in the development of NB have been discussed. It seems that some of these lncRNAs have promising potential to be applied as biomarkers for NB prognosis and treatment.

Potential inhibitors of the main protease of SARS-CoV-2 and modulators of arachidonic acid pathway: Non-steroidal anti-inflammatory drugs against COVID-19.

The main protease of SARS-CoV-2 is one of the key targets to develop and design antiviral drugs. There is no general agreement on the use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19. In this study, we investigated NSAIDs as potential inhibitors for chymotrypsin-like protease (3CLpro) and the main protease of the SARS-CoV-2 to find out the best candidates, which can act as potent inhibitors against the main protease. We also predicted the effect of NSAIDs on the arachidonic pathway and evaluated the hepatotoxicity of the compounds using systems biology techniques. Molecular docking was conducted via AutoDock Vina to estimate the interactions and binding affinities between selected NSAIDs and the main protease. Molecular docking results showed the presence of 10 NSAIDs based on lower binding energy (kcal/mol) toward the 3CLpro inhibition site compared to the co-crystal native ligand Inhibitor N3 (-6.6 kcal/mol). To validate the docking results, molecular dynamic (MD) simulations on the top inhibitor, Talniflumate, were performed. To obtain differentially-expressed genes under the 27 NSAIDs perturbations, we utilized the L1000 final Z-scores from the NCBI GEO repository (GSE92742). The obtained dataset included gene expression profiling signatures for 27 NSAIDs. The hepatotoxicity of NSAIDs was studied by systems biology modeling of Disturbed Metabolic Pathways. This study highlights the new application of NSAIDs as anti-viral drugs used against COVID-19. NSAIDs may also attenuate the cytokine storm through the downregulation of inflammatory mediators in the arachidonic acid pathway.

Design, synthesis, and biological evaluation of symmetrical azine derivatives as novel tyrosinase inhibitors.

A series of symmetrical azine derivatives containing different substituted benzyl moieties were designed, synthesized, and evaluated for their inhibitory activity against tyrosinase. The results showed that compounds 3e, 3f, 3h, 3i, 3j, and 3k possess effective tyrosinase inhibition with IC50 values ranging from 7.30 µM to 62.60 µM. Particularly, compounds 3f displayed around three-fold improvement in the potency (IC50 = 7.30 ± 1.15 µM) compared to that of kojic acid (IC50 = 20.24 ± 2.28 µM) as the positive control. Kinetic study of compound 3f confirmed uncompetitive inhibitory activity towards tyrosinase indicating that it can bind to enzyme-substrate complex. Next, molecular docking analysis was performed to study the interactions and binding mode of the most potent compound 3f in the tyrosinase active site. Besides, the cytotoxicity of 3f, as well as its potency to reduce the melanin content were also measured on invasive melanoma B16F10 cell line. Also, 3f exhibited above 82% cell viability in the A375 cell line at 10 µM. Consequently, compounds 3f could be introduced as a potent tyrosinase inhibitor that might be a promising candidate in the cosmetics, medicine, and food industry.

Pharmacotherapeutic approach toward urological medications and vaccination during COVID-19: a narrative review.

One year after the prevalence of the novel coronavirus pandemic, some aspects of the physiopathology, treatment and progression of coronavirus 2019 disease (COVID-19) have remained unknown. Since no comprehensive study on the use of urological medications in patients with COVID-19 has been carried out, this narrative review aimed to focus on clinically important issues about the treatment of COVID-19 and urologic medications regarding efficacy, modifications, side effects and interactions in different urologic diseases. In this review, we provide information about the pharmacotherapeutic approach toward urologic medications in patients with COVID-19 infection. This study provides an overview of medications in benign prostatic hyperplasia, prostate cancer, impotence and sexual dysfunction, urolithiasis, kidney transplantation and hypertension as the most frequent diseases in which the patients are on long-term medications. Also, the effect of urologic drugs on the efficacy of vaccination is briefly discussed.

Risk Factors Associated with Long COVID Syndrome: A Retrospective Study.

Background: Recently, people have recognized the post-acute phase symptoms of the COVID-19. We investigated the long-term symptoms associated with COVID-19, (Long COVID Syndrome), and the risk factors associated with it. Methods: This was a retrospective observational study. All the consecutive adult patients referred to the healthcare facilities anywhere in Fars province from 19 February 2020 until 20 November 2020 were included. All the patients had a confirmed COVID-19 diagnosis. In a phone call to the patients, at least three months after their discharge from the hospital, we obtained their current information. The IBM SPSS Statistics (version 25.0) was used. Pearson Chi square, Fisher's exact test, t test, and binary logistic regression analysis model were employed. A P value of less than 0.05 was considered to be significant. Results: In total, 4,681 patients were studied, 2915 of whom (62.3%) reported symptoms. The most common symptoms of long COVID syndrome were fatigue, exercise intolerance, walking intolerance, muscle pain, and shortness of breath. Women were more likely to experience long-term COVID syndrome than men (Odds Ratio: 1,268; 95% Confidence Interval: 1,122-1,432; P=0.0001), which was significant. Presentation with respiratory problems at the onset of illness was also significantly associated with long COVID syndrome (Odds Ratio: 1.425; 95% Confidence Interval: 1.177-1.724; P=0.0001). A shorter length of hospital stay was inversely associated with long COVID syndrome (Odds Ratio: 0.953; 95% Confidence Interval: 0.941-0.965; P=0.0001). Conclusion: Long COVID syndrome is a frequent and disabling condition and has significant associations with sex (female), respiratory symptoms at the onset, and the severity of the illness.

Long COVID in children and adolescents.

BACKGROUND: To identify the prevalence and also the full spectrum of symptoms/complaints of children and adolescents who are suffering from long COVID. Furthermore, we investigated the risk factors of long COVID in children and adolescents. METHODS: All consecutive children and adolescents who were referred to the hospitals anywhere in Fars province, Iran, from 19 February 2020 until 20 November 2020 were included. All patients had a confirmed diagnosis of COVID-19. In a phone call to patients/parents, at least 3 months after their discharge from the hospital, we obtained their current status and information if their parents agreed to participate. RESULTS: In total, 58 children and adolescents fulfilled the inclusion criteria. Twenty-six (44·8%) children/adolescents reported symptoms/complaints of long COVID. These symptoms included fatigue in 12 (21%), shortness of breath in 7 (12%), exercise intolerance in 7 (12%), weakness in 6 (10%), and walking intolerance in 5 (9%) individuals. Older age, muscle pain on admission, and intensive care unit admission were significantly associated with long COVID. CONCLUSIONS: Long COVID is a frequent condition in children and adolescents. The scientific community should investigate and explore the pathophysiology of long COVID to ensure that these patients receive appropriate treatments for their condition.

A stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for ocular drug delivery.

Most medications targeting optic neuropathies are administered as eye drops. However, their corneal penetration efficiencies are typically < 5%. There is a clear, unmet need for novel transcorneal drug delivery vehicles. To this end, we have developed a stimulus-responsive, in situ-forming, nanoparticle-laden hydrogel for controlled release of poorly bioavailable drugs into the aqueous humor of the eye. The hydrogel is formulated as a composite of hyaluronic acid (HA) and methylcellulose (MC). The amphiphilic nanoparticles are composed of poly(ethylene oxide) (PEO) and poly(lactic acid) (PLA). Experimental design aided the identification of hydrogel composition and nanoparticle content in the formulation, and the formulation reliably switched between thixotropy and temperature-dependent rheopexy when it was tested in a rheometer under conditions that simulate the ocular surface, including blinking. These properties should ensure that the formulation coats the cornea through blinking of the eyelid and facilitate application of the medication as an eye drop immediately prior to the patient's bedtime. We subsequently tested the efficacy of our formulation in whole-eye experiments by loading the nanoparticles with cannabigerolic acid (CBGA). Our formulation exhibits over a 300% increase in transcorneal penetration over control formulations. This work paves the way for the introduction of novel products targeting ocular diseases to the market.

Comparison of Complications of Arteriovenous Fistula with Permanent Catheter in Hemodialysis Patients: A Six-month Follow-up.

BACKGROUND: Arteriovenous fistula (AVF), permanent catheter (PC), and vascular graft are three vascular access types used for hemodialysis procedure. Due to insufficient reliable information on the comparison between AVF and PC, this study was conducted to compare AVF and PC regarding dialysis adequacy. MATERIALS AND METHODS: This prospective study was carried out from March, 2013 to September, 2013. In this study, 76 hemodialysis patients were enrolled and assigned to two unequal groups of AVF and PC. Before and after the dialysis session, blood samples were taken for laboratory examinations and measurement of urea reduction ratio (URR) and Kt/V. The patients were followed up for six months, and then laboratory examinations were repeated. RESULTS: Of the 76 hemodialysis patients, 30 had AVF and others PC. During the 6-month follow-up, 24 patients in PC group but only one patient in AVF group showed infection (P = 0.006), while in each group, three cases of thrombosis were seen (P = 0.58); however, catheter dysfunction was seen in 13 patients of PC group but no patients of AVF group (P = 0.004). There was no difference between the two groups in Kt/V and URR at the beginning of the study; however, after six months, Kt/V and URR were greater in AVF group (P < 0.05). CONCLUSIONS: In addition to some advantages of AVF over PC, such as lower rate of infection and thrombosis, we also found better dialysis adequacy in AVF group. We recommend that AVF be created in all of patients with chronic kidney disease who are candidates for hemodialysis.