Uncovering the Cardioprotective Potential of Diacerein in Doxorubicin Cardiotoxicity: Mitigating Ferritinophagy-Mediated Ferroptosis via Upregulating NRF2/SLC7A11/GPX4 Axis.

Doxorubicin (DOX)-induced cardiotoxicity (DIC) is a life-threatening clinical issue with limited preventive approaches, posing a substantial challenge to cancer survivors. The anthraquinone diacerein (DCN) exhibits significant anti-inflammatory, anti-proliferative, and antioxidant actions. Its beneficial effects on DIC have yet to be clarified. Therefore, this study investigated DCN's cardioprotective potency and its conceivable molecular targets against DIC. Twenty-eight Wister rats were assigned to CON, DOX, DCN-L/DOX, and DCN-H/DOX groups. Serum cardiac damage indices, iron assay, oxidative stress, inflammation, endoplasmic reticulum (ER) stress, apoptosis, ferritinophagy, and ferroptosis-related biomarkers were estimated. Nuclear factor E2-related factor 2 (NRF2) DNA-binding activity and phospho-p53 immunoreactivity were assessed. DCN administration effectively ameliorated DOX-induced cardiac cytomorphological abnormalities. Additionally, DCN profoundly combated the DOX-induced labile iron pool expansion alongside its consequent lethal lipid peroxide overproduction, whereas it counteracted ferritinophagy and enhanced iron storage. Indeed, DCN valuably reinforced the cardiomyocytes' resistance to ferroptosis, mainly by restoring the NRF2/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling axis. Furthermore, DCN abrogated the cardiac oxidative damage, inflammatory response, ER stress, and cardiomyocyte apoptosis elicited by DOX. In conclusion, for the first time, our findings validated DCN's cardioprotective potency against DIC based on its antioxidant, anti-inflammatory, anti-ferroptotic, and anti-apoptotic imprint, chiefly mediated by the NRF2/SLC7A11/GPX4 axis. Accordingly, DCN could represent a promising therapeutic avenue for patients under DOX-dependent chemotherapy.

Genetic variants in the renin-angiotensin-aldosterone system: Impact on cancer risk, prognosis, and therapeutic directions.

Although renin-angiotensin-aldosterone system (RAAS) is known to maintain blood pressure and electrolyte balance, it has recently been linked to a number of biological processes such as angiogenesis, tumorigenesis, metastasis, and cellular proliferation, increasing the risk of cancer development and progression. Multiple genetic variants have been found to affect the genes encoding RAAS components, altering gene transcription and protein expression. This review provides an up-to-date insight into the role of RAAS in carcinogenesis, as well as the impact of RAAS genetic variants on the risk of cancer development, progression, and patient survival and outcomes, as well as response to treatment. This paves the way for the application of precision medicine in cancer risk assessment and management by implementing preventative programs in individuals at risk and guiding the therapeutic direction in cancer patients.

MicroRNA Let-7a association with glycolysis-induced autophagy in locally advanced gastric cancer: Their role in prognosis and FLOT chemotherapy resistance.

Locally advanced gastric cancer (LAGC) still poses a clinical challenge despite multimodality treatment due to multidrug resistance (MDR). Recently, research suggested that autophagy and metabolic regulation may be potential anticancer targets due to their crucial roles in MDR. Let-7a participates in glycolytic and autophagic regulations which are both essential for tumor progression and resistance to therapy. This study used IHC stains; GLUT4 and LC3B to evaluate glycolysis and autophagy respectively. Moreover, mRNA Let-7a was detected by quantitative reverse transcription PCR (q-PCR) in 53 cases of LAGC. Elevated glycolysis and autophagy in LAGC tissue specimens as indicated by high GLUT4 and LC3B expression were significantly associated with adverse prognostic factors such as high pathological grade, positive nodal metastasis, and advanced T stage. Lower Let-7a levels were significantly associated with high tumor grade and advanced T stage. A significant positive correlation between GLUT4 and LC3B expression was detected. Significant inverse correlations between let7a level and IHC expression of both GLUT4 and LC3B were found. Elevated glycolysis and autophagy were significantly associated with poor overall survival (OS). Furthermore, low levels of let-7a were significantly associated with poor OS compared to high levels. Glycolysis and autophagy in LAGC were significantly associated with poor FLOT chemotherapy response. Let7a mRNA relative expression was significantly decreased in cases showing post therapy partial response and sustained disease. Multivariate analysis showed that histologic tumor type, high GLUT4 and high LC3B expression were independent factors associated with poor OS. Poor survival and post FLOT chemotherapy resistance in LAGC cases were significantly related to elevated glycolysis, elevated autophagy, and reduced Let-7a expression. Accordingly, combined therapeutic targeting of these pathways could enhance chemosensitivity in LAGC.

Ulinastatin ameliorated streptozotocin-induced diabetic nephropathy: Potential effects via modulating the components of gut-kidney axis and restoring mitochondrial homeostasis.

Growing evidence supports the role of the gut-kidney axis and persistent mitochondrial dysfunction in the pathogenesis of diabetic nephropathy (DN). Ulinastatin (UTI) has a potent anti-inflammatory effect, protecting the kidney and the gut barrier in sepsis, but its effect on DN has yet to be investigated. This study aimed to assess the potential mitigating effect of UTI on DN and investigate the possible involvement of gut-kidney axis and mitochondrial homeostasis in this effect. Forty male Wistar rats were divided equally into four groups: normal; UTI-treated control; untreated DN; and UTI-treated DN. At the end of the experiment, UTI ameliorated DN by modulating the gut-kidney axis as it improved serum and urinary creatinine, urine volume, creatinine clearance, blood urea nitrogen, urinary albumin, intestinal morphology including villus height, crypt depth, and number of goblet cells, with upregulating the expression of intestinal tight-junction protein claudin-1, and counteracting kidney changes as indicated by significantly decreasing glomerular tuft area and periglomerular and peritubular collagen deposition. In addition, it significantly reduced intestinal and renal nuclear factor kappa B (NF-κB), serum Complement 5a (C5a), renal monocyte chemoattractant protein-1 (MCP-1), renal intercellular adhesion molecule 1 (ICAM1), and renal signal transducer and activator of transcription 3 (STAT3), mitochondrial dynamin related protein 1 (Drp1), mitochondrial fission 1 protein (FIS1), mitochondrial reactive oxygen species (ROS), renal hydrogen peroxide (H2O2), and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels. Furthermore, it significantly increased serum short chain fatty acids (SCFAs), and mitochondrial ATP levels and mitochondrial transmembrane potential. Moreover, there were significant correlations between measured markers of gut components of the gut-kidney axis and renal function tests in UTI-treated DN group. In conclusion, UTI has a promising therapeutic effect on DN by modulating the gut-kidney axis and improving renal mitochondrial dynamics and redox equilibrium.

Study of antibiotic resistance and virulence genes in Escherichia coli isolated from urinary tract infection patients in Tanta University Hospitals.

This study aimed to investigate the prevalence of antibiotic resistance genes CTX-M and Qnr, as well as the virulence genes HlyA, Pap, CNF1, and Afa, in uropathogenic Escherichia coli (UPEC) isolates from the Egyptian population. In this cross-sectional study, a total of 50 E. coli isolates were collected from urine samples from patients with urinary tract infections (UTIs) admitted to Tanta University Hospital from December 2020 to November 2021. The isolates were cultured, identified, and tested for antibiotic susceptibility by the disc diffusion method. The CTX-M, Qnr (QnrA, B, and S), Pap, CNF1, HlyA, and Afa genes were detected by polymerase chain reaction in UPEC isolates. The Pap, CNF1, HlyA, and Afa genes were found to be positive in 18%, 12%, 10%, and 2% of the isolates, respectively. In addition, CTX-M and QnrS were found to be positive in 44% and 8% of the isolates, while QnrA and B were not detected. Furthermore, positive Pap, CNF1, and HlyA genes were significantly associated with both upper and lower UTIs, increased frequency, urgency, and dysuria, and complicated UTIs, as well as pyuria over 100 white blood cells per high-power field. In conclusion, the prevalence of virulence and antibiotic resistance genes varies by population. At our hospital, the Pap gene is the most prevalent virulence gene and was strongly associated with complicated UTIs, while the CTX-M and QnrS genes were the most prevalent and related to antibiotic resistance. Our findings, however, should be interpreted with caution due to the small sample size.

Cancer chemo-preventive role of grape seed oil and cisplatin as a combination adjuvant therapy in the treatment of tongue squamous cell carcinoma: A biological in-vitro study.

OBJECTIVES: Grape seed oil (GSO) has recently gained popularity due to its anticancer properties. This study aimed to investigate the efficacy of combining cisplatin (CP) and GSO in tongue squamous cell carcinoma (TSCC) treatment. METHODS: In this study, human tongue carcinoma cell line (HNO-97) was treated with CP and GSO alone or in combination. The effects of CP and GSO on cytotoxicity and cell cycle arrest were studied using the MTT assay and flowcytometry, respectively. The apoptotic markers, including p53 and caspase 8, were assessed using reverse-transcription polymerase chain reaction (RT-PCR), caspase 3 using immunohistochemistry, and the angiogenic marker vascular endothelial growth factor (VEGF) using enzyme-linked immunosorbent assay (ELISA). RESULTS: The IC50 drug concentrations were found to be 16.4 ug/mL of GSO and 2.18 ug/mL of CP. When compared to the untreated control group, the percentage of S phase cells and apoptotic cells was significantly higher in the GSO, CP, and GSO/CP combination therapy groups. Furthermore, p53, caspase 8, caspase 3 expression were significantly upregulated in the GSO-and CP-treated groups, with evident upregulation with GSO/CP combination therapy. However, VEGF levels were significantly lower in the GSO-, CP-, and combined GSO/CP-treated groups. CONCLUSIONS: GSO has both an apoptotic and antiangiogenic effect in the treatment of TSCC, suggesting a new strategy for phytochemical-based combination therapy.

Autoimmune Regulator Gene Polymorphisms and the Risk of Primary Immune Thrombocytopenic Purpura: A Case-Control Study.

This study aimed to assess the possible association between two single nucleotide polymorphisms (SNPs) of the autoimmune regulator (AIRE) gene (rs2075876 G/A and rs760426 A/G) with the risk of primary immune thrombocytopenia (ITP), as well as AIRE serum levels, in the Egyptian population. In this case-control study, 96 cases with primary ITP and 100 healthy subjects were included. Two SNPs of the AIRE gene (rs2075876 G/A and rs760426 A/G) were genotyped via Taqman allele discrimination real-time polymerase chain reaction (PCR). Additionally, serum AIRE levels were measured using the enzyme-linked immunosorbent assay (ELISA) technique. After adjusting for age, gender, and family history of ITP, the AIRE rs2075876 AA genotype and A allele were associated with increased ITP risk (adjusted odds ratio (aOR): 4.299, p = 0.008; aOR: 1.847, p = 0.004, respectively). Furthermore, there was no significant association between AIRE rs760426 A/G different genetic models and ITP risk. A linkage disequilibrium revealed that A-A haplotypes were associated with an increased ITP risk (aOR: 1.821, p = 0.020). Serum AIRE levels were found to be significantly lower in the ITP group, positively correlated with platelet counts, and were even lower in the AIRE rs2075876 AA genotype and A allele, as well as A-G and A-A haplotype carriers (all p < 0.001). The AIRE rs2075876 genetic variants (AA genotype and A allele) and A-A haplotype are associated with an increased ITP risk in the Egyptian population and lower serum AIRE levels, whereas the SNP rs760426 A/G is not.

Human umbilical cord blood mesenchymal stem cells as a potential therapy for schistosomal hepatic fibrosis: an experimental study.

The objective of our study was to assess the effect of human umbilical cord blood (HUCB) mesenchymal stem cells (MSCs) transplantation on schistosomal hepatic fibrosis in mice. The study animals were divided into three groups. Group I is a control group, where the mice were infected with Schistosoma mansoni cercariae and remained untreated. The mice of the other two groups were infected and treated with either praziquantel (Group II) or HUCB-MSCs (Group III). Liver function tests, as well as histopathological evaluation of liver fibrosis using hematoxylin and eosin and Masson's trichrome stains, were performed. Additionally, an immunohistochemical study was carried out using anti-glial fibrillary acidic protein (GFAP) in hepatic stellate cells. Compared to the control group, the treated (praziquantel and MSCs) groups showed a substantial improvement, with a significant difference regarding the histopathological evaluation of liver fibrosis in the MSCs-treated group. In conclusion, MSCs could be a promising and efficient cell therapy for liver fibrosis.

The Possible Role of Naringenin in the Prevention of Alcohol-Induced Neurochemical and Neurobehavioral Deficits.

Chronic alcohol consumption is associated with progressive/irreversible neurodegeneration. However, there is not a clear understanding of its discrete pathophysiology or therapeutic intervention. The present study aimed to investigate the protective effect of the natural citrus flavonoid, naringenin (NAG), against alcohol-induced neurodegeneration in the brain cerebral cortex. Thirty-two male albino rats were randomly divided into four equal groups (eight rats each): control group (I); NAG-treated group (II); alcohol-intoxicated group (III) and alcohol + NAG co-treated group (IV). Brain nuclear factor erythroid 2-related factor 2 and receptor-interacting protein kinase 3 expression were assessed by real-time polymerase chain reaction. NAD(P)H quinone oxidoreductase 1 activity and malondialdehyde, reduced glutathione, mixed lineage kinase-like protein, phosphorylated glycogen synthase kinase 3 beta, and ciliary neurotrophic factor levels were all measured biochemically. B-cell lymphoma 2 expression was assessed by immunohistochemistry. A histopathological examination and neurobehavioral tests were performed. The alcohol-treated group showed a significant increase in oxidative stress and necroptosis biomarkers with a significant reduction in neuroprotective proteins. NAG co-administration effectively ameliorated cognitive dysfunction with an apparent neuroprotective effect by targeting various signaling pathways, including nuclear factor erythroid 2-related factor/NAD(P)H quinone oxidoreductase 1, anti-oxidant capacity, attenuated necroptosis, and upregulated neuroprotective ciliary neurotrophic factor. The study findings suggest NAG as a possible management strategy for alcohol-induced neurodegeneration.

Fisetin ameliorates oxidative glutamate testicular toxicity in rats via central and peripheral mechanisms involving SIRT1 activation.

OBJECTIVES: This study aimed to evaluate the potential mitigating effect of fisetin on monosodium glutamate (MSG)-induced testicular toxicity and investigate the possible involvement of silent mating type information regulation 2 homolog 1 (SIRT1) in this effect. METHODS: Forty male rats were divided into normal control, fisetin-treated, MSG-treated, and fisetin + MSG-treated groups. Testosterone, GnRH, FSH, and LH were measured in plasma, as well as SIRT1 and phosphorylated AMP-activated protein kinase (pAMPK) levels in testicular tissues using ELISA. Hydrogen peroxide (H2O2), nitric oxide (NO), and reduced glutathione (GSH) were measured colorimetrically, while Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) expression was relatively quantified using RT-PCR in testicular tissues. RESULTS: After 30 days, fisetin could ameliorate MSG-induced testicular toxicity by acting centrally on the hypothalamic-pituitary-gonadal axis, increasing plasma levels of GnRH, FSH, LH, and testosterone. Peripheral actions of fisetin on the testis were indicated as it increased testicular SIRT1 and pAMPK. Furthermore, it antagonized glutamate-induced oxidative stress by significantly lowering H2O2, NO, and relative NOX4 expression while significantly increasing reduced GSH levels. It also improved the architecture of the seminiferous tubules, reduced sperm abnormality, and increased sperm count. DISCUSSION: Fisetin ameliorates MSG-induced testicular toxicity via central and peripheral mechanisms making it a promising therapeutic target for male infertility.

Fenofibrate Improves Cognitive Impairment Induced by High-Fat High-Fructose Diet: A Possible Role of Irisin and Heat Shock Proteins.

A high-fat, high-fructose diet (HFFD) impairs cognitive functions and increases susceptibility to neurodegenerative disorders. Irisin and heat shock protein 70 (HSP70) are well known for their role in neuroprotection. The possible neuroprotective effects of fenofibrate on HFFD-induced cognitive dysfunction and the involvement of irisin and HSP70 in these effects were investigated in this study. Rats were divided into normal control, HFFD, dimethylsulfoxide+HFFD, and fenofibrate+HFFD groups. At the end of the experiment, fenofibrate treatment restored hippocampus histological characteristics to almost normal and improved HFFD-induced cognitive deficit. It reduced body weight gain and had hypolipidemic effects by significantly lowering total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels while increasing high-density lipoprotein cholesterol levels. It has antioxidant and anti-inflammatory effects as it significantly reduced the hippocampal malondialdehyde, interleukin-6, and tumor necrosis factor-alpha levels, while significantly increasing the reduced glutathione level. It prevented HFFD-induced hypoxia by significantly lowering hippocampal vascular endothelial growth factor and hypoxia-inducible factor-1 alpha levels. It significantly activated the hippocampal peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α)/irisin/brain-derived neurotrophic factor pathway. It significantly increased hippocampal HSP70 while decreasing the HSP90 levels. It enhanced synaptic plasticity by significantly upregulating the hippocampal relative GluR1 gene expression. Furthermore, hippocampal irisin levels in the HFFD group were found to be positively correlated with cognitive function, hippocampal HSP70, and relative GluR1 gene expression levels, while negatively correlated with hippocampal HSP90 and HIF1α levels. Therefore, fenofibrate may be used as a potential medication to treat HFFD-induced neurodegenerative disorders.

Metadherin (AEG-1/MTDH/LYRIC) expression: Significance in malignancy and crucial role in colorectal cancer.

Metadherin (AEG-1/MTDH/LYRIC) is a 582-amino acid transmembrane protein, encoded by a gene located at chromosome 8q22, and distributed throughout the cytoplasm, peri-nuclear region, nucleus, and nucleolus as well as the endoplasmic reticulum (ER). It contains several structural and interacting domains through which it interacts with transcription factors such as nuclear factor-κB (NF-κB), promyelocytic leukemia zinc finger (PLZF), staphylococcal nuclease domain containing 1 (SND1) and lung homing domain (LHD). It is regulated by miRNAs and mediates its oncogenic function via activation of cell proliferation, survival, migration and metastasis, as well as, angiogenesis and chemoresistance via phosphatidylinositol-3-kinase/AKT (PI3K/AKT), NF-κB, mitogen-activated protein kinase (MAPK) and Wnt signaling pathways. In this chapter, metadherin is reviewed highlighting its role in mediating growth, metastasis and chemoresistance in colorectal cancer (CRC). Metadherin, as well as its variants, and antibodies are associated with CRC progression, poorer prognosis, decreased survival and advanced clinico-pathology. The potential of AEG-1/MTDH/LYRIC as a diagnostic and prognostic marker as well as a therapeutic target in CRC is explored.

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.

Verification of quantitative analytical methods in medical laboratories.

BACKGROUND: Globally, all medical laboratories seeking accreditation should meet international quality standards to perform certain specific tests. Quality management program provides disciplines targeted to ensure that quality standards have been implemented by a laboratory in order to generate correct results. The hallmark of the accreditation process is method verification and quality assurance. Before introducing a new method in your laboratory, it is important to assess certain performance characteristics that reflect the concept of method verification. METHODS: In this review, we illustrated how to verify the performance characteristics of a new method according to the recent guidelines. It includes an assessment of precision, trueness, analytical sensitivity, detection limits, analytical specificity, interference, measuring range, linearity, and measurement uncertainty. CONCLUSIONS: Although the presence of several updated guidelines used to determine the performance characteristics of new methods in clinical chemistry laboratories, the real practice raised several concerns with the application of these guidelines which in need for further consideration in the upcoming updates of these guidelines.

Unraveling the biomechanistic role of Rac1/TWEAK/Fn14/NF-κB intricate network in experimentally doxorubicin-induced cardiotoxicity in rats: The role of curcumin.

Doxorubicin (DOX) is an important chemotherapeutic drug. Cardiotoxicity diminishes its clinical efficacy. We aimed to focus on the mechanism of DOX-induced cardiotoxicity, in addition, to evaluate curcumin's protective effect against it. Twenty-eight rats were divided into the normal control group I, curcumin-treated (200 mg/kg body weight [b.w.]) group II, DOX-treated (4 mg/kg b.w.) group III, and DOX + curcumin group IV. Cardiac injury markers, heart tissue oxidative stress indices, interferon-gamma (INF-γ), tumor necrosis factor-like weak inducer of apoptosis (TWEAK), upregulated modulator of apoptosis (PUMA), p53 and nuclear factor kappa-B p65 (NF-κB p65) levels as well as messenger RNA gene expression of Rac1 and fibroblast growth factor-inducible protein 14 (Fn14) were assayed, besides the assay of DNA damage, histopathological changes, survivin immunohistochemistry and electron microscopic examination. Curcumin significantly downregulated Rac1 and Fn14 gene expression and significantly decreased p53, NF-κB p65, INF-γ, and PUMA levels in the cardiac tissue. In addition, curcumin improved oxidative stress indices, DNA damage, and cardiac toxicity markers in the form of lactate dehydrogenase (LD), creatine kinase isoenzyme-MB (CK-MB), and cardiac troponin-I (cTn-I). Meanwhile, upregulated antiapoptotic marker survivin was observed. Light and electron microscopic findings confirmed our biochemical and molecular outcomes. The current study established the antioxidant, anti-inflammatory, and antiapoptotic roles of curcumin against DOX cardiotoxicity.

Oct4 expression in gastric carcinoma: association with tumor proliferation, angiogenesis and survival.

BACKGROUND: Octamer-binding transcription factor 4 (Oct4) is a transcription factor that has an important role in stem cell differentiation and self-renewal. Oct4 has also been implicated in tumorigenicity of different cancers. This study aimed to analyze Oct4 expression in gastric carcinoma (GC) and to evaluate the relation between Oct4 expression and clinicopathologic parameters, tumor proliferation, and angiogenesis in addition to patient survival. RESULTS: Oct4 mRNA was detected by quantitative reverse transcription PCR (qRT-PCR) in 45 GC specimens and adjacent non-cancerous tissues. We found a significant difference in Oct4 mRNA relative expression levels in GC tissue compared with adjacent non-cancerous tissues (p < 0.001). Furthermore, immunohistochemistry (IHC) was performed to study the Oct4 expression in GC cases. High Oct4 immunostaining was detected in 62.2% of GC specimens. High Oct4 expression both by mRNA relative quantitation and IHC were significantly related to poorly differentiated tumors, nodal metastasis, and stage III tumors. Moreover, high Oct4 IHC expression was also associated with cases positive for Ki-67 and VEGF expressions (p < 0.001 and 0.021, respectively). Oct4 expression identified by both mRNA relative quantitation and IHC was significantly related (p < 0.001). As regards patient survival, high Oct4 expression was significantly related to poor overall survival (OS) and disease-free survival (DFS) (p = 0.029 and 0.031, respectively). CONCLUSION: Oct4 plays a valuable role in the progression and prognosis of GC. High Oct4 expression is associated with high tumor grade, nodal metastasis, stage III tumors, and poor OS and DFS. High Oct4 is also significantly associated with Ki-67 and VGEF expression, thus enhancing tumor proliferation and angiogenesis.