Relation Between Interleukin-6, Interleukin-10 And Interleukin-2 Receptor And Mortality In Severely Ill COVID-19 Patients.

Objectives: To investigate the relation involving soluble interleukin-2 receptor, interleukin-6 and interleukin-10 in hospitalised patients with severe coronavirus disease-2019 infection. Method: This single-centre cohort study was conducted at the Kafrelshiekh University Hospital, Egypt, from January to June 2022, and included all patients of either gender who were hospitalised with severe infection with the coronavirus disease-2019 isolation ward. Chemiluminescence immunoassay method was used to measure levels of procalcitonin, ferritin, soluble interleukin-2 receptor, interleukin-6 and interleukin-10. Data was analysed using SPSS version. 25. RESULTS: Of the 250 patients with median age 57.5 years (interquartile range: 45.8-66.0 years), 147(59%) were males and 103(41%) were females. Of them, 102(40.8%) patients died; 68(66.7%) males, 34(33.3%) females, median age 60.0 years (interquartile range: 48.8-70.0). Among the 148(59.2%) survivors, 79(53.4%) were males and 69(46.6%) were females, while the overall median age was 55.0 years (interquartile range: 41.5-65.8 years). The survivors had significantly lower levels of soluble interleukin-2 receptor, interleukin-6 and interleukin-10 (p<0.001). Correlation analysisidentified significant positive correlation between IL-2R, IL-6 and IL-10 levels and almost all the inflammatory and coagulation parameters, including C-reactive protein, lactate dehydrogenase, procalcitonin, ferritin, D-dimer and fibrinogen (p<0.05). CONCLUSIONS: Elevated levels of soluble interleukin-2 receptor, interleukin-6 and interleukin-10 were found to be associated with greater risk of mortality in coronavirus disease-2019 patients.

Cyanidin-3-Glucoside Modulates hsa_circ_0001345/miRNA106b/ATG16L1 Axis Expression as a Potential Protective Mechanism against Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common form of malignancy in the liver. Autophagy was found to have a significant effect in controlling HCC. Anthocyanins, which are naturally occurring pigments in a variety of fruits and vegetables, have been thoroughly documented to be involved in a variety of bioactive activities and are widely employed for their antioxidant capabilities. Cyanidin-3-glucoside (C3G) extracted from Morus alba L. has promising antioxidant and anti-tumour activities. The current study aims to examine the protective action of C3G against hepatocellular carcinoma through the investigation of the autophagy protein ATG16L1 expression along with its related RNA molecules (hsa_circ_0001345 and miRNA106b) in Wistar rats. In vivo precancerous lesions (PCL) were induced using diethylnitrosamine (DEN) and acetamidofluorene (2-AAF). Rats were treated with C3G (10, 15, and 20 mg/kg; 4 times weekly) for 112 days (16 weeks). Liver function tests, alfa fetoprotein, ATG16L1 expression, hsa_circ_0001345, and miRNA106b differential expression were examined. Liver sections were examined by histological and immunohistochemical approaches. The current study's findings indicated that C3G administration protects against the negative effects of DEN-2-AAF on liver functions and liver histopathological sections, which nominated C3G as a potential prophylactic agent against HCC.

Anticancer Effects of New Ceramides Isolated from the Red Sea Red Algae Hypnea musciformis in a Model of Ehrlich Ascites Carcinoma: LC-HRMS Analysis Profile and Molecular Modeling.

Different classes of phytochemicals were previously isolated from the Red Sea algae Hypnea musciformis as sterols, ketosteroids, fatty acids, and terpenoids. Herein, we report the isolation of three fatty acids-docosanoic acid 4, hexadecenoic acid 5, and alpha hydroxy octadecanoic acid 6-as well as three ceramides-A (1), B (2), and C (3)-with 9-methyl-sphinga-4,8-dienes and phytosphingosine bases. Additionally, different phytochemicals were determined using the liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (LC-ESI-HRMS) technique. Ceramides A (1) and B (2) exhibited promising in vitro cytotoxic activity against the human breast adenocarcinoma (MCF-7) cell line when compared with doxorubicin as a positive control. Further in vivo study and biochemical estimation in a mouse model of Ehrlich ascites carcinoma (EAC) revealed that both ceramides A (1) and B (2) at doses of 1 and 2 mg/kg, respectively, significantly decreased the tumor size in mice inoculated with EAC cells. The higher dose (2 mg/kg) of ceramide B (2) particularly expressed the most pronounced decrease in serum levels of vascular endothelial growth factor -B (VEGF-B) and tumor necrosis factor-α (TNF-α) markers, as well as the expression levels of the growth factor midkine in tumor tissue relative to the EAC control group. The highest expression of apoptotic factors, p53, Bax, and caspase 3 was observed in the same group that received 2 mg/kg of ceramide B (2). Molecular docking simulations suggested that ceramides A (1) and B (2) could bind in the deep grove between the H2 helix and the Ser240-P250 loop of p53, preventing its interaction with MDM2 and leading to its accumulation. In conclusion, this study reports the cytotoxic, apoptotic, and antiangiogenic effects of ceramides isolated from the Red Sea algae Hypnea musciformis in an experimental model of EAC.

New Antiproliferative Triflavanone from Thymelaea hirsuta-Isolation, Structure Elucidation and Molecular Docking Studies.

In this study isolates from Thymelaea hirsuta, a wild plant from the Sinai Peninsula of Egypt, were identified and their selective cytotoxicity levels were evaluated. Phytochemical examination of the ethyl acetate (EtOAc) fraction of the methanolic (MeOH) extract of the plant led to the isolation of a new triflavanone compound (1), in addition to the isolation of nine previously reported compounds. These included five dicoumarinyl ethers found in Thymelaea: daphnoretin methyl ether (2), rutamontine (3), neodaphnoretin (4), acetyldaphnoretin (5), and edgeworthin (6); two flavonoids: genkwanin (7) and trans-tiliroside (8); p-hydroxy benzoic acid (9) and ß sitosterol glucoside (10). Eight of the isolated compounds were tested for in vitro cytotoxicity against Vero and HepG2 cell lines using a sulforhodamine-B (SRB) assay. Compounds 1, 2 and 5 exhibited remarkable cytotoxic activities against HepG2 cells, with IC50 values of 8.6, 12.3 and 9.4 µM, respectively, yet these compounds exhibited non-toxic activities against the Vero cells. Additionally, compound 1 further exhibited promising cytotoxic activity against both MCF-7 and HCT-116 cells, with IC50 values of 4.26 and 9.6 µM, respectively. Compound 1 significantly stimulated apoptotic breast cancer cell death, resulting in a 14.97-fold increase and arresting 40.57% of the cell population at the Pre-G1 stage of the cell cycle. Finally, its apoptosis-inducing activity was further validated through activation of BAX and caspase-9, and inhibition of BCL2 levels. In silico molecular docking experiments revealed a good binding mode profile of the isolates towards Ras activation/pathway mitogen-activated protein kinase (Ras/MAPK); a common molecular pathway in the development and progression of liver tumors.

Chemical Constituent Profiling of Phyllostachys heterocycla var. Pubescens with Selective Cytotoxic Polar Fraction through EGFR Inhibition in HepG2 Cells.

Different extracts of the Bamboo shoot skin Phyllostachys heterocycla var. pubescens were screened against panel of cancer cell lines and normal one. The cell viability results exhibited that the ethyl acetate extract showed the least vitality percentage of 2.14% of HepG2 cells. Accordingly, it was subjected to chromatographic separation, which resulted in the isolation of a new natural product; 7-hydroxy, 5-methoxy, methyl cinnamate (1), together with four known compounds. The structures of the pure isolated compounds were deduced based on different spectroscopic data. The new compound (1) was screened against the HepG2 and MCF-7 cells and showed IC50 values of 7.43 and 10.65 µM, respectively. It induced apoptotic cell death in HepG2 with total apoptotic cell death of 58.6% (12.44-fold) compared to 4.71% in control by arresting cell cycle progression at the G1 phase. Finally, compound 1 was validated as EGFR tyrosine kinase inhibitor in both enzymatic levels (IC50 = 98.65 nM compared to Erlotinib (IC50 = 78.65 nM). Finally, in silico studies of compound 1 through the molecular docking indicated its high binding affinity towards EGFR protein and the ADME pharmacokinetics indicated it as a drug-like.

Exosomal miR-1298 and lncRNA-RP11-583F2.2 Expression in Hepato-cellular Carcinoma.

AIM: The aim of this study was to explore the expression of exosomal non-coding RNAs (ncRNAs) in the sera of patients with HCC versus control. METHODS: Firstly, Bioinformatics analysis was conducted to retrieve ncRNAs specific to HCC (hsa-miRNA-1298 and lncRNA-RP11-583F2.2). Afterwards, extraction and characterization of exosomes were performed. We measured the expression of the chosen exosomal RNAs by reverse transcriptase quantitative real-time PCR in sera of 60 patients with HCC, 42 patients with chronic hepatitis C (CHC) infection and 18 healthy normal volunteers. RESULTS: The exosomal ncRNAs [hsa-miRNA-1298, lncRNA-RP11-583F2.2] had better sensitivity and specificity than alpha-fetoprotein (AFP) in HCC diagnosis. CONCLUSION: The exosomal hsa-miRNA-1298, lncRNA-RP11-583F2.2 can be potential biomarkers for HCC diagnosis.

Thalassosterol, a New Cytotoxic Aromatase Inhibitor Ergosterol Derivative from the Red Sea Seagrass Thalassodendron ciliatum.

Thalassodendron ciliatum (Forssk.) Den Hartog is a seagrass belonging to the plant family Cymodoceaceae with ubiquitous phytoconstituents and important pharmacological potential, including antioxidant, antiviral, and cytotoxic activities. In this work, a new ergosterol derivative named thalassosterol (1) was isolated from the methanolic extract of T. ciliatum growing in the Red Sea, along with two known first-reported sterols, namely ergosterol (2) and stigmasterol (3), using different chromatographic techniques. The structure of the new compound was established based on 1D and 2D NMR spectroscopy and high-resolution mass spectrometry (HR-MS) and by comparison with the literature data. The new ergosterol derivative showed significant in vitro antiproliferative potential against the human cervical cancer cell line (HeLa) and human breast cancer (MCF-7) cell lines, with IC50 values of 8.12 and 14.24 µM, respectively. In addition, docking studies on the new sterol 1 explained the possible binding interactions with an aromatase enzyme; this inhibition is beneficial in both cervical and breast cancer therapy. A metabolic analysis of the crude extract of T. ciliatum using liquid chromatography combined with high-resolution electrospray ionization mass spectrometry (LC-ESI-HR-MS) revealed the presence of an array of phenolic compounds, sterols and ceramides, as well as di- and triglycerides.

New Cytotoxic Natural Products from the Red Sea Sponge Stylissa carteri.

Bioactivity-guided isolation supported by LC-HRESIMS metabolic profiling led to the isolation of two new compounds, a ceramide, stylissamide A (1), and a cerebroside, stylissoside A (2), from the methanol extract of the Red Sea sponge Stylissa carteri. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The bioactive extract's metabolomic profiling showed the existence of various secondary metabolites, mainly oleanane-type saponins, phenolic diterpenes, and lupane triterpenes. The in vitro cytotoxic activity of the isolated compounds was tested against two human cancer cell lines, MCF-7 and HepG2. Both compounds, 1 and 2, displayed strong cytotoxicity against the MCF-7 cell line, with IC50 values at 21.1 ± 0.17 µM and 27.5 ± 0.18 µM, respectively. They likewise showed a promising activity against HepG2 with IC50 at 36.8 ± 0.16 µM for 1 and IC50 30.5 ± 0.23 µM for 2 compared to the standard drug cisplatin. Molecular docking experiments showed that 1 and 2 displayed high affinity to the SET protein and to inhibitor 2 of protein phosphatase 2A (I2PP2A), which could be a possible mechanism for their cytotoxic activity. This paper spreads light on the role of these metabolites in holding fouling organisms away from the outer surface of the sponge, and the potential use of these defensive molecules in the production of novel anticancer agents.

Cytotoxic, Apoptosis-Inducing Activities, and Molecular Docking of a New Sterol from Bamboo Shoot Skin Phyllostachys heterocycla var. pubescens.

Phytochemical screening of nonpolar fractions from the methanol extract of the Bamboo shoot skin Phyllostachys heterocycla var. pubescens resulted in the isolation of a new sterol-glucoside-fatty acid derivative (6'-O-octadeca-8'',11''-dienoyl)-sitosterol-3-O-ß-d-glucoside (1), together with six known compounds. The chemical structures of the pure isolated compounds were deduced based on different spectral data. The isolated compounds were assessed to determine their cytotoxic activity, and the results were confirmed by determining their apoptotic activity. Compound 1 was more cytotoxic against the MCF-7 cells (IC50 = 25.8 µM) compared to Fluorouracil (5-FU) (26.98 µM), and it significantly stimulated apoptotic breast cancer cell death with 32.6-fold (16.63% compared to 0.51 for the control) at pre-G1 and G2/M-phase cell cycle arrest and blocked the progression of MCF-7 cells. Additionally, RT-PCR results further confirmed the apoptotic activity of compound 1 by the upregulation of proapoptotic genes (P53; Bax; and caspases 3, 8, and 9) and downregulation of the antiapoptotic genes (BCL2). Finally, the identified compounds, especially 1, were found to have high binding affinity towards both tyrosine-specific protein kinase (TPK) and vascular endothelial growth factor receptor (VEGFR-2) through the molecular docking studies that highlight its mode of action.

Pantoprazole attenuates tumorigenesis via inhibition of exosomal secretion in a rat model of hepatic precancerous lesion induced by diethylnitrosamine and 2-acetamidofluorene.

The present study aimed to evaluate the potential therapeutic effect of pantoprazole, a proton-pump inhibitor, on precancerous lesion (PCL) in rats. diethylnitrosamine and 2-acetylaminofluorene were used to induce PCL in rats, in vivo. The rats were treated with three doses of pantoprazole (100, 50, and 25  mg/kg; three times weekly) during the last 4 weeks of the total 10 weeks of the experiment. Blood and liver tissue samples were collected for measurement of the exosomal abundance and exosomal competing endogenous RNA markers. Results revealed that pantoprazole administration had an ameliorating effect on liver function tests and microscopic features of the liver; and decreased exosome abundance in the liver tissue samples and sera of the rats. Meanwhile, the treatment also resulted in a dose-dependent decrease in exosomal RAB11A mRNA and long noncoding RNA RP11-513I15.6, which is an important participant in th exosomal secretion process with an increase in exosomal miRNA-1262. Based on these results, we postulated that pantoprazole has the potential to attenuate liver tumorigenesis in this rat model.

Role of exosomal competing endogenous RNA in patients with hepatocellular carcinoma.

Recent research has tried to use exosomal RNAs (coding and noncoding) as potential diagnostic markers for hepatocellular carcinoma (HCC). Initially, by using bioinformatics, we selected an HCC-exosomal RNA-based biomarker panel. The choice of this panel depends on the integration of Ras-related in brain (RAB11A) gene expression and its competing endogenous network. This network includes long noncoding RNA RP11-513I15.6 (lncRNA-RP11-513I15.6) and microRNA-1262 (miR-1262). Secondly, we tried to validate the expression of this network in the sera of 60 patients with HCC in comparison with 42 chronic hepatitis C virus-infected patients and 18 healthy controls. Then we assessed the diagnostic efficiency of this panel using a receiver operating characteristic curve analysis. The panel of 3 exosomal RNA-based biomarkers (lncRNA-RP11-513I15.6, miR-1262, and RAB11A) showed excellent sensitivity and specificity in discriminating patients with HCC from patients with chronic hepatitis C virus and healthy controls. Among these 3 RNAs, serum RAB11A mRNA was the most independent prognostic factor. The selected circulatory exosomal RNA-based biomarker panel showed its ability to be used as a diagnostic and prognostic biomarker tool for HCC. Moreover, these biomarkers could be therapeutic targets.

Integrated metabolomic analysis and molecular docking: Unveiling the potential of Nephrolepis exaltata (L.) Schott phytocompounds for mosquito control via glutathione-S-transferase targeting.

Plants contain a wide range of potential phytochemicals that are target-specific, and less toxic to human health. The present study aims to investigate the metabolomic profile of Nephrolepis exaltata (L.) Schott and its potential for mosquito control by targeting Glutathione-S-Transferase, focusing on the larvicidal activity against Culex pipiens. Crude extracts (CEs) were prepared using ethanol, ethyl acetate and n-hexane. CEs have been used for assessment of mosquitocidal bioassay. The metabolomic analyses for CEs were characterized for each CE by gas chromatography-mass spectrometry (GC-MS). The most efficient CE with the highest larval mortality and the least LC50 was the hexane CE. Then, alkaline phosphatase (ALP) activity, and glutathione-S-transferase (GST) activity were assessed in larvae treated with the hexane CE. The results demonstrated a decline in protein content, induction of ALP activity, and reduction in GST activity. Finally, molecular docking and dynamic simulation techniques were employed to evaluate the interaction between the hexane phytochemicals and the GST protein. D-(+)-Glucuronic acid, 3TMS derivative and Sebacic acid, 2TMS derivative showed best binding affinities to GST protein pointing to their interference with the enzyme detoxification functions, potentially leading to reduced ability to metabolize insecticides.

A neuroprotective effect of pentoxifylline in rats with diabetic neuropathy: Mitigation of inflammatory and vascular alterations.

BACKGROUND: Treatment of diabetic neuropathic pain does not change the natural history of neuropathy. Improved glycemic control is the recommended treatment in these cases, given that no specific treatment for the underlying nerve damage is available, so far. In the present study, the potential neuroprotective effect of pentoxifylline in streptozotocin (50 mg/kg) induced diabetic neuropathy in rats was investigated. METHODS: Pentoxifylline was administered at doses equivalent to 50, 100 & 200 mg/kg, in drinking water, starting one week after streptozotocin injection and for 7 weeks. Mechanical allodynia, body weight and blood glucose level were assessed weekly. Epidermal thickness of the footpad skin, and neuroinflammation and vascular alterations markers were assessed. RESULTS: Tactile allodynia was less in rats that received pentoxifylline at doses of 100 and 200 mg/kg (60 % mechanical threshold increased by 48 % and 60 %, respectively). The decrease in epidermal thickness of footpad skin was almost completely prevented by the same doses. This was associated with a decrease in spinal tumor necrosis factor alpha (TNFα) and nuclear factor kappa B levels and a decrease in microglial ionized calcium binding adaptor molecule 1 immunoreactivity, compared to the control diabetic group. In sciatic nerve, there was decrease in TNF-α and vascular endothelial growth factor levels and intercellular adhesion molecule immunoreactivity. CONCLUSION: Pentoxifylline showed a neuroprotective effect in streptozotocin-induced diabetic neuropathy, which was associated with a suppression of both the inflammatory and vascular pathogenic pathways that was not associated with a hypoglycemic effect. Thus, it may represent a potential neuroprotective drug for diabetics.

Rosavin improves insulin resistance and alleviates hepatic and kidney damage via modulating the cGAS-STING pathway and autophagy signaling in HFD/STZ-induced T2DM animals.

Background: Inflammation-mediated insulin resistance in type 2 diabetes mellitus (T2DM) increases complications, necessitating investigation of its mechanism to find new safe therapies. This study investigated the effect of rosavin on the autophagy and the cGAS-STING pathway-related signatures (ZBP1, STING1, DDX58, LC3B, TNF-α) and on their epigenetic modifiers (miR-1976 and lncRNA AC074117.2) that were identified from in silico analysis in T2DM animals. Methods: A T2DM rat model was established by combining a high-fat diet (HFD) and streptozotocin (STZ). After four weeks from T2DM induction, HFD/STZ-induced T2DM rats were subdivided into an untreated group (T2DM group) and three treated groups which received 10, 20, or 30 mg per kg of R. rosea daily for 4 weeks. Results: The study found that rosavin can affect the cGAS-STING pathway-related RNA signatures by decreasing the expressions of ZBP1, STING1, DDX58, and miR-1976 while increasing the lncRNA AC074117.2 level in the liver, kidney, and adipose tissues. Rosavin prevented further weight loss, reduced serum insulin and glucose, improved insulin resistance and the lipid panel, and mitigated liver and kidney damage compared to the untreated T2DM group. The treatment also resulted in reduced inflammation levels and improved autophagy manifested by decreased immunostaining of TNF-α and increased immunostaining of LC3B in the liver and kidneys of the treated T2DM rats. Conclusion: Rosavin has shown potential in attenuating T2DM, inhibiting inflammation in the liver and kidneys, and improving metabolic disturbances in a T2DM animal model. The observed effect was linked to the activation of autophagy and suppression of the cGAS-STING pathway.

Comprehensive machine learning models for predicting therapeutic targets in type 2 diabetes utilizing molecular and biochemical features in rats.

Introduction: With the increasing prevalence of type 2 diabetes mellitus (T2DM), there is an urgent need to discover effective therapeutic targets for this complex condition. Coding and non-coding RNAs, with traditional biochemical parameters, have shown promise as viable targets for therapy. Machine learning (ML) techniques have emerged as powerful tools for predicting drug responses. Method: In this study, we developed an ML-based model to identify the most influential features for drug response in the treatment of type 2 diabetes using three medicinal plant-based drugs (Rosavin, Caffeic acid, and Isorhamnetin), and a probiotics drug (Z-biotic), at different doses. A hundred rats were randomly assigned to ten groups, including a normal group, a streptozotocin-induced diabetic group, and eight treated groups. Serum samples were collected for biochemical analysis, while liver tissues (L) and adipose tissues (A) underwent histopathological examination and molecular biomarker extraction using quantitative PCR. Utilizing five machine learning algorithms, we integrated 32 molecular features and 12 biochemical features to select the most predictive targets for each model and the combined model. Results and discussion: Our results indicated that high doses of the selected drugs effectively mitigated liver inflammation, reduced insulin resistance, and improved lipid profiles and renal function biomarkers. The machine learning model identified 13 molecular features, 10 biochemical features, and 20 combined features with an accuracy of 80% and AUC (0.894, 0.93, and 0.896), respectively. This study presents an ML model that accurately identifies effective therapeutic targets implicated in the molecular pathways associated with T2DM pathogenesis.

Secondary metabolites from Eupenicillium parvum and their in vitro binding affinity for human opioid and cannabinoid receptors.

Phytochemical investigation of the soil microfungus Eupenicillum parvum led to the isolation of two new compounds: a chromone derivative euparvione (1) and a new mycophenolic derivative euparvilactone (2), as well as thirteen known compounds. The structures of the new compounds were elucidated by means of extensive IR, NMR, and MS data and by comparison of data reported in the literature. The structure of the known compound 6 was confirmed by X-ray crystallography. Several isolated compounds were evaluated for in vitro binding assays using opioid receptors (subtypes δ, κ, and µ) and cannabinoid receptors (CB1 and CB2). Compound 10 displayed the best selective µ-opioid receptor and CB1 receptor binding affinities showing values of 47% and 52% at a 10 µM concentration, respectively. These findings provide insight into the potential therapeutic utility of this class of compounds.

Angiotensin receptor-neprilysin inhibitor (thiorphan/irbesartan) improved cardiac function in a rat model of myocardial ischemic reperfusion injury.

Mitochondria-mediated apoptosis plays a critical role in myocardial ischemia reperfusion (IR) injury and causes a negative impact on cardiac efficiency and function. The combined angiotensin receptor-neprilysin inhibitor (ARNI) is a promising cardioprotective pharmacological agent that could rescue the heart from IR injury. This study investigated the cardioprotective effect of thiorphan (TH) in combination with three different doses of irbesartan (IRB) on myocardial IR injury and detected the most effective dose combination. Male Wistar rats were used and divided into five groups (10 rats/group): (I) Sham, (II) ischemia-reperfusion I/R, (III) TH/IRB + IR (0.1/5 mg/kg), (IV) TH/IRB + IR (0.1/10 mg/kg), and (V) TH/IRB + IR (0.1/15 mg/kg) groups. Thiorphan and irbesartan were injected intraperitoneally 15 min before IR induction. Mean arterial blood pressure, left ventricular end diastolic pressure (LVEDP), left ventricular maximum rate of pressure (LVdp/dtmax ), and cardiac levels of creatine kinase-MB, malondialdehyde, superoxide dismutase, and endothelin-1 were measured. Cardiac mitochondria complexes activities, histopathological examination of myocardial tissues, immunohistochemistry studies for myocardial apoptosis (Bax and Bcl-2), and electron microscopy examination of left ventricle were performed. TH/IRB combination preserved cardiac functions and mitochondria complex activities and mitigated cardiac damage, oxidative stress, and apoptosis following IR. Also, there was an evident improvement in histopathological changes and electron microscopy examination of left ventricle compared with I/R group. TH/IRB in a dose of 0.1/10 mg/kg showed significant improvement compared with the other treated groups. Thiorphan/irbesartan improved cardiac functions following IR injury. This could be explained by the reported improvement of mitochondria complex activities and reduction of oxidative stress, endothelin-1, and apoptosis.

A comparative study between angiotensin receptor neprilysin inhibitor (thiorphan/irbesartan) with each of nitrate and carvedilol in a rat model of myocardial ischemic reperfusion injury.

The combined angiotensin receptor neprilysin inhibitor is a promising cardioprotective pharmacological agent. This study investigated the beneficial effects of thiorphan (TH)/irbesartan (IRB), in myocardial ischemia-reperfusion (IR) injury, compared to each of nitroglycerin and carvedilol. Male Wistar rats were divided into five groups (10 rats/group): Sham, untreated I/R, TH/IRB + IR (0.1/10 mg/kg), nitroglycerin + IR (0.2 mg/kg), and carvedilol + IR (10 mg/kg). Mean arterial blood pressure, cardiac functions and arrhythmia incidence, duration and score were assessed. Cardiac levels of creatine kinase-MB (CK-MB), oxidative stress, endothelin-1, ATP, Na+ /K+ ATPase pump activity and mitochondria complexes activities were measured. Histopathological examination, Bcl/Bax immunohistochemistry studies and electron microscopy examination of left ventricle were performed. TH/IRB preserved the cardiac functions and mitochondrial complexes activities, mitigated cardiac damage, reduced oxidative stress and arrhythmia severity, improved the histopathological changes and decreased cardiac apoptosis. TH/IRB showed a comparable effect to each of nitroglycerin and carvedilol in alleviating the IR injury consequences. TH/IRB showed significant preservation of mitochondrial complexes activity I and II compared to nitroglycerin. TH/IRB significantly increased LVdP/dtmax and decreased oxidative stress, cardiac damage and endothelin-1 along with increasing the ATP content, Na+ /K+ ATPase pump activity and mitochondrial complexes activity when compared to carvedilol. TH/IRB showed a cardioprotective effect in reducing IR injury that is comparable to each of nitroglycerin and carvedilol that could be explained in part by its ability to preserve mitochondrial function, increase ATP, decrease oxidative stress as well as endothelin 1.

MiR-150 Expression in Chronic Myeloid Leukemia: Relation to Imatinib Response.

OBJECTIVE: To assess the circulating micro-RNA-150 (miR-150) expression in patients with chronic myeloid leukemia (CML) in relation to imatinib response. METHODS: Sixty patients with CML and 20 age- and sex-matched control subjects were enrolled. Circulating miR-150 levels were assessed by quantitative real-time polymerase chain reaction on days 0, 14, and 90 of imatinib therapy for patients and once for control subjects. RESULTS: The baseline miR-150 expression was significantly lower in patients with CML than in control subjects with subsequent elevation at 14 and 90 days after the start of imatinib treatment. Early treatment response (ETR) at 90 days was the main study outcome. The miR-150 expression had a significantly higher level in patients with CML with ETR. On multivariate analysis, miR-150 on day 14 was significantly related to ETR in patients with CML with predictive efficacy (area under the curve = 0.838, 72.9% sensitivity, and 84.2% specificity). CONCLUSION: We found that miR-150 expression on day 14 of imatinib treatment is a useful early predictive candidate for imatinib response in patients with CML.

Prognostic significance of complement factors in severely ill patients with COVID-19.

Coagulopathy, cytokine release, platelet hyperactivity and endothelial activation are regarded as potential major contributors to COVID-19 morbidity. Complement activation might provide a bridge linking these factors in severe COVID-19 illness. In this study, we investigated the prognostic significance of selected complement factors in hospitalized patients with severe COVID-19 infection. The study included 300 hospitalized adults with severe COVID-19 infection. Complement factors (C3, C3a, C4, sC5b-9) were assessed by commercial ELISA kits. Outcome parameters included mortality, intensive care unit admission and duration of hospital stay. It was found that survivors had significantly higher serum C3 (median (IQR): 128.5 (116.3-141.0) mg/dL vs 98.0 (70.0-112.8) mg/dL, p<0.001) and C4 (median (IQR): 36.0 (30.0-42.0) mg/dL vs 31.0 (26.0-35.0) mg/dL, p<0.001) levels when compared with non-survivors. On the other hand, it was shown that survivors had significantly lower C3a (median (IQR): 203.0 (170.3-244.0) ng/mL vs 385.0 (293.0-424.8) ng/mL, p<0.001) and sC5b-9 (median (IQR): 294.0 (242.0-318.8) ng/mL vs 393.0 (342.0-436.5) ng/mL, p<0.001) levels when compared with non-survivors. Multivariate logistic regression analysis identified C3a (OR: 0.97 (95% CI 0.96 to 0.99), p<0.001) and C4 (OR: 0.92 (95% CI 0.86 to 0.98), p=0.011) levels as significant predictors of mortality. In conclusion, serum levels of complement factors are related to mortality in severely ill patients with COVID-19.