Echinops Asteraceae extract guards against malathion-induced liver damage via minimizing oxidative stress, inflammation, and apoptosis.

Malathion (MAL) is one of the highly toxic organophosphorus (OP) compounds that induces hepatotoxicity. Echinops. ritro leaves extract (ERLE) is traditionally used in the treatment of bacterial/fungal infections. This study's goal was to investigate the potential of extracts from ERLE against hepatotoxicity induced by MAL in male albino rats. Four equal groups of forty mature male albino rats were created: The rats in the first group used as a control. The second group of rats received ERLE orally. The third group received MAL. ERLE and MAL were administered to the fourth group of rats. Six-week treatment groups were conducted. Using lipid peroxidation indicators [malondialdehyde (MDA), alanine aminotransferase (ALT), aspartate aminotransferase (AST)], oxidative stress markers [catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx)], apoptotic markers [Bcl-2 & caspase-3] and tumor necrosis factor alpha (TNF-α). Rats treated with MAL underwent a significant increase on MDA, ALT, AST, caspase-3 and TNF-α marker with a significant decrease in antioxidant markers [CAT, SOD, GPx] and Bcl-2. Histologically, MAL-treated group's liver sections displayed damaged hepatocytes with collapsed portions, pyknotic nuclei, vacuolated cytoplasm, and congested central veins. Ultra structurally, rat livers treated with MAL showed dilated cisternae of endoplasmic reticulum, swollen mitochondria with disrupted cristae, nuclei with disrupted chromatin content, multiple lysosomes, multiple vacuolations and a disrupted blood sinusoid. With rats treated with ERLE, these alterations were essentially non-existent. It is possible to conclude that ERLE protects against MAL hepatotoxicity, and that this protection is related, at least in part, to its antioxidant activities.

Curcumin attenuates doxorubicin-induced cardiotoxicity via suppressing oxidative Stress, preventing inflammation and apoptosis: Ultrastructural and computational approaches.

Currently, doxorubicin (DOX) is one of the medications commonly used in chemotherapy to treat different types of tumors.Nonetheless, despite being effective in multiple tumors, yet its use is limited owing to its cytotoxic effects, the therapeutic use of DOX has been limited. This work aimed to explore whether curcumin (CMN) can prevents DOX-induced cardiotoxicity in rats. Four groups of rats were created, with the first functioning as a control, while the second group received CMN. DOX alone was administered to the third group, whereas CMN and DOX were administered to the fourth group. Lipid peroxidation assessed as Malondialdehyde (MDA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), oxidative stress markers as catalase (CAT), superoxide dismutase (SOD), and inflammatory markers as tumor necrosis factor-alpha (TNF-α) in heart homogenates, each one was assessed. Heart specimens was investigated histologically and ultrastructurally. Increased, AST, and ALT serum levels, increased MDA levels, decreased SOD and CAT levels, and increased TNF-α concentrations in heart homogenates were all signs of DOX-induced myocardial injury. Histological and ultrastructural examinations revealed vacuoles and larger, swollen mitochondria in the cytoplasm. Furthermore, DOX caused significant changes in the myocardium, most notably nuclei disintegration, myofibrillar loss, and myocyte vacuolization. Using CMN with DOX reduced the harmful consequences of DOX on the myocardium by returning the increased AST and ALT levels to their original levels as compared to the control and reducing them. In cardiac tissue, CMN significantly increased the concentrations of SOD and CAT and significantly decreased the concentrations of MDA and TNF-α. Biochemical and histological studies have demonstrated that CMN has a heart-protective effect that might be related to its antioxidant and anti-inflammatory capabilities.

Improvement of Na+-K+ ATPase Activity and Gene Expression Associated with Glomerular Ultrastructural Protection in Diabetic Nephropathy by Acacia senegal: Role of Oxidative Stress Disturbances / Mejora de la actividad Na+-K+ ATPasa y la Expresión Génica Asociada con la Protección Ultraestructural Glomerular en la Nefropatía Diabética por Acacia senegal: Papel de las Alteraciones del Estrés Oxidativo

SUMMARY: This study assessed the effects of Acacia Senegal (AS) combined with insulin on Na+/K+-ATPase (NKA) activity and mRNA expression, serum glucose, renal function, and oxidative stress in a rat model of diabetic nephropathy (DN). Sixty rats were equally divided into six groups: normal control, normal+AS, diabetic (DM), DM+insulin, DM+AS, and DM+insulin+AS groups. Diabetes mellitus (type 1) was induced by a single injection of streptozotocin (65 mg/kg), and insulin and AS treatments were carried until rats were culled at the end of week 12. Serum glucose and creatinine levels, hemoglobin A1c (HbA1c) were measured. Renal homogenate levels of NKA activity and gene expression, malondialdehyde, superoxide dismutase (SOD), catalase and reduced glutathione (GSH) were evaluated as well as kidney tissue histology and ultrastructure. Diabetes caused glomerular damage and modulation of blood and tissue levels of creatinine, glucose, HbA1c, malondialdehyde, NKA activity and gene expression, SOD, catalase and GSH, which were significantly (p<0.05) treated with AS, insulin, and insulin plus AS. However, AS+insulin treatments were more effective. In conclusion, combined administration of AS with insulin to rats with DN decreased NKA activity and gene expression as well as oxidative stress, and improved glycemic state and renal structure and function.

Este estudio evaluó los efectos de Acacia senegal (AS) combinada con insulina sobre la actividad Na+/K+- ATPasa (NKA) y la expresión de ARNm, la glucosa sérica, la función renal y el estrés oxidativo en un modelo de nefropatía diabética (ND) en ratas. Sesenta ratas se dividieron equitativamente en seis grupos: control normal, normal+AS, diabética (DM), DM+insulina, DM+AS y DM+insulina+AS. La diabetes mellitus (tipo 1) se indujo mediante una única inyección de estreptozotocina (65 mg/kg), y los tratamientos con insulina y AS se llevaron a cabo hasta que las ratas fueron sacrificadas al final de la semana 12. Se midieron niveles séricos de glucosa y creatinina, hemoglobina A1c (HbA1c). Se evaluaron los niveles de homogeneizado renal de actividad NKA y expresión génica, malondialdehído, superóxido dismutasa (SOD), catalasa y glutatión reducido (GSH), así como la histología y ultraestructura del tejido renal. La diabetes causó daño glomerular y modulación de los niveles sanguíneos y tisulares de creatinina, glucosa, HbA1c, malondialdehído, actividad y expresión génica de NKA, SOD, catalasa y GSH, los cuales fueron tratados significativamente (p<0,05) con AS, insulina e insulina más AS. Sin embargo, los tratamientos con AS+insulina fueron más efectivos. En conclusión, la administración combinada de AS con insulina a ratas con DN disminuyó la actividad de NKA y la expresión genética, así como el estrés oxidativo, y mejoró el estado glucémico y la estructura y función renal.

Alpha-sitosterol: a new antiviral agent produced by Streptomyces misakiensis and its potential activity against Newcastle disease virus.

BACKGROUND: Newcastle Disease Virus (NDV) causes severe economic losses in the poultry industry worldwide. Hence, this study aimed to discover a novel bioactive antiviral agent for controlling NDV. Streptomyces misakiensis was isolated from Egyptian soil and its secondary metabolites were identified using infrared spectroscopy (IR), gas chromatography-mass spectrometry (GC-MS), and nuclear magnetic resonance (NMR) spectroscopy. The inhibitory activity of bioactive metabolite against NDV were examined. Three experimental groups of 10-day-old specific pathogen-free embryonated chicken eggs (SPF-ECEs), including the bioactive metabolite control group, NDV control positive group, and α-sitosterol and NDV mixture-treated group were inoculated. RESULTS: α-sitosterol (Ethyl-6-methylheptan-2-yl]-10,13-dimethyl-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol), a secondary metabolite of S. misakiensis, completely inhibited hemagglutination (HA) activity of the NDV strain. The HA activity of the NDV strain was 8 log2 and 9 log2 for 0.5 and 0.75% RBCs, respectively. The NDV HA activity for the two concentrations of RBCs was significantly (P < 0.0001) inhibited after α-sitosterol treatment. There was a significant (P < 0.0001) decrease in the log 2 of HA activity, with values of - 0.500 (75%, chicken RBCs) before inoculation in SPF-ECEs and - 1.161 (50%, RBCs) and - 1.403 (75%, RBCs) following SPF-ECE inoculation. Compared to ECEs inoculated with NDV alone, the α-sitosterol-treated group showed improvement in histological lesion ratings for chorioallantoic membranes (CAM) and hepatic tissues. The CAM of the α-sitosterol- inoculated SPF-ECEs was preserved. The epithelial and stromal layers were noticeably thicker with extensive hemorrhages, clogged vasculatures, and certain inflammatory cells in the stroma layer in the NDV group. However, mild edema and inflammatory cell infiltration were observed in the CAM of the treated group. ECEs inoculated with α-sitosterol alone showed normal histology of the hepatic acini, central veins, and portal triads. Severe degenerative alterations, including steatosis, clogged sinusoids, and central veins, were observed in ECEs inoculated with NDV. Mild hepatic degenerative alterations, with perivascular round cell infiltration, were observed in the treated group. CONCLUSION: To the best of our knowledge, this is the first study to highlight that the potentially bioactive secondary metabolite, α-sitosterol, belonging to the terpene family, has the potential to be a biological weapon against virulent NDV. It could be used for the development of innovative antiviral drugs to control NDV after further clinical investigation.

Oncogenic Potential of Replication Factor C Subunit 4: Correlations with Tumor Progression and Assessment of Potential Inhibitors.

Replication Factor C Subunit 4 (RFC4), an oncogene implicated in many human cancers, has yet to be extensively studied in many cancer types to determine its expression patterns and tumor tissue function. Various bioinformatics tools were used to analyze RFC4 as a potential oncogene and therapeutic target across many cancers. We first examined RFC4 expression levels in several human tumor types to determine relationships with tumor grade, stage, metastasis, and patient survival. We also examined RFC4's genetic changes, epigenetic methylation, and effect on tumor microenvironment (TME) immune cell infiltration. We also analyzed RFC4's connections with immunological checkpoints to identify potential molecular pathways involved in carcinogenesis. Our findings show that RFC4 is upregulated in several tumor types and associated with poor prognoses in many human cancers. This study shows that RFC4 significantly affects the tumor immunological microenvironment, specifically immune cell populations. Finally, we screened for RFC4-inhibiting pharmacological compounds with anti-cancer potential. This study fully elucidates RFC4's carcinogenic activities, emphasizing its potential as a prognostic biomarker and a target for anti-cancer therapy.

Epigenetic alterations of miR-155 and global DNA methylation as potential mediators of ochratoxin A cytotoxicity and carcinogenicity in human lung fibroblasts.

Ochratoxin A (OTA) is a well-known mycotoxin that adversely affects different human cells. Inhalational exposure to OTA and subsequent pulmonary diseases have been previously reported, yet its potential carcinogenicity and underlying molecular mechanisms have not been fully elucidated. This study aimed to evaluate the OTA-induced cytotoxicity and the epigenetic changes underlying its potential carcinogenicity in fetal lung fibroblast (WI-38) cells. OTA cytotoxicity was assessed by MTT assay; RT-qPCR was used to determine the expression of BAX, BCL-2, TP53, and miR-155, while ELISA was used for measuring 5-methyl cytosine percentage to assess global DNA methylation in OTA-treated versus control cells. WI-38 cells demonstrated sensitivity to OTA with IC50 at 22.38 µM. Though BAX and Bcl-2 were downregulated, with low BAX/BCL-2 ratio, and TP53 was upregulated, their fold changes showed decline trend with increasing OTA concentration. A significant dose-dependent miR-155 upregulation was observed, with dynamic time-related decline. Using subtoxic OTA concentrations, a significant global DNA hypermethylation with significant dose-dependent and dynamic alterations was identified. Global DNA hypermethylation and miR-155 upregulation are epigenetic mechanisms that mediate OTA toxicity on WI-38 cells. BAX downregulation, reduced BAX/BCL-2 ratio together with miR-155 upregulation indicated either the inhibition of TP53-dependent apoptosis or a tissue specific response to OTA exposure. The aforementioned OTA-induced variations present a new molecular evidence of OTA cytotoxicity and possible carcinogenicity in lung fibroblast cells.

Unraveling Extremely Damaging IRAK4 Variants and Their Potential Implications for IRAK4 Inhibitor Efficacy.

Interleukin-1-receptor-associated kinase 4 (IRAK4) possesses a crucial function in the toll-like receptor (TLR) signaling pathway, and the dysfunction of this molecule could lead to various infectious and immune-related diseases in addition to cancers. IRAK4 genetic variants have been linked to various types of diseases. Therefore, we conducted a comprehensive analysis to recognize the missense variants with the most damaging impacts on IRAK4 with the employment of diverse bioinformatics tools to study single-nucleotide polymorphisms' effects on function, stability, secondary structures, and 3D structure. The residues' location on the protein domain and their conservation status were investigated as well. Moreover, docking tools along with structural biology were engaged in analyzing the SNPs' effects on one of the developed IRAK4 inhibitors. By analyzing IRAK4 gene SNPs, the analysis distinguished ten variants as the most detrimental missense variants. All variants were situated in highly conserved positions on an important protein domain. L318S and L318F mutations were linked to changes in IRAK4 secondary structures. Eight SNPs were revealed to have a decreasing effect on the stability of IRAK4 via both I-Mutant 2.0 and Mu-Pro tools, while Mu-Pro tool identified a decreasing effect for the G198E SNP. In addition, detrimental effects on the 3D structure of IRAK4 were also discovered for the selected variants. Molecular modeling studies highlighted the detrimental impact of these identified SNP mutant residues on the druggability of the IRAK4 ATP-binding site towards the known target inhibitor, HG-12-6, as compared to the native protein. The loss of important ligand residue-wise contacts, altered protein global flexibility, increased steric clashes, and even electronic penalties at the ligand-binding site interfaces were all suggested to be associated with SNP models for hampering the HG-12-6 affinity towards IRAK4 target protein. This given model lays the foundation for the better prediction of various disorders relevant to IRAK4 malfunction and sheds light on the impact of deleterious IRAK4 variants on IRAK4 inhibitor efficacy.

Antibiotic Resistance Profiling and Phylogenicity of Uropathogenic Bacteria Isolated from Patients with Urinary Tract Infections.

Urinary tract infections (UTIs) are healthcare problems that commonly involve bacterial and, in some rare instances, fungal or viral infections. The irrational prescription and use of antibiotics in UTI treatment have led to an increase in antibiotic resistance. Urine samples (145) were collected from male and female patients from Lower Dir, Khyber Pakhtunkhwa (KP), Pakistan. Biochemical analyses were carried out to identify uropathogens. Molecular analysis for the identification of 16S ribosomal RNA in samples was performed via Sanger sequencing. Evolutionary linkage was determined using Molecular Evolutionary Genetics Analysis-7 (MEGA-7). The study observed significant growth in 52% of the samples (83/145). Gram-negative bacteria were identified in 85.5% of samples, while Gram-positive bacteria were reported in 14.5%. The UTI prevalence was 67.5% in females and 32.5% in males. The most prevalent uropathogenic bacteria were Klebsiella pneumoniae (39.7%, 33/83), followed by Escherichia coli (27.7%, 23/83), Pseudomonas aeruginosa (10.8%, 9/83), Staphylococcus aureus (9.6%, 8/83), Proteus mirabilis (7.2%, 6/83) and Staphylococcus saprophyticus (4.8%, 4/83). Phylogenetic analysis was performed using the neighbor-joining method, further confirming the relation of the isolates in our study with previously reported uropathogenic isolates. Antibiotic susceptibility tests identified K. pneumonia as being sensitive to imipenem (100%) and fosfomycin (78.7%) and resistant to cefuroxime (100%) and ciprofloxacin (94%). Similarly, E. coli showed high susceptibility to imipenem (100%), fosfomycin (78.2%) and nitrofurantoin (78.2%), and resistance to ciprofloxacin (100%) and cefuroxime (100%). Imipenem was identified as the most effective antibiotic, while cefuroxime and ciprofloxacin were the least. The phylogenetic tree analysis indicated that K. pneumoniae, E. coli, P. aeruginosa, S. aureus and P. mirabilis clustered with each other and the reference sequences, indicating high similarity (based on 16S rRNA sequencing). It can be concluded that genetically varied uropathogenic organisms are commonly present within the KP population. Our findings demonstrate the need to optimize antibiotic use in treating UTIs and the prevention of antibiotic resistance in the KP population.

Histomorphological, Histochemical and Ultrastructural Studies on the Healthy Liver of Yemen Veiled Chameleon (Chamaeleo calyptratus) in Southern Saudi Arabia / Estudios Histomorfológicos, Histoquímicos y Ultraestructurales en el Hígado Sano del Camaleón Velado de Yemen (Chamaeleo calyptratus) en el Sur de Arabia Saudita

SUMMARY: The livers of reptiles are being studied as a model for the link between the environment and hepatic tissue. There have been few investigations on the histology of reptile livers, and very few or no studies have examined the histology of liver of veiled chameleon (Chamaeleo calyptratus). This paper describes the histomorphological, histochemical and ultrastructural characterization of the liver of veiled chameleons in southern Saudi Arabia. Seven Chamaeleo calyptratus were captured in the summer season in Abha City, Aseer region, southern Saudi Arabia. Chamaeleon liver samples were processed for histomorphology, histochemistry and ultrastructure analyses. Morphologically liver of Chamaeleo calyptratus was observed as a large dark brown organ with lighter speckles, which represent melanin deposits. It located at the ventral part of abdominal cavity forward of the stomach. Its dimensions approximately were 3.7 x 2 cm. The liver was a bilobed organ divided into two lobes, right and left lobes. The right one was bigger than the others. The gallbladder was well developed and had an elongated shape, situated between the two lobes and contained the bile for the digestion. Microscopically, the liver was found to be covered by a thick layer of connective tissue, which formed the hepatic capsule. Hepatic parenchyma probably appeared in cross sections as hepatic glandular-like alveoli "acini" or follicular structures with various diameters, each acinus contains approximately four to six hepatocytes, surrounded by sinusoidal capillaries filled with abundant melanomacrophages, which are absent in birds and mammals. Melanomacrophages are common in the hepatic parenchyma's perisinusoidal areas, particularly near portal spaces. Hepatocytes are polyhedral or pyramidal with and mostly contained large, rounded nuclei mostly peripherally located, with prominent dark oval nucleoli. Some of nuclei are eccentric or central position. The cytoplasm appeared spongy or vacuolated and more eosinophilic when stained by hematoxylin-eosin and strongly reactive to PAS staining technique, indicating abundant glycogen content. The reticular fibers that surround hepatocytes, blood arteries, and sinusoids supported the hepatic parenchyma. The blood sinusoids are seen interspersed among hepatocytes of varying sizes. The sinusoidal lumen was bordered by flattened endothelial cells and includes elliptical nucleated erythrocytes and liver macrophages as phagocytes, which are also known as Kupffer cells. Branches of the portal vein, hepatic artery, small bile duct, and lymph vessels were detected in the hepatic portal area "tract" or triad which made up of connective. Hematopoietic tissue was observed in subcapsular region and portal triads. Ultrastructurally, the hepatocyte appeared polyhedric containing a single large rounded basal or eccentric vesicular nucleus with prominent nucleolus. Extensive network of rough endoplasmic reticulum (RER) often arranged in an array parallel to the nuclear membrane with many mitochondria, and Golgi apparatus were described. The cytoplasm contained glycogen granules, vesicles or vacuoles scattered throughout the cytoplasm especially at the apical region were reported. The bile canaliculi and the hepatic "Kupffer" cells were also discussed. This is the first study on the histological characterization of the healthy liver of Yemen veiled chameleon in southern Saudi Arabia. The findings reported here should be used as a reference to compare with the pathological abnormalities of the liver in this animal.

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Cyclin Dependent Kinase Inhibitor 2A Genetic and Epigenetic Alterations Interfere with Several Immune Components and Predict Poor Clinical Outcome.

Cyclin dependent kinase inhibitor 2A (CDKN2A) is a well-known tumor suppressor gene as it functions as a cell cycle regulator. While several reports correlate the malfunction of CDKN2A with the initiation and progression of several types of human tumors, there is a lack of a comprehensive study that analyzes the potential effect of CDKN2A genetic alterations on the human immune components and the consequences of that effect on tumor progression and patient survival in a pan-cancer model. The first stage of the current study was the analysis of CDKN2A differential expression in tumor tissues and the corresponding normal ones and correlating that with tumor stage, grade, metastasis, and clinical outcome. Next, a detailed profile of CDKN2A genetic alteration under tumor conditions was described and assessed for its effect on the status of different human immune components. CDKN2A was found to be upregulated in cancerous tissues versus normal ones and that predicted the progression of tumor stage, grade, and metastasis in addition to poor prognosis under different forms of tumors. Additionally, CDKN2A experienced different forms of genetic alteration under tumor conditions, a characteristic that influenced the infiltration and the status of CD8, the chemokine CCL4, and the chemokine receptor CCR6. Collectively, the current study demonstrates the potential employment of CDKN2A genetic alteration as a prognostic and immunological biomarker under several types of human cancers.

A Comprehensive Pan-Cancer Analysis Identifies CEP55 as a Potential Oncogene and Novel Therapeutic Target.

Emerging research findings have shown that a centrosomal protein (CEP55) is a potential oncogene in numerous human malignancies. Nevertheless, no pan-cancer analysis has been conducted to investigate the various aspects and behavior of this oncogene in different human cancerous tissues. Numerous databases were investigated to conduct a detailed analysis of CEP55. Initially, we evaluated the expression of CEP55 in several types of cancers and attempted to find the correlation between that and the stage of the examined malignancies. Then, we conducted a survival analysis to determine the relationship between CEP55 overexpression in malignancies and the patient's survival. Furthermore, we examined the genetic alteration forms and the methylation status of this oncogene. Additionally, the interference of CEP55 expression with immune cell infiltration, the response to various chemotherapeutic agents, and the putative molecular mechanism of CEP55 in tumorigenesis were investigated. The current study found that CEP55 was upregulated in cancerous tissues versus normal controls where this upregulation was correlated with a poor prognosis in multiple forms of human cancers. Additionally, it influenced the level of different immune cell infiltration and several chemokines levels in the tumor microenvironment in addition to the response to several antitumor drugs. Herein, we provide an in-depth understanding of the oncogenic activities of CEP55, identifying it as a possible predictive marker as well as a specific target for developing anticancer therapies.

A pan-cancer analysis reveals CHD1L as a prognostic and immunological biomarker in several human cancers.

Introduction: Several recent studies pointed out that chromodomain-helicase-DNA-binding protein 1-like (CHD1L) is a putative oncogene in many human tumors. However, up to date, there is no pan-cancer analysis performed to study the different aspects of this gene expression and behavior in tumor tissues. Methods: Here, we applied several bioinformatics tools to make a comprehensive analysis for CHD1L. Firstly we assessed the expression of CHD1L in several types of human tumors and tried to correlate that with the stage and grade of the analyzed tumors. Following that, we performed a survival analysis to study the correlation between CHD1L upregulation in tumors and the clinical outcome. Additionally, we investigated the mutation forms, the correlation with several immune cell infiltration, and the potential molecular mechanisms of CHD1L in the tumor tissue. Result and discussion: The results demonstrated that CHD1L is a highly expressed gene across several types of tumors and that was correlated with a poor prognosis for most cancer patients. Moreover, it was found that CHD1L affects the tumor immune microenvironment by influencing the infiltration level of several immune cells. Collectively, the current study provides a comprehensive overview of the oncogenic roles of CHD1L where our results nominate CHD1L as a potential prognostic biomarker and target for antitumor therapy development.

Integration of Chemoinformatics and Multi-Omics Analysis Defines ECT2 as a Potential Target for Cancer Drug Therapy.

Epithelial cell transforming 2 (ECT2) is a potential oncogene and a number of recent studies have correlated it with the progression of several human cancers. Despite this elevated attention for ECT2 in oncology-related reports, there is no collective study to combine and integrate the expression and oncogenic behavior of ECT2 in a panel of human cancers. The current study started with a differential expression analysis of ECT2 in cancerous versus normal tissue. Following that, the study asked for the correlation between ECT2 upregulation and tumor stage, grade, and metastasis, along with its effect on patient survival. Moreover, the methylation and phosphorylation status of ECT2 in tumor versus normal tissue was assessed, in addition to the investigation of the ECT2 effect on the immune cell infiltration in the tumor microenvironment. The current study revealed that ECT2 was upregulated as mRNA and protein levels in a list of human tumors, a feature that allowed for the increased filtration of myeloid-derived suppressor cells (MDSC) and decreased the level of natural killer T (NKT) cells, which ultimately led to a poor prognosis survival. Lastly, we screened for several drugs that could inhibit ECT2 and act as antitumor agents. Collectively, this study nominated ECT2 as a prognostic and immunological biomarker, with reported inhibitors that represent potential antitumor drugs.

Lower Extremity Arterial Disease in Type 2 Diabetes Mellitus: Metformin Inhibits Femoral Artery Ultrastructural Alterations as well as Vascular Tissue Levels of AGEs/ET-1 Axis-Mediated Inflammation and Modulation of Vascular iNOS and eNOS Expression.

Lower extremity arterial disease (LEAD) is a major risk factor for amputation in diabetic patients. The advanced glycation end products (AGEs)/endothelin-1 (ET-1)/nitric oxide synthase (NOS) axis-mediated femoral artery injury with and without metformin has not been previously investigated. Type 2 diabetes mellitus (T2DM) was established in rats, with another group of rats treated for two weeks with 200 mg/kg metformin, before being induced with T2DM. The latter cohort were continued on metformin until they were sacrificed at week 12. Femoral artery injury was established in the diabetic group as demonstrated by substantial alterations to the femoral artery ultrastructure, which importantly were ameliorated by metformin. In addition, diabetes caused a significant (p < 0.0001) upregulation of vascular tissue levels of AGEs, ET-1, and iNOS, as well as high blood levels of glycated haemoglobin, TNF-α, and dyslipidemia. All of these parameters were also significantly inhibited by metformin. Moreover, metformin treatment augmented arterial eNOS expression which had been inhibited by diabetes progression. Furthermore, a significant correlation was observed between femoral artery endothelial tissue damage and glycemia, AGEs, ET-1, TNF-α, and dyslipidemia. Thus, in a rat model of T2DM-induced LEAD, an association between femoral artery tissue damage and the AGEs/ET-1/inflammation/NOS/dyslipidemia axis was demonstrated, with metformin treatment demonstrating beneficial vascular protective effects.

Integration of Ultrastructural and Computational Approaches Reveals the Protective Effect of Astaxanthin against BPA-Induced Nephrotoxicity.

BACKGROUND: Bisphenol A (BPA) is an environmental contaminant that can induce deleterious organ effects. Human Cytochrome P450 CYP2C9 enzyme belongs to the essential xenobiotic-metabolizing enzymes, producing ROS as a byproduct. Astaxanthin (ATX) is a powerful antioxidant that protects organs and tissues from the damaging effects of oxidative stress caused by various diseases. AIM OF THE STUDY: This study investigated the possible protective impacts of ATX against BPA-induced nephrotoxicity and its underlying mechanism. MATERIALS AND METHODS: Kidney tissues were isolated and examined microscopically from control, protected, and unprotected groups of rats to examine the potential protective effect of ATX against nephrotoxicity. Moreover, a molecular dynamic (MD) simulation was conducted to predict the performance of ATX upon binding to the active site of P450 CYP2C9 protein receptor as a potential mechanism of ATX protective effect. RESULTS: Implemented computational methods revealed the possible underlying mechanism of ATX protection; the protective impact of ATX is mediated by inhibiting P450 CYP2C9 through binding to its dimeric state where the RMSF value for apo-protein and ATX-complex system were 5.720.57 and 1.040.41, respectively, implicating the ATX-complex system to have lesser variance in its residues, leading to the prevention of ROS excess production, maintaining the oxidant-antioxidant balance and re-establishing the proper mitochondrial functionality. Furthermore, the experimental methods validated in silico outcomes and revealed that ATX therapy effectively restored the typical histological architecture of pathological kidney tissues. CONCLUSIONS: ATX prevents BPA-induced nephrotoxicity by controlling oxidative imbalance and reversing mitochondrial dysfunction. These outcomes shed new light on the appropriate use of ATX as a treatment or prophylactic agent for these severe conditions.

Protective efficacy of luteolin against aflatoxinB1-induced toxicity, oxidative damage, and apoptosis in the rat liver.

One particularly harmful mycotoxin, aflatoxin B1 (AFB1), usually triggers liver toxicity and oxidative stress in both humans and other mammals. Luteolin (LUTN), a popular active phytochemical molecule, exhibits a strong antioxidant potential. The purpose of this investigation was to explore the potential molecular mechanism in rats and determine if LUTN exhibits protective benefits against AFB1-induced hepatotoxicity. Random selection was used to determine the four treatment groups, each consisting of 24 rats (n = 6). Physiological saline was administered to group 1 (CONT); group 2 received LUTN for a dosage of 50-mg/kg BW. AFB1 was administered to group 3 for a dosage of 0.75-mg/kg BW, and AFB1 with LUTN was given to group 4 at the same dosages mentioned in the previous groups. Rats intoxicated with AFB1 alterations of hepatic transaminases, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), displayed periportal mononuclear cell infiltrations, disorganized lobular architecture, and dispersed necrotic cells in their liver tissues. By reducing serum biochemical levels of the hepatic transaminases ALT and AST brought on by AFB1 exposure, our results demonstrated that LUTN treatment considerably restored liver injury. Through lowering the production of malondialdehyde (MDA) and reactive oxygen species (ROS), as well as by boosting the activity of the antioxidant enzyme catalase (CAT) and superoxide dismutase (SOD), LUTN mitigated the oxidative stress brought on by AFB1. Our findings showed that LUTN significantly reversed the liver damage caused by AFB1. When considered as a whole, LUTN may protect the liver from damage brought on by AFB1 by acting as a potential mitigator and may aid in the creation of cutting-edge therapies to treat liver illnesses in humans and/or animals.

The antioxidant effects of coenzyme Q10 on albino rat testicular toxicity and apoptosis triggered by bisphenol A.

Polycarbonate plastics for packaging and epoxy resins are both made with the industrial chemical bisphenol A (BPA). This investigation looked at the histological structure, antioxidant enzymes, and albino rats' testis to determine how coenzyme Q10 (CoQ10) impacts BPA toxicity. For the experiments, three sets of 18 male adult rats were created: group 1 received no therapy, group 2 acquired BPA, and group 3 got the daily BPA treatment accompanied by coenzyme Q10, 1 h apart. The experimental period ran for 14 days. The biochemical biomarkers catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA) were altered as a result of BPA exposure. The testicular histological architecture, which is made up of apoptosis, was also exaggerated. Furthermore, rats given BPA and CoQ10 treatment may experience a diminution in these negative BPA effects. These protective properties of CoQ10 may be correlated with the ability to eliminate oxidizing substances that can harm living species. The outcomes might support the hypothesis that CoQ10 prevented oxidative damage and boosted rats' stress responses when BPA was introduced. Thus, by shielding mammals from oxidative stress, CoQ10 aids in the growth and development of the animals. BPA is extremely hazardous to humans and can persist in tissues. Human reproductive functions are a worry due to human exposure to BPA, especially for occupational workers who are typically exposed to higher doses of BPA. As a result, in order to reduce the health risks, BPA usage must be minimized across a diverse range of industries, and improper plastic container handling must be prohibited. By giving CoQ10 to patients, BPA's harmful effects on reproductive structures and functions may be avoided.

Targeting Cancer Stem Cells as the Key Driver of Carcinogenesis and Therapeutic Resistance.

The emerging concept of cancer stem cells (CSCs) as the key driver behind carcinogenesis, progression, and diversity has displaced the prior model of a tumor composed of cells with similar subsequently acquired mutations and an equivalent capacity for renewal, invasion, and metastasis. This significant change has shifted the research focus toward targeting CSCs to eradicate cancer. CSCs may be characterized using cell surface markers. They are defined by their capacity to self-renew and differentiate, resist conventional therapies, and generate new tumors following repeated transplantation in xenografted mice. CSCs' functional capabilities are governed by various intracellular and extracellular variables such as pluripotency-related transcription factors, internal signaling pathways, and external stimuli. Numerous natural compounds and synthetic chemicals have been investigated for their ability to disrupt these regulatory components and inhibit stemness and terminal differentiation in CSCs, hence achieving clinical implications. However, no cancer treatment focuses on the biological consequences of these drugs on CSCs, and their functions have been established. This article provides a biomedical discussion of cancer at the time along with an overview of CSCs and their origin, features, characterization, isolation techniques, signaling pathways, and novel targeted therapeutic approaches. Additionally, we highlighted the factors endorsed as controlling or helping to promote stemness in CSCs. Our objective was to encourage future studies on these prospective treatments to develop a framework for their application as single or combined therapeutics to eradicate various forms of cancer.

Mannose-binding lectin gene polymorphism in psoriasis and vitiligo: an observational study and computational analysis.

Introduction: Psoriasis and vitiligo are inflammatory autoimmune skin disorders with remarkable genetic involvement. Mannose-binding lectin (MBL) represents a significant immune molecule with one of its gene variants strongly linked to autoimmune diseases. Therefore, in this study, we investigated the role of the MBL variant, rs1800450, in psoriasis and vitiligo disease susceptibility. Methods: The study comprised performing in silico analysis, performing an observational study regarding psoriasis patients, and performing an observational study regarding vitiligo patients. Various in silico tools were used to investigate the impact of the selected mutation on the function, stability, post-translational modifications (PTMs), and secondary structures of the protein. In addition, a total of 489 subjects were enrolled in this study, including their demographic and clinicopathological data. Genotyping analysis was performed using real-time PCR for the single nucleotide polymorphism (SNP) rs1800450 on codon 54 of the MBL gene, utilizing TaqMan genotyping technology. In addition, implications of the studied variant on disease susceptibility and various clinicopathological data were analyzed. Results: Computational analysis demonstrated the anticipated effects of the mutation on MBL protein. Furthermore, regarding the observational studies, rs1800450 SNP on codon 54 displayed comparable results in our population relative to global frequencies reported via the 1,000 Genomes Project. This SNP showed no significant association with either psoriasis or vitiligo disease risk in all genetic association models. Furthermore, rs1800450 SNP did not significantly correlate with any of the demographic or clinicopathological features of both psoriasis and vitiligo. Discussion: Our findings highlighted that the rs1800450 SNP on the MBL2 gene has no role in the disease susceptibility to autoimmune skin diseases, such as psoriasis and vitiligo, among Egyptian patients. In addition, our analysis advocated the notion of the redundancy of MBL and revealed the lack of significant impact on both psoriasis and vitiligo disorders.

HBD-2 variants and SARS-CoV-2: New insights into inter-individual susceptibility.

Background: A deep understanding of the causes of liability to SARS-CoV-2 is essential to develop new diagnostic tests and therapeutics against this serious virus in order to overcome this pandemic completely. In the light of the discovered role of antimicrobial peptides [such as human b-defensin-2 (hBD-2) and cathelicidin LL-37] in the defense against SARS-CoV-2, it became important to identify the damaging missense mutations in the genes of these molecules and study their role in the pathogenesis of COVID-19. Methods: We conducted a comprehensive analysis with multiple in silico approaches to identify the damaging missense SNPs for hBD-2 and LL-37; moreover, we applied docking methods and molecular dynamics analysis to study the impact of the filtered mutations. Results: The comprehensive analysis reveals the presence of three damaging SNPs in hBD-2; these SNPs were predicted to decrease the stability of hBD-2 with a damaging impact on hBD-2 structure as well. G51D and C53G mutations were located in highly conserved positions and were associated with differences in the secondary structures of hBD-2. Docking-coupled molecular dynamics simulation analysis revealed compromised binding affinity for hBD-2 SNPs towards the SARS-CoV-2 spike domain. Different protein-protein binding profiles for hBD-2 SNPs, in relation to their native form, were guided through residue-wise levels and differential adopted conformation/orientation. Conclusions: The presented model paves the way for identifying patients prone to COVID-19 in a way that would guide the personalization of both the diagnostic and management protocols for this serious disease.