Evaluation of the Effect of Biochemistry Parameters on the Clinical Course in COVID-19 Patients Who Received Tocilizumab Treatment.

OBJECTIVES: Patients who develop cytokine storm while they have coronavirus disease 2019 (COVID-19) experience more severe symptoms. This article aims to evaluate the effect of biochemical parameters on the clinical course of the disease in patients treated with tocilizumab (TCZ) due to cytokine storm. METHODS: Medical documents of patients with COVID-19 were searched retrospectively. Patients who entered cytokine storm were classified as group 1 and divided into two subgroups as patients who were followed up in the ward and in the intensive care unit (ICU). Less severe COVID-19 patients who did not enter cytokine storm were included in the control group as group 2. RESULTS: A total of 522 patients with COVID-19 infection were included in the study. The mean age was 62.0 ± 15.6 years, and the majority were male (64.4%). Hypertension and diabetes mellitus were the two most common diseases, seen in 50.8% and 29.9%, respectively. There were 392 patients with TCZ application (group 1) and 130 patients without TCZ (group 2). Significantly higher serum glucose, magnesium, and sodium and lower calcium levels were present in group 1 than in group 2 (<0.001). Hypocalcemia, hypernatremia, hypermagnesemia, and hyperkalemia were more frequently detected in the ICU compared with the patients treated in the wards (P = 0.001, P < 0.001, P = 0.039, and P < 0.001, respectively). CONCLUSIONS: Following up closely electrolyte disturbances may support patient survival and decrease the probability of ICU necessity. This approach should be taken before the development of important disorders to be effective in the treatment process of the main disease.

Characterization of Exopolysaccharides (EPSs) Obtained from Ligilactobacillus salivarius Strains and Investigation at the Prebiotic Potential as an Alternative to Plant Prebiotics at Poultry.

In this study, it was aimed to reveal the potential of using exopolysaccharides (EPS) obtained from Ligilactobacillus salivarius as a prebiotic that regulates chicken intestinal microbiota. Characterization of EPS obtained from L. salivarius BIS312 (EPSBIS312) and BIS722 (EPSBIS722) strains was demonstrated by high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and size-exclusion chromatography (SEC) analyses. It was determined that the molecular weight of both EPS is in the range of 104-106 Daltons, and there are 4 types of monomers in their structure. Anti-biofilm and anti-quorum sensing effects of EPSBIS312 and EPSBIS722 were determined. EPSBIS312 and EPSBIS722 showed a strong anti-biofilm effect on Enterococcus faecalis ATCC 29212, Staphylococcus aureus EB-1, and Escherichia coli ATCC 11229. The anti-quorum sensing study revealed that the EPSBIS722 had a higher effect than the EPSBIS312. The effect of different concentrations of EPS (2.5%, 5%, 10%) on lactobacilli growth stimulator (LGS) was evaluated. The highest LGS was promoted at 10% concentration while the lowest LGS was promoted at 2.5% concentration by EPSBIS722. In addition, adhesion abilities of EPSBIS312 and EPSBIS722 in HT-29 colorectal adenocarcinoma cell line were tested. EPSs significantly increased the ability to adhere to HT-29 cells. The characterized EPSs may be an alternative to plant prebiotics such as inulin at poultry.

Can magnesium sulfate prophylaxis reduce colistin nephrotoxicity?

The study aimed to investigate the role of magnesium sulfate prophylaxis in nephrotoxicity caused by colistin. Thirty Wistar Albino rats were divided into four groups: control, colistin, magnesium (Mg), and Mg+colistin. The drugs were administered to the groups for seven days. Urea-creatinine values were measured at the beginning (T0) and end (T1) of the study. Malondialdehyde (MDA) levels were measured in plasma and kidney tissue, glutathione (GSH) levels were analyzed in the erythrocyte and kidney tissues. At the end of the study, the semiquantitative score (SQS) was calculated by the histopathological examination of the kidneys. Urea values significantly decreased in Mg and Mg+colistin groups compared to the baseline (p=0.013 and p=0.001). At the time of T1, these groups had significantly lower urea values than the colistin and control groups. Creatinine value was significantly increased in the colistin group compared to baseline (p=0.005), the creatinine value in the colistin group was significantly higher than the Mg+colistin group (p=0.011). Plasma MDA levels were significantly higher in the colistin group compared to the other groups at the time of T1 (p<0.001). The Mg+colistin group had lower renal MDA levels than the colistin group. The colistin group had significantly higher renal tubular grade (p=0.035), renal affected area (p<0.001), and SQS (p=0.001) than the Mg+colistin group. The results of the study suggested that Mg sulfate may have a nephrotoxicity-reducing effect on colistin.

Can magnesium sulfate prophylaxis reduce colistin nephrotoxicity?

The study aimed to investigate the role of magnesium sulfate prophylaxis in nephrotoxicity caused by colistin. Thirty Wistar Albino rats were divided into four groups: control, colistin, magnesium (Mg), and Mg+colistin. The drugs were administered to the groups for seven days. Urea-creatinine values were measured at the beginning (T0) and end (T1) of the study. Malondialdehyde (MDA) levels were measured in plasma and kidney tissue, glutathione (GSH) levels were analyzed in the erythrocyte and kidney tissues. At the end of the study, the semiquantitative score (SQS) was calculated by the histopathological examination of the kidneys. Urea values significantly decreased in Mg and Mg+colistin groups compared to the baseline (p=0.013 and p=0.001). At the time of T1, these groups had significantly lower urea values than the colistin and control groups. Creatinine value was significantly increased in the colistin group compared to baseline (p=0.005), the creatinine value in the colistin group was significantly higher than the Mg+colistin group (p=0.011). Plasma MDA levels were significantly higher in the colistin group compared to the other groups at the time of T1 (p<0.001). The Mg+colistin group had lower renal MDA levels than the colistin group. The colistin group had significantly higher renal tubular grade (p=0.035), renal affected area (p<0.001), and SQS (p=0.001) than the Mg+colistin group. The results of the study suggested that Mg sulfate may have a nephrotoxicity-reducing effect on colistin.

The relationship between the structural characteristics of lactobacilli-EPS and its ability to induce apoptosis in colon cancer cells in vitro.

Colon cancer is one of the most common cancer around the world. Exopolysaccharides (EPSs) produced by lactobacilli as potential prebiotics have been found to have an anti-tumor effect. In this study, lyophilized EPSs of four Lactobacillus spp. for their impact on apoptosis in colon cancer cells (HT-29) was evaluated using flow cytometry. The relationship between capability of a lactobacilli-EPS to induce apoptosis and their monosaccharide composition, molecular weight (MW), and linkage type was investigated by HPLC, SEC, and NMR, respectively. Changes in apoptotic-markers were examined by qPCR and Western Blotting. EPSs were capable of inhibiting proliferation in a time-dependent manner and induced apoptosis via increasing the expression of Bax, Caspase 3 and 9 while decreasing Bcl-2 and Survivin. All EPSs contained mannose, glucose, and N-acetylglucosamine with different relative proportions. Some contained arabinose or fructose. MW ranged from 102-104Da with two or three fractions. EPS of L. delbrueckii ssp. bulgaricus B3 having the highest amount of mannose and the lowest amount of glucose, showed the highest apoptosis induction. In conclusion, lactobacilli-EPSs inhibit cell proliferation in HT-29 via apoptosis. Results suggest that a relationship exists between the ability of EPS to induce apoptosis and its mannose and glucose composition.

Synthesis and Functional Investigations of Computer Designed Novel Cladribine-Like Compounds for the Treatment of Multiple Sclerosis.

Cladribine (2-CdA) is used as an anti-cancer drug but is currently studied as a potential treatment for use in relapsing-remitting multiple sclerosis (MS). In this study, we computer designed, synthesized, and characterized two novel derivatives of 2-CdA, K1-5d and K2-4c, and investigated their underlying mechanism of beneficial effect using the CCRF-CEM and RAJI cell lines. For this purpose, we first determined their effect on MS and DNA damage and repair-related gene expression profiles using custom arrays along with 2-CdA treatment at non-toxic doses. Then, we determined whether cells underwent apoptosis after treatment with 2-CdA, K1-5d, and K2-4c in CCRF-CEM and RAJI cells, using the DNA fragmentation assay. It was found that both derivatives modulated the expression of the pathway-related genes that are important in inflammatory signaling, apoptosis, ATM/ATR, double-strand break repair, and the cell cycle. Furthermore, 2-CdA, K1-5d, and K2-4c significantly activated apoptosis in both cell lines. In summary, our data demonstrate that although both derivatives act as anti-inflammatory and apoptotic agents, inducing the accumulation of DNA strand breaks and activating the ultimate tumor suppressor p53 in T and B lymphocytes, the K1-5d derivative has shown more promising activities for further studies.

Computer design, synthesis, and bioactivity analyses of drugs like fingolimod used in the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a very common disease of vital importance. In the MS treatment, some drugs such as fingolimod which help to protect nerves from damage are used. The main goal of the drug therapy in MS is to take control of the inflammation which leads to the destruction of myelin and axons in nerve cell and thus prevent and stop the progression of the disease. Fingolimod (FTY720) is an orally active immunomodulatory drug that has been used for the treatment of relapsing-remitting multiple sclerosis. It is a sphingosine-1-phosphate receptor modulator which prevents lymphocytes from contributing to an autoimmune reaction by inhibiting egress of lymphocytes them from lymph nodes. In this study, we have computer designed, synthesized and characterized two novel derivatives of FTY720, F1-12h and F2-9, and have determined their underlying mechanism of their beneficial effect in SH-SY5Y, SK-N-SH, and U-118 MG cell lines. For this purpose, we first determined the regulation of the cAMP response element (CRE) activity and cAMP concentration by F1-12h and F2-9 together with FTY720 using pGL4.29 luciferase reporter assay and cAMP immunoassay, respectively. Then, we have determined their effect on MS- and GPCR-related gene expression profiles using custom arrays along with FTY720 treatment at non-toxic doses (EC10). It was found that both derivatives significantly activate CRE and increase cAMP concentration in all three cell lines, indicating that they activate cAMP pathway through cell surface receptors as FTY720 does. Furthermore, F1-12h and F2-9 modulate the expression of the pathway related genes that are important in inflammatory signaling, cAMP signaling pathway, cell migration as well as diverse receptor and transcription factors. Expression of the genes involved in myelination was also increased by the treatment with F1-12h and F2-9. In summary, our data demonstrate that the two novel FTY720 derivatives act as anti-inflammatory ultimately by influencing the gene expression via the cAMP and downstream transcription factor CRE pathway. In conclusion, F1-12h and F2-9 might contribute future therapies for autoimmune diseases such as multiple sclerosis.

The Role of Apelin 13 in Progression of Chronic Kidney Disease.

INTRODUCTION: Apelin is an adipokine secreted by the adipose tissue and by the endothelial cells in various parts of the body. Apelin is also expressed by the glomerular arteriolar rectus and glomerular capillary cells. We evaluated the relationship between the initial serum levels of apelin 13 with the trend of glomerular filtration rate (GFR) during a 1-year follow-up of patients with chronic kidney disease (CKD). MATERIALS AND METHODS: Ninety-nine patients with CKD in the predialysis stages were included and completed the study. The demographic data, medications, and comorbidities of the patients were recorded. The relationship between the baseline apelin 13 levels and the 1-year GFR loss was evaluated.   Results. The mean 1-year GFR loss 1.6 mL/min for those with CKD stage 3, 5.1 mL/min for those with CKD stage 4, and 2.6 mL/min for those with CKD stage 5. Fifty-eight patients (58.6%) had a GFR loss less than 5 mL/min and 41 (41.4%) had a GFR loss of 5 mL/min and greater, for whom the mean apelin 13 levels were 2169 ± 1807 mL/min and 2513 ± 1920 mL/min, respectively (P = .36).  There was no significant correlation between the apelin 13 levels and GFR loss (P = .35). CONCLUSIONS: To our knowledge, this study was the first that clinically examined the relationship between apelin 13 and CKD progression. Apart from the diabetic nephropathy, several factors causing comorbidity and progression may have probably masked this potential relationship.

Synthesis and pharmacological evaluation of some novel thebaine derivatives: N-(tetrazol-1H-5-yl)-6,14-endoethenotetrahydrothebaine incorporating the 1,3,4-oxadiazole or the 1,3,4-thiadiazole moiety.

In this study, we synthesized some novel N-(tetrazol-1H-5-yl)-6,14-endoethenotetrahydrothebaine 7α-substituted 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as potential analgesic agents. The structures of the compounds were established on the basis of their IR, ¹H NMR, ¹³C NMR, 2D NMR, and high-resolution mass spectral data. The analgesic activity was evaluated by a rat-hot plate test model and a rat tail-flick model. Compound 12 showed analgesic activity higher than that of morphine. In addition to a histopathological and biochemical evaluation, the LD50 dose for the most active compound 12 was determined.

Fast method for synthesis of alkyl and aryl-N-methylnitrones.

A simple, fast, efficient and eco-friendly procedure was developed for the synthesis of alkyl and aryl-N-methylnitrones. The corresponding nitrones of aromatic aldehydes, aliphatic aldehydes and alicyclic carbonyl compounds were prepared from N-methylhydroxylamine hydrochloride and Na2CO3-Na2SO4 by simply grinding at room temperature without using solvent.

N-Cyano-7α-methoxy-carbonyl-6,14-endo-ethenotetra-hydro-northebaine.

IN THE TITLE COMPOUND (SYSTEMATIC NAME: methyl 17-cyano-3,6-dimeth-oxy-4,5α-ep-oxy-6,14-endo-ethenomorphinan-7-carboxyl-ate), C(23)H(24)N(2)O(5), the dihydro-furan ring adopts a twist conformation, while the piperidine ring is in a chair conformation. The benzene-fused cyclo-hexene ring adopts an envelope conformation. An intra-molecular C-H⋯O hydrogen bond is observed. Inter-molecular C-H⋯N and C-H⋯O hydrogen bonds form C(5) chains along the a and b axes, respectively, and together they form a three-dimensional network.

Dimethyl trans-3-(4-bromo-phen-yl)-2-methyl-isoxazolidine-4,5-dicarboxyl-ate.

In the title compound, C(14)H(16)BrNO(5), the isoxazolidine ring adopts an envelope conformation, with the N atom at the flap. In the crystal, inter-molecular C-H⋯N and C-H⋯O hydrogen bonds generate R(3) (3)(18) ring motifs which are fused into a ribbon-like structure extending along the b axis.

1-Meth-oxy-3-o-tolyl-bicyclo-[2.2.2]oct-5-ene-2,2-dicarbonitrile.

In the title compound, C(18)H(18)N(2)O, the cyclo-hexene and cyclo-hexane rings of the bicyclo-[2.2.2]oct-5-ene unit adopt distorted boat conformations. In the crystal, mol-ecules exist as C-H⋯N hydrogen-bonded centrosymmetric R(2) (2)(14) dimers, which are further linked by C-H⋯π inter-actions.

7α-Methoxy-carbonyl-6,7,8,14-tetra-hydro-6,14-endo-ethenothebaine.

In the mol-ecule of the title compound, C(23)H(27)NO(5), the furan ring adopts an envelope conformation. Intra-molecular C-H⋯O inter-actions result in the formation of S(5) and S(6) motifs. In the crystal structure, weak inter-molecular C-H⋯O hydrogen bonds link the mol-ecules through C(6) and C(8) chains along the [100] and [010] directions, generating a two-dimensional network.

The syntheses of some novel (naphthalen-1-yl-selenyl)acetic acid derivatives.

Some new (naphthalen-1-yl-selenyl)acetic acids derivatives 7a-d have been synthesized by two different methods, using naphthylselenols or naphthylselenocyanates. The structures of the products were investigated by spectroscopic methods.