The prognostic value of Dickkopf-3 (Dkk3), TGFB1 and ECM-1 in prostate cancer.

Prostate cancer (PCa) is considered one of the most common cancers worldwide. Despite advances in patient diagnosis, management, and risk stratification, 10%-20% of patients progress to castration-resistant disease. Our previous report highlighted a protective role of Dickkopf-3 (DKK3) in PCa stroma. This role was proposed to be mediated through opposing extracellular matrix protein 1 (ECM-1) and TGF-ß signalling activity. However, a detailed analysis of the prognostic value of DKK3, ECM-1 and members of the TGF-ß signalling pathway in PCa was not thoroughly investigated. In this study, we explored the prognostic value of DKK3, ECM-1 and TGFB1 using a bioinformatical approach through analysis of large publicly available datasets from The Cancer Genome Atlas Program (TGCA) and Pan-Cancer Atlas databases. Our results showed a significant gradual loss of DKK3 expression with PCa progression (p < 0.0001) associated with increased DNA methylation in its promoter region (p < 1.63E-12). In contrast, patients with metastatic lesions showed significantly higher levels of TGFB1 expression compared to primary tumours (p < 0.00001). Our results also showed a marginal association between more advanced tumour stage presented as positive lymph node involvement and low DKK3 mRNA expression (p = 0.082). However, while ECM1 showed no association with tumour stage (p = 0.773), high TGFB1 expression showed a significant association with more advanced stage presented as advanced T3 stage compared to patients with low TGFB1 mRNA expression (p < 0.001). Interestingly, while ECM1 showed no significant association with patient outcome, patients with high DKK3 mRNA expression showed a significant association with favourable outcomes presented as prolonged disease-specific (p = 0.0266), progression-free survival (p = 0.047) and disease-free (p = 0.05). In contrast, high TGFB1 mRNA expression showed a significant association with poor patient outcomes presented as shortened progression-free (p = 0.00032) and disease-free survival (p = 0.0433). Moreover, DKK3, TGFB1 and ECM1 have acted as immune-associated genes in the PCa tumour microenvironment. In conclusion, our findings showed a distinct prognostic value for this three-gene signature in PCa. While both DKK3 and TGFB1 showed a potential role as a clinical marker for PCa stratification, ECM1 showed no significant association with the majority of clinicopathological parameters, which reduce its clinical significance as a reliable prognostic marker.

Biocompatibility and radiosensitivity of a fiber optical-based dosimeter: biological applications.

This study introduces a cutting-edge fiber-optic dosimetry (FOD) sensor designed for measuring radiation in biological settings. The accuracy and precision of dosimeters for small animals, particularly prolonged exposure to nonuniform radiation fields, are always challenging. A state-of-the-art in-vivo dosimeter utilizing glass-encapsulated Thermoluminescence cylindrical detector (TLD) was introduced. The FODs are implanted into the rat during a prolonged irradiation scenario involving 137Cs where the rat has the freedom to move within a heterogeneous radiation domain. The implantation surgery was verified with X-ray computed tomography (CT) in addition to biochemical and pathological tests to assess the biocompatibility of FOD in vivo. A versatile FOD is designed for industrial and medical fields, which demand accurate and resilient radiation dosimeters. The dose measurements are associated with precise two-dimensional (2D) radiation distribution imaging. Three cylindrical FODs and three standards TLD_100 for each rat were tested. The measurements of peak irradiation before and after exposure reveal greater stability and superior sensitivity when compared to standard thermo-luminescence detectors in an in-vivo animal test. To the best of our knowledge, FOD testing on live animals is presented for the first time in this paper. Regarding the safety and biocompatibility of FOD, no morphological signs with any kind of inflammation or sensitivity toward the FOD material have been remarked. Moreover, with the current FOD, there is no oedema between the epidermal, dermal, and subdermal sections at the site of implantation. The results also show the stable levels of white blood cells (lymphocytes, granulocytes, MID) as blood inflammatory markers before surgery and at the time of extraction of the implanted dosimeters, thus confirming the biocompatibility for each optical fiber cylinder dosimeter. As a result, the new dosimeters have excellent biocompatibility in living tissues and have 100% accurate reusability intensity of the delivered radiation doses compared to TLD_100 which demonstrated a 45% reduction in its intensity accuracy.

Studies on the effect of curcumin and quercetin in the liver of male albino rats exposed to gamma irradiation.

Ionizing radiation produces deleterious effects on living organisms. The present investigation has been carried out to study the prophylactic as well as the therapeutic effects of treated rats with quercetin (Quer) and curcumin (Cur), which are two medicinal herbs known for their antioxidant activities against damages induced by whole-body fractionated gamma irradiation. Exposure of rats to whole-body gamma irradiation induced a significant decrease in erythrocyte (RBC), leukocyte (WBCs), platelet count (Plt), hemoglobin concentration (Hb), hematocrit (Hct %), mean erythrocyte hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and mean erythrocyte volume (MCV); a high increase in plasma thiobarbituric acid reactive substances (TBARS); a nonsignificant statistical decrease in the mean value of serum glutathione (GSH); a significant increase in plasma alanine transferase (ALT), aspartate transferase (AST), alkaline phosphates (ALP), serum total protein, serum total cholesterol levels, total triglycerides levels, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels; and with marked histological changes and structural changes measured by Fourier transform infrared (FTIR). Applying both quercetin and curcumin pre- and postexposure to gamma radiation revealed a remarkable improvement in all the studied parameters. The cellular damage by gamma radiation is greatly mitigated by the coadministration of curcumin and quercetin before radiation exposure.

Integrating Network Pharmacology and Molecular Docking Approach to Elucidate the Mechanism of Commiphora wightii for the Treatment of Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is considered a notable prolonged inflammatory condition with no proper cure. Synovial inflammation and synovial pannus are crucial in the onset of RA. The "tumor-like" invading proliferation of new arteries is a keynote of RA. Commiphora wightii (C wightii) is a perennial, deciduous, and trifoliate plant used in several areas of southeast Asia to cure numerous ailments, including arthritis, diabetes, obesity, and asthma. Several in vitro investigations have indicated C wightii's therapeutic efficacy in the treatment of arthritis. However, the precise molecular action is yet unknown. Material and methods: In this study, a network pharmacology approach was applied to uncover potential targets, active therapeutic ingredients and signaling pathways in C wightii for the treatment of arthritis. In the groundwork of this research, we examined the active constituent-compound-target-pathway network and evaluated that (Guggulsterol-V, Myrrhahnone B, and Campesterol) decisively donated to the development of arthritis by affecting tumor necrosis factor (TNF), PIK3CA, and MAPK3 genes. Later on, docking was employed to confirm the active components' efficiency against the potential targets. Results: According to molecular-docking research, several potential targets of RA bind tightly with the corresponding key active ingredient of C wightii. With the aid of network pharmacology techniques, we conclude that the signaling pathways and biological processes involved in C wightii had an impact on the prevention of arthritis. The outcomes of molecular docking also serve as strong recommendations for future research. In the context of this study, network pharmacology combined with molecular docking analysis showed that C wightii acted on arthritis-related signaling pathways to exhibit a promising preventive impact on arthritis. Conclusion: These results serve as the basis for grasping the mechanism of the antiarthritis activity of C wightii. However, further in vivo/in vitro study is needed to verify the reliability of these targets for the treatment of arthritis.

Challenges and Uncertainties in the Diagnosis of Cardiac Amyloidosis: A Case Report.

Amyloidosis is the condition when starch-like misfolded proteins form insoluble fibrils that deposit in tissues and cause dysfunction. Cardiac amyloidosis occurs due to the deposition of amyloid fibrils at the cardiac level and is an important cause of heart failure. This case reveals a patient with significant heart failure and arrhythmia, which later on turned out to be caused by cardiac amyloidosis. While regarded as a rare disease in practice, in retrospect, there are a lot of signs and imaging indicators, particularly in echocardiography that warrant an investigation of cardiac amyloidosis. In this case review, red flags in echocardiography that should endorse further testing for underlying cardiac amyloidosis are highlighted.

Experimental investigation and analytical verification of buckling of functionally graded carbon nanotube-reinforced sandwich beams.

Carbon nanotube (CNT) reinforcement can lead to a new way to enhance the properties of composites by transforming the reinforcement phases into nanoscale fillers. In this study, the buckling response of functionally graded CNT-reinforced composite (FG-CNTRC) sandwich beams was investigated experimentally and analytically. The top and bottom plates of the sandwich beams were composed of carbon fiber laminated composite layers and hard core. The hard core was made of a pultruded glass fiber-reinforced polymer (GFRP) profile. The layers of FG-CNTRC surfaces were reinforced with different proportions of CNT. The reference sample was made of only a pultruded GFRP profile. In the study, the reference sample and four samples with CNT were tested under compression. The largest buckling load difference between the reference sample and the sample with CNT was 37.7%. The difference between the analytical calculation results and experimental results was obtained with an approximation of 0.49%-4.92%. Finally, the buckling, debonding, interlaminar cracks, and fiber breakage were observed in the samples.

Synergistic effect of KI on the corrosion inhibition of a poly(diallylammonium chloride)-based cyclocopolymer containing bis-cationic motifs for mild steel corrosion in 20% formic acid.

This study entails the syntheses of a homopolymer, poly(diallylammonium chloride) (3), and copolymers (8a-c) containing hydrophilic/hydrophobic pendants and their role in mitigating mild steel in aggressive 20% formic acid, a type of corrosion that is not frequently discussed in the literature. The synthesized homopolymer and copolymers were characterized by FTIR, NMR, viscometry, and TGA. Inhibitor 8b was found to be the most potent, with 81.8% inhibition efficiency (IE) registered via the potentiodynamic polarization method for 100 ppm of inhibitor concentration at 30 °C. Inhibitor 8b, mixed with 2 mmol KI, showed more than 90% IE for a meager 1 ppm inhibitor concentration. For a synergism of 50 ppm inhibitor and 2 mmol KI, the IE reached a high value of 99.1%. The synergism was so good that it helped the inhibitor retain ∼100% of its original IE even after a 24 h weight loss study at 60 °C. The adsorption isotherm study showed that 8b followed the Langmuir adsorption isotherm and adsorbed via chemisorption. A very high value (2.48 × 105 L mol-1) of the equilibrium adsorption constant (Kads) indicated strong adsorption. XPS and SEM surface studies provided evidence of the inhibitor found on the metal surface. Some toxicological parameters, such as LC50, bioaccumulation factor, and developmental toxicity, have been measured computationally. A brief mechanistic insight into how the inhibitors functioned has been offered along with the DFT study.

A state-of-the-art review of the physical and durability characteristics and microstructure behavior of ultra-high-performance geopolymer concrete.

This paper provides a comprehensive review of ultra-high-performance geopolymer concrete (UHPGPC), an innovative, eco-friendly, and cost-effective variant of ultra-high-performance concrete (UHPC), devised to meet the rising request for ultra-high-strength construction materials. Previous research papers have not thoroughly analyzed and compared the rheological, physical, durability, and microstructural properties of UHPGPC with UHPC. Similarly, review articles scarcely investigate UHPGPC's strength properties and microstructural behavior under high temperatures. This paper includes an assessment of the correlation between compressive strength, splitting tensile strength, and modulus of elasticity (MOE). The current study also compares chloride ion penetration test outcomes, elevated temperature, electrical resistivity, and porosity tests to evaluate durability. To analyze the microstructure of UHPGPC, the paper assesses results from Fourier Transform Infrared Spectroscopy (FT-IR), Thermogravimetric Analysis (TGA), Scanning Electron Microscopy (SEM), and Mercury Intrusion Porosimetry (MIP). The findings from the present paper suggest that UHPGPC effectively meets the ideal mechanical property specifications of UHPC. Compared to UHPC, UHPGPC displayed a higher ion passage propensity due to larger pores (>100 nm). Geopolymer technologies present a greener path for producing UHPC by consuming less energy and emitting reduced CO2. Introducing mineral fillers like silica fume impacts the mixture's flowability and increases its water needs. However, adding an optimal ratio of micro-silica as a partial substitute for granulated blast furnace slag further bolsters the strength characteristics of UHPGPC. The strength of UHPC can also be notably improved by adjusting the water-to-binder ratio, with specific ratios yielding considerable enhancements in compression strength. The selection of an alkaline activator plays a pivotal role in UHPC's heat resilience. Among them, a combination of potassium hydroxide and sodium silicate is the prime chemical activator for boosting strength performance, durability behavior, and microstructural attributes, particularly at temperatures beyond 600 °C. Eco-friendly Geopolymer Composites (EGCs) offer lower embodied energy and CO2 emissions than traditional composites, with certain components like polyvinyl alcohol fibers being key contributors to these emissions. Progress in self-healing materials is driving sustainability in construction through innovative techniques, such as bacterial applications and specific chemical reactions. The strength and workability of Engineered Geopolymer Composites are influenced by their fiber content, with certain fibers interacting weaker than others. On a microstructural level, UHPGPC has a relatively weaker structure than UHPC due to differences in pore size, but its durability is improved when reinforced with fibers.

Sex-related differences in delayed doxorubicin-induced cardiac dysfunction in C57BL/6 mice.

Cancer survivors may experience long-term cardiovascular complications due to chemotherapeutic drugs such as doxorubicin (DOX). The exact mechanism of delayed DOX-induced cardiotoxicity has not been fully elucidated. Sex is an important risk factor for DOX-induced cardiotoxicity. In the current study, we identified sex differences in delayed DOX-induced cardiotoxicity and determined the underlying molecular determinants of the observed sexual dimorphism. Five-week-old male and female mice were administered intraperitoneal injections of DOX (4 mg/kg/week) or saline for 6 weeks. Echocardiography was performed 5 weeks after the last dose of DOX to evaluate cardiac function. Thereafter, mice were sacrificed and gene expression of markers of apoptosis, senescence, and inflammation was measured by PCR in hearts and livers. Proteomic profiling of the heart from both sexes was conducted to determine differentially expressed proteins (DEPs). Only DOX-treated male, but not female, mice demonstrated cardiac dysfunction, cardiac atrophy, and upregulated cardiac expression of Nppb and Myh7. No sex-related differences were observed in DOX-induced expression of most apoptotic, senescence, and pro-inflammatory markers. However, the gene expression of Trp53 was significantly reduced in hearts of DOX-treated female mice only. The anti-inflammatory marker Il-10 was significantly reduced in hearts of DOX-treated male mice only, while the pro-inflammatory marker Il-1α was significantly reduced in livers of DOX-treated female mice only. Gene expression of Tnf-α was reduced in hearts of both DOX-treated male and female mice. Proteomic analysis identified several DEPs after DOX treatment in a sex-specific manner, including anti-inflammatory acute phase proteins. This is the first study to assess sex-specific proteomic changes in a mouse model of delayed DOX-induced cardiotoxicity. Our proteomic analysis identified several sexually dimorphic DEPs, many of which are associated with the anti-inflammatory marker Il-10.

Factors that predict development of chronic kidney disease in patients with rheumatoid arthritis receiving biologic DMARDs and mortality rates.

OBJECTIVES: We aimed to determine the choice of biologic/targeted synthetic disease-modifying anti-rheumatic drugs (b/ts-DMARDs), factors associated with the development of chronic kidney disease (CKD), and mortality in RA patients with CKD receiving b/ts-DMARDs. METHODS: Two thousand one hundred forty-one RA (79.4% female) patients were included in the analysis from the HUR-BIO prospective registry. Patients were divided into the CKD group and the non-CKD group. Age and gender-matched patients were selected from the non-CKD group, and then three main groups were determined. CKD was staged according to the glomerular filtration rate criteria. The clinical characteristics of the patients, disease activities, treatment choices, drug retention rate, and mortality rates were compared between the groups. RESULTS: CKD was detected in 90/2141 (4.2%) RA patients on b/ts-DMARDs. Forty patients (2.3%) developed CKD during follow-up after the initiation of b/ts-DMARDs. In the CKD group, anti-TNF agents were chosen as the first-line b/ts-DMARDs therapy in 64.4% of patients, with etanercept leading in 31 (34.4%) patients. In multivariate analysis, age at the start of treatment, DAS-28-ESR at last visit, amyloidosis, hypertension, and history of smoking were the factors associated with the development of CKD in RA patients receiving b/ts-DMARDs. The mortality rate in RA-CKD patients until the onset of the pandemic was 15.41 per 1000 patient years, whereas it was 85.9 per 1000 patient years after the pandemic. CONCLUSION: Comorbidities and control of disease activity are critical in the development of CKD in RA patients receiving b/ts-DMARDs. While there was no significant difference in mortality rate between CKD and non-CKD patients, the overall mortality rate increased after the COVID-19 pandemic duration in both groups.

A Fiber-Optical Dosimetry Sensor for Gamma-Ray Irradiation Measurement in Biological Applications.

In this paper, we propose a novel fiber-optical dosimetry sensor for radiation measurement in biological applications. A two-dimensional (2D) fiber-optical dosimeter (FOD) for radiation measurement is considered. The sensors are arranged as a 2D array in a tailored holder. This FOD targets accurate industrial and medical applications which seek more tolerant radiation dosimeters. In this paper, the FOD sensors are subjected to gamma-ray radiation facilities from the 137Cs gamma-ray irradiator type for low doses and 60Co gamma-ray irradiator for high doses. For better evaluation of radiation effects on the FOD sample, the measurements are performed using eight sensors (hollow cylinder shape) with two samples in each dose. The sensors were measured before and after each irradiation. To the author's knowledge, the measurements of FOD transplanted inside animals are presented for the first time in this paper. A 2D simulation program has been implemented for numerical simulation based on the attenuation factors from the absorbed dose inside the in vivo models. A comparison between the FOD and the standard thermo-luminescence detector is presented based on the test of in vivo animal models. The results indicate that the proposed FOD sensor is more stable and has higher sensitivity.

Radioprotective potential of whey protein against gamma irradiation-induced lingual damage.

Introduction: Ionizing radiation (IR) is effectively used in the treatment of oral malignancies; however, it might also significantly harm the surrounding tissues. Whey protein isolate (WP) is a protein derived from milk that exhibits a wide range of bioactivities. Therefore, the present research aimed to delineate the mitigating impact of WP against gamma irradiation-induced lingual damage. Methods: Rats were randomized into 5 groups: Control (saline, orally, 14 days), WP (WP; 0.5 g/kg b. w., orally, 14 days), IR (saline, orally, 14 days, exposed to 6 and 3 Gy on days 4 and 6, respectively), WP+IR (WP was given orally for 14 days before and after IR exposure; exposed to 6 and 3 Gy on days 4 and 6, respectively), and IR+WP (WP, orally, started 24 h after 1st IR exposure till the end of the experiment) groups. Samples were collected at two-time intervals (on the 7th and 14th days). Results and Discussion: Oxidative stress was stimulated upon IR exposure in tongue, indicated by boosted malondialdehyde (MDA) level, along with a decrease in the total antioxidant capacity (TAC) level, superoxide dismutase (SOD), and catalase (CAT) activities. Additionally, IR exposure depicted an increase of serum IgE, inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, along with overexpression mRNA levels of nuclear factor kappa-B transcription factor/p65 (NF-κB/p65), and down-regulation of nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase (HO-1) mRNA levels in tongue tissue. Moreover, IR triggered alterations in lingual histological architecture. The antioxidant and anti-inflammatory properties of WP mitigated oxidative damage, inflammation, and desquamation that were brought on following IR exposure. The protective administration of WP markedly decreases IR-induced lingual harm compared to the mitigation protocol. Our findings recommend WP supplements to the diets of cancer patients undergoing IR that might aid radioprotective effects.

Polymeric surfactants as ideal substitutes for sustainable corrosion protection: A perspective on colloidal and interface properties.

Surfactants are well known for their colloidal and corrosion inhibition potential (CIP) due to their strong propensity to interact with metallic surfaces. However, because of their small molecular size and the fact that they are only effective at relatively high concentrations, their application in aqueous phase corrosion inhibition is often restricted. Polymeric surfactants, a unique class of corrosion inhibitors, hold the potential to eradicate the challenges associated with using surfactants in corrosion inhibition. They strongly bond with the metallic surface and offer superior CIP because of their macromolecular polymeric structure and abundance of polar functional groups. In contrast to conventional polymeric corrosion inhibitors, the inclusion of polar functional groups also aids in their solubilization in the majority of popular industry-based electrolytes. Some of the major functional groups present in polymeric surfactants used in corrosion mitigation include O (ether), glycidyl (cyclic ether), -CONH2 (amide), -COOR (ester), -SO3H (sulfonic acid), -COOH (carboxyl), -NH2 (amino), - + NR3/- + NHR2/- + NH2R/- + NH3 (quaternary ammonium), -OH (hydroxyl), -CH2OH (hydroxymethyl), etc. The current viewpoint offers state-of-the-art information on polymer surfactants as newly developing ideal alternatives for conventional corrosion inhibitors. The industrial scale-up, colloidal, coordination, adsorption properties, and structural requirements of polymer surfactants have also been established based on the knowledge obtained from the literature. Finally, the challenges, drawbacks, and potential benefits of using polymer surfactants have also been discussed.

Efficacy of iron-silver bimetallic nanoparticles to enhance radiotherapy.

Radiotherapy (RT) is one of the primary cancer treatment methods. Radiosensitizers are used to enhance RT and protect healthy tissue. Heavy metals have been studied as radiosensitizers. Thus, iron oxide and iron oxide/silver nanoparticles have been the main subjects of this investigation. A simple honey-based synthesis of iron (IONPs) and iron-silver bimetallic nanoparticles (IO@AgNPs) were prepared followed by characterization with transmission electron microscope (TEM), absorption spectra, vibrating sample magnetometer (VSM), and X-ray diffraction (XRD). Additionally, Ehrlich carcinoma was induced in 30 adult BALB/c mice and divided into 6 groups. Mice of group G1 were not treated with nanoparticles or exposed to irradiation (control group), and group G2 and G3 were treated with IONPs and IO@AgNPs respectively. Mice of group G4 were exposed to a high dose of gamma radiation (HRD) (12 Gy). Groups G5 and G6 were treated with IONPs and IO@AgNPs followed by exposure to a low dose of gamma radiation (LRD) (6 Gy) respectively. The impact of NP on the treatment protocol was evaluated by checking tumor growth, DNA damage, and level of oxidative stress in addition to investigating tumor histopathology. Additional research on the toxicity of this protocol was also evaluated by looking at the liver's cytotoxicity. When compared to HRD therapy, combination therapy (bimetallic NPs and LRD) significantly increased DNA damage by about 75% while having a stronger efficacy in slowing Ehrlich tumor growth (at the end of treatment protocol) by about 45%. Regarding the biosafety concern, mice treated with combination therapy showed lower alanine aminotransferase (ALT) levels in their liver tissues by about half the value of HRD. IO@AgNPs enhanced the therapeutic effect of low-dose radiation and increased the efficacy of treating Ehrlich tumors with the least amount of harm to normal tissues as compared to high radiation dosage therapy.

Metformin mitigates SASP secretion and LPS-triggered hyper-inflammation in Doxorubicin-induced senescent endothelial cells.

Introduction: Doxorubicin (DOX), a chemotherapeutic drug, induces senescence and increases the secretion of senescence-associated secretory phenotype (SASP) in endothelial cells (ECs), which contributes to DOX-induced inflammaging. Metformin, an anti-diabetic drug, demonstrates senomorphic effects on different models of senescence. However, the effects of metformin on DOX-induced endothelial senescence have not been reported before. Senescent ECs exhibit a hyper-inflammatory response to lipopolysachharide (LPS). Therefore, in our current work, we identified the effects of metformin on DOX-induced endothelial senescence and LPS-induced hyper-inflammation in senescent ECs. Methods: ECs were treated with DOX ± metformin for 24 h followed by 72 h incubation without DOX to establish senescence. Effects of metformin on senescence markers expression, SA-ß-gal activity, and SASP secretion were assessed. To delineate the molecular mechanisms, the effects of metformin on major signaling pathways were determined. The effect of LPS ± metformin was determined by stimulating both senescent and non-senescent ECs with LPS for an additional 24 h. Results: Metformin corrected DOX-induced upregulation of senescence markers and decreased the secretion of SASP factors and adhesion molecules. These effects were associated with a significant inhibition of the JNK and NF-κB pathway. A significant hyper-inflammatory response to LPS was observed in DOX-induced senescent ECs compared to non-senescent ECs. Metformin blunted LPS-induced upregulation of pro-inflammatory SASP factors. Conclusion: Our study demonstrates that metformin mitigates DOX-induced endothelial senescence phenotype and ameliorates the hyper-inflammatory response to LPS. These findings suggest that metformin may protect against DOX-induced vascular aging and endothelial dysfunction and ameliorate infection-induced hyper-inflammation in DOX-treated cancer survivors.

Amygdalin-folic acid-nanoparticles inhibit the proliferation of breast cancer and enhance the effect of radiotherapy through the modulation of tumor-promoting factors/ immunosuppressive modulators in vitro.

INTRODUCTION: Breast cancer (BC) cells often develop multiple mechanisms of chemo- and radio-resistance during tumor progression, which is the major reason for the failure of breast cancer therapy. Targeted nanomedicines have tremendous therapeutic potential in BC treatment over their free drug counterparts. Searching for chemo- and radio-sensitizers to overcome such resistance is therefore urgently required. The goal of this study is to evaluate and compare the radio-sensitizer efficacy of amygdalin-folic acid nanoparticles (Amy-F) on MCF-7 and MDA-MB-231 cells. MATERIALS AND METHODS: The effects of Amy-F on MCF-7 and MDA-MB-231 cell proliferation and IC50 were assessed using MTT assay. The expression of proteins involved in several mechanisms induced by Amy-F in MCF-7 and MDA-MB-231 cells, including growth inhibition, apoptosis, tumor growth regulators, immuno-modulators, and radio-sensitizing activities were evaluated via flow cytometry and ELISA assay. RESULTS: Nanoparticles demonstrated sustained Amy-F release properties and apparent selectivity towards BC cells. Cell-based assays revealed that Amy-F markedly suppresses cancer cell growth and improves radiotherapy (RT) through inducing cell cycle arrest (G1 and sub-G1), and increases apoptosis as well as reduces the proliferation of BC by down-regulating mitogen-activated protein kinases (MAPK/P38), iron level (Fe), nitric oxide (NO), and up-regulating the reactive oxygen species level (ROS). Amy-F has also been shown to suppress the expression of the cluster of differentiation (CD4 and CD80), and interfere with the Transforming growth factor beta (TGF- ß)/Interferon-gamma (INF-g)/Interleukin-2 (IL-2)/Interleukin-6 (IL-6)/Vascular endothelial growth factor (VEGF) induced suppression in its signaling hub, while up-regulating natural killer group 2D receptor (NKG2D) and CD8 expression. CONCLUSIONS: Collectively, the novel Amy-F either alone or in combination with RT abrogated BC proliferation.

Canagliflozin mitigates carfilzomib-induced endothelial apoptosis via an AMPK-dependent pathway.

Carfilzomib (CFZ) is a proteasome inhibitor approved for relapsed/refractory multiple myeloma (MM) but its clinical use is limited by cardiovascular toxicity. The mechanisms of CFZ-induced cardiovascular toxicity are not fully understood but endothelial dysfunction may be a common denominator. Here, we first characterized the direct toxic effects of CFZ on endothelial cells (HUVECs and EA.hy926 cells) and tested whether SGLT2 inhibitors, known to have cardioprotective effects, can protect against CFZ-induced toxicity. To determine the chemotherapeutic effect of CFZ in the presence of SGLT2 inhibitors, MM and lymphoma cells were treated with CFZ with or without canagliflozin. CFZ decreased cell viability and induced apoptotic cell death in endothelial cells in a concentration-dependent manner. CFZ also upregulated ICAM-1 and VCAM-1 and downregulated VEGFR-2. These effects were associated with the activation of Akt and MAPK pathways, inhibition of p70s6k, and downregulation of AMPK. Canagliflozin, but not empagliflozin or dapagliflozin, protected endothelial cells from CFZ-induced apoptosis. Mechanistically, canagliflozin abrogated CFZ-induced JNK activation and AMPK inhibition. AICAR (an AMPK activator) protected from CFZ-induced apoptosis, and compound C (an AMPK inhibitor) abrogated the protective effect of canagliflozin, strongly suggesting that AMPK mediates these effects. Canagliflozin did not interfere with the anticancer effect of CFZ in cancer cells. In conclusion, our findings demonstrate for the first time the direct toxic effects of CFZ in endothelial cells and the associated signaling changes. Canagliflozin abrogated the apoptotic effects of CFZ in endothelial cells in an AMPK-dependent mechanism, without interfering with its cytotoxicity in cancer cells.

Anatomical landscape of oral squamous cell carcinoma: A single cancer center study in UAE.

Objectives: This study aimed to present demographic and clinicopathological aspects of OSCC identified in Pathology service in the UAE over a 13-year period and compare these findings to a cohort of 523 cases of Head and neck squamous cell carcinoma using the Cancer Genome Atlas's cBioPortal database (http://cbioportal.org). Material and methods: Histological examination of all hematoxylin and eosin-stained slides and assessment of all demographic and clinical information from laboratory records were performed on all OSCC diagnosed between 2005 and 2018. Results: Males made up 71.4% of the sample of 231 OSCCs that were evaluated. The patients' average age was 55.38 years. The two most prevalent afflicted sites were the anterior two-thirds of the tongue (57.6%) and the cheek (28.1%). The most prevalent site among smokers were the floor of mouth, cheek, and jaw bones. There was a link between tumor size and numerous anatomical subsites that was shown to be highly significant. OSCC in the FOM was associated with a 25% mortality rate. Patients with OSCC of the anterior tongue and cheek had the best prognosis, with only 15.7% and 15.3% of patients dying during follow-up. Conclusion: The present investigation found a correlation between the diverse clinicopathological characteristics of the various anatomical subsites in OSCC. Different anatomical subsites also displayed varying degrees of gene mutation.

Discovery of novel papain-like protease inhibitors for potential treatment of COVID-19.

The recent emergence of different SARS-CoV-2 variants creates an urgent need to develop more effective therapeutic agents to prevent COVID-19 outbreaks. Among SARS-CoV-2 essential proteases is papain-like protease (SARS-CoV-2 PLpro), which plays multiple roles in regulating SARS-CoV-2 viral spread and innate immunity such as deubiquitinating and deISG15ylating (interferon-induced gene 15) activities. Many studies are currently focused on targeting this protease to tackle SARS-CoV-2 infection. In this context, we performed a phenotypic screening using an in-house pilot compounds collection possessing a diverse skeleta against SARS-CoV-2 PLpro. This screen identified SIMR3030 as a potent inhibitor of SARS-CoV-2. SIMR3030 has been shown to exhibit deubiquitinating activity and inhibition of SARS-CoV-2 specific gene expression (ORF1b and Spike) in infected host cells and possessing virucidal activity. Moreover, SIMR3030 was demonstrated to inhibit the expression of inflammatory markers, including IFN-α, IL-6, and OAS1, which are reported to mediate the development of cytokine storms and aggressive immune responses. In vitro absorption, distribution, metabolism, and excretion (ADME) assessment of the drug-likeness properties of SIMR3030 demonstrated good microsomal stability in liver microsomes. Furthermore, SIMR3030 demonstrated very low potency as an inhibitor of CYP450, CYP3A4, CYP2D6 and CYP2C9 which rules out any potential drug-drug interactions. In addition, SIMR3030 showed moderate permeability in Caco2-cells. Critically, SIMR3030 has maintained a high in vivo safety profile at different concentrations. Molecular modeling studies of SIMR3030 in the active sites of SARS-CoV-2 and MERS-CoV PLpro were performed to shed light on the binding modes of this inhibitor. This study demonstrates that SIMR3030 is a potent inhibitor of SARS-CoV-2 PLpro that forms the foundation for developing new drugs to tackle the COVID-19 pandemic and may pave the way for the development of novel therapeutics for a possible future outbreak of new SARS-CoV-2 variants or other Coronavirus species.

DKK3's protective role in prostate cancer is partly due to the modulation of immune-related pathways.

While it is considered one of the most common cancers and the leading cause of death in men worldwide, prognostic stratification and treatment modalities are still limited for patients with prostate cancer (PCa). Recently, the introduction of genomic profiling and the use of new techniques like next-generation sequencing (NGS) in many cancers provide novel tools for the discovery of new molecular targets that might improve our understanding of the genomic aberrations in PCa and the discovery of novel prognostic and therapeutic targets. In this study, we investigated the possible mechanisms through which Dickkopf-3 (DKK3) produces its possible protective role in PCa using NGS in both the DKK3 overexpression PCa cell line (PC3) model and our patient cohort consisting of nine PCa and five benign prostatic hyperplasia. Interestingly, our results have shown that DKK3 transfection-modulated genes are involved in the regulation of cell motility, senescence-associated secretory phenotype (SASP), and cytokine signaling in the immune system, as well as in the regulation of adaptive immune response. Further analysis of our NGS using our in vitro model revealed the presence of 36 differentially expressed genes (DEGs) between DKK3 transfected cells and PC3 empty vector. In addition, both CP and ACE2 genes were differentially expressed not only between the transfected and empty groups but also between the transfected and Mock cells. The top common DEGs between the DKK3 overexpression cell line and our patient cohort are the following: IL32, IRAK1, RIOK1, HIST1H2BB, SNORA31, AKR1B1, ACE2, and CP. The upregulated genes including IL32, HIST1H2BB, and SNORA31 showed tumor suppressor functions in various cancers including PCa. On the other hand, both IRAK1 and RIOK1 were downregulated and involved in tumor initiation, tumor progression, poor outcome, and radiotherapy resistance. Together, our results highlighted the possible role of the DKK3-related genes in protecting against PCa initiation and progression.