Coenzyme Q10 mitigates cadmium cardiotoxicity by downregulating NF-κB/NLRP3 inflammasome axis and attenuating oxidative stress in mice.

Coenzyme Q10 (CoQ10) occurs naturally in the body and possesses antioxidant and cardioprotective effects. Cardiotoxicity has emerged as a serious effect of the exposure to cadmium (Cd). This study investigated the curative potential of CoQ10 on Cd cardiotoxicity in mice, emphasizing the involvement of oxidative stress (OS) and NF-κB/NLRP3 inflammasome axis. Mice received a single intraperitoneal dose of CdCl2 (6.5 mg/kg) and a week after, CoQ10 (100 mg/kg) was supplemented daily for 14 days. Mice that received Cd exhibited cardiac injury manifested by the elevated circulating cardiac troponin T (cTnT), CK-MB, LDH and AST. The histopathological and ultrastructural investigations supported the biochemical findings of cardiotoxicity in Cd-exposed mice. Cd administration increased cardiac MDA, NO and 8-oxodG while suppressed GSH and antioxidant enzymes. CoQ10 decreased serum CK-MB, LDH, AST and cTnT, ameliorated histopathological and ultrastructural changes in the heart of mice, decreased cardiac MDA, NO, and 8-OHdG and improved antioxidants. CoQ10 downregulated NF-κB p65, NLRP3 inflammasome, IL-1ß, MCP-1, JNK1, and TGF-ß in the heart of Cd-administered mice. Moreover, in silico molecular docking revealed the binding potential between CoQ10 and NF-κB, ASC1 PYD domain, NLRP3 PYD domain, MCP-1, and JNK. In conclusion, CoQ10 ameliorated Cd cardiotoxicity by preventing OS and inflammation and modulating NF-κB/NLRP3 inflammasome axis in mice. Therefore, CoQ10 exhibits potent therapeutic benefits in safeguarding cardiac tissue from the harmful consequences of exposure to Cd.

Corrigendum: CD44 targeted delivery of oncolytic Newcastle disease virus encapsulated in thiolated chitosan for sustained release in cervical cancer: a targeted immunotherapy approach.

[This corrects the article DOI: 10.3389/fimmu.2023.1175535.].

An overview of multiple myeloma: A monoclonal plasma cell malignancy's diagnosis, management, and treatment modalities.

Multiple Myeloma (MM) is a plasma cell cancer with high mortality and morbidity rates. Its incidence rate has increased by 143% since 1975. Adipokines, cytokines, chemokines, and genetic variations influence the development and progression of MM. Chromosomal translocations cause mutations associated with MM. The pathogenesis of MM is complicated by novel issues like miRNAs, RANKL, Wnt/DKK1, Wnt, and OPG. Conventional diagnosis methods include bone marrow biopsy, sPEP or uPEP, sIFE and uIFE, and sFLC assay, along with advanced techniques such as FISH, SNPA, and gene expression technologies. A novel therapeutic strategy has been developed recently. Chemotherapy, hematopoietic stem cell transplantation, and a variety of drug classes in combination are used to treat patients with high-risk diseases. Alkylating agents, PIs, and IMiDs have all been developed as effective treatment options for MM in recent years. This review overviews the current recommendations for managing MGUS, SMM, MM, SP and NSMM and discusses practices in diagnosing and treating MM.

Anticancer Analysis of CD44 Targeted Cyclosporine Loaded Thiolated Chitosan Nanoformulations for Sustained Release in Triple-Negative Breast Cancer.

Introduction: Cyclosporine (CsA), a potent immunosuppressive chemotherapeutic medication, treats numerous cancers, particularly malignant carcinoma, acute leukemia, and triple-negative breast cancer (TNBC). Methodology: A specified polymeric nanoformulation (NF) based drug delivery technique with ligand functionalization at the surface was developed to improve its delivery at the intended area and boost the efficacy for prolonged time. The in silico verified the HA binding to the CD44 receptor at binding sites A and B in triple-negative breast cancer cells. The NF of encapsulated Cyclosporine in thiolated chitosan (TC) with the outermost coating of hyaluronic acid (HA) was formulated and characterized. Results: So, the zeta analysis revealed a particle size of 192 nm and PDI of 0.433, zeta potential of 38.9mV. FTIR and Raman investigations also support the existence of hydrophobic groups, porous surfaces, and non-clumping characteristics. While XRD verified its crystallographic nature while SEM and TEM analysis revealed the spherical nanoparticles with sleek exteriors. DSC demonstrated the stability of NF at high temperatures. The NF showed 85% drug encapsulation followed Higuchi release model for therapeutic moiety at acidic pH for a maximum of 72 hours. When compared to raw Cyclosporine, the in vitro tumor cell inhibition of ThC-HA encapsulated with Cyclosporine was tested using an MTT dye on normal breast epithelial cells compared to triple-negative breast cancer cells. Conclusion: This novel formulation improved the long-term viability, effectiveness, and active targeting as an effective and potent therapeutic moiety against cancer.

Interleukin-35 and Thymoquinone nanoparticle-based intervention for liver protection against paracetamol-induced liver injury in rats.

Paracetamol (PAR) is a commonly used antipyretic and analgesic agent, but its excessive usage can induce liver damage and major health consequences. Interleukin-35 (IL-35) is utilized to treat immunological disorders, intestinal illness, arthritis, allergic disease, hepatitis, and cancer. Thymoquinone (THYO) is also effective against a wide range of disorders. Consequently, this study sought out to explore the ameliorative effects of IL-35 and THYO against PAR-induced hepatotoxicity in rats. Sixty male rats were separated into six groups (10 rats/group): I control (0.5 mL NaCl, 0.9%/rat via oral gavage); II (IL-35), and III (TYHO) received intraperitoneal (i.p) injection of IL-35 (200 ng/kg) or THYO (0.5 mg/kg), respectively. Group IV (PAR) received 600 mg/kg of PAR orally; V (PAR + IL-35) and VI (PAR + TYHO); rats received 600 mg/kg of PAR orally and i.p injection of IL-35 (200 ng/kg) or THYO (0.5 mg/kg), respectively. Administration of IL-35 or THYO markedly mitigated the increasing in the levels of liver parameters triggered by PAR and noticeable enhancement of antioxidant and immunological markers were observed. Additionally, IL-35 or THYO decreased TNF-α, NF-κB, IL-10, IL-6 and IFN-γ in contrast to the PAR control group. Moreover, levels of Capase-3, and cytochrome C were significantly reduced by THYO or IL35, while, levels of Bcl-2 were markedly increased. Furthermore, significant downregulation of IL1-ß, TNF-α, TGF-ß, and Caspas-3 genes, as well as significant upregulation of Bcl-2 and IL-10 expression were detected. In conclusion, IL-35 and THYO insulated liver from PAR toxicity by mitigating oxidative stress, tissue damage, inflammation, and apoptosis.

A flavonoid-rich fraction of Euphorbia peplus attenuates hyperglycemia, insulin resistance, and oxidative stress in a type 2 diabetes rat model.

Background: Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance (IR) and hyperglycemia. Plants are valuable sources of therapeutic agents for the management of T2D. Euphorbia peplus has been widely used as a traditional medicine for the treatment of various diseases, but its beneficial role in T2D has not been fully explored. Methods: The anti-diabetic efficacy of E. peplus extract (EPE) was studied using rats with T2D induced by high-fat diet (HFD) and streptozotocin (STZ). The diabetic rats received 100, 200, and 400 mg/kg EPE for 4 weeks. Results: Phytochemical fractionation of the aerial parts of E. peplus led to the isolation of seven known flavonoids. Rats with T2D exhibited IR, impaired glucose tolerance, decreased liver hexokinase and glycogen, and upregulated glycogen phosphorylase, glucose-6-phosphatase (G-6-Pase), and fructose-1,6-bisphosphatase (F-1,6-BPase). Treatment with 100, 200, and 400 mg/kg EPE for 4 weeks ameliorated hyperglycemia, IR, liver glycogen, and the activities of carbohydrate-metabolizing enzymes. EPE attenuated dyslipidemia, serum transaminases, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and liver lipid accumulation, nuclear factor (NF)-κB p65, and lipid peroxidation, nitric oxide and enhanced antioxidants. All EPE doses upregulated serum adiponectin and liver peroxisome proliferator-activated receptor γ (PPARγ) in HFD/STZ-induced rats. The isolated flavonoids showed in silico binding affinity toward hexokinase, NF-κB, and PPARγ. Conclusion: E. peplus is rich in flavonoids, and its extract ameliorated IR, hyperglycemia, dyslipidemia, inflammation and redox imbalance, and upregulated adiponectin and PPARγ in rats with T2D.

CD44 targeted delivery of oncolytic Newcastle disease virus encapsulated in thiolated chitosan for sustained release in cervical cancer: a targeted immunotherapy approach.

Introduction: Cervical cancer accounts for one of most common cancers among women of reproductive age. Oncolytic virotherapy has emerged as a promising immunotherapy modality but it comes with several drawbacks that include rapid clearance of virus from body due to immune-neutralization of virus in host. To overcome this, we encapsulated oncolytic Newcastle disease virus (NDV) in polymeric thiolated chitosan nanoparticles. For active targeting of virus loaded nanoformulation against CD44 (cluster of differentiation 44) receptors which are overly expressed on cancer cells, these nanoparticles were surface functionalized with hyaluronic acid (HA). Methods: Using half dose of NDV (TCID50 (50% tissue culture infective dose) single dose 3 × 105), virus loaded nanoparticles were prepared by green synthesis approach through ionotropic gelation method. Zeta analysis was performed to analyse size and charge on nanoparticles. Nanoparticles (NPs) shape and size were analysed by SEM (scanning electron microscope) and TEM (transmission electron microscope) while functional group identification was done by FTIR (fourier transform infrared) and XRD (X-ray diffraction). Viral quantification was done by TCID50 and Multiplicity of infection (MOI) determination while oncolytic potential of NPs encapsulated virus was analysed by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and cell morphology analysis. Results: Zeta analysis showed that average size of NDV loaded thiolated chitosan nanoparticles surface functionalized with HA (HA-ThCs-NDV) was 290.4nm with zeta potential of 22.3 mV and 0.265 PDI (polydispersity index). SEM and TEM analysis showed smooth surface and spherical features of nanoparticles. FTIR and XRD confirmed the presence of characteristic functional groups and successful encapsulation of the virus. In vitro release showed continuous but sustained release of NDV for up to 48 hours. TCID50 for HA-ThCs-NDV nanoparticles was 2.63x 106/mL titter and the nanoformulation exhibited high oncolytic potential in cell morphology analysis and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay as compared to naked virus, in dose dependent manner. Discussion: These findings suggest that virus encapsulation in thiolated chitosan nanoparticles and surface functionalization with HA is not only helpful in achieving active targeting while masking virus from immune system but, it also gives sustained release of virus in tumor microenvironment for longer period of time that increases bioavailability of virus.

Arbutin ameliorates hyperglycemia, dyslipidemia and oxidative stress and modulates adipocytokines and PPARγ in high-fat diet/streptozotocin-induced diabetic rats.

Arbutin is a glycosylated hydroquinone with antioxidant and anti-hyperglycemia effects. However, its beneficial effects in type 2 diabetes (T2D) were not clarified. This study evaluated the effect of arbutin on hyperglycemia, dyslipidemia, insulin resistance, oxidative stress, and inflammatory response in T2D. Rats induced by high fat diet and streptozotocin were treated with arbutin (25 and 50 mg/kg) for 4 weeks. Diabetic rats exhibited glucose intolerance, elevated HbA1c%, reduced insulin, and high HOMA-IR. Liver glycogen and hexokinase activity were decreased in T2D rats while glucose-6-phosphatase (G6Pase), fructose-1,6- biphosphatase (FBPase), and glycogen phosphorylase were upregulated. Circulating and hepatic cholesterol and triglycerides and serum transaminases were elevated in T2D rats. Arbutin ameliorated hyperglycemia, dyslipidemia, insulin deficiency and resistance, and liver glycogen and alleviated the activity of carbohydrate-metabolizing enzymes. Both doses of arbutin decreased serum transaminases and resistin, and liver lipids, TNF-α, IL-6, malondialdehyde and nitric oxide, downregulated liver resistin and fatty acid synthase, and increased serum and liver adiponectin, and liver reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). These effects were associated with the upregulation of hepatic PPARγ. Arbutin inhibited α-glucosidase in vitro and in silico investigations revealed the ability of arbutin to bind PPARγ, hexokinase, and α-glucosidase. In conclusion, arbutin effectively ameliorated glucose intolerance, insulin resistance, dyslipidemia, inflammation, and oxidative stress, and modulated carbohydrate-metabolizing enzymes, antioxidants, adipokines and PPARγ in T2D in rats.

Rosmarinic acid mitigates chlorpyrifos-induced oxidative stress, inflammation, and kidney injury in rats by modulating SIRT1 and Nrf2/HO-1 signaling.

Chlorpyrifos (CPF) is a widely used broad-spectrum pesticide with multi-organ toxic effects. Oxidative stress was found to play a role in the deleterious effects of CPF, including nephrotoxicity. This study investigated the protective effect of the antioxidant polyphenol rosmarinic acid (RA) against CPF-induced kidney injury, with an emphasis on oxidative injury, inflammation, SIRT1, and Nrf2/HO-1 signaling. Rats received 10 mg/kg CPF and 25, 50, and 100 mg/kg RA orally for 28 days, and the samples were collected for analysis. CPF increased serum urea and creatinine and kidney Kim-1 and caused several histopathological alterations. ROS, MDA, NO, NF-κB p65, TNF-α, and IL-1ß were elevated in the kidney of CPF-intoxicated rats. RA ameliorated kidney function markers, prevented tissue injury, suppressed ROS, MDA, and NO, and downregulated NF-κB p65, TNF-α, and IL-1ß in CPF-intoxicated rats in a dose-dependent manner. RA decreased Bax, caspase-3, oxidative DNA damage, and Keap1, boosted antioxidant enzymes and Bcl-2, and upregulated Nrf2, HO-1, and SIRT1 in CPF-administered rats. Molecular docking simulation revealed the binding affinity of RA toward NF-κB, Keap1, HO-1, and SIRT1. In conclusion, RA prevented CPF nephrotoxicity by attenuating oxidative stress, inflammation, and apoptosis and upregulating SIRT1 and Nrf2/HO-1 signaling.

Synthesis, Characterization and Biological Activities of New Schiff Base Compound and Its Lanthanide Complexes.

The thermal condensation of 3-(2-Furyl)acrolein with 2-Amino-6-ethoxybenzothiazole generated a new Schiff base, (1E,2E)-N-(6-ethoxybenzo[d]thiazol-2-yl)-3-(furan-2-yl)prop-2-en-1-imine (L), with general formula of C16H14N2O2S. Also, a series of lanthanide complexes of gadolinium, samarium, and neodymium (La-Lc) were synthesized utilizing acetonitrile as the solvent and triethylamine as a buffer and catalyst. Based on elemental analysis, mass spectroscopy, and FTIR analysis, all of the Bis-(1E,2E)-N-(6-ethoxybenzo[d]thiazol-2-yl)-3-(furan-2-yl)prop-2-en-1-iminetri-nitratolanthanide(III) complexes with the general formula [LnL2(NO3)3]·H2O are solids with a 2:1 molar ratio (ligand: metal). Based on conductivity estimates, they are nonelectrolytes and monoatomic paramagnetic according to the magnetic moment measurements, and one mole of lattice water was found after thermal gravimetric measurements and FTIR analysis. Therefore, the lanthanide complexes show a ten-coordination structure with a deformed bicapped square antiprismatic. The Schiff base and its complexes were screened for their antimicrobial, antifungal, antioxidant, and antitumor properties. Their antimicrobial and antifungal activities were strong, and they also produced good antioxidant and antitumor effects.

Umbelliferone prevents isoproterenol-induced myocardial injury by upregulating Nrf2/HO-1 signaling, and attenuating oxidative stress, inflammation, and cell death in rats.

The role of oxidative injury and inflammatory response in cardiovascular diseases and heart failure has been well-acknowledged. This study evaluated the protective effect of umbelliferone (UMB), a coumarin with promising radical scavenging and anti-inflammatory activities, on myocardial injury induced by isoproterenol (ISO) in rats. Rats received 50 mg/kg UMB orally for 14 days and 85 mg/kg ISO twice at an interval of 24 h. Administration of ISO elevated serum troponin I, creatine kinase-MB and lactate dehydrogenase, and caused histopathological alterations, including degeneration, fatty vacuolation, myolysis, and atrophy of myocardial fibers. Malondialdehyde (MDA), nitric oxide (NO), nuclear factor-kappaB (NF-κB) p65, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß were increased, whereas reduced glutathione (GSH), superoxide dismutase (SOD), and catalase were decreased in ISO-administered rats. UMB effectively ameliorated myocardial injury, alleviated cardiac function markers, MDA, NO, NF-κB p65, and the inflammatory mediators, and enhanced cellular antioxidants. Bax, caspase-3, and 8-OHdG were decreased, and Bcl-2 was increased in ISO-administered rats treated with UMB. In addition, UMB upregulated nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and heme oxygenase (HO)-1 in the heart of ISO-administered rats. In conclusion, UMB can protect the myocardium from oxidative injury, inflammatory response, and cell death induced by ISO by upregulating Nrf2/HO-1 signaling and antioxidants.